The aim of this paper, therefore, is to elucidate the evidence for and against commonly applied nutritional supplements, purported to be ketogenic, to inform clinical practice in the growing field of ketogenic diets for common-use. This paper reviews the available scientific literature relevant to improvements in time to ketosis and symptoms of keto-induction, resulting from these nutritional supplements.

These symptoms are often referred to in the mainstream and grey literature as ‘keto-flu’ but are not well illustrated in the scientific literature. For example, a Google search returns over 22,000 results for the term “keto-flu,” but the same term searched in MEDLINE Complete, CINAHL Complete, Alt HealthWatch, Food Science Source, SPORT Discus with Full Text, Psychology, and the EBSCO Behavioural Sciences Collection returns no results. Several studies have described adverse effects during ketogenic diets but to our knowledge, no studies have specifically described symptoms of keto-induction in the short time between commencing a ketogenic diet and the achievement of NK.

So, while the achievement of ketosis has been described in the medical literature, there are inconsistencies in the measurement of, and definition for ketosis in these papers.

Ketogenic diets are now commonly applied, for a range of desired outcomes, and with differing definitions of what constitutes a ketogenic diet. Both low-energy diets and VLCKDs with fewer than 50 g of carbohydrate per day typically result in BOHB levels of ≥0.5 mmol L −1 ( Gibson et al., 2015 ). This threshold has been used as a cut-off point for entry into ketosis by Guerci and colleagues ( Guerci et al., 2003 ), and is commonly applied as a marker for entry into NK in the nutrition field, as compared to the typically higher levels expected in the medical field to elicit beneficial effects for seizure control in epileptic children ( Gilbert, Pyzik & Freeman, 2000 ).

PubMed, Science Direct, CINAHL, MEDLINE, Alt Health Watch, Food Science Source and EBSCO Psychology and Behavioural Sciences Collection electronic databases were searched online. Various purported ketogenic supplements, arising from a qualitative appraisal of forums, social media, message boards, and Google searches for ketogenic supplements, were searched along with the terms “ketogenic diet”, “ketogenic”, “ketosis” and ketonaemia (/ketonemia). Additionally, author names and reference lists were used for further search of the selected papers for related references. There is a paucity of studies on time to NK and mitigation of symptoms of keto-induction an as data related to the effects of various supplements on time to induction of ketosis and on symptoms of keto-induction are limited, and there is a lack of homogeneity between study objectives, outcomes, and measures, a narrative review style was chosen.

While it is clear that exogenous ketones increase serum BOHB, they are not ketogenic, and may, in fact, inhibit endogenous ketone production ( Balasse & Neef, 1975 ). In other words, they promote ketonaemia but do not encourage the creation of ketone bodies in the liver. So, it is more accurate to say that exogenous ketones mimic the effects, many of which are positive, of NK, rather than inducing it.

At a dosage of 395 mg/kg bodyweight, KE increased BOHB in healthy volunteers from 0.2 mmol/L (±0.02) at baseline to 3.3 mmol/L (±0.2) one hour later ( Stubbs et al., 2015a ), and from 0.16 mmol/L (±0.02) at baseline to 3.16 mmol/L (±0.14) ( Stubbs et al., 2015b ) The same dose has been used to determine the effect on ketonaemia of KE taken with or without a meal. BOHB concentration (one-hour post-KE) was lower in those having taken a meal, but both groups achieved levels of ketonaemia consistent with NK; 2.1 mmol/L (±0.2) and 3.1 mmol/L (±0.1) respectively ( Stubbs et al., 2015c ). In a study using higher dosages (0.573 g/kg BW) in healthy male athletes performing an hour of bicycle exercise at 75% of maximal exercise intensity BOHB levels rose from 0.1 to 3.4 mmol/L ( p < 0.01) following ketone drinks ( Cox et al., 2015 ).

After ingestion of MCT at a dosage of 30 g MCT/m ( Paoli et al., 2015 ) body surface area by nine children (in a study of seizure control), BOHB levels rose progressively after administration from a mean of 0.2 ± 0.1 mmol/L after an overnight fast to 1.05 ± 0.3 mmol/L at 180 min. Participants reached NK on average at 30–60 min with most participants in NK by the 90th minute, but there was significant variation in BOHB between individuals ( Ross et al., 1985 ). With a lower dosage of 7.5 g of MCT taken three times per day after an acclimation period of 5 g MCT taken three times per day for one week, plasma BOHB was higher, yet not inducing NK ( Courchesne-Loyer et al., 2013 ).

