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Article

Effect of a Citicoline-Containing Supplement on Lipid Profile and Redox Status in Healthy Volunteers in Relation to Lifestyle Factors

by
Bogdan Roussev
,
Todorka Sokrateva
,
Daniela Vankova
,
Miglena N. Nikolova
,
Diana Ivanova
and
Milka Nashar
*
Department of Biochemistry, Molecular Medicine and Nutrigenomics, Faculty of Pharmacy, Medical University of Varna, 9002 Varna, Bulgaria
*
Author to whom correspondence should be addressed.
Appl. Sci. 2025, 15(19), 10512; https://doi.org/10.3390/app151910512
Submission received: 17 August 2025 / Revised: 24 September 2025 / Accepted: 26 September 2025 / Published: 28 September 2025
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Abstract

This study aimed to investigate the effects of a new formulation combining citicoline, vitamin C, and extracts from green tea and aronia (Cytodeox™) on the lipid profile and redox status in healthy individuals following a six-month intervention. Additionally, we examined whether these effects depend on lifestyle factors such as body mass index (BMI), alcohol consumption, smoking and physical activity. Forty-three volunteers aged 40–65 (F31/M12) completed the study. Prior to the intervention, all participants filled out a questionnaire assessing their health status and lifestyle habits. At baseline and after supplementation, anthropometric and physical parameters were measured, and fasting blood samples were collected from all participants. Furthermore, all participants were grouped based on their gender and lifestyle habits. Cytodeox™ significantly reduced lipid profile parameters and malondialdehyde (MDA) levels in the overall group. The analysis of these effects in relation to lifestyle habits revealed that smoking, but not alcohol consumption, negatively influences the effects of the supplement. Surprisingly, the beneficial effects were observed in the overweight group and those leading a sedentary lifestyle. The results strongly suggest that six months of supplementation with Cytodeox™ can improve the lipid profile and redox status, even in individuals with some poor lifestyle habits.

1. Introduction

Managing lipid profile parameters and redox status is crucial for preventing various pathological conditions such as diabetes, cardiovascular diseases (CVD), and stroke [1,2].
The lipid profile parameters, including total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triacylglycerols (TAG) are key diagnostic and prognostic indicators. Over recent decades, numerous studies have demonstrated a strong association between a high prevalence of CVDs, increased plasma levels of TC and LDL-C and decreased levels of HDL-C [3,4,5,6]. Besides the standard lipid profile, the ratios of TC/HDL-C, LDL-C/HDL-C and TAG/HDL-C are recognised to have significant prognostic value for risk of vascular events, including ischaemic stroke [7,8].
Oxidative stress is an excessive production of reactive oxygen species (ROS) compared to the body’s antioxidant defences. This overproduction of ROS plays a significant role in causing cellular damage, disrupting energy metabolism and promoting systemic inflammation [1,2]. Redox status is typically assessed by measuring serum levels of malondialdehyde (MDA) and thiobarbituric acid reactive substances, along with total thiols (TT), the ratio of reduced to oxidised glutathione and levels of various prooxidant and antioxidant enzymes [9,10]. Elevated serum MDA levels indicate increased lipid peroxidation and inflammation, serving as a reliable, non-invasive biomarker to predict the severity of CVDs [11,12,13]. Conversely, reduced levels of endogenous antioxidants—particularly total thiols—reflect compromised antioxidant defences and have been associated with increased disease severity and poorer prognosis in cardiovascular conditions [14].
The development and progression of dyslipidemia and redox imbalance are closely linked to lifestyle factors. Excess body weight measured by the Body Mass Index (BMI) is a significant risk factor for insulin resistance, dyslipidaemia and chronic inflammation [15]. Furthermore, the sedentary lifestyle increases these risks, while regular physical activity is known to improve lipid profiles and antioxidant defence, and enhance insulin sensitivity [16,17]. Similarly, excessive alcohol consumption and tobacco smoking can strongly contribute to oxidative stress and are independent risk factors for many noncommunicable diseases (NCDs) [18].
Therapies aimed at regulating lipid parameters and redox homeostasis may have varying outcomes, likely influenced by individual lifestyle choices [19]. In this regard, the strategy for preventing NCDs should be comprehensive, addressing biological markers and the lifestyle factors that impact them [4,20,21,22].
Over the past decades there has been a growing interest in developing natural-source supplements with high efficacy and fewer side effects than conventional medications [23,24,25].
Citicoline is the generic name for the endogenous metabolite cytidine-5′-diphosphocholine (CDP-choline), an essential biochemical intermediate in cellular metabolism. Citicoline is crucial for phosphatidylcholine synthesis, which is involved in the biosynthesis of other key phospholipids such as phosphatidylethanolamine, phosphatidylserine and sphingomyelin. These phospholipids are vital components of mammalian cell membranes [26]. Additionally, phosphatidylcholine forms a structural part of the lipoprotein monolayer and serves as the primary endogenous choline source for the neurotransmitter acetylcholine production.
Citicoline is extensively researched for its health-enhancing effects, mainly its neuroprotective activity and potential to improve learning and memory [27,28,29]. When taken orally, citicoline is quickly hydrolysed into choline and cytidine [30]. These compounds have high bioavailability and readily cross the blood–brain barrier where the released choline becomes available for several critical metabolic pathways [26,31]. Since cytidine does not have any health claims, citicoline can be considered a source of choline in a safer form of supplementation. Choline taken orally alone is metabolised by intestinal microbiota and converted to trimethylamine whose oxidised form is implicated in the pathogenesis of many diseases, such as atherosclerosis, kidney failure, diabetes and cancer [30,32].
Citicoline has been widely used in recent years as a nutritional supplement for mild cognitive impairment conditions and glaucoma, with the typical therapeutic dose ranging from 500 to 2000 mg daily [33]. Recently, the effects of citicoline supplementation were explored, either combined with other therapies or in fixed formulations with various biologically active compounds, such as vitamins and plant extracts. The results revealed notable improved outcomes attributed to the additive effects [34,35].
In this context, a new food supplement containing citicoline, combined with vitamin C derived from rosehip and extracts from green tea and aronia has recently been developed (Cytodeox™, Natstim Ltd., Sofia, Bulgaria). Although the health benefits of each ingredient are extensively studied, their effects within this particular combination remain unexplored.
Rosehips, the fruits of Rosa canina, are rich in bioactive compounds—carotenoids, polyphenols, tocopherols and vitamins [36,37,38]. This phytochemical profile gives it considerable antioxidant and anti-inflammatory properties [39,40,41]. Rosehip fruits are one of the richest sources of vitamin C in nature. In addition to being a powerful antioxidant, vitamin C performs a wide range of biological functions in the human body [42].
Green tea (Camellia sinensis) is rich in catechins, most notably epigallocatechin-3-gallate (EGCG) [43]. Further, systematic reviews and meta-analyses provided robust evidence that green tea supplementation significantly reduces TC and LDL-C while increasing HDL-C [44,45,46].
Aronia extract, derived from Aronia melanocarpa, is distinguished by its exceptionally high concentration of anthocyanins and other polyphenols [47]. This rich phytochemical profile contributes to its potent antioxidant activity and promising anti-atherogenic effects. Research indicates that aronia extract has hypoglycemic benefits, can mitigate inflammation, reduce blood pressure and positively influence lipid profiles, further supporting its role in cardiovascular health [48,49,50,51].
As mentioned earlier, lifestyle is recognised as a key factor in maintaining redox and lipid profile homeostasis. It is essential not only for prevention but also for effective management of many diseases [52,53]. The impact of lifestyle factors on the outcomes of citicoline supplementation is still not fully explored and remains largely unclear.
Our study aimed to evaluate the effects of Cytodeox™ on lipid profile and redox status in healthy volunteers after six months of supplementation, as well as to assess the influence of lifestyle factors on these effects.

