Research

Palmitoylethanolamide

71 peer-reviewed studies curated from PubMed and Semantic Scholar.

8
Meta-analyses
8
Systematic reviews
48
RCTs
7
Other studies
Meta-analyses (11%)
Systematic reviews (11%)
RCTs (68%)
Observational (4%)

Studies

Sorted by quality and recency

2025·Nutrition reviews·Isabel Viña, Miguel López-Moreno

Meta-Analysis of Palmitoylethanolamide in Pain Management: Addressing Literature Gaps and Enhancing Understanding.

Meta-analysisn = 1,196Inflammation

This meta-analysis evaluated the efficacy of palmitoylethanolamide (PEA) in alleviating pain across various pathologies. It included 18 studies with 1196 patients and found that PEA significantly reduced pain and improved quality of life, with benefits observed within 4-6 weeks of treatment. PEA was effective for nociceptive, neuropathic, and nociplastic pain types.

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2024·Clinical & experimental ophthalmology·Ting-Kai Yang, Hou-Ting Kuo, Yuh-Jen Ju, et al

Comparative analysis of medical treatments for long-term control of normal tension glaucoma: A systematic review and model-based network meta-analysis.

Meta-analysisn = 795

Systematic review and model-based network meta-analysis comparing the long-term efficacy of medical treatments for normal tension glaucoma in controlling intraocular pressure. Among the eight medications analyzed, palmitoylethanolamide (PEA) demonstrated the highest efficacy, suggesting its potential use as a primary or adjunctive therapy.

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2024·Nutrients·Vittorio Schweiger, Carlo Schievano, Alvise Martini, et al

Extended Treatment with Micron-Size Oral Palmitoylethanolamide (PEA) in Chronic Pain: A Systematic Review and Meta-Analysis.

Meta-analysisn = 742Inflammation

Systematic review and meta-analysis of micron-size palmitoylethanolamide (PEA) for chronic pain management. Analyzed nine studies with 742 patients, showing significant pain reduction after 60 days of PEA supplementation compared to 30 days, with a 35.1% pain reduction in the first month and an additional 35.4% in the second month.

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2024·Natural product research·Lelio Crupi, Anna Paola Capra, Irene Paterniti, et al

Evaluation of the nutraceutical Palmitoylethanolamide in reducing intraocular pressure (IOP) in patients with glaucoma or ocular hypertension: a systematic review and meta-analysis.

Meta-analysisn = 199

Systematic review and meta-analysis evaluating the effectiveness of Palmitoylethanolamide (PEA) in reducing intraocular pressure (IOP) in patients with glaucoma or ocular hypertension. Six studies with 199 patients were included, showing significant efficacy of PEA in reducing IOP.

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2024·Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology·Alon Gorenshtein, Tom Liba, Liron Leibovitch, et al

Intervention modalities for brain fog caused by long-COVID: systematic review of the literature.

Systematic reviewBrain Health

Systematic review of interventions for brain fog in long-COVID patients, including noninvasive brain stimulation, hyperbaric oxygen therapy, and PEA-LUT administration. PEA-LUT was associated with improvements in cognitive impairment, while other interventions also showed promising results.

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2023·Nutrients·Kordula Lang-Illievich, Christoph Klivinyi, Christian Lasser, et al

Palmitoylethanolamide in the Treatment of Chronic Pain: A Systematic Review and Meta-Analysis of Double-Blind Randomized Controlled Trials.

Meta-analysisn = 774Inflammation

Systematic review and meta-analysis of double-blind RCTs evaluating palmitoylethanolamide (PEA) for chronic pain treatment. PEA reduced pain scores with a standard mean difference of 1.68 and showed additional benefits for quality of life and functional status without major side effects.

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2023·Nutrients·Amanda Rao, Rachael Skinner, David Briskey

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

RCTn = 426Immunity

Double-blind, randomized, placebo-controlled trial assessing the effectiveness of Palmitoylethanolamide (Levagen+) on URTI incidence, duration, and severity. The Levagen+ group reported fewer URTI episodes and a significant reduction in symptom severity compared to the placebo group.

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2023·European archives of oto-rhino-laryngology : official journal of the European Federation of Oto-Rhino-Laryngological Societies (EUFOS) : affiliated with the German Society for Oto-Rhino-Laryngology - Head and Neck Surgery·Arianna Di Stadio, Salvatore Gallina, Salvatore Cocuzza, et al

Treatment of COVID-19 olfactory dysfunction with olfactory training, palmitoylethanolamide with luteolin, or combined therapy: a blinded controlled multicenter randomized trial.

RCTn = 202Brain Health

This double-blinded controlled multicenter randomized clinical trial investigated the efficacy of olfactory training, palmitoylethanolamide with luteolin (um-PEA-LUT), or combined therapy in 202 patients with chronic olfactory dysfunction post-COVID-19. At 90 days, combined therapy showed significant improvement in odor identification scores compared to other groups, with 89.2% of patients improving by over 3 points.

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2023·Frontiers in psychiatry·Riccardo Bortoletto, Fabiana Piscitelli, Anna Candolo, et al

Questioning the role of palmitoylethanolamide in psychosis: a systematic review of clinical and preclinical evidence.

