The Role of Exogenous Ketones in Road Cycling: Evidence, Mechanisms, and Performance Claims

Abstract

Background: Ketone body supplementation has emerged as a potential ergogenic aid in cycling. Exogenous ketones, primarily in the form of beta-hydroxybutyrate, offer an alternative fuel source, bypassing the need for strict ketogenic diets. However, the science surrounding their efficacy remains complex, with mixed field findings and unexplored mechanisms. Methods: A narrative review of the current literature was conducted, synthesizing studies on the metabolic and cognitive effects of ketone bodies in cycling. The review included an examination of human and mechanistic studies, along with emerging hypotheses on ketone bodies and their role in modulating red blood cell production and recovery processes. Results: Ketone body supplementation can theoretically spare glycogen, reduce muscle protein breakdown, enhance fat oxidation, and improve recovery by mitigating oxidative stress and inflammation. Additionally, ketone bodies may support cognitive function, reducing perceived mental fatigue. Preliminary evidence also suggests a potential role in modulating erythropoietin levels through histone acetylation, though further research is needed to establish its impact on oxygen delivery. Despite the theoretical potential, the practical assessment of field studies shows disappointing effects on performance from ketone body supplementation. Conclusions: While ketone bodies offer several potential benefits for cyclists, the variability in individual responses, lack of long-term data, and inconsistent findings in performance studies highlight the need for further research. Optimizing dosage, timing, and understanding the broader implications of ketone body supplementation will be crucial for their practical application in cycling.

1. Introduction

In recent years, ketone bodies have gained significant traction in the field of sports nutrition, particularly in endurance disciplines like cycling. This surge in interest is largely driven by the growing use of exogenous ketone body supplements among professional cycling teams, with reports suggesting their incorporation into the nutritional strategies of top-level competitors in Grand Tours and other endurance events. Ketones are a group of organic molecules containing a carbonyl group, which play an important role in metabolism, particularly during states of low carbohydrate availability. The primary ketone bodies relevant to human metabolism are acetoacetate, beta-hydroxybutyrate (BHB), and acetone. Among these, BHB is the most commonly supplemented due to its efficiency as an alternative energy source. BHB exists as two stereoisomers: D-BHB and L-BHB. D-BHB is the biologically active isomer that the body naturally produces and utilizes during ketosis, while L-BHB is metabolized more slowly and has less immediate energetic value. Most commercial ketone supplements contain D-BHB, though some formulations may include a racemic mixture (both D- and L-BHB) that can affect absorption and metabolic efficiency [1,2].

Blood ketone levels can be elevated through dietary strategies or direct supplementation, each with distinct mechanisms and implications. Dietary approaches—primarily the ketogenic diet—rely on restricting carbohydrate intake, prompting the liver to produce ketone bodies from fatty acids as an alternative energy source. This process typically raises the blood ketone levels gradually, reaching a state of nutritional ketosis over several days to weeks. In contrast, supplementary approaches provide an immediate increase in blood ketone levels through exogenous ketone body supplements such as ketone salts or ketone esters. These supplements bypass the liver’s ketone production process, allowing individuals to achieve elevated blood ketone levels within minutes to hours, regardless of dietary carbohydrate intake. While the ketogenic diet induces a sustained ketotic state with metabolic adaptations, ketone supplements offer a rapid but transient rise in blood ketones, which may be advantageous for specific performance or recovery goals but lacks the prolonged metabolic effects associated with dietary ketosis [1,2].

Beyond their role as metabolic substrates, ketone bodies may also influence key physiological processes that affect performance. Recent research suggests that ketone body supplementation could elevate erythropoietin (EPO) levels, a hormone critical for red blood cell production and oxygen transport [3,4]. This raises the possibility of improved oxygen-carrying capacity, an essential determinant of endurance performance. Moreover, ketone bodies have been implicated in the modulation of epigenetic processes, particularly histone acetylation, which regulates gene expression [5,6]. BHB, one of the primary ketone bodies, has been shown to inhibit histone deacetylases (HDACs), potentially influencing the expression of genes involved in erythropoiesis and other metabolic pathways relevant to endurance exercise [5,6].