While there is a paucity of research on the effect of MCTs on the time taken to achieve NK, MCTs are demonstrably ketogenic and thus, allow induction of NK with lower proportions of fat in the diet, than that used in ‘classic’ 3 or 4:1 lipid to non-lipid (or ‘ketogenic ratio’) protocols. When ‘classic’ ketogenic diets with a greater than 3:1 ratio of lipid to non-lipid are compared to MCT ketogenic diets with 60% of calories from MCT, NK can be achieved with a lower lipid intake. Huttenlocher first observed higher BOHB levels in children with epilepsy aged 2–9 years, at up to one month on an MCT ketogenic diet, and marginally lower after this time, when compared to a classic ketogenic diet, although these differences were not significant ( Huttenlocher, 1976 ). In a study of 55 children with severe epilepsy, Schwartz and colleagues found modified ketogenic diets, MCT ketogenic diets, and classic ketogenic diets to all be ‘ketogenic’ (inducing NK) with peak ketone body concentrations of approximately 1 mmol/L, 1.5 mmol/L and 4 mmol/L respectively, after three weeks on the differing ketogenic protocols ( Schwartz, Boyes & Aynsley-Green, 1989 ). Nine children were subsequently trialled on a second diet and profiled three weeks later. Cumulative results over 24 h of metabolic testing demonstrate that expression of ketone bodies rises (in order) from a normal diet (little change) to a modified MCT diet, an MCT ketogenic diet, and the greatest rise in ketone bodies over 24 h resulting from a classic (4:1) ketogenic diet. In a 12-month study, a classic ketogenic diet resulted in higher levels of BOHB (and acetoacetate) over all time periods (three, six, and 12 months) but this was only statistically significant at three and six months ( p < 0.001) ( Neal et al., 2009 ).

MCTs increase BOHB in a linear and dose-dependent fashion. For example, when eleven pre-term infants were fed formulas with either 25% or 50% of fat calories coming from MCTs for at least 96 h (30 kcal/ml, around 50% calories from fat in total, 10% protein, 40% carbohydrate) the 50% MCT formula resulted in a mean plasma level of BOHB of 0.14 ± 0.03 mmol/L/, a nearly three-fold increase over the lower MCT formula (0.06 ± 0.01) ( Wu et al., 1986 ).

In medium chain triglycerides (MCTs) two-to-three of the fatty acid chains attached to the glycerol backbone are medium in length. These medium-chain fatty acids (MCFAs) are comprised of a 6–12 carbon chain. The MCTs are: caproic (C6), caprylic (C8), capric (C10) and lauric acid (C12) ( Marten, Pfeuffer & Schrezenmeir, 2006 ). Similar to the short-chain fatty acids and unlike long-chain triglycerides (LCTs), MCTs do not require the actions of bile, nor micellar-chylomicron mediated absorption into the lymphatics and instead are diffused directly into the hepatic portal vein and preferentially converted into bio-available ketone bodies in the liver. Huttenlocher and colleagues first demonstrated that diets containing fewer calories from lipids than a ‘classic’ ketogenic diet—around 60%–75% of calories—can induce NK if they include a high proportion of medium chain triglycerides (MCTs) ( Huttenlocher, Wilbourn & Signore, 1971 ). A VLCKD with 60% of energy derived from MCTs, a three-fold greater intake of carbohydrate (18% vs. 6%) and a ∼50% (7% vs. 10%) increase in protein compared to a standard ketogenic diet induces NK with no appreciable difference in BOHB levels ( Huttenlocher, 1976 ).

In a recent study in humans, the effect of L-leucine, octanoyl-monoacylglycerol (O-MAG), a monoglyceride consisting of an 8-carbon fatty acid, L-carnitine, and butyric acid on acetoacetate and BOHB were studied. Both 2 g and 4 g of butyric acid were demonstrated to be more ketogenic than either 5 g of leucine, or 5 or 10 g of O-MAG ( St-Pierre et al., 2017 ).