2. Materials and Methods

2.1. Study Participants

Initially, 50 healthy volunteers (men/women = 13/37; mean age 52 ± 5.4) were recruited for this study based on specific inclusion and exclusion criteria. Exclusion criteria included being under 40 or over 65 years old, having neurological or malignant diseases, acute or chronic infectious and inflammatory conditions, serious comorbid somatic illnesses such as chronic kidney, liver, or gastrointestinal diseases, using plant extract supplements, or taking any medicine or supplement containing citicoline in the three months before or during the study. Additionally, known allergies to any ingredients contained in the study supplement and refusal to sign informed consent were grounds for exclusion.

2.2. Study Supplement

The study supplement (Cytodeox™) is a commercially available product (manufactured by Natstim Ltd., Sofia, Bulgaria) with ingredients per tablet, comprising: 250 mg citicoline, 150 mg natural vitamin C derived from 70% standardised fruit extract from rosehip (Rosa canina), 100 mg leaf extract from green tea (Camellia sinensis), and 30 mg fruit extract from aronia (Aronia melanocarpa).

2.3. Study Design and Intervention

The study was designed as a single-arm six-month pilot intervention with the nutritional supplement Cytodeox™ involving healthy adult volunteers. The enrolment of the volunteers occurred between March and June 2023, and the intervention took place between June and December 2023. At the baseline and end of the study, anthropometric and physical measurements of all participants were recorded, such as weight, height, waist and hip circumference and blood pressure. Fasting venous blood samples were also collected before and after the intervention. Before starting supplementation, all participants completed a questionnaire to evaluate their health status, lifestyle habits, and medication and nutritional supplement intake. All participants received the exact amount of Cytodeox™ required for the six-month supplementation, with instructions to take two tablets daily after meals. To evaluate the effect of the supplementation on the lipid profile and oxidative status, we compared the mean levels of the analysed biochemical parameters before and after the intervention for the entire group and by gender. A total of 43 participants (men/women = 12/31) completed the study, with seven dropping out for the following reasons: one for personal reasons, one due to gastrointestinal discomfort, and five due to illness.

2.4. Sample Size Calculation

The sample size was calculated based on the specified parameters for alpha, test power of 0.8, and a medium effect size of 0.5 using G-Power software v. 3.1.9.7. Initially, 50 participants were included in the study, considering the probability of dropout and the analysis by subcategories.

2.5. Lifestyle Variables

The lifestyle-related factors, such as alcohol consumption, smoking, and physical activity, for each participant were collected from the questionnaire before the intervention. BMI was calculated using the formula: weight in kilograms divided by the square of height in metres (kg/m2). Alcohol consumption was assessed by the number of alcohol units per week, with one unit equal to 10 mL or 8 g of pure alcohol according to the British Guidelines on alcohol consumption. Smoking habits and physical activity were also evaluated using the questionnaire. All participants were advised not to change their dietary or lifestyle habits during the intervention; no changes in BMI after the intervention were estimated.
To assess the impact of BMI and lifestyle habits on the response to supplementation, the volunteers were divided into different groups: normal weight (BMI ≤ 25, n = 18) and overweight (BMI > 25, n = 24), low alcohol consumption (<14 units/week, n = 23) and high alcohol consumption (>14 units/week, n = 7), smokers (n = 17) and non-smokers (n = 21), and those with low physical activity (<4 h/week, n = 20) and high physical activity (>4 h/week, n = 18).
All mean levels of the biochemical parameters for lipid profile and redox status were compared before and after the intervention in the total group and by gender. In addition, the corresponding p values were compared between the subgroups of related lifestyle factors.
The study adhered to the principles of the Declaration of Helsinki, and the study design, enrolment criteria, and all related documents received approval from the Research Ethics Committee at the Medical University of Varna (Protocol No 119/21.07.2022). All blood samples and questionnaires were collected after obtaining written informed consent from each participant enrolled in the study.