Systematic reviewBrain Health

Systematic review of clinical and preclinical studies on palmitoylethanolamide (PEA) in psychosis. Evidence suggests increased PEA levels in psychosis patients and potential benefits of PEA supplementation in reducing negative psychotic and manic symptoms without serious adverse events.

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2022·Viruses·Nicola Veronese, Roberta Bonica, Sergio Cotugno, et al

Interventions for Improving Long COVID-19 Symptomatology: A Systematic Review.

Systematic review

Systematic review of interventions for long COVID-19 symptoms. Two studies were included: one RCT on olfactory rehabilitation with oral supplementation of Palmitoylethanolamide and Luteolin, and another on aromatherapy for fatigue. More studies are needed to explore effective interventions.

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2022·Frontiers in psychiatry·Marco Colizzi, Riccardo Bortoletto, Chiara Colli, et al

Therapeutic effect of palmitoylethanolamide in cognitive decline: A systematic review and preliminary meta-analysis of preclinical and clinical evidence.

Systematic reviewBrain Health Mental Clarity

This systematic review and preliminary meta-analysis examined the effects of palmitoylethanolamide (PEA) on neurocognitive disorders. PEA was found to improve neurobehavioral functions in animal models by reducing oxidative stress and inflammation, and promoting neurogenesis. Limited human studies suggest PEA supplementation reduces fatigue and cognitive impairment, improving executive function and daily living activities.

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2021·Nutrients·Marco Colizzi, Riccardo Bortoletto, Rosalia Costa, et al

Palmitoylethanolamide and Its Biobehavioral Correlates in Autism Spectrum Disorder: A Systematic Review of Human and Animal Evidence.

Systematic reviewBrain Health

Systematic review of human and animal studies examining palmitoylethanolamide (PEA) in autism spectrum disorder (ASD). Limited research suggests PEA supplementation reduces autism severity by improving language and social behaviors, potentially through modulation of immune response and neuroinflammation.

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2017·Pain physician·Bekir Berker Artukoglu, Chad Beyer, Adi Zuloff-Shani, et al

Efficacy of Palmitoylethanolamide for Pain: A Meta-Analysis.

Meta-analysisn = 786Inflammation

Meta-analysis of randomized controlled trials examining the efficacy of palmitoylethanolamide (PEA) for pain management. PEA was associated with significantly greater pain reduction compared to inactive control conditions. The analysis included data from 786 patients who received PEA and 512 controls.

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2025·Journal of psychiatric research·Luca Steardo, Martina D'Angelo, Valeria Di Stefano, et al

Targeting PTSD with ultramicronized palmitoylethanolamide: Results from a randomized trial integrating pharmacotherapy and cognitive behavioral therapy.

RCTn = 60Mental Clarity Mood

Randomized, placebo-controlled trial of 60 PTSD patients comparing ultramicronized palmitoylethanolamide (PEA-um) and PEA-um + CBT to placebo and placebo + CBT over 18 months. PEA-um + CBT showed the most significant reduction in PTSD and anxiety symptoms, with no serious adverse events reported.

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2025·Women & health·Amanda Rao, Jane Erickson, David Briskey

Palmitoylethanolamide (Levagen+) for acute menstrual pain: a randomized, crossover, double-blind, placebo-controlled trial.

RCTWomens Health

This randomized, double-blind, placebo-controlled crossover study investigated palmitoylethanolamide (PEA) for menstrual pain relief in adults over 18. PEA resulted in a significant reduction in pain scores at multiple time points post-dosage compared to placebo, demonstrating its safety and effectiveness for reducing menstrual pain.

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2024·European archives of oto-rhino-laryngology : official journal of the European Federation of Oto-Rhino-Laryngological Societies (EUFOS) : affiliated with the German Society for Oto-Rhino-Laryngology - Head and Neck Surgery·Elena Cantone, Luca D'Ascanio, Pietro De Luca, et al

Persistent COVID-19 parosmia and olfactory loss post olfactory training: randomized clinical trial comparing central and peripheral-acting therapeutics.

RCTn = 85Brain Health

RCT of 85 patients with persistent COVID-19 olfactory dysfunction comparing ultramicronized palmitoylethanolamide and luteolin (umPEALUT) with olfactory training, alpha-lipoic acid (ALA) with olfactory training, a combination of both, and olfactory training alone. The umPEALUT and combination groups showed significant improvements in olfactory function and parosmia resolution compared to ALA and control groups.

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2024·Nutrients·Triantafyllos Didangelos, Eleni Karlafti, Evangelia Kotzakioulafi, et al

Efficacy and Safety of the Combination of Palmitoylethanolamide, Superoxide Dismutase, Alpha Lipoic Acid, Vitamins B12, B1, B6, E, Mg, Zn and Nicotinamide for 6 Months in People with Diabetic Neuropathy.

RCTn = 73

RCT of 73 people with diabetic neuropathy comparing a combination supplement of palmitoylethanolamide, superoxide dismutase, alpha lipoic acid, vitamins B12, B1, B6, E, nicotinamide, magnesium, and zinc to placebo for 6 months. The active group showed significant improvements in pain, vibration perception threshold, and vitamin B12 levels.

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2024·Skin pharmacology and physiology·Amanda Rao, Amel A Moussa, Jane Erickson, et al

Efficacy of Topical Palmitoylethanolamide (Levagen+) for the Management of Eczema Symptoms: A Double-Blind, Comparator-Controlled, Randomized Clinical Trial.