Butyric acid (BTA) is a four-carbon, short-chain fatty acid found in the milk of ruminants and present in small amounts in many dairy foods. Most BTA in humans is produced by microbial intestinal fermentation of dietary fibre and resistant starch. Most of the butyric acid produced by this fermentation of starches is absorbed and used directly by colonocytes, with most of the remainder absorbed into the hepatic portal vein, and transported to the liver where it can be converted to ketone bodies ( Bourassa et al., 2016 ; Stilling et al., 2016 ). A small amount is absorbed directly from the large colon and enters systemic circulation, to be used directly by peripheral tissue ( Bourassa et al., 2016 ). Butyrate exerts effects directly on the colonic mucosa, including inhibition of inflammation and carcinogenesis, decreasing oxidative stress, and promotion of satiety ( Hamer et al., 2008 ; Fung et al., 2012 ). Thus, it serves an important role in preserving the health of the colon, microbiota, and may have other beneficial roles for general and systemic health. Animal studies on the ketogenic potential of butyrate are mixed. For example, silage butyrate content has been shown to provide no significant effect on subclinical ketosis in dairy cows ( Samiei et al., 2015 ), however, sub-clinical ketosis is higher in those receiving silage higher in butyrate content ( Vicente et al., 2014 ).

Short-chain fatty acids (SCFAs) have carbon chains between two and five in length. These fatty acids include acetic acid (C:2), propionic acid (C:3), butyric acid (C:4), and valeric acid (C:5). Short chain fatty acids, especially butyric acid, are used extensively as a fuel substrate by intestinal epithelial cells ( Wong et al., 2006 ). It is generally accepted that chain length affects the relative deposition of fatty acids into either lymph or the portal vein ( Mu & Høy, 2004 ). Those short-chain fatty acids that escape metabolism by epithelial cells are, therefore, primarily absorbed via the hepatic portal vein and do not require ‘bundling’ with micelles and chylomicrons for absorption ( Kuksis, 2000 ). The highest quantities of short-chain fatty acids have been observed in portal blood, followed by hepatic, and far less in peripheral blood ( Cummings et al., 1987 ). Thus, they bypass the usual route of absorption (for the more common long-chain fatty acids) into the lymphatics and deposition into the bloodstream via the subclavian vein, and instead, are transported via the hepatic portal vein to the liver where they can be converted into the ketone bodies ( Bugaut, 1987 ; Bourassa et al., 2016 ; Stilling et al., 2016 ).

Progression of fasting increases the conversion of leucine to ketone bodies and peripheral tissue is catabolised to provide leucine for ketogenesis ( Kulaylat et al., 1988 ). Leucine can also be degraded in rat astroglial cells to the ketone bodies, including BOHB, and when released by these cells, used by neighbouring neurones as a fuel substrate ( Bixel & Hamprecht, 1995 ). Leucine also results in hepatic ketogenesis ( Holecek et al., 2003 ). Studies in mice have shown that while ingested L-leucine can reduce seizure activity similarly to a KD, it does not independently increase blood levels of BOHB ( Hartman et al., 2015 ). Evangeliou and colleagues have demonstrated that the addition of 20 g per day of BCAAs, including 9 g of leucine, in 17 children with intractable epilepsy, altering the ratio of lipid to protein from 4:1 to around 2.5:, had no effect on ketosis, along with greater reductions in seizure activity. The authors postulated that this could be due to the ketogenic effect of leucine, but may also result from a greater availability of BCAAs ( Evangeliou et al., 2009 ).

Leucine and lysine are solely ketogenic amino acids. Thus, they do not contribute to gluconeogenesis. Higher leucine (and isoleucine) concentrations result from a ketogenic diet and are related to reduced glutamate-to-GABA ratio and this might explain some of the anti-seizure activity of a ketogenic diet in epilepsy ( Roy et al., 2015 ). There appears to be a high affinity of kidney cells for ketogenesis from leucine ( Noda & Ichihara, 1976 ).

Conclusions

It’s unclear at this time whether an elevation in ketones over and above NK would mitigate the effects of keto-induction. It has, for example, been observed that mood is improved within the first two weeks of a diet irrespective of macronutrient composition (Rosen et al., 1985), and only one study, to our knowledge, has demonstrated a correlation between ketone levels and memory performance (Krikorian et al., 2012).

Except for MCTs, there is limited research on the ketogenic potential of nutritional supplements, especially in human subjects. While the ketogenic amino acid leucine may not independently encourage ketogenesis to levels consistent with NK, more research is required, and the effect on time to NK and symptoms of keto-induction, particularly in a classic KD, are at this stage unknown.

