The Ketogenic Effect of Medium-Chain Triacylglycerides

Medium-chain triacylglycerides (MCTs) are dietary supplements that can induce ketosis without the need for a traditional ketogenic diet or prolonged fasting. They have the potential to marginally delay the progression of neurodegenerative diseases, such as Alzheimer's disease. However, there have been inconsistencies in reports of the MCT dose–response relationship, which may be due to differences in MCT composition, participant characteristics, and other factors that can influence ketone generation. To resolve these discrepancies, we reviewed studies that investigated the ketogenic effect of MCTs in healthy adults. Aside from the treatment dose, other factors that can influence the ketogenic response, such as accompanying meals, fasting duration, and caffeine intake, were assessed. Based on the available literature, four practical recommendations are made to optimize the ketogenic effect of MCTs and reduce unwanted side effects (primarily gastrointestinal discomfort and diarrhea). First, the starting dose should be either 5 g of octanoic acid [caprylic acid (C8); a component of MCTs] or 5 g of a combination of C8 and decanoic or capric acid (C10; another component of MCTs), and the dose should be progressively increased to 15–20 g of C8. Second, MCTs should be consumed after an overnight fast, without an accompanying meal if tolerable, or with a low-carbohydrate meal. Third, the addition of caffeine may slightly increase the ketogenic response. Fourth, emulsifying the MCTs might increase their ketogenic effect and alleviate side effects.


INTRODUCTION
Aging and dementia are two crucial issues that affect people worldwide. The World Health Organization reported that 1 billion people are now aged ≥ 60 years, with 50 million having dementia. Of those with dementia, 60-70% have Alzheimer's disease (1,2). Therefore, the development of a cost-effective intervention to mitigate brain deterioration and prevent Alzheimer's disease is crucial.
One symptom and possible cause of brain function decline later in life is glucose hypometabolism. Older adults show a 7% reduction in glucose metabolic rate in the gray matter of the brain and a 10-14% deficit in the frontal cortex compared with younger adults [(3) (R2)]. Older adults with mild Alzheimer's disease show an additional 13% decrease in global cerebral glucose metabolic rate in the gray matter compared with their healthy counterparts [(4) (R2)]. One way to compensate for a low glucose metabolic rate is to use an alternative energy source such as ketones [β-hydroxybutyrate (βHB) and acetoacetate], which have been reported to be metabolized normally in patients with Alzheimer's disease [(4) (T3)].
Medium-chain triacylglycerides (MCTs) are commercially available, inexpensive dietary supplements that can induce ketosis. Aside from serving as an alternative energy source, βHB has been reported to have health benefits similar to those observed upon calorie restriction, such as antiaging effects via epigenetic regulation [(5) (Pg306, 310-311)]. Therefore, an understanding of the relationship between the amount of MCTs consumed and the level of ketones in the blood is necessary to inform practical applications of MCTs. An earlier review reported an almost linear relationship between the amount of MCTs consumed, up to doses as high as 70 g, and their ketogenic effects [(6) (F6)]. However, another recent study showed a non-linear relationship between these two parameters at relatively low doses of MCTs (10-20 g) [(7) (F1A)]. This inconsistency may arise from differences in the compositions of MCTs and participants' health conditions, limitations of the study designs, and other cofounding factors (discussed in the following section). Thus, we aim to provide a brief review of the available literature on the ketogenic effect of oral MCT administration in healthy participants and related interacting factors, such as accompanying meals, fasting duration, and caffeine intake. We also provide a practical summary on how to maximize the ketogenic benefits of MCTs.

Effect of Carbon Chain Length on the Ketogenic Effect of MCTs
The major ketogenic component of MCTs is caprylic acid (C8), followed by capric acid (C10) or lauric acid (C12) [(8) (R, F1, F3)]. Caproic acid (C6) is excluded because it is not typically consumed as a dietary supplement, partly due to its unpleasant odor. The ketogenic effect (total ketone concentration) of C8 is three and six times higher than the effects of C10 and C12, respectively [(9) (D1, F3)]. Vandenberghe et al. showed that the total plasma ketone concentration increased after the consumption of C8 for ∼4 h, but not after the consumption of C10 [(8) (R5, F3)]. Other studies have shown that consuming 18-20 mL (∼16-18 g) of C8 without an accompanying meal increases the plasma βHB concentration from <0.1 mmol/L to 0.5-0.6 mmol/L at 2 h after administration [(9) (F1)].
Before the results from recent studies, such as that conducted by Vandenberghe et al. [(8) (R)], came to light, all of the MCTs (i.e., C6, C8, C10, and C12) were considered to be ketogenic [(10) (I1)], partly because these molecules are rapidly absorbed and transported to the liver via the portal vein mainly as free fatty acids bound to serum albumin. In contrast, longer-chain triacylglycerides are dependent on acyl-CoA synthetase activity and the lymphatic system for absorption and are transported by chylomicrons [(11) (Pg951)]. However, only fatty acids with carbon chain lengths ≤8 can cross the inner membrane of the mitochondria independent of carnitine palmitoyl transferase I [(12) (T1)]. This may be why C8 has a stronger ketogenic effect than C10 and C12.
In their review, Cunnane et al. suggest the presence of a linear relationship between oral doses of MCTs up to 70 g and the maximal observed plasma βHB concentration [(6) (F6)]. However, some issues were noted after reviewing the studies cited in their figure. First, the cited studies included not only healthy adults (13,14) but also memory-impaired adults (15) and patients with type 1 diabetes (16) and Alzheimer's disease (17). Second, the doses presented in their figure were the sum of all MCT doses (i.e., C6, C8, C10, and C12) and not just the dose of C8, which has been reported to contribute to the majority (9), if not all [(8) (R, F1, F3)], of the ketogenic response. Finally, in their analysis, Cunnane et al. did not consider whether the MCTs had been consumed with or without a meal or the number of hours the participants had fasted.
Based on the above data and other recent findings, the nonlinear relationship between MCT intake and plasma ketone concentration might begin at a relatively low dose of MCTs (6 g of C8 + 4 g of C10 vs. 12 g of C8 + 8 g of C10) [ (7) (F1A)]. Based on the results of several studies (7,8,18), it is clear that 20 g of C8 produces a significantly stronger (but perhaps not twice as high) [(7) (D2)] ketogenic response than 10 g of C8. Further studies are required to determine whether doses higher than 20 g can produce a significantly larger ketogenic response and/or a greater risk of unwanted side effects. Norgren et al. also suggested [(19) (D5)] that the dose of C8 should be limited to 15-20 g per intake to minimize potential side effects.

