The effect of oleoylethanolamide supplementation on cardiometabolic factors: a systematic review and meta-analysis

Abstract

This systematic review and meta-analysis of randomized controlled trials study sought to assess the effects of oleoylethanolamide (OEA) supplementation on many parameters related to cardiometabolic disorders. A thorough search was conducted across major databases using specific keywords to identify randomized controlled trials assessing the impact of OEA on cardiometabolic variables. The weighted mean difference (WMD) and 95% confidence intervals were calculated with a random-effects model. Data from 13 studies indicated substantial reductions in fasting blood sugar (WMD: −5.84 mg/dl), insulin (WMD: −3.26 µU/ml), waist circumference (WMD: −2.15 cm), triglycerides (WMD: −17.73 mg/dl), tumor necrosis factor-alpha (WMD: −2.44 pg/ml), and interleukin 6 (WMD: −0.87 pg/ml). An elevation in total antioxidant capacity (WMD: 0.43 mg/dl) was seen subsequent to OEA treatment. No substantial impacts were seen on other parameters. OEA supplementation, among other lifestyle variables, seems to provide significant improvements in certain cardiometabolic and oxidative stress-related indicators.

Introduction

Globally, noncommunicable illnesses now result in a higher number of fatalities and disability than infectious diseases. Cardiometabolic risk factors are among the main contributors to this trend, exhibiting the most rapid growth in recent years [1]. Reactive oxygen species (ROS) are regarded as pivotal contributors to illnesses such as obesity, hypertension, dyslipidemia, insulin resistance [2], hyperglycemia, cardiovascular diseases, and certain malignancies [3]. Under these circumstances, oxidative stress initiates the activation of inflammatory genes and the secretion of inflammatory mediators, including pro-oxidant molecules, cytokines, enzymes, and eicosanoids [4]. Moreover, persistent oxidative stress might hinder the efficacy of natural antioxidants like as catalase, superoxide dismutase, and glutathione, which are essential for mitigating the overproduction of ROS [5]. Consequently, cellular constituents like DNA, RNA, proteins, and lipids exhibit heightened vulnerability to damage, hence expediting disease development [6]. There has been a recent increase in interest in using natural chemicals as a viable option for controlling noncommunicable illnesses, owing to their diminished adverse effects and improved effectiveness. Oleoylethanolamide (OEA) has attracted considerable interest for its potential in treating cardiometabolic diseases.

OEA is a naturally occurring fatty acid ethanolamide found in various human tissues, such as the small intestine, adipose tissue [7], neurons, and astrocytes [8]. Though OEA is present in small quantities in certain foods like oatmeal, nuts, and cocoa powder (<2 μg/g) [9], it has gained global research interest because of its potential health benefits, particularly for cardiometabolic health. Studies have shown that OEA may play a vital role in regulating critical metabolic functions, including appetite regulation, lipid metabolism [10], and insulin sensitivity [11]. In addition, recent clinical trials highlight the importance of investigating OEA’s effects not only on conventional cardiometabolic markers but also on oxidative stress indicators and the body’s antioxidant defenses, although the findings remain mixed [12]. For instance, a study involving 125 mg of OEA supplementation daily for 8 weeks demonstrated significant reductions in appetite and body weight [13]. Moreover, a study by Tutunchi et al. shown that a daily dosage of 250 mg of OEA, in conjunction with a calorie-restricted diet over 12 weeks, led to decreased levels of inflammatory markers, including nuclear factor kappa B and interleukin (IL)-6, in obese patients with nonalcoholic fatty liver disease (NAFLD). The expression of IL-10 in the OEA group was about double that of the placebo group [14].