2.6. Biochemical Analyses

Fasting glucose and lipid profile parameters (TC, HDL-C, LDL-C, and TAG) were analysed using an automatic biochemical analyser Cobas 6000 (Hitachi High-Tech Corporation, Tokyo, Japan) in a certified clinical laboratory located in University Hospital St. Marina-Varna, Bulgaria. Analyses of MDA and TT were performed using colourimetric methods (absorbance was determined on SynergyTM 2 Microplate Reader, BioTek Instruments, Inc., Winooski, VT, USA). MDA was measured by its thiobarbituric acid (TBA, Loba Chemie PVT. Ltd., Mumbai, India, CAS No 504-17-6) reactivity in serum [54]. The results are expressed in nmol/mL. Ellman’s reagent was used to determine TT [55]. The thiol groups in the serum are oxidised by the sulfhydryl reagent 5,5’-dithio-bis(2-nitrobenzoic acid) (DTNB, Sigma Aldrich Co, St. Louis, MO, USA, CAS No 69-78-3) to produce the yellow derivative 5’-thio-2-nitrobenzoic acid (TNB), which can be measured at 412 nm. The results are shown in µmol/L. In addition to classical lipid profile parameters, the ratios between them were calculated: TC/HDL-C, LDL/HDL-C and TAG/HDL-C.

2.7. Statistical Analyses

Descriptive statistical analyses were employed to determine the mean levels of lipid profile and oxidative status parameters. The Kolmogorov–Smirnov (K-S) test was used to assess whether the data followed a normal or non-normal distribution across the groups. For groups with normal distributions, a paired t-test compared the mean parameter levels before and after Cytodeox™ supplementation. The Wilcoxon rank test was utilised to compare mean parameter levels in groups with non-normal distributions before and/or after the intervention. p values ≤ 0.05 were considered statistically significant. All statistical analyses were performed using GraphPad Prism 7.

3. Results

Table 1 summarises the results showing changes in lipid profile and redox status in the whole group and by gender due to the intervention.
Mean TC and LDL-C plasma levels decreased significantly after supplementation with Cytodeox™ in the overall group (Table 1). Although no changes were observed for HDL-C as a standalone parameter, the TC/HDL-C and LDL-C/HDL-C ratios significantly decreased following the intervention (p = 0.02 and p = 0.04, respectively). When stratified by gender, only LDL-C remained notably lower due to the intervention in the male subgroup. Conversely, in the female subgroup, there was a significant improvement in the lipid profile compared to men. The TAG/HDL-C ratio and Log[TAG/HDL-C] were also calculated to assess the Atherogenic index. Still, no statistically significant differences were observed after the intervention, neither in the overall group nor within the gender groups.
Significantly lower levels of MDA were observed after the intervention for the overall group and for both men and women. No changes were observed in TAG, glucose, and TT levels (Table 1).
The impact of BMI on lipid and oxidative stress parameters before and after Cytodeox™ supplementation is shown in Figure 1. It appears not to affect the influence of supplementation on the lipid profile, as there was an almost equal reduction in TC and LDL-C before and after the intervention in both normal and overweight groups (p > 0.05). However, the supplementation significantly reduces MDA (4 ± 1.7 nmol/mL before to 2.65 ± 1.5 nmol/mL after intervention, p = 0.002) and glucose levels (5.2 ± 0.5 mmol/L to 4.9 ± 0.4 mmol/L, p = 0.05) in normal-weight volunteers, but not in the overweight group (p > 0.05). No differences were observed before and after the intervention in HDL-C and TT levels in the normal or overweight groups.
As illustrated in Figure 2, alcohol intake does not affect the impact of Cytodeox™ supplementation on the lipid profile, as both groups show a similarly significant reduction in TC and LDL-C levels (p < 0.05). Although not statistically significant (p = 0.07), a trend towards a decrease was observed in LDL-C levels in the high alcohol consumption group. The MDA levels decreased significantly only in the low alcohol consumption group after the intervention (p < 0.05), compared to the high regular alcohol consumption group (p > 0.05), confirming that alcohol hampers the supplementation’s effect on oxidative stress. No differences were seen before and after the intervention for HDL-C, TT and glucose levels in either the high or low alcohol consumption groups.
Figure 3 presents the effect of smoking on nutraceutical supplementation before and after the intervention on the lipid and oxidative stress parameters.
As shown in Figure 3, mean levels of TC, LDL-C, and MDA significantly decreased in the non-smoker group (p < 0.05), while in smokers, these parameters remained unchanged (p > 0.05). No differences were observed before and after the intervention for HDL-C, TT, and glucose levels in both smokers and non-smokers.
Finally, we explored the impact of physical activity on the effect of the Cytodeox™ supplementation. The results are presented in Figure 4.
The assessment of lipid profile parameters and redox status in the physical activity subgroups revealed a favourable change in the lipid profile within the sedentary group, demonstrated by a significant reduction in TC (p = 0.01) and LDL-C (p = 0.03) levels, along with decreased MDA levels. Interestingly, the plasma levels of TT in this group also declined significantly after intervention (p = 0.02). In contrast, no statistically significant changes were observed in the high physical activity group, neither in the lipid profile nor in the redox status parameters. However, a trend towards a decrease in MDA was observed in the physical activity group (n = 0.07). Additionally, no differences were found in HDL-C or glucose levels after the intervention across physical and non-physical activity groups.
The changes in non-traditional lipid profile parameters were calculated for all groups classified by lifestyle factors. Results are summarised in Table 2:
The table shows that the significantly reduced TC/HDL-C ratio was calculated for the overweight group (p = 0.02). Similar results were obtained for groups based on alcohol consumption and sedentarism (p = 0.03 for both groups). Additionally, for the group with regular alcohol consumption, the LDL-C/HDL-C ratio was also significantly lower after the intervention (p = 0.04).

