The science of ketogenic supplements for athletes: boosting endurance, efficiency, and energy metabolism

Abstract

Ketogenic supplements have gained much attention in exercise nutrition because they have the potential to enhance endurance, maximize metabolic efficiency, and provide an additional source of fuel during exercise. This review is an examination into the molecular process, physiological alteration, and overall impact of ketogenic supplementation on sport performance. Various forms of ketogenic supplements, including exogenous ketones, medium-chain triglyceride (MCT) oil, and ketone esters, are examined in terms of their ability to induce ketosis and influence cellular energy pathways. The influence of ketone bodies on ATP synthesis, mitochondrial function, and metabolic shifts from carbohydrates to fats is summarized with special attention to endurance and high-intensity exercise implications. Furthermore, the long-term physiological adaptations, including enhanced fat oxidation, improved recovery, and resistance to fatigue, are analyzed. While ketogenic supplementation offers potential performance benefits, it also presents challenges such as muscle glycogen depletion, gastrointestinal distress, and electrolyte imbalances. A risk-benefit analysis is provided, outlining strategies to optimize supplementation while minimizing adverse effects. Finally, gaps in current research and future directions for ketogenic supplementation in sports are explored, emphasizing the need for individualized approaches and further investigation into long-term effects.

Introduction

Use of supplements to enhance sporting performance is presently common among sportsmen and women, as well as sport enthusiasts [1]. From the various types of supplements, the ketogenic supplements have gained significant popularity in the recent past, particularly due to their ability to enhance endurance, fat metabolism, and overall exercise performance. The ketogenic diet, high in fat and low in carbohydrates, aims to induce a metabolic state of ketosis in which fat becomes the dominant energy source [2]. Based on this idea, ketogenic supplements like exogenous ketones, medium-chain triglyceride (MCT) oils, and ketone esters have been created to increase blood ketone levels, allowing athletes to reap the rewards of ketosis without having to adhere to strict dietary limitations [3].

The popularity of ketogenic supplements in sport stems from their potential to improve fat oxidation and endurance especially in long-duration events. Recent evidence also suggests improvements in cognitive performance during exercise, including focus and reaction time, especially with exogenous ketone esters [4]. However, despite their growing popularity, the underlying molecular mechanisms, physiological effects, and possible risks of ketogenic supplementation remain under active investigation.

This review aims to provide a balanced evaluation of ketogenic supplements and their effects on exercise performance, with particular focus on their molecular mechanisms, physiological adaptations, and the balance between potential benefits and adverse outcomes. Based on the synthesis of current scientific literature, the review evaluates how ketogenic supplements influence pathways of energy production, fat metabolism, and performance across different sporting contexts. In addition, it critically examines the available evidence on the long-term safety of these supplements in athletic populations, highlighting both their advantages and limitations.

Overview of ketogenic supplements

Ketogenic supplements have gained growing popularity among athletes due to their potential to promote fat oxidation and serve as an alternative fuel source during exercise [5]. Exogenous ketones, MCT oil, and ketone esters are some of the supplements that increase blood ketone levels, enabling athletes to enjoy the effects of ketosis without having to adhere to a low- carbohydrate or ketogenic diet. When used correctly, these supplements can produce long-lasting energy, improve endurance, and support high-performance exercise [6].

Exogenous ketones, such as beta-hydroxybutyrate (βHB), are among the most widely used ketogenic supplements. These molecules are endogenously produced by the liver during nutritional ketosis, but when consumed exogenously, they rapidly increase circulating ketone levels. Typical dosing in human studies ranges from 0.25 to 0.5 g/kg body weight for βHB salts, achieving peak blood βHB concentrations of approximately 0.5–0.6 mM depending on dose and formulation [7, 8]. This exogenous elevation enables athletes to access the metabolic advantages of ketosis without requiring full dietary adaptation. Such supplementation is particularly beneficial for athletes who are not fully keto-adapted but seek to improve endurance performance through enhanced fat oxidation and glycogen sparing [2, 9].

MCT oil, typically extracted from coconut or palm kernel sources, is rapidly metabolized in the liver into ketones, providing a quick and efficient energy source during moderate to high-intensity activity [10]. In clinical studies, effective doses of MCT oil range from 15 to 30 g per day, which significantly increase ketone levels without causing major gastrointestinal side effects [11]. MCT oil is routinely used by sportspersons looking for an instantly effective supplement that helps support endurance or endurance training as it is capable of maintaining energy stores without causing excess glycogen burnout [12].

Ketone esters are more effective and potent in composition than exogenous ketones in the form of βHB salts or MCT oil as they are designed to elevate blood levels of ketones even further. Typical dosing in human studies ranges from ~ 573 to 600 mg/kg body weight, resulting in plasma βHB concentrations of ~ 2–4 mM during exercise [3]. These products are manufactured in a laboratory to provide a higher dose of ketones per serving. Ketone esters have been discovered to provide a more immediate and higher increase in blood ketone levels, allowing athletes to benefit from enhanced energy production during exercise. Although ketone esters are highly effective, they are likely to taste worse and be more expensive, which may limit their widespread use in athletes [13, 14].

The action mechanism of these ketogenic supplements is through elevating blood ketone levels, thus shifting the body’s energy metabolism from carbohydrates to fats. When ketones are in the bloodstream, they can be used by muscles as an effective source of energy during exercise. This is particularly crucial during extended exercise, where glycogen levels can be exhausted. By providing a constant quantity of fuel, ketogenic supplements reduce the development of fatigue and increase endurance, which is very useful for endurance athletes [15]. In comparison to more traditional performance enhancement supplements like carbohydrate supplements or protein supplements, ketogenic supplements have some advantages. Carbohydrates, the body’s primary source of energy during intense activities, are used quickly, and their depletion could limit endurance in repeated efforts [16]. On the other hand, ketogenic supplements promote fat oxidation, which provides a more stable source of energy that is not depleted as rapidly [17]. While protein supplements are crucial for muscle repair and recovery, they do not have the same immediate energy benefits through exercise [18]. Therefore, ketogenic supplements offer an alternative and useful option for athletes requiring sustained energy for extended periods of time and overall performance improvement (Fig. 1).

