Palmitoylethanolamide Research Articles

Therapeutic Use of Palmitoylethanolamide as an Anti-Inflammatory and Immunomodulator

Palmitoylethanolamine (PEA) is an endocannabinoid-like compound first encountered within the lipid fractions of specific foods and has intrigued researchers since the 1950s due to its therapeutic effects. This survey aims to explore the therapeutic promise held by PEA as an anti-inflammatory and immunomodulatory agent. The therapeutic impact of PEA reverberates across diverse physiological systems, such as the central nervous system, gastrointestinal tract, vascular network, and the digestive and respiratory system. Additionally, it is effective in pain management and reducing inflammation and immune responses. These attributes have fostered collaborations targeting conditions such as Alzheimer’s disease, multiple sclerosis, cerebral ischemia, neuroinflammation, general inflammation, pain, coagulopathy, steatohepatitis, and acute lung injury. PEA operates both independently and in synergy with other compounds, like paracetamol, luteolin, and oxymetazoline. This efficacy stems from its interactions with pivotal targets, including PPARα, PPAR-δ, PPAR-γ, CB1, CB2, GPR55, and TRPV1. Additionally, PEA exerts a direct influence on the inflammatory cascade, orchestrating precise adjustments in immune responses. Numerous animal studies have elucidated the inherent potential of PEA. Nevertheless, the imperative of reinforcing clinical investigation is evident. This review notably underscores the pivotal necessity for methodologically rigorous clinical trials to definitively establish the translational efficacy of PEA in ameliorating diverse inflammatory pathologies within the human milieu.

Exploring the Protective Effect against 7,12-Dimethylbenz[a]anthracene-Induced Breast Tumors of Palmitoylethanolamide.

Breast cancer remains a global health burden, and the need for effective therapies is of chief importance. The current study explored the in vivo chemoprotective activity of palmitoylethanolamide (PEA) against 7,12-dimethylbenz[a]anthracene (DMBA)-induced breast tumor in rats. Results of noninvasive photoacoustic imaging showed real-time progression in the tumor area and volume in DMBA-induced rats, while there was a reduction in tumor area and volume in PEA-treated tumor-bearing rats. The increase in the average oxygen saturation (sO2 %) and decrease in the average total hemoglobin (HbT %) indicated the PEA-mediated attenuation of hypoxia-induced neovascularization in DMBA-induced rats. Histopathological investigations confirmed the efficacy of PEA in mitigating breast carcinoma, hepatotoxicity and nephrotoxicity driven by DMBA. Moreover, PEA-mediated alterations in the metabolic activity of the tumor microenvironment were evidenced by decreased glucose and lactate dehydrogenase enzyme level in the blood plasma and mammary tissue. PEA also maintained the redox balance by inhibiting nitric oxide level, reducing malondialdehyde (a product of lipid peroxidation), and increasing the level of antioxidant enzyme reduced glutathione. PEA altered the expression of apoptosis-related genes (BAX, P53,BCL-XL, CASPASE-8, and CASPASE-9) and induced the activity of Caspase-3 protein in the mammary tissue of tumor-bearing rats, indicating its apoptosis inducing ability. Taken together, the findings of this study suggest that PEA may have a protective effect against DMBA-induced breast tumors.