Similarly, there is a paucity of research on the short-chain fatty acids and their effects on ketogenesis. Their mode of absorption and metabolism, like that of MCTs, but perhaps even more rapid, hints at a potential role for encouraging ketogenesis, and thus, the potential for improving time to NK and reducing symptoms of keto-induction.

There is a considerable amount of research demonstrating that MCTs promote both primary ketonaemia resulting from the conversion of medium chain fatty acids liberated from MCTs into bio-available ketone bodies, and longer-term ketogenesis by facilitating keto-adaptation. Expression of the ketone body BOHB is increased in a linear, dose-dependent manner in response to oral loads of MCT but it is unclear whether MCTs independently improve time to NK. Modified MCT ketogenic diets do not significantly hasten the induction of NK over a classic ketogenic diet with a minimum of three parts lipid to one part non-lipid, but they do allow NK to occur in diets containing greater amounts of non-lipid macronutrients.

There has, however, been little research performed on the application of MCTs to classic ketogenic diets and whether, if applied, they would; (a) improve time to NK, (b) result in significantly higher levels of BOHB, and (c) significantly reduce symptoms of keto-induction. It is also unknown if, in the context of a ketogenic diet, MCTs provide additional benefits, for example for physical and mental performance and mood.

Exogenous ketones are unlikely to be ketogenic per se, and may inhibit ketogenesis, however, the rapid and substantial elevation of BOHB offers potential to mitigate effects of keto-induction, and thus, could play a role in improving adherence to a ketogenic diet. Newport et al. have reported improvements in mood and cognitive performance resulting from ketone ester treatment over 20-months in an Alzheimer’s Disease case. In this case, cognitive performance tracked plasma BOHB concentrations. In a direct, dose-matched comparison, Kesl and colleagues evaluated the effects of ketone esters, salts, MCTs, and MCT + KS on blood BOHB in Sprague-Dawley rats at a dose of 5 g/kg. At 0, 30, and 60 min and 4, 8, and 12 hrs post administration (by intragastric gavage) KS + MCT and MCT supplementation rapidly elevated and sustained significant BOHB elevation compared to control for the duration of the 4-week study. Ketone salts did not significantly elevate BOHB at any time point tested compared to controls. Ketone ester supplements significantly elevated BOHB levels for the duration of the 4-week study. This further demonstrates, albeit, in non-human subjects, the superiority of KE to KS for elevating BOHB, and the utility of MCT for the same purpose, but is likely to limited in applicability to health and performance as we have seen demonstrable increases in BOHB, consistent with NK levels with supplementation of KS in humans (Holdsworth, Cox & Clarke, 2016; Stubbs et al., 2016). Research performed on exogenous ketone supplements is, at this time, highly preliminary, and has been predominantly performed using animal subjects. Further clinical research is required to translate the potential benefits seen in these studies, to human models of disease and disorder.

This review was limited by a dearth of studies demonstrating the effect of supplementation on the time taken to achieve ketosis as defined by the lingua franca of NK, ≥0.5 mmol L −1 and on symptoms of keto-induction during this time.

While studies have described symptoms arising from a ketogenic diet, few studies have specifically evaluated symptoms and adverse effects of a ketogenic diet during the induction phase, and the studies that have been performed typically have not been designed to evaluate these as primary outcomes, and thus, our conclusions are extrapolated from a variety of sources. There is also little consensus on whether greater levels of BOHB (over and above NK threshold) are, in fact, associated with fewer symptoms of ‘keto-flu’, nor for that matter with improved outcomes but as previously noted, Newport and colleagues have observed a linear correlation between mood and cognition, and BOHB levels (Newport et al., 2015). Adverse effects associated with the induction of NK might cause increased drop-out rates and preclude some of the positive effects for those that would otherwise benefit from a VLCKD. For example, Yancy and colleagues noted an 8% overall dropout rate due to difficulties adhering to an LCHF diet, with a further 5% withdrawing from their study due to adverse effects (Yancy Jr et al., 2004). High attrition rates due to tolerability and gastrointestinal side effects have also been noted in childhood epilepsy research utilising VLCKDs (Levy et al., 2012; Chul Kang et al., 2005).

Preliminary research suggests that increased BOHB levels and a faster time-to-NK might improve the acceptability of the KD and improve compliance rates, but more research is required to understand the role that supplementation could play in encouraging ketogenesis, improving time to NK, reducing symptoms associated with keto-induction, and the effect this might have on improving adherence to, and outcomes from a VLCKD.