Search Results (120)

Obesity is a complex, heterogeneous, chronic, and progressive disease, which correlates with an augmented risk of developing several comorbidities, including painful conditions, such as osteoarthritis. In this review, authors present for the first time the term meta-neuroinflammation for describing how the chronic, low-grade systemic inflammation, that occurs in obesity, may trigger oxidative stress and neuroinflammatory processes. Both the peripheral and the central nervous system are involved in neuroinflammation, leading to central sensitization and pain chronification, which leads to the observed increased incidence in obese patients of chronic pain syndromes, particularly osteoarthritis, low back pain, fibromyalgia, headache, and diabetic peripheral neuropathy. Possible mechanisms by which obesity may cause meta-neuroinflammation include adiposopathy, gut microbiota dysbiosis, and compromised integrity of blood–brain barrier, which could explain obesity-related depressive and neurodegenerative disorders. Preclinical data suggest the meta-neuroinflammation as a potential target of treatment in obese patients with degenerative joint disease. Based on these observations, targeted therapeutic strategies may include systemic administration of ultramicronized palmitoylethanolamide (um-PEA), well known for its neuroprotective, anti-neuroinflammatory, and analgesic actions, and comicronized PEA–rutin and hydroxytyrosol to restore intestinal eubiosis, with beneficial effects on body weight and mental disorders. Finally, Adelmidrol, as a PEA congener, could be considered for mitigating intra-articular meta-neuroinflammation in knee osteoarthritis. Full article

Background: Menstrual migraine (MM), including pure menstrual migraine (PMM) and menstrually related migraine (MRM), is characterized by attacks occurring in close temporal association with menstruation and is often more severe, longer lasting, and less responsive to treatment than non-menstrual migraine. Prostaglandin-mediated inflammation and calcitonin gene-related peptide (CGRP) release play a key role in MM pathophysiology. Phycocyanin (PC) and palmitoylethanolamide (PEA) are nutraceutical compounds with anti-inflammatory, analgesic, and neuroprotective properties that may be beneficial as short-term perimenstrual prophylaxis. Objectives: To evaluate the effectiveness of an oral supplementation combining phycocyanin and palmitoylethanolamide as a short-term prophylaxis for menstrual migraine in a real-world clinical setting, a retrospective observational study without a control group was conducted in five Italian centers between May 2023 and June 2025. Methods: Clinical records of 800 women were reviewed, and 220 patients receiving perimenstrual supplementation with phycocyanin and palmitoylethanolamide were screened. Sixty-one women diagnosed with migraine without aura, according to the International Classification of Headache Disorders, met all inclusion criteria and were analyzed. Phycocyanin and palmitoylethanolamide were taken at a dosage of two capsules daily from five days before to five days after the onset of menstruation for three consecutive months. Outcomes during the perimenstrual window were compared with a three-month period without supplementation. Primary outcomes included migraine severity, frequency, and duration of the attacks; secondary outcomes included analgesic consumption and menstrual migraine-associated symptoms. Results: Among the 61 included patients, phycocyanin and palmitoylethanolamide supplementation was associated with a significant reduction in migraine severity across all monitored perimenstrual days (p < 0.0001). While the overall monthly frequency of migraine attacks did not change, the number of migraine days during the perimenstrual window significantly decreased from the first month of supplementation (p < 0.05). Moreover, migraine duration during the perimenstrual window was significantly reduced at one, two, and three months of phycocyanin and palmitoylethanolamide supplementation compared with baseline. Analgesic use and the number of days with migraine-associated symptoms (nausea, vomiting, photophobia/phonophobia) were also significantly reduced. Treatment was well tolerated. Conclusions: In this real-world retrospective study, perimenstrual supplementation with phycocyanin and palmitoylethanolamide was associated with reduced severity, duration, and perimenstrual frequency of menstrual migraine attacks, along with decreased analgesic use, suggesting a safe and potentially beneficial short-term prophylactic strategy for women with menstrual migraine. Full article

Alzheimer’s disease (AD) is increasingly recognized as a disorder not only of cognition but also of motivation and emotional regulation. Apathy and anhedonia often precede memory deficits, implicating early dysfunction in reward-related circuits. This study investigated whether chronic infusion of palmitoylethanolamide (PEA), a lipid-derived PPARα agonist, could restore motivational behavior and dendritic plasticity in the Tg2576 mouse model of AD. The motivational behavior of mice that received sustained-release PEA pellets for 6 months was assessed by using the conditioned place preference (CPP) paradigm. Morphological and molecular analyses were conducted in the entorhinal cortex (EC), dentate gyrus (DG), and prefrontal cortex (PFC). In Tg2576 mice, PEA significantly rescued CPP performance, increased basal dendritic spines in WT mice in the EC, and both basal and apical dendritic expression in EC and DG from Tg2576 mice, and upregulated the expression of both PPAR-α and brain-derived neurotrophic factor (BDNF) in the PFC. Interestingly, the BDNF increase occurred even in the absence of baseline deficits, suggesting a trophic-enhancement effect. These findings suggest that the PEA-PPARα-BDNF axis may be a potential mechanism for restoring motivation and synaptic integrity in an AD-like mouse model. Lipid-based neuromodulation may therefore offer novel therapeutic routes for addressing non-cognitive symptoms and affective circuitopathy in neurodegenerative diseases. Full article