Despite the promising biochemical findings in the laboratory-based studies and the theoretical potential of ketone bodies for improving cycling performance, much of the current understanding of ketone bodies and their proposed mechanisms stems from (1) studies outside of sports science; (2) exercise research not specifically focused on cycling, or (3) short-term intervention studies characterized by non-elite cyclists. While the mechanisms discussed in this manuscript were derived from broader physiological studies, they were reframed here within a cycling context due to the sport’s unique demands on energy metabolism and endurance. Although these mechanisms are bioplausible and offer valuable insights, it is important to acknowledge that they have not been directly validated in cycling-specific exercise settings yet. This limitation emphasizes the need for future experimental research to confirm the relevance and efficacy of these mechanisms in competitive cycling.

This review aimed to evaluate the potential performance-enhancing effects of ketone bodies in endurance sports, exploring both their metabolic roles and the molecular mechanisms that may contribute to improved endurance. In addition, we examine the relationship between ketone bodies, EPO regulation, and histone acetylation, offering new insights into how these factors might synergistically impact red blood cell production and overall endurance performance. The review concludes with a critical assessment of field studies on exogenous ketone supplementation in cycling and current scientific and practical limitations.

2. Ketone Bodies and Endurance Performance Enhancement: Mechanisms of Action

2.1. Glycogen Sparing and Enhanced Fat Oxidation

Ketone bodies could potentially spare glycogen by providing an alternative fuel source for skeletal muscle during exercise. Ketones are oxidized by mitochondria, especially in slow-twitch muscle fibers, which are predominantly utilized during prolonged, submaximal exercise. Studies indicate that during exercise at moderate intensities, such as 65–75% of VO_2max, the utilization of ketones increases significantly when they are available, leading to a reduction in glycogen consumption [7]. Ketones may also influence hormonal responses that affect glycogen metabolism. For example, ketone body supplementation has been associated with increased insulin sensitivity, which could enhance glucose uptake during exercise and promote glycogen synthesis post-exercise [7,8]. Additionally, ketone bodies may have a direct impact on glycogen phosphorylase, the enzyme responsible for glycogen breakdown. By modulating the activity of glycogen phosphorylase, ketone bodies could potentially slow the rate of glycogen utilization during prolonged exercise [8].

In addition to glycogen sparing, ketone bodies may enhance fat oxidation during exercise. Endurance athletes have long sought to increase their fat oxidation rates to spare glycogen and improve performance during prolonged efforts. Ketone bodies have been shown to upregulate enzymes involved in fat metabolism, such as carnitine palmitoyltransferase I (CPT-1), which is responsible for transporting fatty acids into the mitochondria for oxidation [9,10]. Furthermore, exercise metabolism is altered during exogenous ketosis, with increased fat oxidation and preservation of intramuscular glycogen observed in previous studies [11]. Paradoxically, ketone bodies can also reduce the body’s reliance on endogenous fat oxidation. This reduction occurs because elevated blood ketones can suppress lipolysis and shift the body’s substrate preference away from fatty acids. Additionally, high ketone levels can lead to an increase in blood acidity, which might affect muscle function and endurance performance [1,2]. These metabolic shifts may limit the utility of exogenous ketones in scenarios where high rates of fat oxidation are advantageous such as long-duration, low-intensity endurance events.

2.2. Improved Recovery and Muscle Preservation

The capacity for rapid recovery and the preservation of muscle mass are critical factors in optimizing performance, particularly in endurance sports like cycling where competitors often undergo repeated bouts of high-intensity exercise or participate in multistage events. Ketone body supplementation has been suggested to offer benefits in this regard through several distinct mechanisms including the modulation of muscle protein metabolism, reduction in oxidative stress and inflammation, and attenuation of muscle damage [2,11].

2.2.1. Inhibition of Muscle Protein Breakdown

A key proposed effect of ketone body supplementation is its potential to reduce muscle protein breakdown during and after exercise. Muscle protein breakdown occurs as part of the catabolic response to prolonged or intense exercise, where protein is degraded to provide amino acids for gluconeogenesis or repair cellular damage. The proteasome, a large protein complex responsible for degrading damaged or misfolded proteins, plays a central role in muscle catabolism [12].