Because of its capacity to regulate essential cardiometabolic risk variables, oxidative stress, and inflammation, OEA emerges as a viable therapeutic agent for the management of metabolic syndrome and associated illnesses. Notwithstanding its promise, no meta-analysis has thoroughly evaluated the effects of OEA supplementation on cardiometabolic variables, oxidative stress, and antioxidant indicators. This systematic review and meta-analysis seeks to investigate the impact of OEA supplementation on these parameters, offering a thorough evaluation of its therapeutic potential for enhancing cardiometabolic health.

Methods

Search strategy

In accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, this systematic review and meta-analysis was carried out without any restrictions on time or language [15]. The PROSPERO database has already received a copy of the study protocol (registration number: ID 656237). A thorough search was performed by October 2024 across key databases, such as PubMed/MEDLINE, Web of Science, SCOPUS, and Embase, adhering to the general search criteria for the articles included in this study. This search also incorporated medical subject headings (MeSH) and Emtree terms (Embase subject title) such as: (oleoylethanolamide OR ‘OEA’ OR ‘N-acylethanolamides’ OR ‘NAEs’ OR ‘fatty acid ethanolamides’ OR ‘N‐oleyl‐phosphatidyl‐ethanolamine’ OR ‘NOPE’) AND (‘Glycated Hemoglobin A’ OR HbA1c OR ‘Insulin Resistance’ OR Insulin OR Glucose OR ‘Glucose Intolerance’ OR ‘Waist Circumference’ OR ‘BMI’ OR BMI OR Triglycerides OR ‘Cholesterol, HDL’ OR ‘HDL’ OR ‘Cholesterol, LDL’ OR LDL OR ‘High-density lipoprotein’ OR ‘Low-density lipoprotein’ OR ‘total cholesterol’ OR inflammation OR C-reactive protein OR CRP OR TNF-α OR ‘oxidative stress’ OR ‘antioxidant capacity’ OR TAC OR MDA OR IL-6) AND (‘Clinical Trials as Topic’ OR ‘Cross-Over’ OR ‘Double-Blind’ OR ‘Single-Blind’ OR ‘Random Allocation’ OR ‘Clinical Trial’). In addition, to ensure no relevant studies were missed, we thoroughly reviewed and assessed the reference lists of all retrieved papers, as well as meta-analyses and review articles relevant to the study’s objectives.

Eligibility criteria

Following a comprehensive review of articles (including titles, abstracts, and full texts), duplicate studies were removed. Two independent authors verified the eligibility of the remaining studies using the Population, Intervention, Comparison, Outcomes, Study Design (PICOS) framework. The following criteria were used for study selection:

• (1) Population: Studies included both healthy and unhealthy individuals aged 18 years or older.

• (2) Intervention: The intervention was limited to OEA supplementation.

• (3) Outcomes: The study outcomes encompassed various factors, including glucose metabolism [fasting blood sugar (FBS) and insulin], anthropometric measurements (weight, BMI, waist circumference), lipid profiles [total cholesterol, triglycerides, low-density lipoprotein (LDL), and high-density lipoprotein (HDL)], as well as inflammatory biomarkers, oxidative stress markers, and antioxidant parameters [C-reactive protein (CRP), tumor necrosis factor-alpha (TNF-α), IL-6, IL-1β, total antioxidant capacity (TAC), and malondialdehyde (MDA)].

• (4) Comparison: The control group included individuals receiving a placebo or no product.

• (5) Study design: Only randomized controlled trials (RCTs) were considered eligible for inclusion.

Furthermore, studies were included if they presented both baseline and postintervention data for the aforementioned outcomes. In instances where studies included data from many follow-up periods, only the most recent follow-up data were used for analysis. Animal studies, research using longitudinal data, studies without control groups, and systematic reviews or meta-analyses were omitted. The EndNote program was used to organize the eligible research and efficiently remove duplicates.

Data extraction

Data from the qualifying studies were separately retrieved by two writers for evaluation and analysis. Disagreements between the miners were resolved by a third review author. The extracted data comprised the first author’s name, publication year, sample sizes for the intervention and control groups, mean age and BMI of participants, intervention dosage, intervention specifics for both groups, and the mean and SD of outcomes at baseline and postintervention (or the change from baseline to follow-up).