Targeting p38 Mitogen Activated Protein Kinase to Ameliorate Pain in SCD

Pain is a major comorbidity of sickle cell disease (SCD). Central sensitization is associated with chronic sickle cell pain. Earlier studies showed that p38 mitogen activated protein kinase (MAPK) is activated in the spinal cords of sickle mice with nociceptor sensitization of 2˚ neurons (Cataldo et al., Pain 2015). Novel approaches targeting p38 MAPK phosphorylation or its upstream targets may alleviate chronic pain. Cannabinoids represent a novel approach for ameliorating pain, including the endogenous cannabinoid-like lipid mediator palmitoylethanolamide (PEA). PEA has been shown to reduce neuropathic pain and depression scores, while improving sleep concomitant with reduced c-reactive protein (CRP) in a clinical evaluation of diabetic peripheral neuropathic pain and inflammation (Pickering et al., Inflammopharmacology 2022). We therefore examined if, [i] p38 MAPK is activated in dorsal root ganglion (DRG) which transmits action potentials to spinal neurons; [ii] if PEA administration reduces spinal neuroinflammation, oxidative stress and neuronal p38 MAPK phosphorylation; and [iii] inhibition of p38 MAPK phosphorylation ameliorates chronic pain in SCD. Female Berkeley (BERK) sickle (HbSS) expressing >99% human sickle hemoglobin and/or control (HbAA) expressing normal human HbA, mice (3.5-5.0 months) were treated for 14-days with PEA (i.p., 20 mg/kg/d) or vehicle (veh; i.p., 7.5% DMSO, 7.5% Tween 20, in sterile PBS). At endpoint, spinal cords and plasma were collected. HbSS mice have constitutively higher spinal malondialdehyde (MDA) levels, a marker of oxidative stress, compared to HbAA mice (~50%, P<.05), and PEA treatment significantly reduced HbSS spinal MDA levels (~53%, P<.05, vs veh); pro-apoptotic caspase-3 (~91%, P<.01) and pro-inflammatory interleukin (IL)-1β (~42%, P<.05), which are constitutively elevated in HbSS compared to HbAA mice (~45%, P<.05). Concomitant with reduced spinal inflammation, PEA reduced global marker of inflammation, serum amyloid P (~42%, P<.01) in the circulation, an analog for human CRP, which is significantly higher in HbSS compared to HbAA mice (~700%, P<.01). Thus, PEA ameliorates spinal inflammation and oxidative stress, and inhibits apoptosis. DRG neurons in vitro isolated from sickle mice were treated with tumor necrosis factor α (TNF α; 1 ng/mL) and hemin (40 mM) to create a sickle microenvironment replete with inflammation and oxidative stress, which significantly increased p38 MAPK phosphorylation (~494%, P<.001). PEA (30 mM) treatment of the neurons significantly inhibited TNF α and hemin-induced MAPK phosphorylation and its nuclear translocation (~65%, P<.001). Thus, it is likely that both peripheral and central mechanisms mediated by p38 MAPK signaling contribute to the initiation and maintenance of pain in SCD which are inhibited by PEA. Neflamapimod (Nef) is a novel inhibitor of p38 MAPK phosphorylation with significant anti-inflammatory effects, mediated by IL-1β and TNF α. Nef is orally bioavailable and has been suggested to improve synaptic transmission. We evaluated the effect of orally administered Nef (6 and 12 mg/kg 2x daily; veh 0.1% pluronic acid in sterile H 2O) in female sickle mice (9.0 months) with hyperalgesia. Treatment with Nef 12 mg/kg/d for 7-days reduced mechanical (~42% & ~34%, both P<.01, vs veh & baseline, respectively) and cold hyperalgesia (~46% & ~34%, both P<.001, vs veh & baseline, respectively). A decrease was also observed in mechanical (~29%, P<.05, vs veh) and cold hyperalgesia (~24%, P<.05, vs veh) after 7 days with 6 mg/kg Nef treatment. These data suggest p38 MAPK signaling contributes to chronic pain in SCD. Together, our observations demonstrate the therapeutic potential of PEA and Nef in targeting p38 MAPK as novel interventions to ameliorate sickle cell pain and central sensitization. PEA is a safe nutraceutical which has shown effectiveness in many pain conditions including osteoarthritis. Nef has shown efficacy in improving cognitive function in Phase II clinical trials in dementia patients. Pain and cognitive impairment co-exist in SCD. Therefore, Nef has the potential to reduce pain and improve cognitive function in SCD.

Palmitoylethanolamide Modulates Gait By Targeting Purkinje Cells in the Brain of Sickle Mice