N-arachidonoylethanolamine (AEA) and 2-arachidonoylglycerol (2-AG) are lipid signalling molecules within the endocannabinoid system, which regulates numerous physiological processes and is implicated in diverse pathological conditions. Given the limited feasibility of obtaining human tissue samples, quantifying AEA and 2-AG in biological matrices is essential for understanding the endocannabinoid system in humans. While many studies have used blood samples for this purpose, the collection of this matrix typically requires invasive venipuncture, which limits the scalability and practicality of endocannabinoid research. This study validated extraction and LC–MS/MS methods for quantifying AEA and 2-AG (co-quantified with its isomer 1-AG) in minimally invasive matrices, including saliva and finger-prick blood microsamples, with acceptable linearity, recovery, reproducibility, and matrix effects. The assay additionally enabled exploratory quantification of arachidonic acid, oleoylethanolamide (OEA), palmitoylethanolamide (PEA), and selected steroid hormones, supporting multiplexed assessment from a single sample. Analyte concentrations measured in blood microsamples did not directly correspond to plasma concentrations, indicating that microsampling is suited for assessing relative within-study changes rather than absolute plasma equivalence. Application of the method demonstrated that venipuncture did not significantly alter salivary AEA or 2-AG concentrations. Overall, this method provides a minimally invasive and accessible approach for investigating endocannabinoid dynamics alongside other physiological biomarkers. Full article

Background: Chronic neuropathic low back pain (LBP) is a prevalent health condition and difficult to treat. Conventional therapies often provide limited relief and raise safety concerns. Supplemental palmitoylethanolamide (PEA), an endogenous fatty acid amide with analgesic and anti-inflammatory properties, has shown benefits in neuropathic pain, but its application as a supportive strategy has been limited by poor oral bioavailability. Objectives: This study aimed to investigate a phospholipid-based palmitoylethanolamide formulation (PEA-PL, Cronilief™), developed using Phytosome™ delivery technology, with respect to solubility optimization, systemic exposure, and associated clinical effects in individuals with chronic neuropathic LBP. Methods: PEA-PL solubility was assessed in fasted-state simulated intestinal fluid and compared with unformulated PEA. Plasma PEA concentrations were evaluated in healthy volunteers after 2 weeks of supplementation with unformulated PEA (300 mg/day) or PEA-PL (300 or 600 mg/day). Clinical efficacy was assessed in a double-blind, placebo-controlled randomized, trial in which 120 adults with neuropathic LBP received PEA-PL 600 → 300 mg (n = 40), PEA-PL 450 mg (n = 40), or placebo (n = 40), daily for 8 weeks in addition to Standard of Care. Primary outcomes were effects on neuropathic pain (Douleur Neuropathique 4, DN4) and its intensity (Numeric Pain Rating Scale, NPRS). Secondary outcomes included effect on functional disability (Oswestry Disability Index, ODI), sleep quality (Pittsburgh Sleep Quality Index, PSQI), quality of life (QoL) (SF-12), and concomitant analgesic use. Safety was monitored throughout the 8-week supplementation period. Results: PEA-PL increased PEA solubility approximately eight-fold and resulted in higher plasma PEA concentrations than unformulated PEA. Both PEA-PL regimens significantly improved pain, functional disability, sleep, and QoL outcomes versus placebo (all p < 0.0001), with greater effects for the 600 → 300 mg regimen. Analgesic discontinuation occurred more frequently in PEA-PL groups (65–70%). Supplementation was well tolerated. Conclusions: A phospholipid-based (Phytosome™) PEA formulation (Cronilief™) was developed and associated with optimized systemic exposure and clinically meaningful reductions in pain severity and functional disability in individuals with chronic neuropathic LBP. Full article