Ketone bodies, particularly beta-hydroxybutyrate (BHB), have been suggested to exert an inhibitory effect on proteasome activity [13,14]. BHB may act as a signaling molecule that suppresses proteolysis through various pathways including the inhibition of protein breakdown via the ubiquitin-proteasome system (UPS). The UPS is a major proteolytic pathway responsible for muscle protein degradation, and its inhibition by BHB could result in reduced muscle wasting during periods of prolonged exercise or caloric restriction. BHB supplementation could lead to a reduction in markers of muscle protein breakdown such as the expression of ubiquitin ligases [14].

The inhibition of muscle protein breakdown following ketone body supplementation is a complex outcome and may not universally be viewed as beneficial. From a biological and adaptive perspective, muscle protein breakdown is an essential process in post-exercise recovery as it initiates the remodeling and strengthening of muscle tissue in response to training stress [12]. While ketone bodies may attenuate this process by decreasing proteolysis, potentially aiding in short-term muscle preservation, it is unclear whether this effect supports long-term training adaptations. Therefore, while reduced muscle protein breakdown may offer temporary benefits, such as reduced muscle soreness or enhanced recovery between sessions, it is important to consider that chronic inhibition could potentially interfere with the natural adaptive processes necessary for optimal endurance performance. Further research is required to determine if, and under what conditions, this effect of ketone bodies might be advantageous for athletes.

2.2.2. Promotion of Muscle Protein Synthesis

Ketone bodies may not only reduce muscle breakdown, but also promote muscle protein synthesis (MPS), the anabolic process through which new proteins are synthesized to repair and rebuild muscle tissue. MPS is activated by signaling pathways such as the mammalian target of rapamycin (mTOR) pathway, which is upregulated in response to various stimuli including resistance exercise and nutrient availability [15,16,17].

Although the direct effects of ketone bodies on the mTOR pathway remain to be fully elucidated, some evidence suggests that BHB may have a role in modulating anabolic signaling. BHB has been shown to act as a signaling molecule that affects various metabolic pathways including those involved in cell growth and protein synthesis. For instance, some studies have proposed that a ketogenic diet and BHB could reduce the activation of AMP-activated protein kinase (AMPK), a key energy sensor that inhibits mTOR and suppresses protein synthesis under conditions of cellular energy deficit. By reducing AMPK activity, ketone bodies may indirectly promote muscle protein synthesis, although this remains an area of active investigation [15,16,17].

2.2.3. Reduction of Oxidative Stress and Inflammation

Prolonged endurance exercise is associated with increased oxidative stress as it leads to the excessive production of reactive oxygen species (ROS) from NADPH oxidases [18]. High levels of oxidative stress can result in cellular damage including lipid peroxidation, protein oxidation, and DNA damage, which impair muscle recovery and contribute to muscle fatigue. By reducing oxidative stress, athletes may experience less muscle damage and recover more quickly between training sessions or races.

Ketone bodies, particularly BHB, have been shown to possess antioxidant properties [19,20]. Curiously, most of the effective ergogenic aids on the market are characterized by their redox properties [21]. BHB can reduce oxidative stress by upregulating endogenous antioxidant defense systems, such as superoxide dismutase (SOD) and catalase, both of which are crucial for neutralizing ROS [19,20]. By enhancing the body’s natural antioxidant defenses, ketone bodies may reduce the accumulation of oxidative damage in muscle tissue, facilitating quicker recovery, and allowing athletes to maintain higher training volumes with less muscle fatigue.

2.2.4. Anti-Inflammatory Effects of Ketone Bodies

Inflammation is a natural response to exercise-induced muscle damage, but excessive or prolonged inflammation can impair recovery and contribute to delayed-onset muscle soreness (DOMS) [22]. Ketone bodies, particularly BHB, can exert anti-inflammatory effects by inhibiting pathways that lead to the overproduction of pro-inflammatory cytokines. BHB may inhibit the NLRP3 inflammasome, a multiprotein complex that triggers the release of pro-inflammatory cytokines such as interleukin-1β (IL-1β) and interleukin-18 (IL-18) [23]. These cytokines are key mediators of the inflammatory response following intense exercise. By attenuating the inflammatory response, ketone bodies may promote faster recovery and reduce muscle soreness following intense training or racing. This anti-inflammatory effect could be particularly beneficial in cycling, where rapid recovery between consecutive stages of a race is essential for maintaining performance.