Chronic pain is a major comorbidity of sickle cell disease (SCD). Transgenic humanized (BERK) sickle mice recapitulate many clinical features of SCD, including chronic pain. Motor impairments concomitant with increased pyknotic cerebellar Purkinje cells occur in BERK sickle mice. Neurological, neuropathic, and immunological factors, including Purkinje cell damage and chronic inflammation, may contribute to peripheral and central mechanisms that drive gait dysfunction. Pathological changes in Purkinje cells of sickle mice include a significantly greater number of pyknotic cells with smudged nuclei, condensed chromatin, and lack of well-formed nucleoli, & may contribute to alterations in gait as Purkinje cells regulate sensory-motor functions. Subjects with SCD often use cannabinoids for pain relief, but the intoxicating effects and social stigma associated with their use represent barriers to utilizing this treatment. Palmitoylethanolamide (PEA) is a non-intoxicating endocannabinoid-like lipid mediator naturally produced throughout the body that may act via indirect cannabinoid receptor activation. In clinical studies associated with movement and pain, including chronic arthritic and multiple sclerosis, PEA has demonstrated a reduction of motor dysfunction and pain. Therefore, we examined the effect of PEA on hyperalgesia and gait in humanized HbSS-BERK sickle (HbSS) mice. We utilized ~6-month-old female, HbSS mice, expressing >99% human α- and ßS- sickle hemoglobin and complete knockout of murine α- and β-globins. Mice were treated with PEA (ip, 20 mg/kg/d) or vehicle (7.5% DMSO, 7.5% Tween 20, in sterile saline) for 2 weeks (2-wks). Gait measurements were gathered for each mouse at baseline (BL) and 2-wks post treatment during normal walking in MouseWalker's transparent corridor with a floor panel mounted with LED lights to produce a detectable touch sensor. Physical contact of paw pads with the surface during natural walking disrupts the light path, causing frustrated total internal reflection detected by a high-speed camera and analyzed using artificial intelligence-based algorithms for gait parameters. Mechanical hyperalgesia was analyzed as paw withdrawal frequency (PWF) in response to 10 applications of 1.0 g von Frey monofilaments. Complete blood counts and brain histopathology on hematoxylin- and eosin-stained sections were evaluated after 2-wks post-treatment. We observed that PEA ameliorates features of dysfunctional gait in HbSS mice. PEA-treated mice show increased limb swing speed (~30%, P<0.01) and shortened swing duration (20%, P<0.05) without affecting walking speed (P >0.05) Vs. vehicle-treated mice. Also, PEA significantly reduced body instability (~75%, P<0.05) and improved stance duration (~65%, P<0.05) Vs. BL. This suggests improved limb coordination and reduced sensitivity to mechanical forces during walking. Complementary to gait changes, PEA significantly decreased mechanical hyperalgesia, indicated by lower PWF, 1-hour following initial treatment and following 2-wks post-treatment (~55%, P< 0.001 and ~65%, P< 0.001, respectively) Vs. BL. PEA decreased the number of circulating white blood cells (P< 0.05), with the greatest reduction in circulating lymphocytes (P< 0.1). PEA had no adverse effects on organ weight Vs. vehicle treatment. PEA-treated mice showed a significant reduction in pyknotic cerebellar Purkinje cells (~23.9% p<.006) in the brain Vs. vehicle. Thus, Purkinje cell pathology may contribute to impaired gait, and PEA may improve motor coordination by reducing Purkinje cell damage. We provide the first evidence that PEA administration in a humanized sickle mouse model improves features of gait, restores Purkinje cell morphology, and reduces inflammation. Our data demonstrate that PEA may have a disease-modifying effect and restoration of sensory-motor function in SCD. Impairment in gait may also be due to avascular necrosis. Therefore gait measurements may provide a non-invasive analysis of movement associated pathology and pain as well as effectiveness of targeted interventions.

The Effect of Levagen+ (Palmitoylethanolamide) Supplementation on Symptoms of Allergic Rhinitis—A Double-Blind Placebo-Controlled Trial

Background: Allergic rhinitis (AR) is an inflammatory, symptomatic disorder stimulated by antigen-specific immunoglobulin E inflammation in response to allergens. Current treatments include the use of corticosteroids and antihistamines to reduce inflammation by preventing histamine release. Palmitoylethanolamide (PEA) is reported to be an alternative treatment, shown to downregulate mast cell activation and increase the synthesis of endocannabinoid 2-Arachidonoylglycerol to reduce histamine and the symptoms of AR. Method: A double-blind, randomised, placebo-controlled clinical trial in which 108 participants presenting with seasonal AR were supplemented with either 350 mg of PEA (Levagen+) or a placebo daily for two weeks. Symptom scores were recorded using the reflective total nasal symptom score (rTNSS) twice a day (morning and evening) for the two weeks, and blood was taken at baseline and week 2. Results: 101 participants completed the study with no baseline group differences. No significant difference was seen between groups for allergy symptoms scores (rTNSS) throughout the 14 days of treatment. A sub-group analysis of participants scoring over four (mild-to-moderate) on the total rTNSS at baseline showed that Levagen+ significantly reduced scores compared to the placebo group. Only 36 participants had full sets of blood taken due to COVID-19. The pathology results showed a significant difference in change from baseline between groups. The Levagen+ group had a significant decrease from baseline in histamine, IL-4, IL-8, IL-10, and TNF-α. The placebo group only had a reduction in IL-4. Conclusion: The results of this study show that Levagen+ can alleviate AR symptoms, resulting in a reduction in histamine and inflammatory markers.