Palmitoylethanolamide (PEA) among N-acylethanolamides displays a noteworthy impact on different inflammatory conditions and promises to become a valuable anti-inflammatory tool that does not interfere with the cyclooxygenase pathway. Mounting evidence confirms the multi-dimensional PEA-mediated crosstalk between microglia and mast cells, which would open new therapeutic opportunities targeting a neuroimmune axis and influencing both health and disease. In particular, PEA acts as a preserver of cellular homeostasis by regulating microglia cell activity and inhibiting mast cell activation in the central nervous system. The improved bioavailability and efficacy of ultramicronized formulations of PEA reflect its ultimate usefulness for different clinical applications, including significantly relieving inflammation but also reducing the pro-inflammatory burden of complex patients with either neuropathies or non-neurologic afflictions. This review aims to comprehensively delineate the therapeutic potential of PEA beyond its mere indication for acute inflammation and to highlight PEA activity as a broad-spectrum pan-tissue protective agent through the results of different preclinical and also some clinical studies. Much more remains to be learned about further PEA mechanisms of action that regulate neuroinflammation, and additional studies will have to investigate the exact role of microglia and mast cells in inflammatory diseases. Full article

Pain remains a major clinical challenge due to its complex physiopathology and limited treatment options. In this context, several supplements based on palmitoylethanolamide (PEA) and alpha-lipoic acid (ALA) are known for their neuroprotective properties. ALA-based supplements have shown potential, but concerns about adverse effects persist. This study examines the formulations of two commercial products based on ALA and PEA, IperALA^® and IperALA^® Forte, in which ALA and vitamin D3 are replaced with Coriandrum sativum extract (C. sativum e.s.), N-acetylcysteine (NAC) and glutathione (GSH), assessing improvement of neuroprotective, anti-inflammatory and analgesic properties of the new formulation. Intestinal, blood–brain barrier (BBB), and central nervous system (CNS) models were sequentially stimulated with the test compounds. Both formulations were assessed for cytotoxicity, barrier integrity, permeability, oxidative stress, inflammation, and neuroprotection-related biomarkers. IperALA^® Forte demonstrated superior performance compared to IperALA^® and individual agents. It enhanced cell viability, preserved intestinal and BBB integrity, and improved compound permeability. Notably, it reduced ROS and pro-inflammatory cytokines (TNFα, IL-1), while increasing analgesic markers (CB2R, GABA) in the central system. The replacement of ALA and vitamin D3 with C. sativum, NAC, and GSH in IperALA^® Forte significantly improved the neuroprotective, antioxidant, and anti-inflammatory profile of the supplement. These results indicate a possible connection between the observed neuroprotective properties and the pathways involved in nociception and pain regulation, stating the hypothetical potential relevance of this approach for the treatment of pain-related conditions. Full article

Background/Objectives: Palmitoylethanolamide (PEA) is an endogenous lipid mediator with endocannabinoid-like activity. Despite its therapeutic potential in muscle-related inflammatory disorders, including sarcopenia, its clinical use is limited by poor solubility and bioavailability. To overcome these issues, we developed hybrid nanoparticles combining poly(lactic-co-glycolic acid) (PLGA) and lipids to enhance PEA encapsulation and ok delivery. Methods: PEA-loaded hybrid nanoparticles (PEA-Hyb-np) were produced via a modified single-emulsion solvent evaporation method using stearic acid and Gelucire^® 50/13 as lipid components. Characterization included particle size, morphology, PDI, and zeta potential, as well as DSC, FT-IR, and XRD analyses. For the biological evaluation in a C2C12 myoblasts cell culture, coumarin-6-labeled nanoparticles were employed. Results: PEA-Hyb-np showed mean particle sizes of ~150 nm, with internal lipid–polymer phase separation. This structure enabled high encapsulation efficiency (79%) and drug loading (44.2 mg/g). Drug release in physiological and non-physiological media was enhanced due to drug amorphization, confirmed by DSC, FT-IR, and XRD analyses. Cytocompatibility studies showed no toxicity and improved cell viability compared to unloaded nanoparticles. Cellular uptake studies by confocal microscopy and flow cytometry demonstrated efficient and time-dependent internalization. Conclusions: PEA-Hyb-np represent a promising delivery platform to improve the solubility, bioavailability, and therapeutic efficacy of PEA for muscle-targeted applications. Full article