RCTn = 72Skin Hair Health

This double-blind, randomized, comparator-controlled trial evaluated the effectiveness of topical palmitoylethanolamide (Levagen+) compared to a standard moisturizer in reducing eczema severity. Levagen+ significantly reduced redness, dryness, and total POEM score over 4 weeks, supporting its use as a potential treatment for eczema.

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2024·Nutrition (Burbank, Los Angeles County, Calif.)·Giovanni Di Nardo, Luca Bernardo, Cesare Cremon, et al

Palmitoylethanolamide and polydatin in pediatric irritable bowel syndrome: A multicentric randomized controlled trial.

RCTn = 70Gut Health

This multicenter RCT evaluated the efficacy and safety of co-micronized palmitoylethanolamide (PEA) and polydatin (PD) in treating abdominal pain symptoms in pediatric IBS patients. The study involved 70 children, with the treatment group showing significant improvement in complete remission rates and reduction in abdominal pain compared to placebo, particularly in the IBS-diarrhea subtype.

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2024·ORL; journal for oto-rhino-laryngology and its related specialties·Janine Gellrich, Linda Czaplewski, Antje Hähner, et al

Palmitoylethanolamide and Luteolin for Postinfectious Olfactory Disorders: How Clinically Meaningful Is Its Effect?

RCTn = 50

RCT of 50 patients with post-viral olfactory dysfunction comparing olfactory training (OT) with and without palmitoylethanolamide (PEA) and luteolin (LUT). The study group showed significant improvements in odor discrimination and overall olfactory function, but no clinically meaningful difference was found between the groups.

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2024·Current allergy and asthma reports·Sabrina Bischoff, Mathilde Moyaert, Marnick Clijsters, et al

Treatment of COVID-19 Associated Olfactory Dysfunction: A Systematic Review.

Systematic review

Systematic review of 36 studies on treatments for COVID-19 associated olfactory dysfunction, including vitamin supplements like palmitoylethanolamide with luteolin. PRP and calcium chelators showed significant improvements in olfactory function score, while olfactory training and corticosteroids did not.

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2023·Clinical and experimental rheumatology·Fausto Salaffi, Sonia Farah, Piercarlo Sarzi-Puttini, et al

Palmitoylethanolamide and acetyl-L-carnitine act synergistically with duloxetine and pregabalin in fibromyalgia: results of a randomised controlled study.

RCTn = 130Inflammation

RCT evaluating the efficacy of supplementing ongoing pregabalin and duloxetine treatment with palmitoylethanolamide and acetyl-L-carnitine in fibromyalgia patients. Group 2, which received the supplements, showed significant improvements in Widespread Pain Index, Fibromyalgia Impact Questionnaire, and Fibromyalgia Assessment Status scores over 24 weeks.

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2023·Nutrients·David Briskey, Phillippa Ebelt, Amanda Rao

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

RCTn = 108Inflammation

Double-blind, placebo-controlled trial of 108 participants with seasonal allergic rhinitis, testing 350 mg of palmitoylethanolamide (Levagen+) daily for two weeks. No significant difference in allergy symptom scores overall, but significant reduction in symptoms for those with mild-to-moderate baseline scores. Levagen+ group showed significant decreases in histamine and inflammatory markers.

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2022·Current neuropharmacology·Arianna Di Stadio, Luca D'Ascanio, Luigi Angelo Vaira, et al

Ultramicronized Palmitoylethanolamide and Luteolin Supplement Combined with Olfactory Training to Treat Post-COVID-19 Olfactory Impairment: A Multi-Center Double-Blinded Randomized Placebo- Controlled Clinical Trial.

RCTn = 185

Multicenter double-blinded randomized placebo-controlled trial of 185 patients with post-COVID-19 olfactory impairment. The intervention group received ultramicronized PEA-LUT supplements plus olfactory training, showing significantly greater improvement in olfactory function compared to controls receiving olfactory training with placebo.

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2022·Inflammopharmacology·Emily Pickering, Elizabeth L Steels, Kathryn J Steadman, et al

A randomized controlled trial assessing the safety and efficacy of palmitoylethanolamide for treating diabetic-related peripheral neuropathic pain.

RCTn = 70Inflammation Sleep Mood

This randomized controlled trial assessed the safety and efficacy of palmitoylethanolamide (PEA) for treating diabetic-related peripheral neuropathic pain in 70 participants. The PEA group showed significant reductions in pain, improved sleep quality, reduced depression scores, and decreased inflammation markers compared to placebo. The treatment was well tolerated with no significant safety concerns.

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2022·Cells·Pietro De Luca, Angelo Camaioni, Pasquale Marra, et al

Effect of Ultra-Micronized Palmitoylethanolamide and Luteolin on Olfaction and Memory in Patients with Long COVID: Results of a Longitudinal Study.

RCTn = 69Brain Health Mental Clarity

RCT investigating the effects of palmitoylethanolamide and luteolin (PEA-LUT) on olfactory dysfunction and mental clouding in long COVID patients. PEA-LUT therapy significantly improved odor identification scores and reduced mental clouding severity over three months.