Simultaneous determination of fatty acids and related N-Acylethanolamines in rat plasma, rat tissue, and human plasma using UPLC-MS/MS

A sensitive and specific method for the simultaneous determination of palmitoyl ethanolamide (PEA), oleoyl ethanolamide (OEA), linoleoyl ethanolamide (LEA), 1-palmitoyl glycerol (1-PG), 1-oleoyl glycerol (1-OG), 1-linoleoyl glycerol (1-LG), palmitic acid (PA), oleic Acid (OA), and linoleic acid (LA) in rat plasma and liver by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) has been developed. Multiple-reaction mode (MRM) of a triple quadrupole mass spectrometer was used for detection. A reverse phase C8 column was used for chromatographic separation, and an 11.5-minute gradient elution time was used. Deuterated internal standards included 2-AG-d5, OEA-d4, LEA-d4, and OA-d9. In terms of linearity, accuracy, repeatability, intermediate precision, recovery, matrix effect, and stability, this newly designed method was approved. These nine lipids were successfully determined using this method in two sample groups: plasma from individuals with non-alcoholic fatty liver diseases (NAFLD) (n = 40) and healthy individuals (n = 40), as well as plasma and liver samples from rats with NAFLD (n = 15) and healthy ones (n = 11).

Endocannabinoid-related molecules predict the metabolic efficacy of GLP-1 receptor agonism in humans with obesity.

N-acylethanolamines (NAEs) include endocannabinoid (EC) and EC-related molecules that impact the anti-obesity and anti-diabetic efficacy of glucagon-like peptide-1 receptor agonists (GLP-1RA) in animal studies. However, the clinical relevance of these findings remains to be determined. Here, we tested whether GLP-1RA treatment affects circulating NAE levels and whether NAEs may predict the efficacy of GLP-1RA treatment in humans with obesity undergoing weight loss maintenance. We profiled plasma levels of NAEs in participants with obesity undergoing weight loss maintenance with (n = 23)/or without (n = 20) treatment with the GLP-1RA liraglutide. NAE levels were measured at three different time points: before the start of the study, at the end of the diet-induced weight loss, and after 52-weeks treatment. Linear regression analyses were used to investigate whether pharmacological responses could be predicted by NAEs levels. Liraglutide treatment reduced plasma concentrations of the NAE and oleoyl-ethanolamide (OEA), without altering arachidonoyl-ethanolamide (AEA) levels and palmitoyl-ethanolamide (PEA) levels. High pre-treatment levels of OEA were predictive of superior compound-mediated effects on fasting insulin and triglyceride levels. High pre-treatment PEA and AEA levels were also predictive of superior Liraglutide-mediated effects on triglyceride levels. Our data suggests that specific NAEs such as OEA and AEA are promising biomarkers of GLP-1RA metabolic efficacy in humans with obesity during weight loss maintenance. Plasma profiling of EC-related molecules may be a promising strategy to tailor GLP-1R-based therapies to individual needs in obesity and diabetes management.

Phytochemical characterization and anti-arthritic potential of Croton bonplandianus leaves extract: In-vivo and in-silico approach

Croton bonplandianus, a natural source traditionally used for treating various illnesses, including rheumatoid arthritis, was evaluated in this study. The effects of ethanolic extracts (CBEE) and aqueous fractions (CBAF) of C. bonplandianus leaves on arthritis-induced inflammation were studied using an albino rat model of inflammation induced by Freund's complete adjuvant. Eight test groups (n = 5 per group) and one vehicle control were used to evaluate the antiarthritic effects of different doses of CBEE and CBAF (125 mg.kg−1, 250 mg.kg−1, and 500 mg.kg−1) on days 5, 10, 15, and 20 compared to arthritic and vehicle controls. Arthritis severity was assessed using macroscopic arthritis grading, histological analysis, body weights, and paw thickness. CBEE and CBAF were found to reduce the prevalence of arthritis, increase body weight, and decrease paw inflammation compared to the vehicle control group by the 23rd day. In addition, they showed no effect on biochemical parameters, but a significant difference (p < 0.05) in hematological parameters compared to the arthritic control group. The study identified Hentriacontane compound as a potential contributor to the anti-inflammatory effect of C. bonplandianus, as it showed the lowest dock score for IL-1β and IL-6. Palmitoylethanol amide was identified as a potential contributor to the anti-inflammatory effect of TNF-α. Gene expression of IL-6, IL-1β, and TNF-α was down-regulated significantly (p < 0.05) in a dose-dependent manner in all treatment groups compared to the arthritic control group. In conclusion, this study validated the anti-arthritic and anti-inflammatory properties of CBEE and CBAF in a time and dose-dependent manner.

The Efficacy of Palmitoylethanolamide (Levagen+) on the Incidence and Symptoms of Upper Respiratory Tract Infection-A Double Blind, Randomised, Placebo-Controlled Trial.