2.2.5. Attenuation of Exercise-Induced Muscle Damage

Muscle damage occurs as a natural consequence of prolonged or high-intensity exercise, and the extent of damage can influence recovery time and subsequent performance. The anti-catabolic and anti-inflammatory properties of ketone bodies suggest that they may also play a role in reducing exercise-induced muscle damage. Markers of muscle damage, such as creatine kinase (CK) and lactate dehydrogenase (LDH), are often elevated following intense endurance exercise. Elevated levels of these enzymes are indicative of muscle cell membrane damage and the subsequent leakage of intracellular contents into the bloodstream. Previous research has highlighted the potential of ketone body supplementation to reduce the levels of CK and LDH after prolonged exercise, suggesting that ketone bodies may help protect muscle fibers from damage [24].

2.3. Cognitive Benefits and Central Nervous System (CNS) Protection

2.3.1. Ketones as an Efficient Fuel Source for the Brain

The brain is an energy-intensive organ, primarily relying on glucose for its energy needs. However, during periods of prolonged exercise, fasting, or carbohydrate depletion, glucose availability may become limited, leading to a reduction in mental performance. Under these conditions, ketone bodies serve as an efficient alternative fuel for the brain. Unlike fatty acids, which cannot cross the blood–brain barrier in significant quantities, ketone bodies such as BHB can enter the brain and be metabolized by neurons as a source of ATP [25].

Ketone bodies are considered a highly efficient substrate for cerebral metabolism. BHB has been shown to yield more energy per unit of oxygen consumed (P/O ratio) compared to glucose, meaning that neurons can produce ATP more efficiently when ketones are available [25,26]. This increase in metabolic efficiency may contribute to maintaining cognitive function during extended exercise bouts, particularly when glucose stores are depleted. Studies in clinical populations have demonstrated that ketogenic diets and exogenous ketone body supplementation can enhance cognitive function in aging individuals or in those with neurodegenerative diseases/cognitive impairment [27,28]. While these effects are well-documented in clinical settings, their implications for healthy athletes, particularly endurance athletes, are only beginning to be explored. Enhanced cognitive function and sustained mental clarity during prolonged exercise may be critical factors in endurance performance, as cyclists often need to make split-second decisions or maintain high levels of concentration over many hours of racing.

2.3.2. Reduction in Perceived Mental Fatigue

Mental fatigue is a common issue during long-duration exercise, where extended cognitive and physical efforts lead to a decline in focus, reaction time, and decision-making ability. Mental fatigue is also known to affect motor coordination, which is crucial in a sport like cycling, where balance, control, and strategic decision-making play a vital role. Ketone bodies have been proposed to reduce perceived mental fatigue by providing the brain with a stable and continuous energy supply, even when glucose levels are low [29]. The ability of ketone bodies to provide energy without the fluctuations in blood sugar associated with carbohydrate ingestion may contribute to a more stable cognitive environment, allowing athletes to sustain mental focus over prolonged periods [25,29].

2.3.3. Neuroprotective Effects of Ketone Bodies

The neuroprotective properties of ketone bodies have been extensively studied in the context of neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease, where ketone bodies have been shown to mitigate neuronal damage, reduce oxidative stress, and improve mitochondrial function in the brain [30,31]. Although these findings stem from clinical settings, they raise the possibility that similar protective effects could benefit athletes during training and competition. Prolonged exercise generates significant amounts of reactive oxygen species (ROS) in the brain, leading to the oxidative damage of neuronal cells. Ketone bodies, especially BHB, could potentially upregulate antioxidant defenses, such as superoxide dismutase (SOD) and catalase, which neutralize ROS and reduce oxidative damage in neurons [32]. By reducing oxidative stress in the brain, ketone bodies may protect the CNS from the detrimental effects of exercise-induced oxidative damage, thereby preserving cognitive function during prolonged bouts of exercise.

Intense or prolonged physical activity is also known to increase the release of pro-inflammatory cytokines, such as interleukin-6 (IL-6), which can lead to neuroinflammation. Elevated levels of neuroinflammation are associated with cognitive impairment, mood disturbances, and central fatigue. BHB may inhibit the activation of the NLRP3 inflammasome, a key regulator of the inflammatory response, thereby reducing the release of pro-inflammatory cytokines [32,33]. This anti-inflammatory effect could help attenuate exercise-induced neuroinflammation and contribute to improved cognitive resilience during long-duration exercise. Ketone bodies may also enhance mitochondrial function by increasing the efficiency of oxidative phosphorylation, promoting mitochondrial biogenesis, and reducing the production of ROS [32,33]. By improving mitochondrial efficiency in neurons, ketone bodies may support sustained cognitive function during endurance efforts, reducing the likelihood of CNS-related fatigue.