4. Discussion

The study aimed to investigate how different lifestyle factors affect the outcomes of a supplement that combines citicoline and plant extracts (Cytodeox™) over a six-month period involving healthy volunteers. Participants were categorised based on their lifestyle as reported in the pre-intervention questionnaires. Serum levels of lipid profile parameters, MDA, TT and fasting glucose were measured before and after the intervention.
Diet and lifestyle can significantly affect lipid profiles and redox status, which are indicators of the development and progression of various diseases, such as cardiovascular and metabolic disorders [19,56]. Furthermore, poor lifestyle habits like smoking, high alcohol consumption, and a sedentary lifestyle can impair responses to medications and supplementations, reducing the probability of successful outcomes [57].
According to our results, the six-month intervention with Cytodeox™ significantly improved the lipid profile parameters demonstrated by significantly reduced TC and LDL-C levels in the overall group. Regarding gender, LDL-C decreased substantially in both men and women, but TC did not change in men and was lower in women. It should be noted that these changes are within the reference range, as the participants in our study were healthy, with no abnormalities in the baseline lipid profile. However, these results demonstrate the potential of Cytodeox™ to improve the lipid profile, and it can be expected that when administered to patients with dyslipidemia, either alone or alongside basic therapy, it would contribute to better treatment outcomes.
In addition to traditional lipid parameters, the effect of Cytodeox™ on the TC/HDL-C and LDL-C/HDL-C ratios was also assessed, showing significantly lower values for both indices, indicating an improved lipid profile and reduced cardiovascular risk. After stratifying by gender, only the TC/HDL-C ratio was significantly lower in females. No other differences in non-traditional parameters were observed in either subgroup.
Dyslipidemia is characterised by elevated plasma TC, LDL-C, TAG and decreased HDL-C levels. These traditional lipid parameters are usually regarded as modifiable risk factors for CVD and ischaemic stroke. Furthermore, non-traditional lipid indices, such as TC/HDL-C and LDL-C/HDL-C ratios, are found to be better predictive factors for CVD than individual lipid parameters [7]. Some authors suggest that parameters of non-traditional lipid profiles have significant prognostic value for identifying predisposition to ischaemic stroke [8]. In addition, their role as risk predictors should be considered depending on gender, age, morbidity, and medications [58,59].
Lipid-lowering therapies reduce TAG, TC, and LDL-C levels, lowering the risk of vascular events. Several new strategies for managing dyslipidemia have been discussed in recent years, in addition to the well-known statins [8,60,61].
The supplement used in this pilot study contains several active ingredients, such as citicoline, green tea and aronia extracts, and natural vitamin C extracted from rose hip. Although citicoline does not directly influence lipid profile parameters like TAG and TC, its role in phospholipid metabolism can indirectly affect the overall lipid environment within cells and tissues [62]. Furthermore, citicoline reduces lipid peroxidation, which may help improve redox status, an essential factor in regulating LDL-C levels [63].
Unlike citicoline, the direct effects of green tea on lipid profiles are well documented. In addition to numerous interventional studies showing the benefits of daily green tea consumption on lipid profiles [44,64,65], many experimental studies reveal the mechanisms behind these effects, attributed to the catechins contained in green tea. Thanks to their antioxidant effects, green tea polyphenols, particularly catechins, help maintain a favourable redox environment, thereby protecting LDL particles from oxidation. In an experimental dyslipidemia model, catechins stimulate liver LDL receptors, contributing to the clearance of these lipoprotein complexes from the blood [66,67]. Studies have also indicated that catechins can influence overall lipid production and accumulation by inhibiting the differentiation and proliferation of preadipocytes, promoting lipolysis, and reducing intestinal cholesterol absorption [67,68,69].
In addition to the green tea extract, aronia fruit extracts have beneficial effects similar to those of green tea. The most abundant group of flavonoids in aronia fruits are anthocyanins, recognised as potent antioxidants. Although they target different molecular pathways, anthocyanins, similar to catechins, have been shown to exert anti-obesity and anti-dyslipidemic effects by inhibiting enzymes and transcription factors responsible for lipogenesis [70]. Besides these effects, both green tea and aronia extracts can lower leptin and increase adiponectin levels, as seen in vitro in preadipocyte cell culture and obese individuals, thereby contributing to reducing appetite and improving insulin sensitivity and glucose tolerance [70,71,72,73].
Based on these data, we can assume that the effect of Cytodeox™ on the lipid profile is due to the cumulative effect of all ingredients.
Besides the positive effects of the Cytodeox™ supplementation on the lipid profile, the antioxidant potential was also revealed in this study. Malondialdehyde was one of the markers used in our study to evaluate the antioxidant effects of the supplement. MDA has been widely utilised as a byproduct of lipid peroxidation as a marker for assessing oxidative stress. Lipid peroxidation is a free radical-cascade of reactions preferentially affecting polyunsaturated fatty acids in membrane phospholipids. The propagation of peroxyl radicals generates reactive aldehydes that can dramatically change the oxidative status of the cells [74,75]. Based on this, elevated MDA levels have been linked to various pathological conditions, such as diabetes, autoimmune diseases, inflammatory conditions and ischemic stroke [76,77,78,79]. Furthermore, MDA has been recognised as a reliable indicator for evaluating the effectiveness of antioxidant therapies [80].
As shown in the Section 3, MDA levels measured in this study significantly decreased after six months of supplementation with Cytodeox™ for the entire group and all subgroups classified by gender and lifestyle factors.
We can assume that all ingredients in Cytodeox™—citicoline and the plant extracts—contribute to these beneficial effects. The potential of citicoline to effectively reduce MDA levels has been demonstrated in various studies, including human interventional studies and experimental models of neurodegenerative diseases and brain injury [63,81,82]. This is believed to be one of the effects of citicoline that contributes to its neuroprotective potential. Preventing membrane lipid peroxidation is vital for maintaining neuronal integrity, particularly in conditions such as cerebral ischaemia where oxidative stress is critical [83]. In addition to citicoline, green tea and aronia extracts or active compounds isolated from the plants can improve the oxidative balance by reducing oxidative stress markers such as MDA and, at the same time, upregulate the endogenous antioxidants, such as reduced glutathione and antioxidant enzymes which neutralise lipid peroxides [50,84,85]. Finally, vitamin C, as a powerful exogenous antioxidant, may prevent lipid peroxidation, thus decreasing the MDA levels [38,86].
The positive effect of Cytodeox™ on the conventional lipid profile reported for the whole group was not confirmed in the BMI groups in our study. However, evaluating the ratios between lipid parameters revealed significantly reduced TC/HDL-C ratio in the overweight group, showing the supplement’s potential to reduce the cardiovascular risk in overweight individuals.