Upper respiratory tract infections (URTIs) are caused by bacteria or viruses, with the most common causes being the common cold and influenza. The high occurrence of URTI means therapies that are effective with minimal side effects are in constant demand. Palmitoylethanolamide (PEA) is a signaling lipid previously shown to be effective in improving the incidence of URTIs. The aim of this study was to assess the effectiveness of PEA (Levagen+) on URTI incidence, duration, and severity. Participants (n = 426) consumed either 300 mg of Levagen+ or a placebo (maltodextrin) twice daily for 12 weeks. Participants completed the Wisconsin Upper Respiratory Symptom Survey 24 questionnaire daily upon the commencement of symptoms until symptoms subsided. The Levagen+ group reported fewer URTI episodes (39 vs. 64) compared to the placebo group. The Levagen+ group reported a significant reduction in the median severity score of URTI symptoms for scratchy throat (3 vs. 7) and cough (2 vs. 7) compared to the placebo group. The results of this study show Levagen+ to be safe and effective in reducing the incidence and symptoms associated with URTIs.

Plasma endocannabinoids in cocaine dependence and their relation to cerebral metabotropic glutamate receptor 5 density

Animal models indicate that the endocannabinoid system (ECS) plays a modulatory role in stress and reward processing, both crucially impaired in addictive disorders. Preclinical findings showed endocannabinoid-modulated synaptic plasticity in reward brain networks linked to the metabotropic-glutamate-5 receptor (mGluR5), contributing to drug-reinforcing effects and drug-seeking behavior. Although animal models postulate a link between ECS and cocaine addiction, human translational studies are lacking. Here, we tested previous preclinical findings by investigating plasma endocannabinoids (eCBs) anandamide (AEA), 2-arachidonoylglycerol (2-AG), and the related N-acylethanolamines (NAEs) palmitoylethanolamide (PEA) and oleoylethanolamide (OEA), including their interaction with cerebral mGluR5, in chronic cocaine users (CU). We compared basal plasma concentrations between chronic CU (N = 103; 69 recreational CU and 34 dependent CU) and stimulant-naïve healthy controls (N = 92). Follow-up basal eCB/NAE plasma levels after 12 months were used for reliability and stability check (CU: N = 33; controls: N = 43). In an additional analysis using 11C-ABP688 positron emission tomography (PET) in a male subsample (CU: N = 18; controls: N = 16), we investigated the relationships between eCBs/NAEs and mGluR5 density in the brain. We found higher 2-AG plasma levels in dependent CU compared to controls and recreational CU. 2-AG levels were stable over time across all groups. In the PET-subsample, a positive association between 2-AG and mGluR5 brain density only in CU was found. Our results corroborate animal findings suggesting an alteration of the ECS in cocaine dependence and an association between peripheral 2-AG levels and cerebral mGluR5 in humans. Therefore, the ECS might be a promising pharmaco-therapeutic target for novel treatments of cocaine dependence.

Antidepressant Medication Does Not Contribute to the Elevated Circulating Concentrations of Acylethanolamides Found in Substance Use Disorder Patients.

Circulating acylethanolamides (NAEs) are bioactive signaling molecules that modulate multiple homeostatic functions including mood and hedonic responses. Variations in their plasma concentrations are associated with substance use disorders (SUD) and recent studies suggest that psychotropic medication might influence its circulating levels, limiting its use as a clinical biomarker of addiction. In addition, they might have a role as mediators of the pharmacological effects of psychotropic drugs. Thus, in mild depression, the response to selective serotonin reuptake inhibitor-type antidepressants (SSRI) is associated with a marked increase in circulating NAEs. To further investigate if antidepressants are able to modify the plasma concentration of NAEs in SUD patients, we analyzed the circulating levels of NAEs in 333 abstinent and 175 healthy controls on the basis of the treatment with SSRI antidepressants. As described previously, SUD patients display higher concentrations of NAEs than those measured in a control population. This increase was not further modified by antidepressant therapy. Only marginal increases in palmitoylethanolamide (PEA), oleoylethanolamide (OEA), or docosatetraenoyl-ethanolamide (DEA) were found, and the net effect was very small. Thus, our study shows that treatment with SSRI-type antidepressants does not modify the clinical utility of monitoring enhanced NAE production as biomarkers of SUD. In addition, the possibility that a blunted NAE response to antidepressant therapy might be related to the loss of efficacy of SSRIs in dual depression emerges as an attractive hypothesis that needs to be addressed in future studies.

Palmitoylethanolamide shows limited efficacy in controlling cerebral cryptococcosis in vivo.