Quality assessment

The quality of the trials was assessed using the latest version of the Cochrane Risk of Bias tool (RoB 2) [16]. Authors evaluated potential biases, such as random sequence generation, blinding, allocation concealment, and incomplete outcome data. Each study was classified as having low, high, or uncertain risk of bias, with a third author involved to resolve discrepancies. To assess the strength of the evidence, the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system was employed. This detailed 10-point checklist evaluates study quality based on seven factors: (1) study design, (2) precision, (3) heterogeneity, (4) directness, (5) publication bias, (6) funding bias, and (7) risk of bias [17].

Data synthesis and statistical analysis

Data analysis was conducted with STATA version 12.0. The EndNote program was used to manage and eliminate duplicates. Data from many sources were normalized by turning them into means and SDs [18,19]. If SDs were unavailable, the result change was computed using the formula for the square root of the sum of squared baseline and final SDs, while controlling for correlation coefficients. For SEM data, the SD was calculated by multiplying SEM by the square root of the sample size. A random-effects model was used for data analysis, and the inverse variance approach was applied to weight the research. This method facilitated the integration of several tests into a singular result group predicated on the temporal maximum. The assumed correlation coefficient when estimating the SD from the SEM or the pre- and postchange values was considered to be r = 0.5. Heterogeneity was evaluated using Q statistics and I², classified as modest (0–25%), moderate (26–50%), or large (51–100%) [20]. A subgroup analysis was conducted to ascertain potential causes of heterogeneity, including participant BMI, dose, and intervention duration. A sensitivity analysis was conducted to assess the impact of specific studies on the overall findings. Egger’s test, a well-established statistical method, was employed to assess publication bias [21].

Results

Figure 1 illustrates the process followed for the study, covering the stages of identification, screening, eligibility assessment, and the final sample selection. A total of 341 articles were initially imported into the EndNote program after a comprehensive search of the specified primary databases. Of these, 143 studies were eliminated because of duplication, resulting in 198 articles for additional evaluation. After reviewing titles, abstracts, and compliance with the inclusion and exclusion criteria, 178 papers were eliminated in the first phase, resulting in 198 publications for comprehensive assessment. Thirteen papers were ultimately chosen for inclusion in this meta-analysis after removing nine of the 22 studies for different reasons, as shown in Fig. 1.

Fig. 1.

Flow chart of study selection process. RCT, randomized controlled trial.

Study attributes

Table 1 delineates the attributes of the studies included. Among the chosen studies, 11 were executed in Iran and two in Australia. All investigations used a parallel design. The follow-up periods varied from 1 to 12 weeks, and the papers examined in this research were released between 2018 and 2024. The baseline characteristics of the study population included mean ages ranging from 20.67 to 68.6 years, BMI values from 23.35 to 34.69 kg/m², and the percentage of male participants varied between 0 and 52.63%. The average dosage of OEA supplementation ranged from 125 to 600 mg, with the most common study populations being individuals with obesity, cardiovascular or rheumatoid diseases, metabolic syndrome, or NAFLD.

Table 1.