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2022·Psychiatry and clinical neurosciences·Talieh Abedini, Reyhaneh Hosseyni, Farnaz Ghannadi, et al

Efficacy and safety of palmitoylethanolamide as an adjunctive treatment for acute mania: A randomized, double-blind, placebo-controlled trial.

RCTn = 63Mood

RCT investigating palmitoylethanolamide as an adjunctive treatment for acute mania. 63 patients were assigned to receive either palmitoylethanolamide or placebo alongside lithium and risperidone. The palmitoylethanolamide group showed a significantly greater decrease in Young Mania Rating Scale scores compared to placebo, indicating improved manic symptoms.

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2022·The Journal of nutrition·Samantha N Fessler, Li Liu, Yung Chang, et al

Palmitoylethanolamide Reduces Proinflammatory Markers in Unvaccinated Adults Recently Diagnosed with COVID-19: A Randomized Controlled Trial.

RCTn = 60Inflammation Immunity

This randomized controlled trial examined the effects of palmitoylethanolamide (PEA) supplementation on proinflammatory biomarkers in unvaccinated adults recently diagnosed with COVID-19. After 4 weeks, the PEA group showed significant reductions in sP-selectin, IL-1β, and IL-2 concentrations compared to the placebo group, indicating anti-inflammatory effects.

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2022·Psychiatry research·Anahita Salehi, Parsa Namaei, Fateme TaghaviZanjani, et al

Adjuvant palmitoylethanolamide therapy with risperidone improves negative symptoms in patients with schizophrenia: A randomized, double-blinded, placebo-controlled trial.

RCTn = 50Mental Clarity

This 8-week double-blind, placebo-controlled trial assessed the efficacy of 600 mg twice a day of palmitoylethanolamide (PEA) as adjunctive therapy with risperidone in patients with schizophrenia. The PEA group showed significant improvement in negative symptoms compared to placebo, with no significant differences in safety outcomes.

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2022·The Cochrane database of systematic reviews·Lisa O'Byrne, Katie E Webster, Samuel MacKeith, et al

Interventions for the treatment of persistent post-COVID-19 olfactory dysfunction.

Systematic reviewn = 30

Systematic review evaluating interventions for persistent post-COVID-19 olfactory dysfunction. Included two small RCTs: one with systemic corticosteroids and intranasal treatment, and another with palmitoylethanolamide plus luteolin. Both studies had very low certainty of evidence, preventing meaningful conclusions.

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2019·The American journal of hospice & palliative care·Mellar P Davis, Bertrand Behm, Zankhana Mehta, et al

The Potential Benefits of Palmitoylethanolamide in Palliation: A Qualitative Systematic Review.

Systematic reviewMood Brain Health

Qualitative systematic review of palmitoylethanolamide (PEA), a nutraceutical endocannabinoid, highlighting its pain-relieving effects and potential benefits for nonpain symptoms related to depression, Parkinson's disease, strokes, and autism. PEA targets nonclassical cannabinoid receptors and has minimal reported adverse effects.

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2017·Annali dell'Istituto superiore di sanita·Ugo Indraccolo, Salvatore Renato Indraccolo, Fiorenzo Mignini

Micronized palmitoylethanolamide/trans-polydatin treatment of endometriosis-related pain: a meta-analysis.

Meta-analysisWomens Health

Meta-analysis of four studies assessing the effectiveness of micronized palmitoylethanolamide/trans-polydatin in reducing endometriotic chronic pelvic pain. The combination provided clinically relevant improvement in chronic pelvic pain and dysmenorrhea, with limited improvement in deep dyspareunia. No significant improvement was found for dyschezia.

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2016·Pain physician·Antonella Paladini, Mariella Fusco, Teresa Cenacchi, et al

Palmitoylethanolamide, a Special Food for Medical Purposes, in the Treatment of Chronic Pain: A Pooled Data Meta-analysis.

Meta-analysisInflammation

Pooled meta-analysis of 12 studies evaluating the efficacy and safety of micronized and ultra-micronized palmitoylethanolamide (PEA) on pain intensity in chronic and neuropathic pain patients. Results showed PEA significantly reduced pain intensity compared to control, with a progressive reduction of 1.04 points every 2 weeks. No serious adverse events related to PEA were reported.

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2025·Brain communications·Martina Assogna, Francesco Di Lorenzo, Sonia Bonnì, et al

Phase 2 study of palmitoylethanolamide combined with luteoline in frontotemporal dementia patients.

RCTn = 48Brain Health

Phase 2 RCT evaluating the safety and efficacy of co-ultramicronized palmitoylethanolamide combined with luteoline in 48 frontotemporal dementia patients. The treatment group showed less decline in cognitive and functional symptoms compared to placebo, indicating promising efficacy in slowing disease progression.

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2025·Nutrients·Kevin Cornali, Manuela Di Lauro, Giulia Marrone, et al

The Effects of a Food Supplement, Based on Co-Micronized Palmitoylethanolamide (PEA)-Rutin and Hydroxytyrosol, in Metabolic Syndrome Patients: Preliminary Results.

RCTn = 19Inflammation Physique

Randomized crossover double-blind placebo-controlled pilot study of a food supplement containing co-micronized PEA-rutin and hydroxytyrosol in 19 metabolic syndrome patients. The supplement led to significant reductions in body weight, BMI, fat mass, and inflammation biomarkers, while increasing fat-free mass, phase angle, and body cell mass compared to placebo.

