Search Results (109)

Fibromyalgia is a complex disorder characterized by chronic widespread pain and a variety of related symptoms. Growing evidence suggests that the central and peripheral nervous systems are involved, with small fiber neuropathy playing a key role in its development. We retrospectively reviewed the medical records of 100 patients diagnosed with primary fibromyalgia. Those showing symptoms indicative of small fiber dysfunction who were treated with L-Acetyl Carnitine (LAC) and Palmitoylethanolamide (PEA) alongside standard care (SOC) were compared to matched controls who received only SOC. To ensure comparable groups, propensity score matching was used. Changes in Fibromyalgia Impact Questionnaire Revised (FIQR) scores over 12 weeks were analyzed using non-parametric tests due to the data’s non-normal distribution. After matching, 86 patients (43 in each group) were included. The group receiving LAC and PEA as add-on therapy experienced a significant median reduction in FIQR scores (−19.0 points, p < 0.001), while the SOC-only group showed no significant change. Comparisons between groups confirmed that the improvement was significantly greater in the LAC+PEA group (p < 0.001). These results suggest that adding LAC and PEA to standard care may provide meaningful symptom relief for fibromyalgia patients with suspected small fiber involvement. This supports the hypothesis that peripheral nervous system dysfunction contributes to the disease burden in this subgroup. However, further prospective controlled studies are needed to confirm these promising findings. Full article

Background: The blood–brain barrier (BBB) plays a critical role in protecting the central nervous system (CNS) but also limits drug delivery. Insufficient knowledge of how the CNS promotes the onset and maintenance of peripheral neuropathic pain limits therapeutic methods for the treatment of persistent neuropathic pain. Thus, this study aimed to evaluate the ability of a novel combination of Palmitoylethanolamide (PEA) and Equisetum arvense L. (Equisetum A.L.) to cross the BBB and modulate nociceptive pathways. Methods: Using a humanised in vitro BBB tri-culture model, the permeability, cytotoxicity, and integrity of the barrier were assessed after exposure to two different PEA forms, PEA ultramicronized (PEA-um) and PEA80mesh, Equisetum A.L., and a combination of the last two samples. The samples exhibited no cytotoxicity, maintained tight junction integrity, and efficiently crossed the blood–brain barrier (BBB), with the combination displaying the highest permeability. The eluate from the BBB model was then used to stimulate the co-culture of CCF-STTG1 astrocytes and SH-SY5Y neurons pre-treated with H₂O₂ 200 µM. Results: Treatment with the combination significantly increased cell viability (1.8-fold, p < 0.05), reduced oxidative stress (2.5-fold, p < 0.05), and decreased pro-inflammatory cytokines (TNFα, IL-1β) compared to single agents. Mechanistic analysis revealed modulation of key targets involved in pain pathways, including decreased FAAH and NAAA activity, increased levels of endocannabinoids (AEA and 2-AG), upregulation of CB2 receptor expression, enhanced PPARα activity, and reduced phosphorylation of PKA and TRPV1. Conclusions: These findings suggest that the combination of PEA and Equisetum A.L. effectively crosses the BBB and exerts combined anti-inflammatory and analgesic effects at the CNS level, suggesting a possible role in modulating neuroinflammatory and nociception responses. Full article

Palmitoylethanolamide (PEA) is an endogenous lipid mediator belonging to the N-acyl-ethanolamine family, widely recognized for its multifaceted effects on neuroprotection, chronic pain management, and immune modulation. As a naturally occurring compound, PEA plays a crucial role in maintaining homeostasis under conditions of cellular stress and inflammation. Its pharmacological effects are primarily mediated through peroxisome proliferator-activated receptor-alpha (PPAR-α) activation, alongside indirect modulation of cannabinoid receptors CB1 and CB2, as well as interactions with novel targets such as GPR55 and TRPV1. These molecular mechanisms underpin its broad therapeutic potential, particularly in the management of neuroinflammatory and neurodegenerative disorders, pain syndromes, and immune dysregulation. A major advancement in PEA research has been the development of ultramicronized palmitoylethanolamide (umPEA), which significantly enhances its bioavailability and therapeutic efficacy by facilitating better tissue absorption and interaction with key molecular pathways. Preclinical and clinical studies have demonstrated that umPEA is particularly effective in reducing neuroinflammation, stabilizing mast cells, and enhancing endocannabinoid system activity, making it a promising candidate for integrative approaches in neuropsychiatric and chronic inflammatory diseases. Given its well-established safety profile, umPEA represents an attractive alternative or adjunct to conventional anti-inflammatory and analgesic therapies. This communication provides a comprehensive overview of the mechanisms of action and therapeutic applications of both PEA and umPEA, emphasizing their emerging role in clinical practice and personalized medicine. Full article