2.3.4. Stabilization of Neurotransmitter Systems

The balance of neurotransmitters in the brain plays a key role in regulating mood, focus, and cognitive performance. Prolonged exercise can lead to imbalances in neurotransmitter systems, particularly serotonin and dopamine, which are involved in the regulation of mood and motivation. Excessive serotonin release during long-duration exercise has been linked to the onset of central fatigue, while dopamine depletion can reduce motivation and focus. Ketone bodies may modulate neurotransmitter systems, particularly by reducing the release of serotonin and stabilizing dopamine levels [11,34]. This may help prevent the onset of central fatigue and maintain motivation during prolonged efforts. By supporting neurotransmitter balance, ketone bodies may contribute to the preservation of cognitive function, focus, and motivation, which are critical for performance in endurance sports like cycling.

2.4. Ketone Bodies and Mitochondrial Efficiency

Mitochondrial function is a key determinant of endurance performance, as the mitochondria are responsible for producing ATP through oxidative phosphorylation. Improving mitochondrial efficiency can enhance an athlete’s ability to sustain prolonged exercise by increasing the capacity for fat oxidation and reducing the reliance on glycogen. Ketone bodies may improve mitochondrial efficiency through several mechanisms [11,35,36].

Ketone bodies, particularly BHB, have been shown to increase the amount of ATP produced per unit of oxygen consumed. This effect, known as the “mitochondrial coupling” effect, makes energy production more efficient, allowing athletes to produce more power with the same oxygen supply. One of the by-products of mitochondrial ATP production is reactive oxygen species (ROS), which can cause oxidative damage to cells and tissues. High levels of ROS have been associated with muscle fatigue and impaired recovery. Ketone bodies have been shown to reduce ROS production, protecting the mitochondria from oxidative stress and potentially enhancing endurance performance by delaying fatigue. Ketone bodies may also stimulate mitochondrial biogenesis, the process by which new mitochondria are formed. Increased mitochondrial density improves the capacity for fat oxidation and enhances endurance performance. PGC-1α, a key regulator of mitochondrial biogenesis, has been shown to be upregulated in response to ketone body metabolism, further supporting the role of ketone bodies in improving mitochondrial function [11,35,36].

2.5. Ketone Bodies, EPO and Histone Acetylation

One of the most intriguing areas of research regarding ketone bodies and endurance performance is their potential impact on erythropoietin (EPO) production. EPO is a hormone that stimulates red blood cell production, increasing the oxygen-carrying capacity of the blood and enhancing endurance performance. Traditional methods of increasing EPO include altitude training, and controversially, EPO doping. However, recent studies suggest that ketone bodies may influence EPO production through epigenetic mechanisms such as histone acetylation [37,38].

2.5.1. Erythropoietin (EPO) and Endurance Performance

EPO plays a central role in oxygen transport during endurance exercise. By stimulating the production of red blood cells in the bone marrow, EPO increases the blood’s oxygen-carrying capacity, which can improve VO_2max and endurance performance. In cycling, a higher VO_2max is often associated with better performance in time trials, hill climbs, and long-distance races. Hypoxia, or low oxygen availability, is the primary stimulus for EPO production [37]. Athletes often train at high altitudes to take advantage of the hypoxia-induced increase in EPO. However, recent evidence suggests that metabolic factors, such as ketone body levels, may also influence EPO production [3,4].

2.5.2. Histone Acetylation: A Mechanism for EPO Regulation

Histone acetylation is an epigenetic modification that alters gene expression by loosening the chromatin structure, allowing transcription factors to access DNA more easily. This process plays a critical role in regulating various genes including those involved in EPO production. Histone acetylation is regulated by enzymes known as histone acetyltransferases (HATs) and histone deacetylases (HDACs). The acetylation of histones typically enhances gene transcription, while deacetylation represses it.