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2024·Nutrients·Nadia Kim, Brenda Parolin, Derek Renshaw, et al

Formulated Palmitoylethanolamide Supplementation Improves Parameters of Cognitive Function and BDNF Levels in Young, Healthy Adults: A Randomised Cross-Over Trial.

RCTn = 39Brain Health Mental Clarity

A randomised double-blinded placebo-controlled cross-over trial assessed the effects of a 6-week 700 mg/day course of formulated PEA supplementation on serum BDNF levels and cognitive function in 39 healthy adults. PEA supplementation significantly increased serum BDNF levels and improved memory performance on cognitive tests compared to placebo.

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2024·Medicine and science in sports and exercise·Moniek Schouten, Sebastiaan Dalle, Domiziana Costamagna, et al

Palmitoylethanolamide Does Not Affect Recovery from Exercise-Induced Muscle Damage in Healthy Males.

RCTn = 11Recovery -Physical Performance -

Double-blind crossover study with 11 healthy males evaluating the effect of palmitoylethanolamide (PEA) supplementation on recovery from exercise-induced muscle damage. PEA supplementation did not improve muscle soreness, muscle strength, jump performance, or affect markers of muscle damage, catabolism, or regeneration following eccentric exercise.

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2022·Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology·Viviana Versace, Paola Ortelli, Sabrina Dezi, et al

Co-ultramicronized palmitoylethanolamide/luteolin normalizes GABA-ergic activity and cortical plasticity in long COVID-19 syndrome.

RCTn = 39Brain Health

RCT of 39 long COVID-19 patients with cognitive dysfunction and fatigue, testing co-ultramicronized palmitoylethanolamide/luteolin (PEA-LUT) versus placebo. PEA-LUT treatment significantly increased long-interval intracortical inhibition (LICI) and LTP-like cortical plasticity, suggesting restoration of GABAergic activity and cortical plasticity.

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2022·Nutrients·Kordula Lang-Illievich, Christoph Klivinyi, Gudrun Rumpold-Seitlinger, et al

The Effect of Palmitoylethanolamide on Pain Intensity, Central and Peripheral Sensitization, and Pain Modulation in Healthy Volunteers-A Randomized, Double-Blinded, Placebo-Controlled Crossover Trial.

RCTn = 14

This randomized, double-blinded, placebo-controlled crossover trial investigated the effects of palmitoylethanolamide (PEA) on pain modulation in 14 healthy volunteers. PEA treatment significantly decreased repetitive heat pain, increased cold pain tolerance, pressure pain tolerance, and conditioned pain modulation, and decreased the wind-up ratio and allodynia distance, demonstrating its analgesic properties.

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2021·European review for medical and pharmacological sciences·L D'Ascanio, F Vitelli, C Cingolani, et al

Randomized clinical trial "olfactory dysfunction after COVID-19: olfactory rehabilitation therapy vs. intervention treatment with Palmitoylethanolamide and Luteolin": preliminary results.

RCTn = 12Inflammation

RCT of 12 COVID-19 patients with post-infection olfactory impairment comparing olfactory rehabilitation alone to rehabilitation plus daily oral supplement with Palmitoylethanolamide and Luteolin. The supplement group showed greater improvement in olfactory threshold, discrimination, and identification scores.

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2020·Nutrients·Alistair Mallard, David Briskey, Andrew Richards, et al

The Effect of Orally Dosed Levagen+™ (palmitoylethanolamide) on Exercise Recovery in Healthy Males-A Double-Blind, Randomized, Placebo-Controlled Study.

RCTn = 28Recovery

This double-blind, randomized, placebo-controlled study evaluated the effect of palmitoylethanolamide (PEA) on exercise recovery in 28 healthy young males. PEA supplementation reduced myoglobin and blood lactate concentrations and increased protein kinase B phosphorylation, suggesting it may aid in muscle recovery from repeat bouts of exercise.

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2019·Inflammopharmacology·Elizabeth Steels, Ruchitha Venkatesh, Eleanor Steels, et al

A double-blind randomized placebo controlled study assessing safety, tolerability and efficacy of palmitoylethanolamide for symptoms of knee osteoarthritis.

RCTn = 111Joint Bone Health Inflammation Stress

A double-blind randomized placebo-controlled study assessed the safety, tolerability, and efficacy of palmitoylethanolamide (PEA) at 300 mg and 600 mg per day on symptoms of knee osteoarthritis in 111 participants. Significant reductions were observed in WOMAC scores, NRS pain evaluations, and anxiety (DASS) in both PEA groups compared to placebo, indicating PEA's potential as a treatment for knee osteoarthritis.

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2019·CNS & neurological disorders drug targets·Giorgio Cruccu, Giulia Di Stefano, Paolo Marchettini, et al

Micronized Palmitoylethanolamide: A Post Hoc Analysis of a Controlled Study in Patients with Low Back Pain - Sciatica.

RCT

Post hoc analysis of a controlled study on micronized palmitoylethanolamide in patients with low back pain - sciatica. Palmitoylethanolamide 600 mg/die was found to be extremely effective for pain and function, with a number needed to treat of 1.7 for pain and 1.5 for function compared to placebo.