Background: Metabolic syndrome (MetS) patients have impaired hypothalamic regulatory functions involved in food intake and energy expenditure and suffer from a state of meta-inflammation. Pre-clinical studies demonstrated that ultramicronized palmitoylethanolamide (PEA) acts both on the adipose tissue and the central nervous system, while hydroxytyrosol (HTyr) counteracts several types of dysmetabolism. Objectives: The aim of our randomized crossover double-blind placebo-controlled pilot study was to evaluate the potential effects of a food supplement (FS) containing a co-micronized formulation of PEA and rutin along with HTyr, combined with a tailored calorie-controlled Mediterranean diet, in patients with MetS. Methods: Nineteen patients were enrolled and block-randomized to an eight-week MD together with the FS or placebo. After a two-week washout period, the treatments were reversed. Data on laboratory parameters and those detected by capillary sampling, anthropometry, body composition analysis, ultrasound examination, blood pressure monitoring, the 36-Item Short-Form Health Survey questionnaire, handgrip strength test, and physical performance tests were collected at each time point (protocol code R.S. 262.22, registered on 20 December 2022). Results: At the end of the study, patients supplemented with the FS showed a significant reduction in body weight, body mass index, fat mass, and inflammation biomarkers (CRP and ESR), compared to placebo-supplemented patients. In contrast, the fat-free mass, phase angle, and body cell mass were increased in FS compared to placebo patients. Conclusions: Although preliminary, the results of our clinical study suggest that co-micronized PEA–rutin and HTyr may be of help against adiposopathy in patients with MetS. Full article

Background: Chemotherapy-induced peripheral neuropathy (CIPN) from oxaliplatin and taxane drugs is a bothersome toxicity. Palmitoylethanolamide (PEA) has been reported to improve myelinated nerve fiber function in patients experiencing painful CIPN. We conducted a double-blind, placebo-controlled, randomized trial of PEA in patients with established CIPN. Methods: Eligible patients were adults who had pain, numbness, tingling, or other symptoms of CIPN for at least three months following completion of paclitaxel, oxaliplatin, or cisplatin-based chemotherapy. Study patients were randomized to one of the two treatment groups (PEA versus placebo, both administered either once or twice daily). The CIPN20 questionnaire was assessed weekly. Results: A total of 17 males and 71 females participated in the study; most had neuropathy from paclitaxel. Most (85%) finished 8 weeks of treatment. There was no suggestion that either of the PEA arms did any better than the combined placebo arms. There was no signal of significant toxicity differences between the three study arms. Quality of life outcome measures were similar between the study arms, as were cognitive function evaluations. Discussion: PEA failed to improve established CIPN. Future trials might explore whether PEA may be effective in preventing CIPN or cognitive changes based on data that suggest it may be helpful in this situation. Conclusions: PEA failed to improve established chemotherapy-induced neuropathy. Full article

Menopause leads to a decline in estrogen levels, resulting in significant metabolic alterations that increase the risk of developing metabolic syndrome—a cluster of conditions including central obesity, insulin resistance, dyslipidemia, and hypertension. Traditional interventions such as hormone replacement therapy carry potential adverse effects, and lifestyle modifications alone may not suffice for all women. This review explores the potential role of palmitoylethanolamide (PEA), an endogenous fatty acid amide, in managing metabolic syndrome during the postmenopausal period. PEA primarily acts by activating peroxisome proliferator-activated receptor-alpha (PPAR-α), influencing lipid metabolism, energy homeostasis, and inflammation. Evidence indicates that PEA may promote the browning of white adipocytes, enhancing energy expenditure and reducing adiposity. It also improves lipid profiles by boosting fatty acid oxidation and decreasing lipid synthesis, potentially lowering low-density lipoprotein cholesterol and triglyceride levels while increasing high-density lipoprotein cholesterol. Additionally, the anti-inflammatory properties of PEA enhance insulin sensitivity by reducing pro-inflammatory cytokines that interfere with insulin signaling. PEA may aid in weight management by influencing appetite regulation and improving leptin sensitivity. Furthermore, its neuroprotective effects may address the mood disturbances and cognitive decline associated with menopause. Given these multifaceted biological activities and a favorable safety profile, PEA may represent a promising non-pharmacological supplement for managing metabolic syndrome in postmenopausal women. However, further large-scale clinical studies are necessary to establish its efficacy, optimal dosing, and long-term safety. If validated, PEA could become an integral part of strategies to improve metabolic and neuropsychological health outcomes in this population. Full article