The antioxidant effect of the supplementation is manifested only in the group with BMI < 25 but not in the overweight group. These results are consistent with other studies indicating that higher serum levels of MDA and lower non-enzymatic antioxidants are associated with obesity [87,88]. Since overweight is linked to the accumulation of adipose tissue, which can significantly alter redox homeostasis, improving diet and reducing BMI should be recommended alongside Cytodeox™ supplementation.
In addition to its antioxidant effect, a positive impact of the supplement was observed on blood glucose levels, but only in the normal-weight group. It is known that there is a negative association between high BMI and insulin sensitivity at the receptor level, which decreases glucose tolerance and increases the risk of type 2 diabetes and metabolic syndrome [89]. Conversely, studies suggest that anthocyanin extracts present in aronia upregulate the gene expression of GLUT4 in muscles and adipose tissue, enhancing the hypoglycaemic effect of insulin [48]. A significant reduction in glucose levels following green tea intake was also reported, indicating that it may improve adipocyte glucose uptake capability and increase GLUT4 content in rat adipocytes [90,91]. In our study, the BMI appears to influence the effect of supplementation on glucose tolerance. We can conclude that treatment with this nutraceutical supplement is more likely to enhance glucose tolerance among individuals with a normal BMI.
Regular alcohol consumption is recognised as a risk factor for CVD and metabolic disorders, overweight and obesity [18]. However, in our study alcohol consumption did not appear to affect the beneficial effects of the supplement on the lipid profile observed in the overall group. TC and LDL-C levels decreased significantly after the intervention, nearly equally in both groups classified by alcohol intake. Interestingly, the cardiovascular risk indices TC/HDL-C and LDL-C/HDL-C were significantly reduced in the group that frequently consumed alcohol. Since the participants in this group are healthy and not alcohol-dependent, their reported alcohol consumption can be considered moderate. Depending on the amount, frequency, and type of alcohol consumed, it can have hormetic physiological effects. Low-to-moderate alcohol intake may be linked to a reduced risk of coronary heart disease, partly because moderate alcohol consumption can increase HDL cholesterol levels [92]. However, other factors such as sex, age, and health status should also be considered when assessing health risks. Ethanol metabolism involves several pathways with different enzymes; one of them uses the liver-inducible enzyme cytochrome P450 2E1 (CYP2E1). Regular alcohol consumption leads to increased activity of the CYP2E1 which generates ROS that in turn would increase MDA production [93]. In this aspect, our results only manifest the positive effect of the Cytodeox™ supplementation by a significant decrease in the MDA levels only in the low alcohol consumption group, but not in the high alcohol consumption group.
In contrast to alcohol consumption, the results of this study indicate that smoking adversely affects the Cytodeox™ effect on lipid profile and redox status. The beneficial effects of the supplement observed across the entire group were confirmed only in the non-smokers subgroup.
Smoking is recognised to disrupt lipid metabolism and severely impair the redox balance [94]. Toxins in cigarette smoke hinder reverse cholesterol transport by affecting key enzymes such as lecithin-cholesterol acyltransferase and cholesterol ester transfer protein, leading to lower levels of HDL-C and a loss of its atheroprotective functions [95]. Smoking is considered one of the most harmful habits, increasing cardiovascular risk as it is closely associated with elevated levels of TAG and LDL-C [96,97].
Cigarette smoke contains more than 4000 chemicals that are able to generate ROS, increasing oxidative stress and carcinogenic effects [98]. The higher oxidative stress in smokers decreases the total antioxidant capacity, leading to a redox imbalance compared to non-smokers [98,99]. In this aspect, our results confirm the decrease in the total antioxidant capacity in smokers due to the non-significant decrease in MDA after the supplementation, compared to the non-smokers, where the MDA was reduced significantly. However, it should be noted that even without a significant reduction in MDA in smokers, we have a high tendency towards a decrease in MDA in this group, which is close to the significance limit. This indicates that, even with the overall negative impact of smoking, the positive antioxidant effects of Cytodeox™ are still manifested to some extent, suggesting the contribution of plant antioxidants contained in the supplement.
Regular physical activity is considered a healthy lifestyle habit, contributing to improved lipid profiles and reduced risk of CVD and metabolic disorders [19]. However, there are notable individual differences in how physical activity affects the lipid profile. Factors such as the type, duration, and intensity of exercise, as well as age and sex, can influence levels of specific markers, including lipid parameters [100]. Furthermore, it has been reported that HDL-C responds more to exercise than LDL-C and TAG [16].
In groups stratified by physical activity in this study, significantly reduced TC and LDL-C levels were observed due to supplementation with Cytodeox™ but only for participants with a sedentary lifestyle (NP group). In addition to conventional lipid parameters, the ratio TC/HDL-C in the same group was significantly lowered, suggesting a reduced cardiovascular risk after six months of supplementation. However, in line with other studies [16,17], volunteers who reported a physically active lifestyle in this study (P group) had higher initial HDL-C levels compared to the NP group.
Regarding the effect of supplementation on redox status, a notable beneficial effect was observed in the NP group, evidenced by significantly lower MDA levels. An unexpected result was the reduced TT levels in the same group, with no significant differences in either marker for the P group. It can be suggested that MDA is a more sensitive marker to supplementation than TT. On the other hand, decreased thiol groups indicate a lower plasma antioxidant capacity [101].
The thiols containing plasma compounds are proteins, such as albumins, as well as low molecular weight amino acids and peptides, such as cystein, cysteinylglisin, homocystein, glutathione and γ-glutamylcystein, which could form disulfide bonds due to oxidative stress. The primary role of thiol groups as endogenous antioxidants is well-documented, with their depletion indicating a compromised redox status in various metabolic disorders and pathological conditions. The sedentary lifestyle can contribute to increased oxidative stress and in this context it is recognised as a risk factor for CVD and metabolic disorders [102]. In accordance to our results, other studies have reported that impaired thiol homeostasis strongly correlates with sedentary lifestyle [14,103]. In addition, endothelial and mitochondrial dysfunction in sedentary individuals was reported due to enhanced ROS generation and decreased effectiveness of endogenous antioxidant systems [104,105]. It could be suggested that the compromised redox status in sedentary individuals may lead to increased utilisation of TT.
Unlike other factors such as alcohol consumption and smoking, daily physical activity in non-athletes includes various activities like walking, cycling, aerobics, yoga, gardening, and others. Due to this diversity and possibly the sample size in the stratification, the improvements in the lipid profile and the reduced MDA levels in the overall group were not confirmed in the P group. Simultaneously, better outcomes were observed in the sedentary group, such as an improved lipid profile and a lower risk of lipid peroxidation, suggesting the potential of the supplement to positively influence lipid dysregulation and redox homeostasis. However, these findings, although promising, were achieved immediately after the intervention, and it remains unclear how sustainable they are over time without subsequent lifestyle improvements.