Characteristics of eligible studies

First author et al.	Years	Country	Population	Mean age (years)	Sex (male %)	Sample size study		Follow-up of intervention (weeks)	Type of RCTs	Intervention group	Control group	Baseline of BMI (kg/m2)
						Intervention	Control
Batacan et al. [22]	2024	Australia	Overweight adult	49.8	34/4	29	15	12	Parallel	OEA supplementation (350 mg/day)	Placebo	34.37
Tutunchi et al. [23]	2023	Iran	Obese patients with NAFLD	41.78	46/64	30	30	12	Parallel	OEA supplementation (250 mg/day) combined with calorie restriction	Placebo combined with calorie restriction	33.79
Kazemi et al. [24]	2022	Iran	Girls with primary dysmenorrhea	20.67	0	22	21	8	Parallel	OEA supplementation (125 mg/day)	Placebo	23.35
Akbari [25]	2022	Iran	Patients with COVID-19	38.9	30	10	10	4	Parallel	OEA supplementation (400 mg/day)	Placebo	23.83
Sabahi et al.[26]	2022	Iran	Patients with Acute ischemic stroke	68.6	51.66	20	20	1	Parallel	OEA supplementation (600 mg/day)	Placebo	26.9
Payahoo et al.[13]	2019	Iran	Patients with obesity	37.37	39.45	27	29	8	Parallel	OEA supplementation (250 mg/day)	Placebo	34.69
Steel et al. [27]	2019	Australia	Adults with mild-to-moderate knee osteoarthritis	57	44.7	35	40	8	Parallel	OEA supplementation (300 mg/day)	Placebo	26
Shivyari et al.[28]	2024	Iran	Polycystic ovary syndrome	27.36	0	45	45	8	Parallel	OEA supplementation (250 mg/day)	Placebo	28
Pouryousefi et al. [11]	2022	Iran	Prediabetic individuals	49.64	NA	23	23	8	Parallel	OEA supplementation (250 mg/day)	Placebo	27.22
Payahoo et al.[13]	2019	Iran	Patients with obesity	37.4	39.45	27	29	8	Parallel	OEA supplementation (250 mg/day)	Placebo	34.7
Tutunchi et al.[14]	2021	Iran	Obese patients with NAFLD	41.73	52.63	38	38	12	Parallel	OEA supplementation (250 mg/day) combined with calorie restriction	Placebo combined with calorie restriction	34.19
Tutunchi et al.[23]	2020	Iran	Obese patients with NAFLD	40.84	52.63	38	38	12	Parallel	OEA supplementation (250 mg/day) combined with calorie restriction	Placebo combined with calorie restriction	33.13
Ostadrahimi et al. [29]	2024	Iran	People with obesity	37.37	39.45	27	29	8	Parallel	OEA supplementation (250 mg/day)	Placebo	34.69

COVID-19, coronavirus disease 2019; NAFLD, nonalcoholic fatty liver disease; OEA, oleoylethanolamide; RCT, randomized controlled trial.

Quality assessment

The quality of the studies was evaluated, and the results are presented in Table 2. The NutriGRADE scoring method was used to assess the quality of the meta-analysis itself, which resulted in a high-quality score of 8.5, indicating excellent methodological rigor.

Table 2.

Risk of bias assessment according to the Cochrane collaboration’s risk of bias assessment tool

Study, year (reference)	Random sequence generation	Allocation concealment	Blinding of participants and personnel	Blinding of outcome assessment	Incomplete outcome data	Selective reporting	Overall assessment of risk of bias
Batacan et al.[22]	Low	Low	Low	Low	Unclear	Low	Low
Tutunchi et al.[23]	Low	Unclear	Low	Low	Unclear	Low	Unclear
Kazemi et al.[24]	Low	Low	Low	High	Unclear	Low	Unclear
Akbari et al.[25]	Low	Low	Unclear	Unclear	Unclear	Low	Unclear
Sabahi et al.[26]	Low	Low	High	Low	Unclear	Low	Unclear
Payahoo et al.[13]	Low	Low	Unclear	Low	Unclear	Low	Low
Steels et al. [27]	Low	High	Low	Low	Unclear	Low	Low
Shivyari et al.[28]	Low	Low	Unclear	Low	Unclear	Low	Low
Pouryousefi et al. [11]	Low	Unclear	Low	Low	Unclear	Low	Unclear
Payahoo et al.[13]	Low	Low	Low	Low	Unclear	Low	Low
Tutunchi et al.[14]	Low	Unclear	Unclear	Low	Unclear	Low	Low
Tutunchi et al.[23]	Low	Low	Unclear	Low	Unclear	Low	Low
Ostadrahimi et al. [29]	Low	Low	Unclear	Low	Unclear	Low	Low

Meta-analysis results

Glucose metabolism

The meta-analysis demonstrated that OEA supplementation significantly reduced FBS levels [WMD: −5.84 mg/dl, P = 0.011; 95% confidence interval (CI): −10.33 to −1.35, I² = 65.7%) and insulin levels (WMD: −3.26 µU/ml, P = 0.030; 95% CI: −6.22 to −0.31, I² = 94.5%) (Fig. 2).