To date, no psychotropic medication has shown to effectively halt progression to psychosis among individuals at Clinical High-Risk for psychosis (CHR), fueling the search for novel therapeutic agents. Recent evidence supports Palmitoylethanolamide (PEA) signaling as a potential psychosis biomarker, also indicating a therapeutic role for its supplementation in the treatment of psychotic disorders. Nonetheless, the effect of sustained PEA intake in CHR subjects has never been explored so far. We will assess the feasibility of enrolling 20 CHR young adults presenting with attenuated psychotic symptoms (APS) in a 12-week, open-label, investigator-initiated, proof-of-concept, single-arm trial of ultramicronized-PEA (um-PEA) 600 mg/day. Once completed the 12-week phase, participants will be proposed to enter a 24-week extension phase of the study. We will examine um-PEA ability to reduce APS and psychic distress, um-PEA safety and tolerability, and the biological basis of um-PEA effect in terms of modulation of inflammatory response, endocannabinoid (eCB) signaling, and microbiome composition. Our trial aims to address an unmet clinical need in CHR subjects, providing an initial solid basis for the development of future studies evaluating the efficacy and tolerability of PEA supplementation in this group of patients. Full article

Phospholipids and their metabolites play an important role in maintaining the membrane integrity and the metabolic functions of keratinocytes under physiological conditions and in the regeneration process after exposure to high-energy UVB radiation. Therefore, in the search for compounds with a protective and regenerative effect on keratinocyte phospholipids, the effectiveness of two antioxidant compounds has been tested: a stable derivative of ascorbic acid, 3-O-ethyl ascorbic acid (EAA) and cannabigerol (CBG), both of which are primarily located in the membrane structures of keratinocytes. In addition, this study has demonstrated that EAA and CBG, especially in a two-component combination, enhance the antioxidant properties of keratinocytes and reduce lipid peroxidation assessed at the level of MDA (malondialdehyde)/neuroprostanes. Moreover, by reducing the activity of enzymes that metabolise phospholipids, free PUFAs (polyunsaturated fatty acids) and endocannabinoids (PLA2; phospholipase A2, COX1/2; cyclooxygenases 1/2, LOX-5; lipoxygenase 5, FAAH; fatty acid amide hydrolase, MAGL; monoacylglycerol lipase), antioxidants have been found to regulate the levels of endocannabinoids (AEA; anandamide, 2-AG; 2-arachidonoylglycerol, PEA; palmitoylethanolamide) and eicosanoids (PGD2; prostaglandin D2, PGE2; prostaglandin E2, 15-d-PGJ2; 15-deoxy-Δ12,14-prostaglandin J2, 15-HETE; 15-hydroxyeicosatetraenoic acid), that are enhanced by UVB radiation. The metabolic effect of both groups of PUFA metabolites is mainly related to the activation of G protein-related receptors (CB1/2; cannabinoid receptor 1 and 2, PPARγ; peroxisome proliferator-activated receptor gamma, TRPV1; transient receptor potential cation channel subfamily V member 1), the expression of which is reduced under the influence of EAA, CBG, and especially the two-component combination. It promotes the regeneration of keratinocyte metabolism disrupted by UVB, particularly in relation to redox balance and inflammation. Full article

Gastroesophageal reflux disease (GERD) is a digestive disorder that can lead to chronic mucosal damage, causing esophagitis, Barrett’s esophagus and esophageal cancer. GERD currently affects about 13% of the world’s population and represent a major public health concern due to the increasing prevalence and incidence. The aim of this study was to explore complementary strategies for GERD management based the natural compound palmitoylethanolamide (PEA), alone or associated with plant extracts with demonstrated anti-GERD activity (Zingiber officinale, Musa × paradisiaca, Opuntia ficus-indica and Olea europaea). For this purpose, two in vitro models based on the esophageal mucosa CP-B cell line were chosen. The first one was based on the exposure of esophageal cells to HCl, while the second one was based on lipopolysaccharide (LPS) treatment to cause a strong inflammatory cell response. Inflammation induced was assessed using a Luminex^® assay, measuring the secretion of IL-1β, IL-6, IL-10, IL-8 and TNF-α. Results obtained demonstrate that PEA strongly decreased the inflammatory response elicited by HCl exposure. Moreover, the effect of PEA was enhanced by the presence of natural extracts of Zingiber officinale, Musa × paradisiaca, Opuntia ficus-indica and Olea europaea. PEA should be considered as an anti-GERD natural compound of interest. Full article