Fig. 1.

Ketogenic supplements like exogenous ketones, MCT oil, and ketone esters enhance athletic performance by increasing blood ketone levels, promoting fat metabolism, and providing sustained energy for endurance and reduced fatigue

Metabolic mechanisms and fat oxidation pathways

Ketogenic supplementation alters substrate utilization by providing readily available ketone bodies such as βHB, which bypass glycolysis and enter mitochondrial metabolism directly. These ketones are converted into acetyl-CoA and feed into the tricarboxylic acid (TCA) cycle, allowing for efficient ATP production even in low-glucose conditions [19, 20]. Compared to glucose, ketones yield more ATP per carbon and generate fewer reactive oxygen species (ROS), thereby improving mitochondrial efficiency and reducing oxidative stress [21, 22].

This metabolic rerouting is especially beneficial during prolonged exercise when muscle glycogen stores begin to deplete. In such cases, ketogenic supplements offer an alternative and sustained fuel source, delaying fatigue and supporting energy homeostasis. Instead of relying on the slower endogenous ketogenesis through fat mobilization, exogenous ketones elevate blood ketone concentrations rapidly and accelerate the shift toward fat utilization [23].

At the molecular level, βHB functions not only as an energy substrate but also as a signaling metabolite that modulates key cellular pathways involved in metabolic adaptation. βHB inhibits class-I histone deacetylases (HDACs) and promotes histone β-hydroxybutyrylation, thereby enhancing the expression of genes related to mitochondrial biogenesis and oxidative metabolism [24]. Moreover, ketone metabolism influences the cellular redox state by altering the NAD⁺/NADH ratio, which activates sirtuins (SIRT1/2/3) [25]. Together with AMP-activated protein kinase (AMPK), sirtuin activation stimulates the peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) signaling axis, leading to mitochondrial biogenesis and upregulation of oxidative enzymes [26].

Collectively, these adaptations enhance mitochondrial quality and oxidative capacity, increasing the muscle’s ability to utilize fatty acids and ketones efficiently while sparing glycogen for high-intensity demands later in performance (Fig. 2). Recent findings also suggest that exogenous ketones support redox balance and reduce oxidative stress, contributing to improved endurance efficiency and faster post-exercise recovery.

Building upon the molecular mechanisms described earlier, ketogenic supplementation further influences substrate utilization at the whole-body level, particularly by promoting lipid oxidation during exercise. Fat oxidation is a central metabolic process during prolonged and submaximal exercise, providing a sustainable and efficient source of ATP [27]. Under normal dietary conditions, the body primarily utilizes carbohydrates for rapid energy production. However, when carbohydrate availability is limited either through prolonged exercise, fasting, or ketogenic supplementation the body shifts toward using fats as a predominant fuel source via β-oxidation and oxidative phosphorylation pathways in mitochondria [28, 29].

This metabolic shift is critical for athletes engaging in prolonged or moderate-intensity exercise, as it allows for more efficient energy production through fat metabolism by increasing circulating ketone bodies such as ΒHB [30]. Exogenous ketone supplements, particularly ketone esters and ΒHB, promote this metabolic shift by elevating circulating ketone levels and reducing reliance on glucose metabolism.

At the transcriptional level, βHB has been shown to activate AMPK and upregulate peroxisome proliferator-activated receptor alpha (PPARα) in preclinical models, a key nuclear receptor regulating genes responsible for fatty acid transport and β-oxidation enzymes [20]. This pathway enhances mitochondrial uptake and oxidation of long-chain fatty acids, reinforcing the metabolic transition toward fat-based energy production during exercise [31, 32]. Although much of the evidence for AMPK and PPARα activation by βHB arises from preclinical studies, these signaling pathways are crucial for exercise-induced metabolic adaptations.

Supporting these mechanistic insights, studies using indirect calorimetry in humans have demonstrated that ketone supplementation markedly alters substrate utilization during endurance exercise. The respiratory exchange ratio (RER), the ratio of CO₂ output to O₂ uptake, declines following ingestion of exogenous ketone esters, indicating a metabolic shift toward increased reliance on fat and ketone oxidation. This is advantageous because fats and ketones provide greater oxidative efficiency and ATP yield per gram compared to carbohydrates. While glycogen stores are limited and deplete rapidly during exercise, fat stores are abundant and provide a sustainable energy source, especially under ketogenic conditions. Ketone supplementation may therefore spare muscle glycogen, delaying fatigue in endurance performance [33].

Nevertheless, the magnitude of this enhancement depends on factors such as training status, metabolic flexibility, and ketone dose. For example, O’Malley et al. reported that ingestion of ketone salts providing 0.3 g/kg βHB elevated plasma βHB concentrations to approximately 0.6–0.8 mM, leading to a significant reduction in RER and a corresponding increase in fat oxidation during low- to moderate-intensity cycling exercise. However, during a subsequent high-intensity 150-kJ cycling time-trial, performance declined by about 7%, indicating that while exogenous ketones can shift substrate utilization toward greater fat reliance, this metabolic shift may impair power output when rapid glycolytic energy production is required [34].

Therefore, exogenous βHB supplementation may, in theory, potentiate training-induced mitochondrial adaptations by engaging similar signaling pathways while supporting enhanced fat oxidation during endurance activity. In summary, ketogenic supplementation promotes efficient energy production by elevating βHB levels, stimulating mitochondrial pathways via AMPK and PPARα, lowering RER, and reducing glucose reliance. These combined effects may enhance endurance efficiency, promote glycogen sparing, and increase metabolic flexibility, although individual responses can vary depending on exercise intensity, metabolic state, and supplementation strategy.