Fig. 2.

Forest plots from the meta-analysis of clinical trials investigating the effects oleoylethanolamide on (a) glucose and (b) insulin. CI, confidence interval; WMD, weighted mean difference.

Anthropometric data

No significant effect was found for weight (WMD: −2.15 kg, P = 0.285; 95% CI: −3.25 to 0.96, I² = 0.0%) and BMI (WMD: −0.36 kg/m², P = 0.148; 95% CI: −0.84 to 0.13, I² = 19.4%); however, a significant reduction in waist circumference was observed (WMD: −4.89 cm, P = 0.004; 95% CI: −8.26 to −1.52, I² = 11.1%) (Fig. 3).

Fig. 3.

Forest plots from the meta-analysis of clinical trials investigating the effects oleoylethanolamide on (a) weight, (b) BMI, and (c) waist circumference. CI, confidence interval; WC, waist circumference; WMD, weighted mean difference.

Lipid profiles

No significant effects were found on LDL cholesterol (LDL-C) (WMD: 2.88 mg/dl, P = 0.499; 95% CI: −5.47 to 11.23, I² = 0.0%), HDL cholesterol (HDL-C) (WMD: 0.25 mg/dl, P = 0.943; 95% CI: −6.55 to 7.04, I² = 81.9%), or total cholesterol (WMD: 2.19 mg/dl, P = 0.557; 95% CI: −5.13 to 9.51, I² = 0.0%); however, triglyceride levels showed a significant reduction (WMD: −17.73 mg/dl, P = 0.013; 95% CI: −31.86 to −3.79, I² = 0.0%) (Fig. 4).

Fig. 4.

Forest plots from the meta-analysis of clinical trials investigating the effects of oleoylethanolamide on (a) cholesterol, (b) LDL-C, (c) HDL-C, and (d) triglyceride. CI, confidence interval; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; TG, triglyceride; WMD, weighted mean difference.

Inflammatory biomarkers, oxidative stress, and antioxidant parameters

OEA supplementation significantly reduced TNF-α (WMD: −2.44 pg/ml, P = 0.001; 95% CI: −3.89 to −0.09, I² = 86.7%) and IL-6 (WMD: −0.87 pg/ml, P = 0.001; 95% CI: −1.38 to −0.35, I² = 39.2%), while it increased TAC (WMD: 0.43 mg/dl, P = 0.002; 95% CI: 0.16–0.69, I² = 98.1%) (Fig. 5); however, no significant effects were observed for CRP (WMD: −1.02 mg/L, P = 0.060; 95% CI: −2.09 to 0.04, I² = 85.0%), IL-1β (WMD: −1.56 pg/ml, P = 0.063; 95% CI: −3.21 to 0.08, I² = 0.0%), or MDA (WMD: −0.27 mg/dl, P = 0.156; 95% CI: −0.64 to 0.10, I² = 97.0%).

Fig. 5.

Forest plots from the meta-analysis of clinical trials investigating the effects of oleoylethanolamide on (a) CRP, (b) TNF-α, (c) IL-β, (d) IL-6, (e) TAC, and (f) MDA. CI, confidence interval; CRP, C-reactive protein; IL, interleukin; MDA, malondialdehyde; TAC, total antioxidant capacity; TNF-α, tumor necrosis factor alpha; WMD, weighted mean difference.