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2019·Inflammatory bowel diseases·Daniel G Couch, Hollie Cook, Catherine Ortori, et al

Palmitoylethanolamide and Cannabidiol Prevent Inflammation-induced Hyperpermeability of the Human Gut In Vitro and In Vivo-A Randomized, Placebo-controlled, Double-blind Controlled Trial.

RCTGut Health Inflammation

This study examined the effects of cannabidiol (CBD) and palmitoylethanolamide (PEA) on gut permeability in vitro and in vivo. Both substances reduced inflammation-induced hyperpermeability in human gut models and decreased the absorption of lactulose and mannitol in humans taking aspirin, suggesting potential benefits for conditions like inflammatory bowel disease.

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2018·Journal of psychiatric research·Mona Khalaj, Amene Saghazadeh, Elham Shirazi, et al

Palmitoylethanolamide as adjunctive therapy for autism: Efficacy and safety results from a randomized controlled trial.

RCTn = 70Inflammation

RCT of 70 children with autism testing co-treatment with risperidone and palmitoylethanolamide (PEA) over 10 weeks. The combination showed superior efficacy in reducing irritability and hyperactivity symptoms compared to risperidone plus placebo.

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2017·Journal of orthopaedics and traumatology : official journal of the Italian Society of Orthopaedics and Traumatology·Jordi Faig-Martí, Adriana Martínez-Catassús

Use of palmitoylethanolamide in carpal tunnel syndrome: a prospective randomized study.

RCTn = 61Inflammation -Joint Bone Health -

A prospective double-blinded randomized study on 61 patients with low to moderate carpal tunnel syndrome (CTS) evaluated the effects of 600 mg/day palmitoylethanolamide (PEA) versus placebo over 60 days. No significant differences were observed in clinical and electrophysiological parameters, though some improvement in the functional status scale was noted with PEA.

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2017·Alimentary pharmacology & therapeutics·C Cremon, V Stanghellini, M R Barbaro, et al

Randomised clinical trial: the analgesic properties of dietary supplementation with palmitoylethanolamide and polydatin in irritable bowel syndrome.

RCTn = 54Gut Health

A 12-week, randomised, double-blind, placebo-controlled study assessed the effect of palmitoylethanolamide/polydatin supplementation on IBS patients. The treatment significantly improved abdominal pain severity compared to placebo, suggesting a promising natural approach for pain management in IBS.

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2016·Pain·Sven R Andresen, Jette Bing, Rikke M Hansen, et al

Ultramicronized palmitoylethanolamide in spinal cord injury neuropathic pain: a randomized, double-blind, placebo-controlled trial.

RCTn = 68Inflammation -Sleep -

This randomized, double-blind, placebo-controlled trial investigated the effect of ultramicronized palmitoylethanolamide (PEA-um) as add-on therapy on neuropathic pain in individuals with spinal cord injury. The study found no significant difference in mean pain intensity, spasticity, insomnia, or psychological functioning between PEA-um and placebo treatments.

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2016·Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics·Nicola S Orefice, Mireille Alhouayek, Antonio Carotenuto, et al

Oral Palmitoylethanolamide Treatment Is Associated with Reduced Cutaneous Adverse Effects of Interferon-β1a and Circulating Proinflammatory Cytokines in Relapsing-Remitting Multiple Sclerosis.

RCTInflammation

This randomized, double-blind, placebo-controlled study evaluated the effect of ultramicronized palmitoylethanolamide (um-PEA) added to interferon-β1a in patients with relapsing-remitting multiple sclerosis. Patients receiving um-PEA reported improved pain sensation and quality of life, with a significant reduction in proinflammatory cytokines compared to placebo. No significant difference was observed in EDSS score, and um-PEA was well tolerated.

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2016·Trials·Maura Marcucci, Federico Germini, Anna Coerezza, et al

Efficacy of ultra-micronized palmitoylethanolamide (um-PEA) in geriatric patients with chronic pain: study protocol for a series of N-of-1 randomized trials.

RCTInflammation

This study protocol outlines a series of N-of-1 randomized trials to test the effectiveness of ultra-micronized palmitoylethanolamide (um-PEA) in geriatric patients with chronic pain. The trials will be placebo-controlled, randomized crossover trials to evaluate pain intensity, need for analgesics, and impact on daily activities.

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2015·Minerva ginecologica·S Caruso, M Iraci Sareri, E Casella, et al

Chronic pelvic pain, quality of life and sexual health of women treated with palmitoylethanolamide and α-lipoic acid.

RCTn = 56Womens Health Sexual Health

RCT evaluating the effects of palmitoylethanolamide (PEA) and alpha-lipoic acid (LA) on quality of life and sexual function in women with endometriosis-associated pelvic pain. By the 6th and 9th month, pain symptoms and all categories of QoL improved significantly, as did sexual function and distress scores.

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2011·Minerva medica·R Conigliaro, V Drago, P S Foster, et al

Use of palmitoylethanolamide in the entrapment neuropathy of the median in the wrist.

RCTInflammation Joint Bone Health

RCT investigating the effect of palmitoylethanolamide (PEA) on carpal tunnel syndrome (CTS). PEA treatment significantly improved median nerve latency time and reduced Tinel's sign presence and symptoms of discomfort in patients with moderate CTS.