5. Conclusions

This pilot study demonstrates, for the first time, the effect of a new dietary supplement containing citicoline and plant extracts on lipid and redox status in healthy subjects. The results strongly suggest that six months of supplementation with Cytodeox™ can improve the lipid profile and redox status in healthy individuals. Additionally, the supplementation could have beneficial effects even in overweight and sedentary individuals, but these effects may be reduced in smokers. In this context, the supplementation should be combined with an improved diet, smoking cessation, and regular physical activity to sustain these positive outcomes over the long term. Furthermore, these findings will enhance understanding of how the ingredients in the supplement positively influence human health and their potential to act cumulatively in combined formulations. The results of this pilot study will serve as a starting point for subsequent long-term research to evaluate the sustainability of the effects in larger groups of participants, including patients with CVD and stroke.

6. Study Limitations

This pilot study has some limitations. The absence of a placebo group for comparison makes it difficult to formulate general conclusions about the effects of the supplement on the lipid profile and markers of redox status. The time and the budget of the study were limited factors for manufacturing a placebo formulation. Another limitation was the lack of similar studies with combined supplements. When correlating the results obtained in our research, we can refer to data on the biological effects of the individual ingredients, but not in combination, which prevents us from considering possible synergistic effects.

Author Contributions

Conceptualization, M.N.; methodology, M.N.; software, B.R.; validation, M.N., B.R. and T.S.; formal analysis, B.R. and M.N.; investigation, M.N., D.V. and M.N.N.; writing—original draft preparation, M.N., B.R., T.S. and D.V.; writing—review and editing, M.N. and D.I.; visualisation, B.R.; supervision, M.N.; project administration, M.N.; funding acquisition, M.N. and D.I. All authors have read and agreed to the published version of the manuscript.

