Ketogenic diets — characterized by extreme reduction in carbohydrate intake to induce a state of nutritional ketosis, in which the body relies on ketone bodies derived from fat oxidation as a major source of fuel — have been touted for numerous health benefits, including effects on the brain, an organ that normally relies exclusively on carbohydrates (i.e., glucose) for energy. But for many, the high-fat and low-carb requirements with these diets can be challenging to maintain, and as a result, increasing attention has been devoted to possible strategies for achieving ketosis without the need for such strict dietary limitations.
One option is supplementation with 1,3-butanediol (BD), which, upon ingestion, is converted in the liver to the ketone body β-hydroxybutyrate (βHB), thus inducing ketosis without dietary intervention. But although we know that BD is capable of raising βHB levels, we have relatively little information on how this might recreate the benefits of a ketogenic diet. Investigators Cigliano et al. recently sought to fill this gap, examining whether treatment with BD led to discernible neurological effects in rats.1 What did they discover, and how might their findings apply to humans?
About the study
This study assessed several cellular-level readouts related to the health and function of neurons in the hippocampus, an area of the brain that is critical for memory and learning. Over the 14-day treatment period, rats in the experimental (BD) group were given BD through their normal food. Because BD — like a ketogenic diet itself — tends to decrease calorie intake and lead to an overall reduction in body weight, two groups of untreated control animals were also included: 1) ad-libitum controls (AL controls), which had unlimited access to food; and 2) pair-fed controls (PF controls), which were restricted to eating only as many calories as the BD animals consumed. Thus, the authors were able to disentangle any benefits due to caloric restriction from those of BD treatment per se.
After the 14 days of treatment, BD animals exhibited significant improvements relative to AL controls in nearly all metrics of inflammation and oxidative stress in the hippocampus. (Note that precise quantitation is challenging with the methodology employed in this study, but differences across metrics between BD and AL groups generally ranged from ~10-50% relative to the AL group.) For inflammatory markers, results from PF controls tended to be at intermediate levels between the AL and BD groups, while markers of oxidative stress generally did not differ significantly between BD and PF animals. These data suggest that calorie restriction likely accounted for all effects of BD on oxidative stress and partly accounted for apparent improvements in neuroinflammation.
However, not all benefits observed with BD treatment could be explained by lower energy intake. Markers of endoplasmic reticulum (ER) stress — which can itself arise from inflammation or oxidative damage and is often a sign of cellular stress more generally — were reduced in BD-treated animals relative to both the AL and PF groups, while levels of BDNF (a critical protein for neuronal growth and survival) were increased relative to the control groups. Accordingly, Cigliano et al. found that two key proteins for synaptic function (synaptophysin and synaptotagmin) were also elevated exclusively in animals that had received BD. These results collectively suggest that induction of ketosis through BD administration promotes neuronal health and neural signaling in the hippocampus.
Preliminary, but promising
Preclinical animal studies are a long way from proof of efficacy in humans, and even by the standards of rodent studies, Cigliano et al.’s findings should be regarded as very preliminary. They did not include any functional assessments of memory or other domains of cognitive function. Indeed, given that the animals were cognitively and neurologically healthy at baseline, the intervention likely would have been too short to see any meaningful divergence between groups in functional tests. A two-week intervention in a rat is roughly equivalent to one year for humans, whereas dementia or age-related memory loss can take decades to develop. Therefore, determining whether the neuroprotective effects of BD treatment are truly clinically significant for cognitive function would require much longer experiments.
The investigators also did not test BD treatment against a true ketogenic diet, which might have provided valuable insight as to how closely the supplement mimics the physiological effects of diet-induced ketosis. It’s very possible that the apparent benefits of BD would pale in comparison to those of a ketogenic diet itself, and when we look more closely at the degree of ketosis achieved in this study, we have some reason to believe that this could indeed be the case. While βHB levels in BD-treated rats were over double the levels of the control groups, this translated to a serum concentration of just under 0.6 mM — a mere fraction of the levels seen in rat studies using true ketogenic diets.2,3
Still, this study adds to a growing body of literature that ketosis-inducing supplements can reduce neuroinflammation and oxidative stress and improve neurological health. Perhaps more importantly, Cigliano et al. also report distinct effects of BD treatment relative to equivalent calorie restriction. Researchers have long debated whether the apparent benefits seen with ketosis are truly unique to this unusual metabolic state or instead are merely due to reduced energy intake and reductions in body fat. The present results offer compelling evidence that calorie restriction alone cannot fully account for improvements in inflammation and synaptic function, as BD-treated animals diverged substantially from both AL controls and PF controls in these areas.
Looking ahead
Again, we’re a very long way off from any possible regulatory approval for BD as a treatment or prevention strategy for neurodegenerative disease or cognitive impairment, though 1,3-butanediol has been granted GRAS (“Generally Recognized As Safe”) status by the FDA. It’s also worth noting that a couple of small, early-phase clinical trials are currently underway to investigate the compound’s efficacy and safety for blood glucose management (NCT05273411) and alcohol use disorder (NCT06559995).
However the more immediate utility of these data is probably in the simple proof-of-principle that ketosis has unique benefits — beyond those of calorie restriction — for neurological health at the cellular level, which might translate to long-term cognitive protection. Though this remains an area of debate, it should be encouraging to those considering a ketogenic diet, as the breadth and magnitude of the effects observed by Cigliano et al. are difficult to deny. Further, despite the lack of a control group on a ketogenic diet, we can nevertheless conclude that positive effects can be achieved (at least to some extent) with ketosis-inducing supplements, potentially offering an effective alternative for those who struggle to adhere to strict ketogenic diets.
Preliminary as these results may be, they offer intriguing possibilities that merit further exploration.
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References
- Cigliano L, De Palma F, Petecca N, et al. 1,3-butanediol administration as an alternative strategy to calorie restriction for neuroprotection – Insights into modulation of stress response in hippocampus of healthy rats. Biomed Pharmacother. 2025;182(117774):117774. doi:10.1016/j.biopha.2024.117774
- Zhao M, Huang X, Cheng X, et al. Ketogenic diet improves the spatial memory impairment caused by exposure to hypobaric hypoxia through increased acetylation of histones in rats. PLoS One. 2017;12(3):e0174477. doi:10.1371/journal.pone.0174477
- Zhao Q, Stafstrom CE, Fu DD, Hu Y, Holmes GL. Detrimental effects of the ketogenic diet on cognitive function in rats. Pediatr Res. 2004;55(3):498-506. doi:10.1203/01.PDR.0000112032.47575.D1