Subgroup analysis

Stratified analysis based on OEA dosage, baseline BMI, and intervention duration showed that OEA supplementation was more effective in reducing FBS in studies with follow-up durations of less than or equal to 8 weeks compared to those with longer durations (>8 weeks). In addition, OEA supplementation at doses less than or equal to 250 mg resulted in greater reductions in FBS and CRP compared with doses greater than 250 mg. Furthermore, individuals with a BMI greater than 30 experienced a more significant decrease in CRP levels following OEA supplementation. No significant differences were observed for other variables in the subgroup analyses (Supplementary Table S1, Supplemental digital content 1, https://links.lww.com/CAEN/A71).

Analysis of sensitivity

The sensitivity analysis, conducted using the leave-one-out technique, revealed that the overall effect size remained stable despite the sequential exclusion of individual studies (Supplemental Figures S1–S4, Supplemental digital content 2, https://links.lww.com/CAEN/A72).

Publication bias

The examination of the funnel plot showed no evidence of publication bias in the meta-analysis of OEA’s impacts on the different outcome measures. Moreover, Egger’s regression test indicated no significant publication bias for the majority of outcomes, including weight, BMI, waist circumference, lipid profiles, FBS, insulin, CRP, TNF-α, IL-6, TAC, MDA, and IL-1β (P values ranging from 0.117 to 1.00) (Supplemental Figures S5–S8, Supplemental digital content 3, https://links.lww.com/CAEN/A73). The meta-trim and fill analysis revealed no missing studies.

Discussion

Research on the impact of OEA supplementation on cardiometabolic variables, oxidative stress, and antioxidant parameters is limited, despite their significance in the genesis and progression of numerous chronic illnesses. This systematic review and meta-analysis is, to our knowledge, the first thorough investigation evaluating the influence of OEA on these significant parameters. This meta-analysis, derived from 13 RCTs, demonstrated that OEA supplementation substantially decreased FBS and insulin levels. Concerning anthropometric measurements, OEA did not substantially influence body weight or BMI; however, it was linked to a substantial decrease in waist circumference. Despite the absence of notable alterations in LDL-C, HDL-C, or total cholesterol after OEA administration, a substantial decrease in triglyceride levels was seen. The investigation revealed that OEA supplementation markedly decreased TNF-α and IL-6 levels, while enhancing TAC. No notable impacts were seen for CRP, IL-1β, or MDA. The research includes subgroup analyses that account for differences in OEA dose, individuals’ average BMI, and the intervention length.