Fig. 2.

Molecular and metabolic mechanisms of ketogenic supplementation in skeletal muscle. Exogenous ketone bodies enter muscle cells and are converted to acetyl-CoA, fueling the TCA cycle and enhancing ATP production with reduced ROS generation. Beyond serving as an energy substrate, ketones act as signaling molecules that activate AMPK and SIRT1, leading to PGC-1α–mediated mitochondrial biogenesis and upregulation of oxidative enzymes. These adaptations improve mitochondrial efficiency, enhance fat and ketone utilization, spare glycogen, and support endurance performance and recovery. Abbreviations: AMPK, AMP-activated protein kinase; SIRT1, sirtuin 1; PGC-1α, peroxisome proliferator-activated receptor gamma coactivator 1-alpha; ROS, reactive oxygen species; TCA, tricarboxylic acid cycle

Improving endurance: the impact of ketogenic supplements on aerobic performance

Ketogenic supplements have been extensively studied for their potential to enhance endurance performance by promoting fat oxidation, sparing muscle glycogen, and increasing circulating ketone availability during prolonged aerobic exercise. This is particularly relevant for athletes participating in cycling, long-distance running, or triathlon events, where carbohydrate depletion can lead to fatigue and reduced output [35].

In a controlled, randomized crossover trial by Cox et al., trained endurance athletes (n = 39) ingested a ketone ester drink at a dose of 573 mg/kg body weight, corresponding to approximately 500 mg/kg β-hydroxybutyrate equivalent, which elevated circulating D-βHB concentrations to ~ 3 mM within 30–60 min. The drink provided 40% of total calories from ketone esters and the remainder from carbohydrates (dextrose), ensuring isocaloric intake across conditions. Participants then completed cycling exercise at 70–75% of maximal workload (W_max) for 1–2 h, under single-blind, randomized crossover design conditions. Compared with carbohydrate-only trials, the ketone ester condition resulted in significantly lower RER values, reflecting a greater contribution of lipid- and ketone-derived substrates to oxidative metabolism. This was accompanied by decreased plasma lactate concentrations, reduced glycolytic intermediates (e.g., pyruvate), and increased intramuscular triacylglycerol (IMTAG) oxidation, even in the presence of normal muscle glycogen and elevated insulin levels. Muscle biopsies confirmed elevated β-hydroxybutyrate and acetyl-carnitine levels, indicating enhanced acetyl-CoA formation from ketones and fatty acids to support oxidative phosphorylation. These data collectively demonstrate that exogenous ketone supplementation induces a distinct metabolic phenotype in working muscle characterized by suppressed glycolysis, enhanced fat oxidation, and improved mitochondrial efficiency, potentially contributing to greater endurance performance by preserving carbohydrate stores and sustaining oxidative ATP production during prolonged submaximal exercise [36].

In contrast, Dearlove et al. investigated the acute effects of ketone ester ingestion (330 mg/kg body weight of (R)−3-hydroxybutyl (R)−3-hydroxybutyrate) in a double-blind crossover trial involving twelve trained individuals undergoing an incremental cycling test to exhaustion, a protocol that predominantly challenges the aerobic energy system up to maximal oxygen uptake (VO₂max). While βHB levels rose significantly and induced mild ketoacidosis (reflected by reductions in blood pH and bicarbonate), no performance improvements were observed. Moreover, compensatory hyperventilation and an earlier ventilatory threshold were recorded, suggesting that acid-base imbalances may attenuate potential aerobic performance benefits under certain physiological conditions [37].

In addition, a study investigated βHB oxidation rates in six trained male athletes under varying substrate availability. Participants consumed 573 mg/kg body weight of a 13 C-labeled ketone ester prior to performing 1 h of cycling at 75% Wmax. The study examined βHB utilization under three distinct metabolic conditions: (i) high carbohydrate with normal fat availability (KE + CHO), (ii) high carbohydrate with high fat availability (KE + CHO + FAT), and (iii) low carbohydrate with high fat availability (KE + FAT). Blood βHB levels increased to ~ 4.5 mM before exercise in all conditions. βHB oxidation was modestly greater when carbohydrate availability was high and tended to be impaired under low-CHO conditions. Moreover, a positive correlation between intramuscular glycogen content and βHB oxidation was observed, suggesting that adequate glycogen facilitates more efficient ketone oxidation during exercise. These findings highlight that substrate availability modulates the energetic contribution of exogenous ketones in endurance performance [38].

In a randomized crossover trial, ketone ester supplementation was provided during a simulated endurance cycling race with three boluses of 25, 20, and 20 g (R)−3-hydroxybutyl (R)−3-hydroxybutyrate) at 60 and 20 min before, and at 30 min during exercise. Despite achieving significant elevations in circulating ΒHB, there were no differences between the ketone and control groups in muscle glycogen breakdown, 15-minute time trial output, or sprint to exhaustion. Moreover, ketone ingestion induced mild acidosis (pH drop to ~ 7.36) and reduced bicarbonate levels, potentially impairing buffering capacity during the final phase of exercise. These findings suggest that, under conditions of sufficient carbohydrate availability, exogenous ketosis may not confer endurance benefits and could even compromise performance toward the end of prolonged aerobic efforts [39].

These mixed findings highlight the context-dependent nature of ketone supplementation in aerobic performance. While acute ketone ingestion may enhance metabolic flexibility and spare muscle glycogen in certain scenarios such as fasted states or low-glycogen conditions it may not consistently translate into measurable performance gains, particularly when carbohydrate availability is sufficient. Factors such as acid-base disturbance, exercise intensity, supplementation timing, and individual metabolic responses all modulate the efficacy of ketone esters in endurance contexts. Therefore, more targeted research is needed to identify which subpopulations and exercise conditions may benefit most from exogenous ketone supplementation in aerobic sports.

Strength and power: how ketogenic supplements affect anaerobic performance

Anaerobic performance, such as sprinting, resistance training, and high-intensity interval exercise, relies primarily on rapid ATP generation via glycolysis and the phosphagen (phosphocreatine) system. These energy systems support the high rates of energy turnover required for short-duration, high-intensity efforts, unlike fat oxidation and ketone metabolism, which are oxygen-dependent and produce ATP at a slower rate. While ketogenic supplementation has been primarily explored for its potential benefits in endurance exercise, recent research has started to investigate its influence on strength, power, and anaerobic performance. However, given the slower rate of ATP production from ketone metabolism, its ergogenic potential in anaerobic domains remains controversial [23, 40].

Initial findings regarding ketone supplementation and anaerobic performance have been largely inconclusive. A systematic review and meta-analysis of 13 randomized controlled trials found no significant benefits of acute ketone ingestion on exercise performance ranging from sprint bouts to events lasting up to ~ 50 min. Despite consistent increases in circulating βHB levels, no consistent improvements were observed in performance outcomes, nor in metabolic, respiratory, cardiovascular, or perceptual responses [41]. These findings reinforce the notion that ketone bodies may not supply ATP rapidly enough to support short, high- intensity anaerobic activities.

However, emerging long-term data suggest that chronic keto-adaptation might yield different outcomes. In a 12-week intervention study on endurance-trained athletes, participants following a low-carbohydrate ketogenic diet (LCKD; 6% carbohydrate, 17% protein, 77% fat) experienced enhanced anaerobic power. Compared to a high-carbohydrate control group, the LCKD group exhibited significantly greater improvements in six-second sprint output and critical power testing, accompanied by elevated fasting β-hydroxybutyrate concentrations from 0.1 to 0.5 mmol/L, suggesting possible neuromuscular adaptation and improved glycolytic capacity under ketogenic conditions [42].

Overall, while acute ketone supplementation appears to offer minimal benefits for short-duration efforts, chronic adaptation through sustained ketogenic dietary strategies may support certain aspects of anaerobic performance, particularly when combined with structured resistance training. Table 1 provides a comprehensive overview of clinical trials on exogenous ketogenic supplements and exercise performance.

Table 1.

Clinical trials of exogenous ketogenic supplements and effects on endurance, energy metabolism and performance

Population	Supplement/Dose	Exercise protocol	Metabolic outcomes	Performance outcome	Ref. No.
Trained endurance athletes (n = 39)	Ketone monoester ≈ 573 mg·kg⁻¹	Cycling for 1–2 h	↑ plasma D-βHB (~ 3 mM); ↓ RER; ↓ lactate; ↑ IMTAG oxidation	Enhanced fat oxidation and mitochondrial efficiency; potential glycogen sparing	[36]
Healthy trained males (n = 10)	Ketone salts 0.3 g·kg⁻¹ βHB	Steady-state cycling (low–moderate intensity) then 150-kJ TT	↓ RER; ↑ fat oxidation	↓ mean power during high-intensity TT	[34]
Trained individuals (n = 12)	Ketone monoester 330 mg·kg⁻¹ [(R)−3-hydroxybutyl (R)−3-hydroxybutyrate]	Incremental cycling test to exhaustion	↑ βHB (~ 3.7 mM); ↓ pH (7.37); ↓ HCO₃⁻ (18.5 mM); ↑ ventilation	No improvement in performance; earlier ventilatory threshold	[37]
Trained male athletes (n = 6)	13 C-labeled ketone ester 573 mg·kg⁻¹	1 h cycling under varied CHO/fat availability	βHB oxidation ↑ with high CHO; peak βHB ~ 4.5 mM	βHB oxidation impaired under low CHO; context-dependent effects	[38]
Trained male cyclists (n = 12)	Three boluses (25 g, 20 g, 20 g) of ketone monoester at − 60, −20, and + 30 min relative to exercise start	Simulated 3-h cycling race + 15-min TT + sprint	βHB ↑ to ~ 3 mM; ↓ pH (7.36); ↓ bicarbonate (21.6 mM)	No glycogen sparing; no improvement in TT or sprint performance	[39]
Endurance-trained athletes (n = 20)	Low-carbohydrate ketogenic diet	100-km TT, 6-sec sprint	↑ βHB ↑ fat oxidation	↑ sprint & critical power; ↓ fat mass	[42]
Elite professional cyclists (n = 10)	Ketone diester (1,3-butanediol acetoacetate diester; 2 × 250 mg·kg⁻¹), pre-exercise	~ 31-km cycling TT simulating 2017 World Championships course	↑ serum βHB, ↑ AcAc, ↑ urinary ketones; hyperketonemia during CHO-fed state	Performance ↓ ~2%; ↑ gut discomfort, ↑ perceived exertion	[43]
Highly-trained cyclists (n = 12)	Two 30 mL servings of oral βHB supplement (timed pre- and mid-exercise)	90-min cycling followed by 4-min maximal cycling test	Large ↑ blood βHB vs. placebo; moderate ↑ RER during submax and 4-min test; VO₂ ↑ slightly in final phase	No significant difference in 4-min TT power output; altered substrate metabolism without ergogenic benefit	[44]
Endurance-trained runners (n = 8)	Ketone monoester 573 mg·kg⁻¹ co-ingested with 8% CHO-electrolyte solution	1 h submaximal run + 10-km TT	Plasma βHB ↑ to 1.0–1.3 mM during exercise; no change in glucose or lactate; similar VO₂, RER, HR, RPE	No improvement in 10-km TT time or cognitive performance vs. CHO alone	[45]
Healthy college-aged males (n = 15)	11.38 g βHB beverage (absolute dose, not per kg) vs. placebo	Four 15-s Wingate tests with 4-min rest; cognitive task before & after	βHB ↑ (0.53 vs. 0.21 mmol/L vs. placebo); ↑ lactate post-exercise	No improvement in power output or cognition; fatigue index slightly ↑ with βHB	[46]
Healthy trained men (n = 9)	Ketone monoester (R)−3-hydroxybutyl (R)−3-hydroxybutyrate, 0.29 g·kg⁻¹ immediately postexercise and at 1 h, 2 h post	1 h cycling	↑ Serum βHB; ↓ glucose	↑ postexercise erythropoietin; suggests stimulation of erythropoiesis	[47]
Trained healthy males (n = 8)	Ketone ester [0.5 g·kg⁻¹ (R)−3-hydroxybutyl (R)−3-hydroxybutyrate] immediately post-exercise + 0.25 g·kg⁻¹·h⁻¹ for 5 h with CHO/PRO recovery drink	One-leg glycogen-depleting exercise + 5-h recovery	↓ AMPK phosphorylation; ↑ mTOR1 activation; no change in glycogen resynthesis	Enhanced post-exercise protein synthesis signaling; supports muscle remodeling potential	[48]
11 male runners	Ketone ester [1,3-butanediol, 500 mg/kg body weight] combined with CHO	Submaximal (60-min) run preceding a 5-km TT	↑ βHB; ↓ blood lactate after 30 min; ↑ post-TT blood glucose	↑ plasma D-βHB; ↓ lactate during exercise; no improvement in 5 km TT performance	[49]

βHB, beta-hydroxybutyrate; AcAc, acetoacetate; AMPK, AMP-activated protein kinase; CHO, carbohydrate; IMTAG, intramuscular triacylglycerol; mTOR1, mammalian target or rapamycin; RER, respiratory exchange ratio; TT, time trial; VO₂, Oxygen Uptake

Physiological adaptations: long-term effects of ketogenic supplements on muscle function and recovery

Muscle adaptation to ketones

Long-term ketogenic supplementation leads to the deep adaptation in muscle function and endurance. The muscles gain a greater capacity for metabolizing fat and ketones if the body is utilizing the ketones consistently as an energy source. It increases the performance of the mitochondria so the muscles have enhanced capacity for creating energy over periods of longer duration. As a result, athletes experience increased endurance, as they can sustain activity for longer periods without depleting glycogen stores. Also, changing to ketone utilization can give increased rates of fat oxidation, still increasing endurance and performance at long-duration exercise [49]. Acclimatization to ketones results in a reduction in the utilization of carbohydrates, making it possible for the body to utilize a more stable form of energy, which can assist in delivering consistent performance and reduced risk of exhaustion during prolonged exercise. Over time, the body becomes more metabolically adaptable to alternate between carbohydrate and fat metabolism more effectively, thereby enhancing overall sporting performance (Fig. 3) [50]. Emerging evidence also suggests that βHB may enhance muscle mitochondrial bioenergetics through epigenetic mechanisms such as HDAC inhibition and SIRT1 activation. These pathways contribute to mitochondrial biogenesis and may further increase muscle endurance and efficiency beyond simple energy substrate shifting [51, 52].

Fig. 3.

Physiological adaptations to long-term use of ketogenic supplements, including enhanced mitochondrial function, increased fat and ketone oxidation, reduced carbohydrate dependence, and improved overall athletic performance

Recovery enhancement

Ketogenic supplementation not only enhances performance but also facilitates recovery by mitigating oxidative stress and inflammation. Prolonged or high-intensity exercise increases the production of ROS, leading to oxidative stress [53]. This leads to cell damage, including lipid peroxidation, protein oxidation, and DNA damage, that hinders muscle recovery and causes fatigue. Ketone bodies, in particular βHB, possess antioxidant properties that nullify these effects. βHB elevates endogenous antioxidant defenses, such as superoxide dismutase (SOD) and catalase, that neutralize ROS and reduce oxidative damage to muscle tissue. By elevating the body’s own antioxidant systems, ketone bodies may aid in recovery, allowing athletes to sustain higher volumes of training with reduced muscle fatigue [54].

In addition to their antioxidant role, ketone bodies also possess anti-inflammatory properties. High-intensity exercise will exacerbate inflammation as a natural response to muscle breakdown, but too much inflammation will delay recovery and cause delayed-onset muscle soreness (DOMS) [55]. βHB has been shown to inhibit pro-inflammatory pathways, such as the NLRP3 inflammasome responsible for cytokine release like interleukin-1β (IL-1β) and interleukin-18 (IL-18) [56]. By suppressing the formation of these inflammatory mediators, ketone bodies can suppress the inflammatory response, enabling faster recovery and reduced muscle soreness. This anti-inflammatory effect is particularly useful for athletes who compete in sports with fast recovery demands, such as cycling, where successive stage performance in a race depends on successful recuperation.

Furthermore, βHB may improve central fatigue resistance by supporting brain energy metabolism and reducing neuroinflammation. Recent studies suggest that ketone monoester supplementation, a source of βHB, can attenuate declines in cognitive performance during prolonged, high-intensity intermittent exercise such as simulated soccer matches. Specifically, ketone monoester reduced the typical deterioration observed in choice reaction task (CRT) performance under mentally fatiguing conditions, suggesting enhanced cognitive resilience during competition. These central effects potentially mediated by more efficient cerebral energy utilization and reduced reliance on glucose could indirectly support neuromotor coordination and decision-making during sport-specific activity, thereby benefiting overall muscle performance and technical execution under fatigue [57].

Moreover, ketogenic supplementation also facilitates muscle repair by way of enhanced protein synthesis, the process through which the body repairs and strengthens muscle tissue after a workout. And since a steady ketone supply provides energy for muscle cells and the brain, athletes recover faster, experience less soreness, and are less prone to injury [58]. All these benefits are especially helpful for those athletes with successive training sessions or competitions, as it enables them to maintain high-level performance over a consistent period of time.