Aim: To investigate the efficacy of Palmitoylethanolamide (PEA, 300 mg), Superoxide Dismutase (SOD, 70 UI), Alpha Lipoic Acid (ALA, 300 mg), vitamins B6 (1.5 mg), B1 (1.1 mg), B12 (2.5 mcg), E (7.5 mg), nicotinamide (9 mg), and minerals (Mg 30 mg, Zn 2.5 mg) in one tablet in people with Diabetic Neuropathy (DN). Patients–methods: In the present pilot study, 73 people (age 63.0 ± 9.9 years, 37 women) with type 2 Diabetes Mellitus (DMT2) (duration 17.5 ± 7.3 years) and DN were randomly assigned to receive either the combination of ten elements (2 tablets/24 h) in the active group (n = 36) or the placebo (n = 37) for 6 months. We used the Michigan Neuropathy Screening Instrument Questionnaire and Examination (MNSIQ and MNSIE), measured vibration perception threshold (VPT) with biothesiometer, and Cardiovascular Autonomic Reflex Tests (CARTs). Nerve function was assessed by DPN Check [sural nerve conduction velocity (SNCV) and amplitude (SNAP)]. Sudomotor function was assessed with SUDOSCAN, which measures electrochemical skin conductance in hands and feet (ESCH and ESCF). Pain score (PS) was assessed with Pain DETECT questionnaire. Quality of life was assessed by questionnaire. Results: In the active group, there was a large improvement of pain (PS from 20.9 to 13.9, p < 0.001). There was also a significant improvement of vitamin B12 (B12) levels, MNSIQ, SNCV, VPT, and ESCF (222.1 vs. 576.3 pg/ mL, p < 0.001; 6.1 vs. 5.9, p = 0.017; 28.8 vs. 30.4, p = 0.001; 32.1 vs. 26.7, p = 0.001; and 72.2 vs. 74.8, p < 0.001 respectively). In the placebo group, neither pain (21.6 vs. 21.7, p = 0.870) or any other aforementioned parameters changed significantly, and MNSIE worsened (2.9 vs. 3.4, p < 0.001). As a result, changes from baseline to follow-up in pain, B12 levels, VPT, and MNSIQ differed significantly between the two groups (p < 0.001, 0.025, 0.009, and <0.001, respectively). CARTs, SNAP, ESCH did not significantly change in either of the two groups. Conclusions: The combination of the ten elements in one tablet for 6 months at a daily dose of two tablets in people with DN significantly improves pain, vibration perception threshold, and B12 levels. Full article

Palmitoylethanolamide (PEA) is a highly lipophilic molecule with low solubility, making absorption difficult. Recent techniques like micronisation, ultra-micronisation and combining PEA with solvents have improved their bioavailability and stability. Our study analysed particle size differences and absorption kinetics using specific solvents (PEAΩ and PEA DynoΩ) over time (0.5 h–6 h) in a dose-dependent manner (200 mg–1800 mg). The results showed that PEAΩ and PEA DynoΩ achieved 82–63% absorption at 3 h, compared to 30–60% for micronised, ultra-micronised PEA and a commercial product, highlighting the optimal dose range of 300 mg–600 mg. In addition, a 3D model of the peripheral nerve was utilised to explain the efficacy after gut passage and support the most effective dose (300 mg or 600 mg) achieved at the gut level. PEAΩ and PEA DynoΩ, which are associated with better intestinal bioavailability compared to PEA-micronised, PEA ultra-micronised and a commercial product, have allowed not only a reduction in the inflammatory context but also an improvement of peripheral nerve well-being by increasing specific markers like MPZ (26–36% vs. 8–15%), p75 (25–32% vs. 13–16%) and NRG1 (22–29.5% vs. 11–14%). These results highlight the potential of advanced PEA formulations to overcome solubility challenges and maintain in vitro efficacy, modulating peripheral nerve well-being. Full article