Repeated Use of MCTs May Influence the Acute Ketogenic Response
It is unclear whether the repeated use of MCTs can augment the acute ketogenic response. In a previous study, Freund and Weinsier showed that repeated administration of MCTs to the same participants showed reproducible responses within narrow limits [(20) (A)]. However, a 1-month interventional study showed that the daily mean plasma βHB concentration increased from ∼0.1 mmol/L to ∼0.2 mmol/L after consuming ∼6 g of C8 twice a day for 30 days [(21) (F1A-B)].

Effect of an Accompanying Meal on the Ketogenic Effect of MCTs
Consuming MCTs without an accompanying meal produces a stronger ketogenic effect than with an accompanying meal that has a substantial carbohydrate content. For example, adding 50 g of glucose to 20 g of C8 (0.27 mmol/L vs. 0.10 mmol/L from control) decreased the ketogenic effect (measured as the venous whole blood βHB concentration) by 63% [(19) (T3)]. Another study showed that the plasma ketone response was ∼2-fold higher after consuming C8 without an accompanying meal than with a meal [470 calories in the meal; 19.5 g of fat (36%), 24.2 g of protein (20%), and 55 g of carbohydrate (44%)] [(9) (A)]. As the amount of carbohydrate consumed with the MCTs increases, the ketogenic response decreases [(20) (R4, F4)]. Therefore, consuming C8 without an accompanying meal can maximize the ketogenic effect, i.e., it can be consumed as a replacement for breakfast or as a stand-alone snack [(9) (D2)].
Consuming carbohydrates after consuming MCTs also decreases their ketogenic effect. For instance, the subsequent consumption of sucrose suppresses the ketogenic effect of MCTs. As the amount of sucrose consumed increases, the maximal acetone concentration in alveolar air decreases [(20) (R5, D5, F5-6)].
Although it may not inhibit the ketogenic effect, consuming a low-carbohydrate meal with C8 may prolong the time required to attain the maximal plasma βHB concentration. A lowcarbohydrate ketogenic breakfast with ∼110 g of fat (∼28 g of C8 and ∼43 g of C10), 25 g of protein, and 3 g of carbohydrate can elevate the plasma βHB concentration to approximately 0.7 mmol/L at 1 h and 2 h after administration, with a peak at 6 h after administration (∼1 mmol/L) [(13) (R1, F1)].

Emulsification Might Influence MCT Absorption
The emulsification of MCTs with beverages increases their ketogenic effect compared with the same dose of non-emulsified MCTs (increase in the 4-h area under the curve from 0.147 ± 0.094 to 0.560 ± 0.095 mmol * h/L with 12 g of C8 and from 0.311 ± 0.097 to 1.320 ± 0.336 mmol * h/L with 18 g of C8) [(18) (F1)]. However, the effect of emulsification and the optimal technique of emulsification (e.g., using a blender) require further investigation.  (M, F1)]. As the study design did not include randomization or even a counterbalance, it remains unclear whether aerobic exercise indeed augments the ketogenic effect of MCTs. Additional studies with a more robust design are required to address this question.

PRACTICAL SUMMARY
1. Start with a low dose (5 g or 6 mL) of C8 or C8 + C10.
If there are no adverse effects such as diarrhea or other abdominal issues, then increase the dose up to 15-20 g of C8 (17-22 mL

AUTHOR CONTRIBUTIONS
T-YL conceived and conducted the research and collected and analyzed the data. He is the guarantor of the study and responsible for writing the manuscript. H-WL provided advice to improve the clarity of the manuscript. T-MH is the supervisor and is responsible for reviewing the manuscript. All authors have contributed to drafting the manuscript and have approved of the final version.