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2020·Pain research & management·Laura Papetti, Giorgia Sforza, Giulia Tullo, et al

Tolerability of Palmitoylethanolamide in a Pediatric Population Suffering from Migraine: A Pilot Study.

Studyn = 70Inflammation

Open-label study evaluating the efficacy of ultramicronized palmitoylethanolamide (umPEA) in the prophylactic treatment of migraine in 70 pediatric patients. After three months, headache frequency was reduced by >50% in 63.9% of patients, and attack intensity decreased significantly. The study suggests umPEA may reduce pain intensity and attack frequency in pediatric migraine patients.

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2018·CNS & neurological disorders drug targets·Maurizio Evangelista, Cilli, R De Vitis, et al

Ultra-micronized Palmitoylethanolamide Effects on Sleep-wake Rhythm and Neuropathic Pain Phenotypes in Patients with Carpal Tunnel Syndrome: An Open-label, Randomized Controlled Study.

RCTn = 42Sleep

Open-label, randomized controlled study on 42 patients with carpal tunnel syndrome assessing ultramicronized palmitoylethanolamide (600 mg twice daily) for sleep quality and pain reduction. Significant improvements in sleep quality and reduction in pain symptoms were observed in the treated group.

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2018·Clinical oral investigations·Giulia Ottaviani, Katia Rupel, Margherita Gobbo, et al

Efficacy of ultramicronized palmitoylethanolamide in burning mouth syndrome-affected patients: a preliminary randomized double-blind controlled trial.

RCTn = 35

This preliminary randomized double-blind controlled trial tested the efficacy of ultramicronized palmitoylethanolamide in patients with burning mouth syndrome. A statistically significant reduction in burning mouth sensation was observed in the treatment group compared to placebo, with no reported side effects.

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2017·Archivio italiano di urologia, andrologia : organo ufficiale [di] Societa italiana di ecografia urologica e nefrologica·Bruno Giammusso, Rosaria Di Mauro, Renato Bernardini

The efficacy of an association of palmitoylethanolamide and alpha-lipoic acid in patients with chronic prostatitis/chronic pelvic pain syndrome: A randomized clinical trial.

RCTn = 44

Randomized clinical trial comparing Palmitoylethanolamide (PEA) plus Alpha-lipoic acid (ALA) to Serenoa Repens in 44 patients with chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). The PEA and ALA combination significantly improved IPSS and NIH-CPSI scores over 12 weeks, with no significant improvement in IIEF5 score.

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2017·Journal of ocular pharmacology and therapeutics : the official journal of the Association for Ocular Pharmacology and Therapeutics·Antonio Di Zazzo, Gloria Roberti, Alireza Mashaghi, et al

Use of Topical Cannabinomimetic Palmitoylethanolamide in Ocular Surface Disease Associated with Antiglaucoma Medications.

RCTn = 30Inflammation

Pilot clinical trial evaluating the effect of topical palmitoylethanolamide (PEA) in glaucomatous patients using antiglaucoma drugs. PEA improved ocular surface inflammation markers such as Schirmer test, tear film breakup time, and conjunctival hyperemia by day 30.

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2017·Drugs & aging·Federico Germini, Anna Coerezza, Luca Andreinetti, et al

N-of-1 Randomized Trials of Ultra-Micronized Palmitoylethanolamide in Older Patients with Chronic Pain.

RCTn = 10Joint Bone Health

N-of-1 randomized trials of ultra-micronized palmitoylethanolamide (um-PEA) in older patients with chronic pain. A small statistically significant effect in favor of um-PEA was seen in two patients for pain reduction, and a significant impact on function was found in one patient.

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2016·Proceedings of the National Academy of Sciences of the United States of America·Eleonora Palma, Jorge Mauricio Reyes-Ruiz, Diego Lopergolo, et al

Acetylcholine receptors from human muscle as pharmacological targets for ALS therapy.

Cohort studyn = 76Physical Performance

The study investigates the effects of palmitoylethanolamide (PEA) on acetylcholine receptor function in ALS patients. PEA reduced desensitization of acetylcholine-evoked currents and improved muscle force and respiratory efficacy in ALS patients, suggesting potential benefits for pulmonary function.

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2014·Journal of medicinal food·Ciro Costagliola, Mario R Romano, Roberto dell'Omo, et al

Effect of palmitoylethanolamide on visual field damage progression in normal tension glaucoma patients: results of an open-label six-month follow-up.

RCTn = 32

Open-label study assessing the effect of palmitoylethanolamide (PEA) on intraocular pressure (IOP) and visual field damage in normal-tension glaucoma patients. Thirty-two patients were randomized to receive PEA or no treatment. PEA significantly reduced IOP and improved visual field indices over six months, with no side effects reported.

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2013·Investigative ophthalmology & visual science·Ernesto Strobbe, Mauro Cellini, Emilio C Campos

Effectiveness of palmitoylethanolamide on endothelial dysfunction in ocular hypertensive patients: a randomized, placebo-controlled cross-over study.

RCTn = 40Heart Health

This randomized, placebo-controlled crossover study assessed the effect of palmitoylethanolamide (PEA) on systemic endothelial function in ocular hypertensive patients. PEA intake for three months reduced intraocular pressure and significantly improved flow-mediated vasodilation values compared to placebo, with effects lasting beyond the consumption period. No adverse events were recorded.