Impact of ketone supplementation on muscle protein metabolism

Ketone supplementation, and particularly with βHB, has been shown to impact muscle protein metabolism in two critical ways: through a reduction of muscle protein breakdown and potentially stimulating muscle protein synthesis (MPS) [59]. During intensive or prolonged exercise, muscle protein breakdown is higher as part of the body’s catabolic response, whereby proteins are broken down to be used to make amino acids to produce energy or repair tissues [60]. The ubiquitin-proteasome pathway (UPS), the primary mechanism of protein degradation, is the focus of this process. βHB has been shown to suppress proteasome activity and therefore reduce muscle protein degradation. It is a signaling molecule that suppresses proteolysis and may decrease the expression of ubiquitin ligases, which are markers of muscle degradation. This process has the ability to preserve muscle mass during excess physical stress or caloric restriction [61].

However, the reduction of muscle protein breakdown is not without complexity. While it may provide short-term benefits such as decreased muscle soreness and faster recovery, it could also interfere with long-term adaptive processes. Muscle protein breakdown is a natural part of post-exercise remodeling, essential for strengthening and adapting muscle tissue to training demands. Chronic suppression of this process might hinder these adaptations, raising questions about the long-term benefits of ketone supplementation for athletes [54].

In addition to reducing muscle breakdown, ketone bodies also increase muscle protein synthesis, the process by which new proteins are synthesized to repair and rebuild muscle [62]. MPS is regulated by processes like the mammalian target of rapamycin (mTOR), which is stimulated by stimulants like resistance exercise and nutritional status. βHB might influence anabolic signaling by inhibiting the function of AMPK, an energy sensor that inhibits mTOR under low energy conditions. Inhibiting possibly AMPK would indirectly support MPS, promoting growth and recovery in muscle. Mechanisms of ketone body interaction with mTOR and other anabolic pathways remain unclear, and therefore more research is needed to understand the whole range of their involvement in adaptation in muscle [59]. In systemic inflammatory conditions, such as those induced by LPS challenges, βHB may still preserve muscle protein but without stimulating MPS, suggesting context-dependent effects. This highlights the need to differentiate between adaptive response during training versus pathological conditions [3, 58].

Longevity of benefits

The benefits of ketogenic supplementation on muscle function and recovery can be sustained over time, but their duration and effectiveness depend on several factors, including the consistency of supplementation and the individual’s adaptation to the ketogenic state [63]. Some studies suggest that athletes who maintain a long-term ketogenic regimen experience persistent improvements in endurance, fat oxidation, and recovery. However, the full extent of these benefits may plateau after a certain period as the body fully adapts to ketone utilization [64]. It is thus wise for athletes to have their use of ketogenic supplements in check so as to maintain the desired outcome. While the long-term effects of ketogenic supplementation are yet to be found, evidence shows that with proper use, ketogenic supplements are able to provide extended performance improvements, particularly in endurance sports, and enhance recovery, leading to overall improvements in muscle function and sports performance over time (Table 2). It is important to note that most long-term adaptations reported in the literature stem from keto-adaptation via dietary interventions, rather than from exogenous supplementation alone. The degree to which supplementation without dietary change can mimic these effects remains unclear.

Table 2.

Physiological effects of Long-Term ketogenic supplementation on muscle function and recovery

Physiological effect	Mechanism	Evidence type	Ref. No.
Enhanced mitochondrial function and biogenesis	HDAC inhibition and SIRT1 activation stimulate mitochondrial genes	Animal & cellular studies; emerging human data	[52, 53]
Increased fat and ketone oxidation	Upregulation of fat oxidation enzymes during long-term ketone exposure	Exercise metabolism trials with adaptation	[50]
Reduced carbohydrate dependence	Shift in substrate preference away from glucose toward ketones	Endurance athlete studies; crossover trials	[50]
Improved recovery through antioxidant effects	↑ endogenous antioxidant enzymes (SOD, catalase) via βHB	Human trials + biochemical markers (SOD/catalase)	[55]
Reduced inflammation and DOMS via NLRP3 inhibition	↓ IL-1β and IL-18 through inhibition of NLRP3 inflammasome	Preclinical + inflammation biomarkers (e.g., IL-1β)	[57]
Improved central fatigue resistance (cognitive performance)	KME attenuates cognitive performance decline during intermittent exercise	Human simulated sport trials (e.g., CRT performance)	[58]
Reduced muscle protein breakdown (↓ UPS)	Suppression of proteasome activity and ubiquitin ligases by βHB	Mechanistic studies on muscle protein turnover	[62]
Increased muscle protein synthesis (↑ mTOR)	↓ AMPK leads to ↑ mTOR signaling and protein synthesis	Signaling pathway investigations (AMPK/mTOR)	[60]
Improved endurance and performance during prolonged efforts	Sustained metabolic adaptation under consistent supplementation	Longitudinal observations in trained athletes	[64, 65]

βHB, beta-hydroxybutyrate; HDAC, histone deacetylase; SIRT1, sirtuin 1; SOD, superoxide dismutase; DOMS, delayed onset muscle soreness; NLRP3, NACHT, LRR, and PYD domains-containing protein 3; IL, interleukin; KME, ketone monoester; CRT, cognitive reaction time; UPS, ubiquitin–proteasome system; AMPK, AMP-activated protein kinase; mTOR, mechanistic target of rapamycin

Risk-benefit analysis: potential side effects and risks of ketogenic supplements in athletes

Common side effects

Although ketogenic supplements provide many performance advantages, they will also present some side effects upon initial use by athletes. The most common complaint is gastrointestinal upset that is experienced in the form of nausea, bloating, and diarrhea. Side effects typically occur during the initial adaptation phases when the body adapts to higher intakes of fats and ketones. Electrolyte imbalance, in the form of low sodium, potassium, and magnesium levels, is another potential side effect because the ketosis induces excessive loss of these electrolytes through urine [65]. Dehydration is also potential through the diuretic effect of a ketogenic diet and supplements, contributing to the risk of electrolyte imbalance. Athletes should be cautious with hydration and ensure they are consuming adequate electrolytes, particularly during intense training sessions or competitions.

In a related context, ketogenic diets also have a proven history of eliciting natriuretic and diuretic response, as in starvation. This has a tendency to produce rapid weight loss when initiating the diet. When sodium intake does not compensate for the sodium excess loss, though, one will start to feel the effects of hypovolemia and manifested by dizziness, lethargy, and muscle cramps. To avoid these effects, appropriate electrolyte supply is crucial. For individuals with normal renal function, totaling 4–5 g/day sodium and 3–4 g/day of potassium, and adequate fluids are recommended [65, 66].

Aside from the common side effects, ketogenic supplementation also has risks of performance and health impact in the long run. One of these is muscle loss since ketogenic supplements and diets result in decreased muscle glycogen levels, which are necessary for maintaining muscle mass and strength [67]. Prolonged reliance on fat as a primary fuel source can result in compromised muscle performance during anaerobic exercise requiring rapid flashes of energy, such as sprinting or weight training. This may limit an athlete’s ability to perform at their best level in high-intensity sports [68]. Secondly, altered hydration status resulting from the body’s increased water loss when on a ketogenic diet can impair physical and mental performance [69]. In the long run, if not properly managed, the glycogen depletion and potential loss of lean body mass can undermine the effectiveness of the supplement, particularly in athletes requiring endurance as well as power. Last, while the long-term effects of ketogenic supplementation on overall health continue to be examined, there has been concern for adverse effects of impact on kidney function, bone mineralization, and cardiovascular disease from long-term use.

Mitigating risks

To minimize the risks of ketogenic supplementation, there are a number of proactive measures that can be taken by athletes. Hydration is key, as dehydration will exacerbate the side effects of electrolyte imbalance and decrease performance. Athletes should ensure that they drink lots of fluids, especially water, and should consider adding electrolyte-containing drinks or supplements to maintain balance. Monitoring the intake of key electrolytes such as sodium, potassium, and magnesium is essential to staving off imbalances and facilitating muscle function. Athletes should gradually incorporate ketogenic supplements into their routines to allow their bodies to adapt without causing undue gastrointestinal stress. Athletes must also make sure they are eating balanced diets with adequate protein to prevent muscle breakdown while using ketogenic supplements. Careful monitoring of physical performance and health is necessary to identify any negative adaptations earlier, so that the athletes can make changes accordingly. Athletes should carefully evaluate the long-term use of ketogenic supplements. Careful evaluation of the prolonged use of ketogenic supplements is essential, as incorporating periodic breaks or alternating fueling strategies may help athletes avoid excessive dependence on a single energy source. By following these recommendations and being mindful of their supplementation, athletes can optimize the potential benefits of ketogenic supplements and minimize the potential risks to performance and health (Fig. 4).

Fig. 4.

Key strategies to ensure the safe and effective use of ketogenic supplements in athletes

Timing, dosing, and individual response variability

Although exogenous ketone supplementation shows promise across a range of exercise contexts, its effects are highly contingent on the timing of ingestion, the administered dosage, and individual physiological differences. Misalignment within any of these parameters may reduce efficacy or even attenuate performance benefits.

Timing of ingestion

Exogenous ketone formulations, including ketone monoesters and βHB with medium-chain triglycerides (βHB + MCT), generally elevate circulating βHB levels within 30 to 60 min after ingestion. Pre-exercise administration, typically 30–45 min before activity, is a widely adopted protocol aimed at matching peak ketone availability with exercise onset. However, recent findings indicate that such strategies do not uniformly enhance aerobic performance, with some studies showing no ergogenic effect despite substantial increases in βHB levels [70]. A practical alternative to ketogenic diets, which can be difficult to maintain, is using exogenous ketone drinks to raise blood D- βHB concentrations. In randomized studies on healthy volunteers, drinks containing ketone esters like (R)−3-hydroxybutyl (R)−3-hydroxybutyrate or ketone salts, such as sodium plus potassium βHB, significantly increased blood D- βHB levels that typically returned to baseline within 3–4 h. KS drinks contained 50% L- βHB, which stayed elevated for over 8 h but was undetectable after 24 h. Urinary excretion of D- βHB and L- βHB was under 1.5% of total intake and proportional to blood AUC. Metabolically, only D- βHB was slowly converted to breath acetone. KE drinks slightly lowered blood pH, while KS drinks raised urinary pH. Consuming a meal before KE ingestion reduced peak blood D- βHB by about 33%, though acetoacetate and breath acetone levels remained unchanged. All ketone drinks lowered blood glucose, free fatty acids, and triglycerides, while maintaining electrolyte balance. Prolonged dosing, via repeated KE drinks or continuous nasogastric infusion, effectively sustained blood D- βHB above 1 mM, demonstrating the feasibility of maintaining nutritional ketosis through exogenous ketones [71].

Collectively, these findings indicate that exogenous ketone drinks provide a practical and efficacious method to induce ketosis. However, the timing of ingestion whether pre-exercise, post-exercise, or in the fed versus fasted state significantly modulates ketone kinetics and metabolic outcomes, which should be carefully considered to optimize performance and recovery benefits.

Dosing considerations

Most clinical and athletic studies utilize doses between 200 and 600 mg/kg, aiming to elevate plasma βHB concentrations within a physiological ketosis range (typically 1.5–3.5 mmol/L). In a randomized, double-blind, crossover study involving recreational male runners, ingestion of either 22.1–44.2 g of a βHB plus medium-chain triglycerides (MCTs) formulation resulted in dose-dependent increases in circulating R-βHB levels, with the higher dose producing more sustained elevations. These findings support the importance of appropriate dosing strategies to achieve and maintain effective circulating ketone concentrations [70]. While doses over ~ 400 mg/kg often yield higher βHB concentrations, they are also associated with a greater risk of gastrointestinal symptoms particularly nausea, bloating, and cramps especially when using high-dose ketone salts. Although symptoms are typically mild and resolve within a few hours, they may still reduce compliance [72].