Palmitoylethanolamide (PEA) is a naturally occurring fatty acid amide and an endocannabinoid-related lipid that has been extensively studied for its analgesic, immunomodulatory, antimicrobial, and anti-inflammatory properties. It has demonstrated efficacy in various applications and is currently utilized as a nutraceutical for its antinociceptive, neuroprotective, and immunomodulatory effects, particularly in supporting brain and joint health and in mitigating inflammatory processes. Background/Objectives: Despite its significant therapeutic potential, the clinical effectiveness of PEA is limited by its poor water solubility and, consequently, low oral bioavailability. Additionally, degradation in the acidic gastrointestinal environment further compromises its absorption. To address these challenges, several technological strategies have been explored to improve its pharmacokinetic profile, including conventional micronization and ultra-micronization techniques. The objective of this study was to characterize a novel liposomal formulation based on PEA and evaluate its intestinal permeation and absorption. Methods: Comparative permeation studies of PEA were conducted using ex vivo models to evaluate its absorption characteristics across gastrointestinal mucosae. The experiments were performed in a Franz diffusion cell system using a porcine colon mucosa in two physiologically relevant media: Simulated Gastric Fluid (SGF) and Fasted State Simulated Intestinal Fluid (FaSSIF). Results: Liposomal PEA showed a more efficient and continuous release over time, reaching higher concentrations of PEA permeated through the membrane. Conclusions: Our findings demonstrate a significant improvement in PEA’s permeability and absorption in an ex vivo simulated gastrointestinal environment. Liposomal PEA appears to be more affine to biological membranes. These results suggest that liposomal PEA may represent a promising therapeutic strategy for managing chronic pain and inflammatory conditions such as chronic pelvic pain. Full article

Previous research has demonstrated that the transient bilateral common carotid artery occlusion and reperfusion (BCCAO/R) effectively models early brain inflammation resulting from sudden hypoperfusion and subsequent reperfusion. According to studies showing that diet and nutrition strongly influence brain neuroplasticity, in this study we evaluated whether kaempferol (KAM), a dietary flavonoid, offers neuroprotection in a rat BCCAO/R model. Adult Wistar rats were gavage fed a single dose of KAM (40 mg) six hours before surgery. Comprehensive lipidomic and molecular analyses were conducted on samples from the frontal and temporal-occipital cortices, as well as the plasma. In the frontal cortex, KAM elevated anti-inflammatory N-acylethanolamines palmitoylethanolamide (PEA), oleoylethanolamide (OEA), and docosahexaenoylethanolamide (DHAEA) and reduced oxidized arachidonic acid metabolites. KAM also downregulated cyclooxygenase- 2 (COX-2) protein and selectively decreased the endocannabinoid 2-arachidonoylglycerol (2-AG), showing a shift in AA metabolism. These molecular changes correlated with increased levels of peroxisome proliferator-activated receptor alpha (PPARα) and cannabinoid receptors CB1R and CB2R, supporting activation of both nuclear and membrane-bound anti-inflammatory pathways. No significant changes were observed in the temporal-occipital cortex. In plasma, DHAEA levels increased similarly to those in the cortex. However, rises in PEA and OEA were detected only in sham-operated KAM-treated animals, suggesting possible central redistribution under hypoperfusion/reperfusion stress. In summary, these findings demonstrate that KAM exerts dual anti-inflammatory effects by inhibiting COX-2-mediated prostanoid synthesis and promoting PPARα-driven lipid signaling. This dual mechanism highlights the potential of KAM as a dietary intervention to reduce neuroinflammation associated with hypoperfusion–reperfusion challenges. Full article

Background: Chronic pain represents a major therapeutic challenge due to the limited efficacy and tolerability of conventional pharmacological treatments. Equisetum arvense L., a medicinal plant with potent antioxidant properties, and palmitoylethanolamide (PEA), an endogenous fatty acid amide with well-established anti-inflammatory and analgesic effects, are increasingly recognised as promising nutraceutical agents. Methods: This prospective, single-centre clinical trial aimed to evaluate the efficacy and safety of a novel oral supplement (Assonal^®PEA) combining 600 mg of PEA and 300 mg of Equisetum arvense L. in improving the reduction of pain and quality of life in patients with chronic pain, also obtaining information on the patient’s state of satisfaction after the treatment. Fifty patients suffering from chronic pain (low back pain and radiculopathy) for two months were enrolled and received the supplement over eight weeks in a tapered regimen (two tablets daily for two weeks, followed by one tablet daily). Results: Clinical outcomes were evaluated using validated instruments, including the Numeric Pain Rating Scale (NPRS), Verbal Rating Scale (VRS), Short-Form McGill Pain Questionnaire (SF-MPQ), Global Perceived Effect (GPE), and EuroQol-5D-5L. Results showed a significant decrease in pain intensity (NPRS: −3.8 points; VRS: −2.1 points; p < 0.0001), along with meaningful improvements in patient-perceived benefit, pain descriptors, and quality of life (EQ-5D-5L: +35%; p < 0.0001). Conclusions: These findings endorse the use of this novel PEA–Equisetum arvense formulation as a safe, well-tolerated, and potentially effective supplementary intervention for managing chronic pain. No adverse events were reported, and the overall response rate reached 94%. Full article

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