Cryptococcus neoformans (Cn) is an encapsulated neurotropic fungal pathogen and the causative agent of cryptococcal meningoencephalitis (CME) in humans. Recommended treatment for CME is Amphotericin B (AmpB) and 5-fluorocytosine (5-FC). Though effective, AmpB has displayed numerous adverse side effects due to its potency and nephrotoxicity, prompting investigation into alternative treatments. Palmitoylethanolamide (PEA) is an immunomodulatory compound capable of promoting neuroprotection and reducing inflammation. To investigate the efficacy of PEA as a therapeutic alternative for CME, we intracerebrally infected mice with Cn and treated them with PEA or AmpB alone or in combination. Our results demonstrate that PEA alone does not significantly prolong survival nor reduce fungal burden, but when combined with AmpB, PEA exerts an additive effect and promotes both survivability and fungal clearance. However, we compared this combination to traditional AmpB and 5-FC treatment in a survivability study and observed lower efficacy. Overall, our study revealed that PEA alone is not effective as an antifungal agent in the treatment of CME. Importantly, we describe the therapeutic capability of PEA in the context of Cn infection and show that its immunomodulatory properties may confer limited protection when combined with an effective fungicidal agent.

EXPRESS: Plasma endocannabinoids and cannabimimetic fatty acid derivatives are altered in cyclic vomiting syndrome: The effects of sham feeding.

Cyclic vomiting syndrome (CVS) is an underdiagnosed disorder of the gut-brain interaction. Our understanding of the pathophysiology of CVS is evolving. Here, we tested the hypotheses that: (1) the levels of endocannabinoids and related lipids are altered in CVS, and (2) cephalic-vagal stimulation drive changes in endolipid levels. Ten adult patients with CVS and 8 healthy controls were included. Indirect measurements of parasympathetic (RFa) functions were performed with spectral analysis of heart rate variability and respiratory activity. Plasma levels of endocannabinoids and related lipids were measured at baseline and during a sham feeding. Values are reported as mean ± SEM and compared using t-test or ANONA. CVS patients had a lower parasympathetic tone and response to Valsalva maneuver and deep breathing than the controls. The baseline 2-Arachidonoylglycerol (2-AG) had a significantly higher concentration in CVS (5.9e-008 ± 3.7e-008 mole/L) than control (3.7e-008 ± 1.3e-008 mole/; p<0.05). Sham feeding did not change the concentration of 2-AG. 2-linoleoylglycerol and 2-oleoylglycerol were significantly higher in CVS than control and did not change with sham feeding. Levels of N-acyl ethanolamines, including Anandamide (AEA), were not different in CVS vs. control. After sham feeding, AEA showed a trend toward increasing (P=0.08) in CVS, but not in control. With sham feeding, palmitoyl ethanolamine significantly increased in both CVS and control groups; oleoyl ethanolamine in CVS only, and stearoyl ethanolamine in the control group. Levels of endocannabinoids and related lipids are altered in CVS patients. Sham feeding affects endogenous signaling lipids in a disease and time-dependent manner.

Sex differences in endocannabinoid tone in a pilot study of cannabis use disorder and acute cannabis abstinence.

Cannabis use disorder (CUD) presents differently in men and women, particularly in symptoms of cannabis withdrawal. Novel pharmacotherapeutic interventions for CUD, such as those that target the endocannabinoid (eCB) system, must be developed in a manner consistent with these sex differences. The present pilot study sought to prospectively assess sex differences in cannabis withdrawal in a small sample of adults with moderate-to-severe CUD and to determine if withdrawal was associated with peripheral eCB and eCB congener tone. Men and women (n= 5/sex) completed 2 weeks of study participation separated by 1 month; in the latter week, participants abstained from cannabis use. Each week, participants attended in-person laboratory visits during which blood was drawn repeatedly to assess plasma eCB and eCB congener tone. Participants also completed multiple daily ambulatory assessments to assess cannabis use and withdrawal symptoms. As anticipated, women reported a greater increase in withdrawal symptoms during the abstinent week [Δ = 9.4 (SE = 1.1); p<0.001] than men [Δ = 1.2 (SE = 1.2); p=0.35]. Sex differences in levels of the eCB N-arachidonoylethanolamide (AEA), as well as the eCB congeners stearoylethanolamide (SEA) and linoleylethanolamide (LEA), were evident during abstinence at the morning time point only (p's <0.05). LEA was associated with withdrawal symptom expression in both sexes [β = 0.16 (SE = 0.09)] and palmitoylethanolamide (PEA) [β = 0.22 (SE = 0.13)] and 2-arachidonoylglycerol (2-AG) [β = 0.32 (SE = 0.15)] were associated with withdrawal symptoms in women only. Pharmacotherapeutic development for CUD should consider evident sex differences in eCB and eCB congener tone during abstinence and their associations with cannabis withdrawal, as eCB-based interventions may produce differential effects by sex.