Individual response variability

Despite standardized protocols, individuals show considerable variability in physiological and performance responses to exogenous ketone supplementation. Some athletes exhibit minimal or no improvements in endurance capacity, substrate oxidation, or recovery outcomes despite significant elevations in circulating βHB levels.

Recent trials have highlighted substantial inter-individual variability in response to exogenous ketone supplementation. In a randomized crossover study on recreational runners, identified both responders and non-responders, with some individuals failing to demonstrate improvements in performance or metabolic efficiency despite significant elevations in circulating βHB levels [70]. These findings align with a recent systematic review, which reported that among 16 performance outcomes across 10 trials, only 3 showed positive effects while the majority were either neutral (n = 10) or negative (n = 3), with marked heterogeneity observed between studies using both ketone esters and salts suggesting broad variability in individual responses to ketone-based interventions [73].

This “non-responder” phenomenon may be influenced by factors such as metabolic flexibility, habitual macronutrient intake (e.g., low- vs. high-carb diets), training status, and hormonal fluctuations (e.g., menstrual cycle phase), all of which alter substrate preference and energy efficiency during exercise. For example, recent research has demonstrated that females exhibit greater metabolic flexibility than males across different exercise intensities and metabolic challenges, such as glycogen depletion and heat stress, which may contribute to variability in ketone metabolism and exercise performance outcomes [74, 75]. Additionally, a study in active women reported that habitual low carbohydrate and high protein intake were associated with greater post-exercise metabolic flexibility, suggesting that diet composition may alter substrate selection and possibly modulate the efficacy of exogenous interventions such as ketone supplementation [76].

Conclusion and future directions

Summary of key findings

This review has addressed the molecular mechanisms, physiological acclimatization, and benefits and risks of ketogenic supplements during exercise. The key findings are that ketogenic supplements, such as exogenous ketones, MCT oil, and ketone esters, hold tremendous potential to enhance sports performance by altering the body’s primary source of energy from carbohydrates to fats, particularly in endurance and long-duration exercise. These supplements enable ketosis, providing a backup fuel that enables continued energy production and reduced reliance on glycogen. The physiological adaptations to ketogenic supplementation, including improved fat oxidation, improved mitochondrial efficiency, and improved recovery, offer distinct advantages for athletes. There are also risks, including gastrointestinal distress, electrolyte imbalance, and potential impacts on muscle mass and short-burst performance, which must be carefully controlled. Overall, the ketogenic supplement benefits appear to be promising, but these need to be balanced with possible side effects and long-term health consequences.

Gaps in current research

While the encouraging findings, there is still limited knowledge regarding ketogenic supplementation during exercise. Perhaps the most significant area that requires more research is the long-term effect of ketogenic supplementation because most of the studies have been conducted on short-term intervention. More studies are needed to establish how the application of ketogenic supplements over a long period affects muscle function, bone density, and overall metabolic health in athletes. Lastly, further individualized treatment methods need to be created for supplementation, as different athletes will respond to ketogenic strategies differently depending on their own metabolic profiles, training regimens, and stressors imposed upon them by their own sport. Sport-specific applications of ketogenic supplementation also need more targeted research, as the effect can differ greatly between endurance competitions and anaerobic activities. Follow-up studies will also be important to examine the most effective dosages and timing of supplementation for optimal benefits at minimal risks.

Future perspectives

Looking ahead, the future of ketogenic supplementation in sports performance is promising, with several areas of innovation on the horizon. Personalized ketogenic strategies, based on an athlete’s genetic, metabolic, and physiological characteristics, will likely become more common as the science behind individualized nutrition continues to grow. This could allow athletes to personalize their ketogenic supplementation to optimize performance in their respective sports. In addition, new forms of ketogenic supplements with higher bioavailability, improved taste, and fewer side effects are possible. Combining ketogenic supplementation with other nutritional strategies, such as intermittent fasting or carbohydrates cycling, can also be explored as a means to optimize performance. As understanding of ketosis and its applications to exercise becomes more precise, athletes may find themselves capable of using more advanced and personalized supplementation protocols that better address their training and competition requirements. Ultimately, ongoing research and development will be essential in capturing the full benefit of ketogenic supplements in exercise performance and recovery.

Abbreviations

AcAc

Acetoacetate

AMPK

AMP-Activated Protein Kinase

ATP

Adenosine Triphosphate

βHB

Beta-Hydroxybutyrate

D-βHB

D-Beta-Hydroxybutyrate

CHO

Carbohydrate

CKD

Chronic Kidney Disease

DOMS

Delayed-Onset Muscle Soreness

GFR

Glomerular Filtration Rate

HIIT

High-Intensity Interval Training

IMTAG

Intramuscular Triacylglycerol

IL-1β

Interleukin-1 Beta

IL-18

Interleukin-18

MCT

Medium-Chain Triglyceride

MPS

Muscle Protein Synthesis

mTOR

Mammalian Target of Rapamycin

NLRP3

NLR Family Pyrin Domain Containing 3 (inflammasome)

PGC-1α

Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-Alpha

PPARα

Peroxisome Proliferator-Activated Receptor Alpha

ROS

Reactive Oxygen Species

RER

Respiratory Exchange Ratio

SIRT

Sirtuin

SOD

Superoxide Dismutase

UPS

Ubiquitin-Proteasome System/Pathway

VO₂

Oxygen Uptake

VO₂max

Maximal Oxygen Uptake

W_max

Maximal Workload

Author contributions

MS and MHM were responsible for conceptualization. MS also managed the project and contributed to visualization. EMH, SAM, PJ, NY, EN, and MHM contributed to writing original draft. MS, KS, AM, and MAR contributed to writing – review & editing. MS prepared the final version of the manuscript. All authors read and approved the final manuscript.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Competing interests

The authors declare no competing interests.