Funding

This study was supported by European Union-NextGenerationEU, through the National Recovery and Resilience Plan of the Republic of Bulgaria, project No. BG-RRP-2.004-0009-C02 (MUVE-TEAM project) and Medical University of Varna, Science Fund, Project 21015.

Institutional Review Board Statement

The study was conducted according to the principles of the Declaration of Helsinki and approved by The Research Ethics Committee at the Medical University “Prof. Dr. Paraskev Stoyanov”—Varna (protocol number 119, 21 July 2022).

Informed Consent Statement

Informed consent was obtained from all subjects involved in the study to publish this paper.

Data Availability Statement

The original contributions presented in this study are included in the article. Further inquiries can be directed to the corresponding author.

Acknowledgments

The authors acknowledge Yoana-Kiselova-Kaneva for her valuable support in administering the MUVE-TEAM Project.

Conflicts of Interest

The authors declare no conflicts of interest.

Abbreviations

The following abbreviations are used in this manuscript:
BMIBody mass index
CVDCardiovascular disease
HDL-CHigh-density lipoprotein cholesterol
LDL-CLow-density lipoprotein cholesterol
MDAMalondialdehyde
NCDsNoncommunicable diseases
ROSReactive oxygen species
TAGTriacylglycerols
TCTotal cholesterol
TTTotal thiols