G protein-coupled receptor 55 activated by palmitoylethanolamide is associated with the development of nocturia associated with circadian rhythm disorders

AimsBladder function is regulated by clock genes and dysregulation of circadian bladder function can cause nocturia. The blood concentration of palmitoylethanolamide (PEA), a fatty acid metabolite, changes with circadian rhythm. Clock gene abnormalities demonstrate the highest PEA levels during the sleep phase. PEA is a GPR55 agonist that influences urination; therefore, increased PEA during the sleep phase may cause nocturia. Herein, we investigated the function of GPR55 to evaluate the relationship between GPR55 and nocturia that evoked higher PEA during the sleep phase in patients with circadian rhythm disorders. Main methodsMale C57BL/6 mice were used. GPR55 localization was evaluated by immunofluorescence staining, qRT-PCR, and western blotting. Variations in PEA-induced intracellular Ca2+ concentrations were measured in primary cultured mouse urothelial cells (UCs) using Ca2+ imaging. PEA-induced NGF and PGI2 release in UCs was measured by ELISA. The micturition reflex pathway after PEA administration was evaluated using immunofluorescence staining. Key findingsGPR55 was predominant in the UC layer. PEA induced release of Ca2+ from the endoplasmic reticulum into the UC cytoplasm. ELISA and immunofluorescence staining revealed that NGF and PGI2 were released from bladder UCs, stimulated the pontine micturition center in mice, and induced nocturia. SignificanceThe loss of regular circadian metabolizing rhythm in fatty acids causes higher blood PEA levels during the sleep phase. Binding of PEA to GPR55 in UC may activate the downstream processes of the micturition reflex, leading to nocturia. These findings suggest a new mechanism for nocturia and its potential as a therapeutic target.

Efficacy of Palmitoylethanolamide and Luteolin Association on Post-Covid Olfactory Dysfunction: A Systematic Review and Meta-Analysis of Clinical Studies.

Post-Covid Olfactory Dysfunction (PCOD) is characterized by olfactory abnormalities, hyposmia, and anosmia, which are among the most often enduring symptoms in individuals who have recovered from SARS-CoV-2 infection. This disorder has been reported to persist in subsets of patients well after 12 months following infection, significantly affecting their quality of life. Despite the high prevalence of PCOD among patients who suffered from SARS-CoV-2 infection, specific therapeutic strategies are still limited. Among these, emerging evidence seems to indicate the administration of CoUltraPEALut, a combination of micronized Palmitoylethanolamide (PEA), an endogenous fatty acid amide, and Luteolin, a natural antioxidant flavonoid, as a viable therapy, especially when given as an adjuvant to olfactory training. Based on the above, a systematic review and a meta-analysis of the literature were conducted, with the aim of evaluating the efficacy of CoUltraPEALut as an addition to olfactory training (OT), in treating PCOD symptoms. Pubmed (MEDLINE), Embase (OVID), and Web of Science scientific databases were screened from the inception until 31 May 2023, and a total of 407 articles were recovered; only five of these studies (441 total patients between treated and control groups) were included in the systematic review. CoUltraPEALut demonstrated significant efficacy in the overall recovery of the olfactory function, compared to the conventional therapy, suggesting that it could represent a possible future adjuvant treatment for PCOD.

In Vitro and In Vivo Safety of Hyaluronic Acid-Decorated Microparticles for Intravitreal Injection of Palmitoylethanolamide, Citicoline, or Glial-Cell-Derived Neurotrophic Factor.

The treatment of posterior eye segment diseases through intravitreal injection requires repeated injections of an active molecule, which may be associated with serious side effects and poor patient compliance. One brilliant strategy to overcome these issues is the use of drug-loaded microparticles for sustained release, aiming at reducing the frequency of injections. Therefore, the aim of this work was to assess the safety features of poly(lactic-co-glycolic acid) (PLGA)-based, hyaluronic acid-decorated microparticles loaded with palmitoylethanolamide (PEA), citicoline (CIT), or glial-cell-derived neurotrophic factor (GDNF). Microparticles were prepared by double emulsion-solvent evaporation and fully characterized for their technological features. Microparticles possessed a satisfactory safety profile in vitro on human retinal pigment epithelial (ARPE-19) cells. Interestingly, the administration of free GDNF led to a loss of cell viability, while GDNF sustained release displayed a positive effect in that regard. In vivo results confirmed the safety profile of both empty and loaded microparticles. Overall, the outcomes suggest that the produced microparticles are promising for improving the local administration of neuroprotective molecules. Further studies will be devoted to assess the therapeutic ability of microparticles.

Palmitoylethanolamide counteracts high-fat diet-induced gut dysfunction by reprogramming microbiota composition and affecting tryptophan metabolism.