BHB, one of the primary ketone bodies, may inhibit histone deacetylases (HDACs). By inhibiting HDACs, BHB promotes histone acetylation, which may enhance the expression of genes involved in EPO production [39,40]. This mechanism provides a potential link between elevated ketone body levels and increased EPO production.

2.5.3. Ketone Bodies and Hypoxia-Inducible Factors (HIFs)

In addition to histone acetylation, ketone bodies may also influence the production of EPO through their interaction with hypoxia-inducible factors (HIFs). HIFs are transcription factors that regulate the expression of EPO in response to low oxygen levels. Under normoxic conditions, HIFs are degraded by prolyl hydroxylases (PHDs), but during hypoxia, PHD activity is inhibited, allowing HIFs to accumulate and stimulate EPO production. BHB has been shown to modulate the activity of PHDs, potentially stabilizing HIFs and enhancing EPO production [39,40]. In this context, ketone bodies may act as a metabolic signal that mimics the effects of hypoxia, promoting EPO production, even in the absence of low oxygen availability.

3. Ketone Bodies and Cycling Performance: Real World Results

The potential benefits of ketone body supplementation in endurance sports like cycling are multifaceted, spanning metabolic, physiological, and cognitive domains. Given the findings outlined above, ketone bodies offer, at least in theory, promising strategies for performance enhancement across several key areas relevant to cyclists including energy metabolism, recovery, cognitive function, and endurance capacity.

Research indicates that exogenous ketone bodies supplementation can significantly increase serum EPO concentrations post-exercise. In a study by Evans et al., the ingestion of ketone monoester supplements resulted in a 20% increase in serum EPO levels 4 h post-exercise compared to a placebo [3]. Similarly, Poffé et al. found that chronic ketone monoester supplementation during a 3-week training period led to a 26% increase in serum EPO levels 12 h after the final exercise session [41]. These findings suggest that exogenous ketone bodies can acutely and chronically elevate EPO levels, potentially enhancing endurance performance by improving oxygen-carrying capacity and muscle perfusion [3,4,41].

Despite the potential and theoretical mechanisms (Figure 1), and the apparent ability of ketone bodies for elevating EPO, practical research with real-world cyclists shows inconsistent findings regarding performance outcomes. While some studies have demonstrated improvements in endurance performance, glycogen sparing, and recovery, others have shown no significant effects or even detrimental impacts on performance. Systematic reviews and meta-analyses corroborate the general tendency from individual studies, indicating that exogenous ketone body supplementation does not significantly enhance endurance exercise performance. These reviews highlight the heterogeneity in study designs and outcomes but generally conclude that the ergogenic effects of ketone bodies are minimal or non-existent [2,42,43]. Two factors may contribute to these mixed results. First, many studies have been conducted with recreationally active participants, making it challenging to generalize the findings to elite athletes, whose physiological profiles, training backgrounds, and adaptive responses differ significantly. Additionally, predicting performance outcomes based solely on biochemical and molecular biology markers remains difficult, as these measures do not always directly translate to functional performance gains. Exercise performance is a complex, multifactorial phenomenon, and while cellular and molecular changes provide valuable insights, they may not fully capture the integrated physiological demands and adaptations associated with elite athletic performance. Addressing these challenges in future research could provide a clearer understanding of the true ergogenic potential of ketone bodies.

4. Limitations in Current Ketone Body Research for Cycling Performance

4.1. Individual Variability and Length of Intervention

Inter-individual variability in response to ketone body supplementation remains a significant and unresolved challenge in evaluating its ergogenic potential. Physiological responses to ergogenic interventions can vary widely among individuals due to genetic, metabolic, and lifestyle differences, among other factors. This variability complicates the ability to make generalizable claims about the performance-enhancing effects of ketone bodies, as responses may differ not only between individuals, but also under varying exercise conditions and intensities. As such, the present work acknowledges that while ketone body supplementation appears promising as an ergogenic aid, further research is needed to clarify which athletes, if any, may consistently benefit and under what specific conditions these benefits might be optimized [44]. Furthermore, most studies on ketone body supplementation have focused on short-term interventions, with acute or relatively brief supplementation periods [2,42,43]. As a result, there is a limited understanding of the long-term effects of regular ketone body use on performance, recovery, and health. The effects of chronic ketone body supplementation on adaptations to endurance training, metabolic health, and potential side effects remain underexplored. In the context of cycling, which often involves prolonged training blocks and multistage events, it is crucial to understand whether the acute benefits of ketone bodies observed in laboratory settings translate into long-term improvements in performance or recovery. Additionally, questions remain regarding the long-term metabolic effects of regularly shifting between carbohydrate-based and ketone-based fuel systems.