To our knowledge, no systematic review or meta-analysis has investigated the varied effects of OEA supplementation on cardiometabolic variables, oxidative stress, and antioxidant metrics. Nonetheless, several research have investigated similar results. Tutunchi et al. [30] executed a clinical trial involving obese individuals with fatty liver, demonstrating that daily administration of 250 mg of OEA over 12 weeks resulted in significant decreases in fasting blood glucose (FBG), insulin, insulin resistance, and triglyceride levels, alongside an elevation in HDL-C, which stands in contrast to our findings. Similarly, a study by Laleh et al. [8] found that OEA supplementation (125 mg/day) in healthy obese individuals significantly reduced waist circumference, despite no changes in weight or BMI [29]. While OEA had no significant impact on LDL-C, HDL-C, or total cholesterol in most studies, we observed a significant reduction in triglyceride levels. A retrospective study by Verma et al. [31], however, reported significant reductions in triglyceride, TC, and LDL-C following supplementation with OEA (200 mg), along with pantethine and valine. In animal studies, Fu et al. [32] and Tovar et al. [33] demonstrated reductions in triglyceride levels with OEA supplementation, although results on glucose metabolism were more mixed. Chen et al. [34] demonstrated that daily administration of 5 mg/kg OEA in mice led to a reduction in liver triglyceride accumulation and prevented increases in serum triglyceride levels. The differences between our findings and those previously mentioned could be attributed to variations in study designs, dosages of OEA, and the duration of supplementation. In our meta-analysis, the results concerning anthropometric measurements indicated that OEA supplementation did not significantly affect weight and BMI but did lead to a notable reduction in waist circumference. These findings are consistent with those of Laleh et al. [8], who showed that two 125 mg OEA capsules daily in healthy obese individuals significantly decreased waist circumference, while also reducing weight and BMI, possibly because of increased proliferator-activated receptor-alpha (PPAR-α) gene expression and reduced appetite. PPAR-α is a group of nuclear receptors activated by ligands that regulate gene expression related to lipid metabolism and energy balance [35]. According to animal studies, OEA binds to PPAR-α, promoting its gene expression and fatty acid β-oxidation, which may influence appetite and obesity-related measurements [30]. Our findings are consistent with those of Mangine et al. [36], who reported no significant changes in BMI or body composition after 8 weeks of treatment with 120 mg of N‐oleyl‐phosphatidyl‐ethanolamine (NOPE) and 105 mg of epigallocatechin gallate (EGCG) in 50 healthy overweight individuals. In contrast, Barbaro et al. [37] observed that supplementing 38 obese individuals with two capsules containing 170 and 120 mg daily of NOPE and EGCG, respectively, for 2 months resulted in a significant decrease in both weight and hip circumference. Similarly, Rondanelli et al. [38] demonstrated that two capsules of NOPE–EGCG (85 mg NOPE and 50 mg EGCG) daily for 2 months in 138 healthy overweight individuals led to increased feelings of fullness and a significant reduction in weight. The discrepancies between these studies might be because of differences in baseline anthropometric measurements in overweight and obese individuals.

Our data indicated that OEA supplementation increased TAC and reduced TNF-α and IL-6 levels. Nonetheless, no substantial effects were seen on CRP, IL-β, and MDA. The results align with Shivyari et al.’s [28] research, which showed that a daily dosage of 125 mg of OEA over 8 weeks dramatically decreased TNF-α and FBS levels while enhancing TAC in women diagnosed with polycystic ovarian syndrome. In contrast to our findings, their investigation also identified substantial decreases in CRP and MDA levels. Kazemi et al. [24] demonstrated that a daily intake of 125 mg of OEA decreased TNF-α levels and elevated TAC in women with dysmenorrhea. In a research conducted by Sabahi et al. [26], patients with acute ischemic stroke administered 300 mg of OEA for three days exhibited a significant rise in TAC and, in contrast to our results, a decrease in MDA levels relative to baseline. Because of significant variability among studies, subgroup analyses were conducted, but the limited number of studies per group made it challenging to identify the source of heterogeneity. Nonetheless, subgroup analyses indicated that CRP reduction was greater at doses below 250 mg compared to those above 250 mg. In addition, CRP levels decreased more in individuals with a BMI greater than 30 after OEA supplementation; however, no significant differences were observed for other variables in subgroup analyses.

OEA, a potent endogenous PPAR-α agonist, exhibits anti-inflammatory effects by promoting IkB expression, an inhibitor of nuclear factor kappa B (NF-κB). It prevents NF-κB activation triggered by lipopolysaccharides, reduces cyclooxygenase-2 expression regulated by NF-κB, and lowers levels of vascular cell adhesion molecule-1 and intracellular adhesion molecule-1, which are involved in the inflammatory response. Moreover, OEA interferes with the ERK1/2-dependent signaling pathway and reduces the expression of genes associated with inflammatory biomarkers such as IL-6, IL-1β, and TNF-α [13,30,39]. A recent animal study also showed a significant reduction in MDA levels following OEA treatment [40]. Thus, caution is advised in interpreting these findings because of significant heterogeneity across studies and the limited number of available studies. Overall, the differences in study designs, participant populations, baseline inflammatory markers, OEA dosages, intervention durations, dietary habits, and physical activity levels may contribute to the varying outcomes observed in existing studies.