Obesity is associated with gastrointestinal (GI) tract and central nervous system (CNS) disorders. High-fat diet (HFD) feeding-induced obesity in mice induces dysbiosis, causing a shift toward bacteria-derived metabolites with detrimental effects on metabolism and inflammation: events often contributing to the onset and progression of both GI and CNS disorders. Palmitoylethanolamide (PEA) is an endogenous lipid mediator with beneficial effects in mouse models of GI and CNS disorders. However, the mechanisms underlining its enteroprotective and neuroprotective effects still need to be fully understood. Here, we aimed to study the effects of PEA on intestinal inflammation and microbiota alterations resulting from lipid overnutrition. Ultramicronized PEA (30 mg/kg/die per os) was administered to HFD-fed mice for 7 weeks starting at the 12th week of HFD regimen. At the termination of the study, the effects of PEA on inflammatory factors and cells, gut microbial features and tryptophan (TRP)-kynurenine metabolism were evaluated. PEA regulates the crosstalk between the host immune system and gut microbiota via rebalancing colonic TRP metabolites. PEA treatment reduced intestinal immune cell recruitment, inflammatory response triggered by HFD feeding, and corticotropin-releasing hormone levels. In particular, PEA modulated HFD-altered TRP metabolism in the colon, rebalancing serotonin (5-HT) turnover and reducing kynurenine levels. These effects were associated with a reshaping of gut microbiota composition through increased butyrate-promoting/producing bacteria, such as Bifidobacterium, Oscillospiraceae and Turicibacter sanguinis, with the latter also described as 5-HT sensor. These data indicate that the rebuilding of gut microbiota following PEA supplementation promotes host 5-HT biosynthesis, which is crucial in regulating intestinal function.

Changes in plasma endocannabinoids concentrations correlate with 18F-FDG PET/MR uptake in brown adipocytes in humans.

Introduction: Recent data suggest a possible role of endocannabinoids in the regulation of brown adipose tissue (BAT) activity. Those findings indicate potential treatment options for obesity. The aim of this study was to evaluate the relationship between plasma endocannabinoids concentrations and the presence of BAT in humans. Methods: The study group consisted of 25 subjects divided into two groups: BAT positive BAT(+), (n = 17, median age = 25years) and BAT negative BAT(-), (n = 8, median age = 28years). BAT was estimated using 18F-FDG PET/MR after 2h of cold exposure. The level of plasma endocannabinoids was assessed at baseline, 60min and 120min of cold exposure. Results: In both groups, BAT(+) and BAT(-), during the cooling, we observed a decrease of the same endocannabinoids: arachidonoylethanolamide (AEA), eicosapentaenoyl ethanolamide (EPEA) and oleoyl ethanolamide (OEA) with a much more profound decline in BAT(+) subjects. Statistically significant fall of PEA (palmitoylethanolamide) and SEA (stearoylethanolamide) concentrations after 60min (FC = 0.7, p = 0.007 and FC = 0.8, p = 0.03, respectively) and 120min (FC = 0.81, p = 0.004, and FC = 0.9, p = 0.01, respectively) of cooling was observed only in individuals with BAT. Conclusion: We noticed the profound decline of endocannabinoids concentrations in subjects with increased 18F-FDG PET/MR uptake in BAT. Identification of a new molecules related to BAT activity may create a new target for obesity treatment.

Inhibiting immunoregulatory amidase NAAA blocks ZIKV maturation in Human Neural Stem Cells

Recent evidence suggests that lipids play a crucial role in viral infections beyond their traditional functions of supplying envelope and energy, and creating protected niches for viral replication. In the case of Zika virus (ZIKV), it alters host lipids by enhancing lipogenesis and suppressing β-oxidation to generate viral factories at the endoplasmic reticulum (ER) interface. This discovery prompted us to hypothesize that interference with lipogenesis could serve as a dual antiviral and anti-inflammatory strategy to combat the replication of positive sense single-stranded RNA (ssRNA+) viruses.To test this hypothesis, we examined the impact of inhibiting N-Acylethanolamine acid amidase (NAAA) on ZIKV-infected human Neural Stem Cells. NAAA is responsible for the hydrolysis of palmitoylethanolamide (PEA) in lysosomes and endolysosomes. Inhibition of NAAA results in PEA accumulation, which activates peroxisome proliferator-activated receptor-α (PPAR-α), directing β-oxidation and preventing inflammation.Our findings indicate that inhibiting NAAA through gene-editing or drugs moderately reduces ZIKV replication by approximately one log10 in Human Neural Stem Cells, while also releasing immature virions that have lost their infectivity. This inhibition impairs furin-mediated prM cleavage, ultimately blocking ZIKV maturation. In summary, our study highlights NAAA as a host target for ZIKV infection.