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Figure 1. Impact of BMI on lipid profile and oxidative stress parameters before and after six-month supplementation. TC: total cholesterol; LDL-C: LDL-cholesterol; MDA: malonedialdehyde; BMI: body mass index; statistical significance was set at p ≤ 0.05 (when comparing variables before and after the intervention in the subgroup); ns—non-significant differences in variables before and after the intervention.
Figure 1. Impact of BMI on lipid profile and oxidative stress parameters before and after six-month supplementation. TC: total cholesterol; LDL-C: LDL-cholesterol; MDA: malonedialdehyde; BMI: body mass index; statistical significance was set at p ≤ 0.05 (when comparing variables before and after the intervention in the subgroup); ns—non-significant differences in variables before and after the intervention.
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Figure 2. Impact of alcohol consumption on lipid profile and oxidative stress parameters before and after six-month supplementation. TC: total cholesterol; LDL-C: LDL-cholesterol; MDA: malondialdehyde; statistical significance was set at p ≤ 0.05 (when comparing variables before and after the intervention in the subgroup); ns—non-significant differences in variables before and after the intervention.
Figure 2. Impact of alcohol consumption on lipid profile and oxidative stress parameters before and after six-month supplementation. TC: total cholesterol; LDL-C: LDL-cholesterol; MDA: malondialdehyde; statistical significance was set at p ≤ 0.05 (when comparing variables before and after the intervention in the subgroup); ns—non-significant differences in variables before and after the intervention.
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Figure 3. Impact of smoking on lipid profile and oxidative stress parameters before and after six-month supplementation. TC: total cholesterol; LDL-C: LDL-cholesterol; MDA: malondialdehyde; NS: non-smokers; S: smokers; statistical significance was set at p ≤ 0.05 (when comparing variables before and after the intervention in the subgroup); ns—non-significant differences in variables before and after the intervention.
Figure 3. Impact of smoking on lipid profile and oxidative stress parameters before and after six-month supplementation. TC: total cholesterol; LDL-C: LDL-cholesterol; MDA: malondialdehyde; NS: non-smokers; S: smokers; statistical significance was set at p ≤ 0.05 (when comparing variables before and after the intervention in the subgroup); ns—non-significant differences in variables before and after the intervention.
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Figure 4. Impact of physical activity on lipid profile and oxidative stress parameters before and after six-month supplementation. TC-NP: total cholesterol in non-physical activity group; TC-P: total cholesterol in physical activity group LDL-NP: LDL-cholesterol in non-physical activity group; LDL-P: LDL-cholesterol in physical activity group; MDA-NP: malondialdehyde in non-physical activity group; MDA-P: malondialdehyde in physical activity group; TT-NP: total thiols in non-physical activity group; TT-P: total thiols in physical activity group; statistical significance was set at p ≤ 0.05 (when comparing variables before and after the intervention in the subgroup); ns—non-significant differences in variables before and after the intervention.
Figure 4. Impact of physical activity on lipid profile and oxidative stress parameters before and after six-month supplementation. TC-NP: total cholesterol in non-physical activity group; TC-P: total cholesterol in physical activity group LDL-NP: LDL-cholesterol in non-physical activity group; LDL-P: LDL-cholesterol in physical activity group; MDA-NP: malondialdehyde in non-physical activity group; MDA-P: malondialdehyde in physical activity group; TT-NP: total thiols in non-physical activity group; TT-P: total thiols in physical activity group; statistical significance was set at p ≤ 0.05 (when comparing variables before and after the intervention in the subgroup); ns—non-significant differences in variables before and after the intervention.
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Table 1. Lipid profile and antioxidant status before and after the nutraceutical supplementation.
Table 1. Lipid profile and antioxidant status before and after the nutraceutical supplementation.
Total Group (n = 43)
MarkersBefore Intervention (Mean ± SD)After Intervention (Mean ± SD)p ValueStatistical Method
TC (mmol/L)5.6 ± 1.15.3 ± 1.1 *0.02Paired t-test
LDL-C (mmol/L)3.4 ± 13.2 ± 0.9 *0.02Wilcoxon
HDL-C (mmol/L)1.7 ± 0.51.6 ± 0.5nsWilcoxon
TC/HDL-C3.6 ± 1.23.5 ± 1.1 *0.02Wilcoxon
LDL-C/HDL-C2.2 ± 0.92.1 ± 0.80.04Paired t-test
TAG (mmol/L)1.2 ± 0.81.2 ± 0.6nsWilcoxon
Glucose (mmol/L)5.3 ± 0.55.2 ± 0.6nsPaired t-test
MDA (nmol/mL)3.6 ± 1.42.9 ± 1.5 *0.003Wilcoxon
TT (µmol/L)357.4 ± 45.9348.5 ± 41.5nsPaired t-test
Men (n = 12)
TC (mmol/L)5.7 ± 1.25.5 ± 1.1nsPaired t-test
LDL-C (mmol/L)3.7 ± 1.13.6 ± 0.9 *0.03Paired t-test
HDL-C (mmol/L)1.4 ± 0.21.3 ± 0.2nsPaired t-test
TC/HDL-C4.4 ± 1.34.2 ± 1nsWilcoxon
LDL-C/HDL-C2.8 ± 12.6 ± 0.8nsWilcoxon
TAG (mmol/L)1.5 ± 11.3 ± 0.6nsWilcoxon
Glucose (mmol/L)5.6 ± 0.65.5 ± 0.5nsPaired t-test
MDA (nmol/mL)3.4 ± 1.22.7 ± 1.2 *0.04Wilcoxon
TT (µmol/L)355.2 ± 51.2360.5 ± 31.4nsPaired t-test
Women (31)
TC (mmol/L)5.5 ± 1.15.3 ± 1.3nsPaired t-test
LDL-C (mmol/L)3.2 ± 13 ± 0.9 *0.05Wilcoxon
HDL-C (mmol/L)1.8 ± 0.51.76 ± 0.57nsWilcoxon
TC/HDL-C3.3 ± 1.13.2 ± 1 *0.05Wilcoxon
LDL-C/HDL-C2 ± 0.81.8 ± 0.7nsWilcoxon
TAG (mmol/L)1.2 ± 0.71.1 ± 0.6nsWilcoxon
Glucose (mmol/L)5.2 ± 0.45.2 ± 0.7nsWilcoxon
MDA (nmol/mL)3.8 ± 1.53.1 ± 1.7 *0.02Wilcoxon
TT (μmol/L)356.8 ± 44.8344.1 ± 44.3nsPaired t-test
* Statistical significance was set at p ≤ 0.05 (when comparing variables before and after the intervention in the subgroup); ns—non-significant differences in variables before and after the intervention.
Table 2. Non-traditional lipid parameters before and after the intervention with Cytodeox™ in groups classified by lifestyle variables.
Table 2. Non-traditional lipid parameters before and after the intervention with Cytodeox™ in groups classified by lifestyle variables.
TC/HDL-C LDL-C/HDL-C
Lifestyle Variable GroupsBeforeAfterpBeforeAfterp
BMI < 253.27 ± 1.323.18 ± 1.08ns1.99 ± 1.101.77 ± 0.76ns
BMI > 253.88 ± 1.143.71 ± 1.02 *0.022.37 ± 0.832.26 ± 0.78ns
Alcohol
<14 units/week		3.54 ± 0.933.41 ± 0.900.092.11 ± 0.642.00 ± 0.65ns
Alcohol
>14 units/week 		4.11 ± 1.633.58 ± 1.25 *0.032.67 ± 1.322.22 ± 0.99 *0.04
Non-smokers3.19 ± 0.793.10 ± 0.70ns1.90 ± 0.691.81 ± 0.59ns
Smokers3.83 ± 1.393.59 ± 1.14ns2.34 ± 1.022.14 ± 0.84ns
Non-physical
activity		3.64 ± 1.013.50 ± 0.89 *0.032.17 ± 0.722.08 ± 0.64ns
Physical activity3.31 ± 1.263.12 ± 0.98ns2.01 ± 1.061.82 ± 0.82ns
* Statistical significance was set at p ≤ 0.05 (when comparing variables before and after the intervention in the subgroup); ns—non-significant differences in variables before and after the intervention.
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Roussev, B.; Sokrateva, T.; Vankova, D.; Nikolova, M.N.; Ivanova, D.; Nashar, M. Effect of a Citicoline-Containing Supplement on Lipid Profile and Redox Status in Healthy Volunteers in Relation to Lifestyle Factors. Appl. Sci. 2025, 15, 10512. https://doi.org/10.3390/app151910512

AMA Style

Roussev B, Sokrateva T, Vankova D, Nikolova MN, Ivanova D, Nashar M. Effect of a Citicoline-Containing Supplement on Lipid Profile and Redox Status in Healthy Volunteers in Relation to Lifestyle Factors. Applied Sciences. 2025; 15(19):10512. https://doi.org/10.3390/app151910512

Chicago/Turabian Style

Roussev, Bogdan, Todorka Sokrateva, Daniela Vankova, Miglena N. Nikolova, Diana Ivanova, and Milka Nashar. 2025. "Effect of a Citicoline-Containing Supplement on Lipid Profile and Redox Status in Healthy Volunteers in Relation to Lifestyle Factors" Applied Sciences 15, no. 19: 10512. https://doi.org/10.3390/app151910512

APA Style

Roussev, B., Sokrateva, T., Vankova, D., Nikolova, M. N., Ivanova, D., & Nashar, M. (2025). Effect of a Citicoline-Containing Supplement on Lipid Profile and Redox Status in Healthy Volunteers in Relation to Lifestyle Factors. Applied Sciences, 15(19), 10512. https://doi.org/10.3390/app151910512

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