According to our results, although the effects of interventions with OEA caused significant statistical results on the investigated factors, but it does not seem to have significant clinical effects to improve the risk factors of cardiovascular diseases including lipid profile and glucose metabolism. So that the documents reported that clinically significant improvement was defined as a decrease in FBG of 20 mg/dl, LDL-C of 10 mg/dl, triglyceride of 40 mg/dl, and an increase in HDL-C of 5 mg/dl [41]; however, the results of the study show that OEA can be used as a complementary medicine along with other lifestyle factors including physical activity and effective drugs in this field.

The observation that OEA appears more effective at doses less than or equal to 250 mg or within shorter intervention periods (≤8 weeks) may indeed be related to mechanistic factors such as receptor saturation or biological adaptation. OEA acts primarily through activation of peroxisome PPAR-α, which plays a key role in lipid metabolism, appetite regulation, and energy homeostasis. Evidence suggests that PPAR-α activation follows a dose–response curve that can plateau or even desensitize with chronic or high-dose stimulation [35]. This supports the hypothesis that higher doses or prolonged use of OEA could lead to receptor downregulation or diminished responsiveness, blunting its metabolic and anorexigenic effects over time. In addition, homeostatic feedback mechanisms may counteract the effects of OEA after prolonged exposure, which is a known phenomenon in other lipid-derived signaling pathways. This could explain why shorter durations yield more consistent benefits, while longer interventions may exhibit attenuated responses.

This meta-analysis faces several limitations. First, the limited number of studies addressing various cardiometabolic factors, oxidative stress, and antioxidant parameters restricted our ability to explore these areas in detail. Second, many of the included trials had relatively short treatment periods (≤8 weeks). Third, the studies covered a broad spectrum of disease conditions, risk factors, and potential confounders. Moreover, participants in the trials represented diverse health conditions, such as NAFLD, prediabetes, metabolic syndrome, obesity, acute ischemic stroke, knee osteoarthritis, polycystic ovary syndrome, primary dysmenorrhea, and coronavirus disease 2019. Another limitation was the small number of studies included, which made it challenging to examine the effects of OEA across such a wide range of diseases. Each of these conditions has distinct underlying mechanisms and pathophysiological processes, potentially influencing the cardiometabolic factors, oxidative stress, and antioxidant parameters. One of the major limitations of this study is the heterogeneity among studies. These may be explained by the differences in the intervention-specific factors (e.g. doses of OEA and duration of intervention), patient-specific factors (e.g. genes, age, sex, ethnicity, and any history of the disease, drug or supplement consumption, and substance allergies), and outcomes-specific factors (e.g. baseline severity and its methods of screening and diagnosis). Nonetheless, we attempted to identify some possible sources of heterogeneity in the data by performing a subgroup analysis.

Conclusion

In conclusion, the available evidence suggests that OEA supplementation may reduce FBS, insulin, waist circumference, triglycerides, TNF-α, and IL-6, while increasing TAC. Subgroup analyses indicate that lower OEA dosages, longer intervention durations, and its use in individuals with a BMI above 30 may yield more favorable outcomes in terms of cardiometabolic factors, oxidative stress, and antioxidant parameters; however, because of the limited number of trials, these findings should be interpreted with caution, particularly for the subgroup analysis. Future prospective studies with larger sample sizes, diverse populations, and longer follow-up periods are necessary to confirm whether OEA truly has anti-inflammatory and antioxidant effects.

Acknowledgements

R.P., S.M.H., F.S., And E.M.: Conception, design, statistical analysis, data collection, writing – original draft, supervision. E.M. and S.M.H.: Data collection and writing – original draft. All authors approved the final version of the manuscript.

The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.

This study was approved by the research council and Ethics Committee of Tehran University of Medical Sciences, Tehran, Iran.

Conflicts of interest

There are no conflicts of interest.

Supplementary Material

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