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2013·Minerva ginecologica·G Lo Monte, I Soave, R Marci

[Administration of micronized palmitoylethanolamide (PEA)-transpolydatin in the treatment of chronic pelvic pain in women affected by endometriosis: preliminary results].

RCTn = 24Womens Health

RCT evaluating the effectiveness of micronized palmitoylethanolamide (PEA)-transpolydatin in treating chronic pelvic pain in women with endometriosis. Significant improvements were found in pelvic pain, dysmenorrhea, and dyspareunia, leading to improved quality of life and reduced NSAID use.

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2013·Journal of lower genital tract disease·Filippo Murina, Alessandra Graziottin, Raffaele Felice, et al

Vestibulodynia: synergy between palmitoylethanolamide + transpolydatin and transcutaneous electrical nerve stimulation.

RCTn = 20

RCT assessing the effect of palmitoylethanolamide + transpolydatin combination in 20 women with vestibulodynia undergoing TENS therapy. The study found that while all scores improved significantly, the combination was more effective in cases with more recent disease onset compared to placebo.

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2012·Pain medicine (Malden, Mass.)·Antonio Gatti, Marzia Lazzari, Valentina Gianfelice, et al

Palmitoylethanolamide in the treatment of chronic pain caused by different etiopathogenesis.

Observationaln = 610Inflammation

Observational study on 610 patients assessing the efficacy and safety of palmitoylethanolamide (PEA) in reducing chronic pain severity. PEA treatment significantly decreased pain intensity across various pathological conditions, with no adverse effects reported.

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2012·Journal of orofacial pain·Ida Marini, Maria Lavinia Bartolucci, Francesco Bortolotti, et al

Palmitoylethanolamide versus a nonsteroidal anti-inflammatory drug in the treatment of temporomandibular joint inflammatory pain.

RCTn = 24Inflammation Joint Bone Health

A triple-blind randomized clinical trial compared the effect of palmitoylethanolamide (PEA) versus ibuprofen for pain relief in temporomandibular joint osteoarthritis or arthralgia. PEA showed a significantly higher decrease in pain and improvement in maximum mouth opening compared to ibuprofen after 2 weeks of treatment.

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2011·CNS & neurological disorders drug targets·A Truini, A Biasiotta, G Di Stefano, et al

Palmitoylethanolamide restores myelinated-fibre function in patients with chemotherapy-induced painful neuropathy.

RCTn = 20

RCT assessing the effect of palmitoylethanolamide (PEA) on pain and nerve function in 20 patients with chemotherapy-induced painful neuropathy. PEA treatment significantly improved pain and neurophysiological measures of myelinated fibres, though warmth thresholds remained unchanged.

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2011·Journal of ocular pharmacology and therapeutics : the official journal of the Association for Ocular Pharmacology and Therapeutics·Nicola Pescosolido, Aloisa Librando, Marta Puzzono, et al

Palmitoylethanolamide effects on intraocular pressure after Nd:YAG laser iridotomy: an experimental clinical study.

RCTn = 15Inflammation

This experimental clinical study evaluated the effects of palmitoylethanolamide (PEA) on intraocular pressure (IOP) after Nd:YAG laser iridotomy in 15 patients. Pretreatment with PEA prevented the significant increase in IOP observed in placebo-treated patients, suggesting PEA's role in controlling the inflammatory process post-iridotomy.

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2021·Minerva medica·S. Parisi, M. C. Ditto, R. Borrelli, et al

Efficacy of a fixed combination of Palmitoylethanolamide and acetyl-l-carnitine (PEA + ALC FC) in the treatment of Neuropathies secondary to Rheumatic Diseases.

Observationaln = 18Inflammation

The study evaluated the efficacy of a fixed combination of Palmitoylethanolamide (PEA) and Acetyl-L-Carnitine (ALC) in patients with peripheral neuropathy secondary to rheumatic diseases. Patients treated with PEA + ALC showed significant improvement in pain VAS and specific scores compared to those receiving standard therapy alone.

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2021·International Journal of Molecular Sciences·Alessio Ardizzone, R. Fusco, Giovanna Casili, et al

Effect of Ultra-Micronized-Palmitoylethanolamide and Acetyl-l-Carnitine on Experimental Model of Inflammatory Pain

Animal studyInflammation

Animal study testing the effects of ultra-micronized palmitoylethanolamide (um-PEA) and acetyl-l-carnitine (LAC) on carrageenan-induced paw edema in rats. The combination of um-PEA and LAC significantly reduced edema, thermal hyperalgesia, inflammatory cell infiltration, and MPO activity, demonstrating superior anti-inflammatory and anti-nociceptive effects compared to separate administration.

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2015·Veterinary dermatology·Chiara Noli, M Federica Della Valle, Alda Miolo, et al

Efficacy of ultra-micronized palmitoylethanolamide in canine atopic dermatitis: an open-label multi-centre study.

Studyn = 160Inflammation Skin Hair Health

An 8-week open-label multi-centre study evaluated the efficacy of oral ultra-micronized palmitoylethanolamide (PEA-um) in 160 dogs with moderate atopic dermatitis. Results showed significant reductions in pruritus and skin lesions, with improvements in quality of life. Tolerability was good-to-excellent with minimal adverse events.

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2019·CNS & neurological disorders drug targets·Emanuela Onesti, