Database searches resulted 1,039 articles: PubMed (n = 206), Cochrane (n = 237), Embase (n = 424), and Web of Science (n = 172). After removing 301 duplicates, 541 records underwent screening. Following full text screening, 484 records were excluded, leaving 57 reports sought for retrieval. Eight reports could not be obtained. Of 49 full-text reports assessed, 8 were excluded (5 animal studies, 3 non-ketogenic interventions). Ultimately, 41 studies met inclusion criteria [7, 8, 12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42]. We included 8 abstracts as well. The PRISMA flow diagram is shown in (Fig. 1).

PRISMA 2020 flow diagram for new systematic reviews included searches of databases and registers only

A total of 41 published studies were included, comprising a mix of prospective and retrospective cohorts, clinical trials, case series, and case reports, with most conducted in the United States, Europe, and Asia. Study sample sizes ranged from single-patient reports to cohorts of over 100 patients, primarily focusing on glioblastoma multiforme (GBM) and other high-grade gliomas. Ketogenic interventions varied, including the classic 4:1 ketogenic diet, modified Atkins diet, medium-chain triglyceride diets, and calorie-restricted or intermittent fasting protocols, often combined with standard treatments such as chemoradiotherapy or temozolomide. Duration of interventions ranged from days to over two years. Survival outcomes, including overall survival (OS) and progression-free survival (PFS), were reported variably across studies. Adverse events were mostly mild, with gastrointestinal symptoms, weight loss, and fatigue being the most common. No grade 3/4 toxicities directly related to the ketogenic diet were reported. Full details of study design, population, intervention type, outcomes, and adverse events are presented in (Supplementary Table 3).

Over the past three decades, there has been a steady increase in interest in using ketogenic dietary interventions (KD) to target altered tumor metabolism in gliomas. Pilot trials, observational cohorts, and more organized feasibility studies have progressively replaced the initial isolated case observations.

Nebeling et al. (1995) reported the first clinical evidence when they used an 8-week ketogenic diet high in medium-chain triglyceride oil in addition to standard therapy to treat two pediatric patients with advanced malignant astrocytomas. Positron emission tomography (PET) revealed a 21.8% decrease in tumor glucose uptake in both kids, along with an unexpectedly long survival of 60 and 48 months, respectively, and no notable side effects. This seminal study offered preliminary clinical evidence that metabolic modification could affect glioma tumor biology [12]. A remarkable case involving a 65-year-old woman with multicentric glioblastoma multiforme (GBM) who was treated with a strict 4:1 ketogenic diet along with therapeutic fasting in addition to conventional therapy was reported by Zuccoli et al. (2010) more than ten years later. Both MRI and PET imaging showed complete radiological remission. The study crucially showed that even strict ketogenic regimens could be used safely in GBM patients, with hyperuricemia being the only documented side effect [13]. Through a number of observational and pilot studies involving patients with high-grade gliomas, clinical experience with KD increased between 2014 and 2016. 11 patients treated with KD had a mean survival of 38 ± 13 months, according to Han et al. [14]. Concurrently, Rieger et al.'s ERGO study evaluated feasibility in 20 patients with recurrent GBM and confirmed that dietary ketosis could be attained, albeit with limited benefits for survival [15]. A median overall survival of 14 months was found in a larger retrospective analysis by Champ et al. that included 134 patients with grade III–IV gliomas [16]. According to a 2015 case report by Schwartz et al., two patients with WHO grade IV anaplastic astrocytoma were treated with an energy-restricted ketogenic diet [17]. Although survival and progression data were not disclosed, the diet was implemented over a 12-week period. There were no negative effects mentioned, and the report's main focus was on metabolic response and feasibility.

Patients with recurrent GBM treated with KD alone or in conjunction with bevacizumab showed disease stabilization, according to Artzi Moran et al. [18]. Santos et al. (Brazil) combined KD with intranasal perillyl alcohol in 37 recurrent GBM patients [19] and Martin-McGill et al. (UK, 2018) enrolled six glioma patients aged 16–69 on a restrictive KD for 3 months. The study focused on safety and adherence [20]. A 2018 prospective study by Van der Louw et al. evaluated the feasibility and clinical outcomes of a carbohydrate-restricted ketogenic diet in pediatric patients with diffuse intrinsic pontine glioma (DIPG0. The study included three patients, aged 4.4, 11.5, and 14.5 years, respectively. Individual overall survival times were 16.5, 6.4, and 18.7 months. Several side effects were observed, including hypoglycemia, hyperkeratosis, vomiting, refusal to eat, asthenia, and constipation. Despite these adverse effects, the study demonstrated that implementation of a carbohydrate-restricted ketogenic diet in pediatric DIPG patients is feasible [21]. In a 2018 case study, Elsakka and associates described how a 38-year-old patient with glioblastoma multiforme (GBM) used a calorie-restricted ketogenic diet. The long-term viability of metabolic therapy in the treatment of an aggressive brain tumor was investigated in this single-patient intervention. For an extended period of 24 months, the patient adhered to a rigorously calorie-restricted ketogenic diet while undergoing concurrent clinical monitoring. The report did not indicate whether chemotherapy or radiation was given concurrently with the diet, but it was implemented in conjunction with standard care measures. The patient continued to follow the dietary plan during the 24-month follow-up period [22].

Research began to concentrate more on integrating ketogenic techniques with conventional cancer treatments. The safety of KD during radiotherapy and adjuvant treatment phases was further supported by additional feasibility studies and case series by van der Louw et al., Woodhouse et al., and Berrington et al. [23,24,25]. Tóth et al. (2019) published a particularly noteworthy report that detailed a patient with recurrent GBM who was treated solely with a paleolithic ketogenic diet, without the use of chemotherapy or radiation. The patient's 46-month overall survival and 38 months of progression-free survival raise the intriguing possibility that, in carefully chosen cases, metabolic therapy alone may be beneficial [26]. In 2020, Martin-McGill et al. enrolled 12 patients with GBM (median age: 57) in a trial comparing MKD and MCTKD over 3 months. Median survival was 67.3 weeks. Electrolyte imbalances and constipation were the most common side effects [27].

Studies became more methodologically structured after 2020, frequently using intermittent fasting and calorie restriction. In one treatment arm, Klein et al.'s evaluation of a traditional 4:1 ketogenic diet as complete meal replacement in patients with terminal GBM revealed longer survival [28]. Panhans et al.'s retrospective analyses consistently confirmed an acceptable safety profile despite highlighting significant variability in outcomes [29]. Short-term calorie-restricted ketogenic diets combined with intermittent fasting were shown to be metabolically safe and feasible in patients with recurrent GBM in the ERGO2 studies by Voss et al. and Wenger et al. [30, 31]. Foppiani and colleagues (2020) ran a single-arm prospective study in Italy with six patients (median age: 45 years) diagnosed with high-grade gliomas. Over one month on an isocaloric KD, participants showed a 5% reduction in both body weight and waist circumference, suggesting effective metabolic engagement. Adverse effects and survival outcomes were not detailed [32]. Schreck et al. conducted a prospective study in 25 patients with astrocytomas (grade 2 to 4) who followed the Glioma Atkins-Based Diet for eight weeks. Although survival outcomes weren’t reported, the diet was associated with several adverse events. These included grade 2 leukopenia, nausea, diarrhea, fatigue, and seizures, along with one case of grade 3 neutropenia [33]. In a smaller retrospective study of five glioma patients, Perez et al. found a median survival of 18.7 months under ketogenic dietary therapy. Adverse events included hypoglycemia, constipation, vomiting, asthenia, hyperkeratosis, and hyperuricemia, highlighting the need for close monitoring even in small-scale implementations [34].

A patient with IDH-mutant GBM treated with ketogenic therapy alone, without radiation or chemotherapy, had an amazing 80-month overall survival, according to Seyfried et al. [35]. When KD was used in conjunction with standard treatment, phase-1study by Porper et al. showed sustained ketosis, good adherence, and manageable toxicity [36]. In a separate randomized trial, Voss et al. investigated the safety of a short, calorie-restricted ketogenic diet in 50 patients with recurrent glioblastoma [37]. Patients followed the diet for just three days prior to resuming standard therapy, with follow-up ranging from 250 to 485 days. While muscle cramps, gastrointestinal discomfort, and headaches were noted, these effects were temporary, suggesting that brief KD cycles can be tolerated even in advanced-stage disease. In a prospective case series from New Zealand, Phillips et al. enrolled ten patients with GBM who followed a modified ketogenic diet for an average of 127± 59 days [38]. The median survival was 13 months, in line with standard treatment expectations. The diet was well tolerated, with only mild side effects such as fatigue, irritability, and lightheadedness, and no grade 3 or higher toxicities were reported. A 2022 prospective study by Schwartz et al. (USA) investigated the feasibility of a ketogenic diet in patients with GBM. The study enrolled 12 patients. Participants followed the ketogenic diet for six weeks, with no clearly defined follow-up duration reported [39].

Smith K and colleagues conducted a retrospective observational study in the U.S., evaluating ketogenic metabolic therapy in 16 glioma patients. The cohort included a mix of WHO grade II–IV gliomas. KMT was provided as a standalone intervention over an average of 20.6 months. Mean progression-free survival was 20.0 months. The intervention was safe, with no diet-related adverse events reported [40]. A 64-year-old patient with IDH-wildtype glioblastoma was treated with a time-restricted ketogenic diet, according to a more recent 2024 case report by Phillips et al. With an overall survival of 36 months, the diet was maintained for two years, which is much higher than the median for this molecular subtype. During extended fasting, mild side effects such as fatigue, diarrhea, and cold intolerance were observed; however, no adverse events directly linked to KD were reported [41]. A multicenter observational study in adults with high-grade gliomas was recently published by Laguado et al. (2024), which confirmed the long-term viability, good tolerability, and lack of serious adverse events during a 12-month ketogenic intervention [42]. A 2025 prospective study by Kiryttopoulos et al. (USA) evaluated the use of a ketogenic diet in patients with newly diagnosed GBM. The study included 18 patients with a median age of 57.5 years, who followed a ketogenic diet for six months, with a reported follow-up period of six months. Among the sub-group with available long-term outcome data, the 3-year survival rate was 66.7%, which appears higher than typically reported for glioblastoma [8]. At Cedars-Sinai Medical Center, Amaral and colleagues carried out an open-label study involving 20 glioblastoma patients. The ketogenic intervention was administered alongside temozolomide chemotherapy for 16 weeks. Outcomes were promising, with a median overall survival of 29.4 months and a progression-free survival of 12.9 months. Importantly, the diet was well tolerated, with no reported adverse events or discontinuations [7].

In abstracts, we found that William M and colleagues (UK) initiated two parallel, open-label Phase 2 trials to explore modified KD (MKD) in both high- and low-grade glioma patients. The MKD was planned in conjunction with standard chemoradiotherapy for high-grade gliomas or standard care for low-grade gliomas. Data from these trials are pending [43]. Shen et al. (2016), who successfully used a modified ketogenic formula during chemo-radiation in a child with GBM, provided additional evidence of feasibility in pediatric settings [44]. Across these studies, KD was generally well tolerated, with adverse effects largely limited to weight loss, gastrointestinal symptoms, and occasional hypoglycemia. With an overall survival of 29.3 months, Dardis et al. (2017) showed that starting KD during chemo-radiation and subsequently switching to a Modified Atkins Diet was both practical and well tolerated [45]. Gresham G and team (2019) began an open-label feasibility trial in 20 newly diagnosed GBM patients. The 16-week KD was introduced during standard therapy. Full outcome data were not yet available, but preliminary results indicated feasibility and tolerability [46]. Schwartz K et al. (2019) conducted a pilot trial in nine GBM patients on a 3:1 isocaloric KD during standard therapy. Younger patients had no tumor progression at 31–49 months, while older patients experienced shorter survival. The KD was safe and well tolerated [47]. N. Shinojima et al. described the clinical course of a 37-year-old male patient with progressive GBM who was treated with palliative care in addition to a ketogenic diet in a case report from Japan. After standard therapies showed signs of disease progression, dietary intervention was started. Although the composition of the KD regimen was not specified, it was followed for a minimum of eight months, and an MRI at that time revealed a favorable therapeutic response. The patient remained clinically stable under the ketogenic protocol for the entire 20-month clinical follow-up period following the diagnosis. Crucially, during the course of treatment, the patient did not encounter any negative consequences related to the ketogenic diet [48]. Smiti S (Morocco) ran a small prospective study comparing KD during radiotherapy versus usual diet in 10 GBM patients over three months [49]. Nelson T et al. (2021) shared early findings from a U.S. Phase 1 trial involving 14 newly diagnosed GBM patients (median age: 55). Participants followed KD for 16 weeks alongside standard therapy. Target ketone levels (> 0.3 mmol/L) were maintained. The median overall survival at the time of reporting was 14.6 months, consistent with standard care [50].

The cumulative clinical evidence points to the viability, general safety, and biological activity of ketogenic dietary interventions for glioma patients. Firm conclusions regarding efficacy are limited by significant heterogeneity in dietary protocols, study designs, and outcome reporting, even though sporadic reports describe remarkably prolonged survival, particularly in selected patients with favorable molecular profiles. These results highlight the critical need for carefully planned, sufficiently powered randomized controlled trials to validate the actual therapeutic role of ketogenic approaches in the treatment of gliomas.

All included studies were rated as high methodological quality using JBI appraisal tools, with scores ranging from 77 to 100%, and were of high quality. Minor limitations included lack of blinding in non-randomized studies and unclear consecutive inclusion in some case series. No studies were excluded based on quality. The complete detail is given in (Supplementary Table 4).