This study investigates the effects of palmitoylethanolamide (PEA) on the gut microbiome of overweight adults. Fifty-eight participants (twenty males, thirty-eight females) aged 18–65 years with a BMI range of 30–40 kg/m² were recruited. Participants were randomised to receive PEA (n = 36) or a placebo (n = 22) for 12 weeks. Microbiota composition, richness, diversity, and metabolic functions, faecal short chain fatty acids and calprotectin, pathology markers, and health-related questionnaires were analysed throughout the 12 weeks of supplementation. PEA supplementation significantly reduced triglyceride levels and IL-2 concentrations. No significant differences were found in the overall microbiota composition between the groups, and microbiota richness and diversity remained consistent for both groups. Functional analysis demonstrated no differences in functional richness and diversity, but specific pathways were modified. PEA supplementation resulted in a decrease in the abundance of pathways related to aromatic compound degradation, NAD interconversion, and L-glutamate degradation, while pathways associated with molybdopterin biosynthesis and O-antigen building blocks exhibited increased abundance. Increased production of O-antigen results in smooth LPS associated with reduced pathogenic stealth and persistence. PEA supplementation may influence specific microbial species, metabolic pathways, and reduce serum triglyceride and IL-2 concentration, shedding light on the intricate relationship between PEA, the microbiome, and host health. Full article

Sepsis-induced multiple organ dysfunction arises from the highly complex pathophysiology encompassing the interplay of inflammation, oxidative stress, endothelial dysfunction, mitochondrial damage, cellular energy failure, and dysbiosis. Over the past decades, numerous studies have been dedicated to elucidating the underlying molecular mechanisms of sepsis in order to develop effective treatments. Current research underscores liver and cardiac dysfunction, along with acute lung and kidney injuries, as predominant causes of mortality in sepsis patients. This understanding of sepsis-induced organ failure unveils potential therapeutic targets for sepsis treatment. Various novel therapeutics, including melatonin, metformin, palmitoylethanolamide (PEA), certain herbal extracts, and gut microbiota modulators, have demonstrated efficacy in different sepsis models. In recent years, the research focus has shifted from anti-inflammatory and antioxidative agents to exploring the modulation of energy metabolism and gut microbiota in sepsis. These approaches have shown a significant impact in preventing multiple organ damage and mortality in various animal sepsis models but require further clinical investigation. The accumulation of this knowledge enriches our understanding of sepsis and is anticipated to facilitate the development of effective therapeutic strategies in the future. Full article

Palmitoylethanolamide (PEA) exhibits multiple skincare functions such as anti-nociceptive and anti-inflammatory effects. However, its topical application is limited due to its difficulty in bypassing the stratum corneum barrier, relatively low bioavailability, and low stability. Herein, elastic nano-liposomes (ENLs) with excellent deformability and elasticity were utilized as a novel drug delivery system to encapsulate PEA to overcome the abovementioned issues and enhance the biological effects on the skin. ENL was prepared with phosphatidylcholine, cholesterol, and cetyl-PG hydroxyethyl palmitamide with a molar ratio mimicking skin epidermal lipids, and PEA was loaded. The PEA-loaded ENL (PEA-ENL) demonstrated efficient transdermal delivery and enhanced skin retention, with negligible cytotoxicity toward HaCaT cells and no allergic reaction in the human skin patch test. Notably, PEA-ENL treatment increased cell migration and induced significant regulation in the expression of genes associated with anti-nociceptive, anti-inflammatory, and skin barrier repair. The mechanism of the anti-nociceptive and anti-inflammatory effects of PEA was further investigated and explained by molecular docking site analysis. This novel PEA-ENL, with efficient transdermal delivery efficiency and multiple skincare functionalities, is promising for topical application. Full article

Symptoms of fibromyalgia (FM) fluctuate and vary in severity. The current study aimed to evaluate the efficacy of palmitoylethanolamide (PEA) and acetyl-L-carnitine (ALC) in FM patients over a 24-month period and to investigate the mediating function of pain catastrophizing subdomains in unfavorable relationships with disease severity levels in patients with FM. Patients were evaluated at baseline, after 12 months, and after 24 months, using different patient-reported measures (FIQR, FASmod, PSD, and PCS) to distinguish different levels of FM disease severity. A reduction of 30% or more from baseline was considered clinically important (“markedly improved”). A multivariate analysis was performed to identify the variables predictive of an FIQR reduction. Twenty-two patients (28.6%) were classified as “markedly improved”, 16 patients (20.8%) as “slightly/moderately improved”, and 39 patients (50.6%) as “not improved.” The FIQR, FASmod, and PSD scores were significantly reduced at 24 months. The pain magnification domain score of the PCS was the only variable predictive of worse FIQR scores (Wald coefficient: −2.94; p = 0.047). These results suggest a potential long-term therapeutic role for the PEA + ALC combination, with pain magnification being the primary predictor of poor efficacy. Full article