4.2. Side Effects, Optimal Dosage, Timing and Cost

Although the long-term effects on health remain unknown, there is evidence regarding the potential short-term side effects: high doses of exogenous ketone body supplements, particularly ketone salts, have been associated with gastrointestinal distress including nausea, vomiting, and diarrhea [45]. These side effects can impair performance during competition, particularly in endurance sports where maintaining gut health and nutrient absorption is critical. Ketone salts, while more palatable, are less potent than ketone esters and can cause an increase in sodium levels, potentially leading to electrolyte imbalances [46].

Another limitation is the lack of consensus on the optimal dosage and timing of ketone body supplementation to maximize performance benefits. Studies have used varying dosages of ketone esters or salts, often with significant differences in the resulting blood ketone concentrations achieved. Most field studies used doses of 300–800 mg/kg of ketone monoesters during acute supplementation [2,42,43]. However, the ideal dose and formulation remain unclear due to mixed results across studies, with ketone diesters and ketone salts resulting in disappointing outcomes. The type of ketone, the presence of co-ingestants like bicarbonate, and the specific exercise conditions all seem to play crucial roles in determining the effectiveness of ketone body supplementation for cycling performance. The timing of ketone body ingestion also plays a crucial role, with some studies suggesting that pre-exercise ingestion is most beneficial, while others have proposed that ingestion during or even after exercise could enhance recovery or maintain endurance [2,42,43].

Ketone body supplements, especially ketone esters, are relatively expensive compared to other performance supplements like carbohydrates, electrolytes, or protein powders. The high cost of these supplements limits their accessibility, particularly for amateur cyclists or those without sponsorship. This presents a barrier to widespread use, making ketone body supplementation more practical for elite or well-funded cyclists, while others may not find it financially feasible. Furthermore, due to the cost, long-term research involving daily or frequent ketone body use is often limited to short-term studies, creating a gap in understanding the real-world implications for sustained use over months or seasons.

4.3. Limited Understanding of Mechanisms and Ethical Concerns

While there is a growing body of research on the physiological effects of ketone bodies, some of the underlying mechanisms, particularly in relation to endurance performance, remain poorly understood. For example, the exact mechanisms by which ketone bodies may enhance EPO production or influence gene expression through histone acetylation have not been fully established. Although promising data exist, these molecular mechanisms need to be validated in human athletic populations before firm conclusions can be made about their role in performance enhancement. Similarly, while studies have shown potential cognitive benefits from ketone bodies, the precise ways in which ketone bodies impact neurotransmitter balance and neuroprotective pathways during exercise require further exploration. As a result, the broader implications of ketone bodies on CNS function in athletes remain speculative and warrant more focused research.

As ketone bodies become more prevalent in competitive sports, there are growing concerns regarding the ethical and regulatory implications of their use. While ketone bodies are not currently classified as banned substances by anti-doping agencies such as the World Anti-Doping Agency (WADA), the potential for ketone bodies to enhance EPO production or alter oxygen delivery has raised questions about whether their use may provide an unfair advantage. The boundary between legitimate nutritional strategies and performance enhancement that skirts the edges of the doping regulations is a topic of ongoing debate. If ketone body supplementation was to be demonstrated as having significant erythropoietic effects, it could come under increased scrutiny by governing bodies, further complicating its use in professional sports.

5. Conclusions

The potential benefits of ketone body supplementation in endurance sports like cycling are multifaceted, spanning metabolic, physiological, and cognitive domains. However, despite the growing interest in ketone body supplementation, the current science applied to the practical field is limited by inconsistent findings, individual variability, and a lack of long-term data. Given the conflicting field findings that to date have not matched the theoretical promise of ketone bodies as an ergogenic aid, cyclists and coaches should approach ketone body supplementation with caution, balancing the potential benefits with the practical limitations, individual responses, and current gaps in the scientific knowledge.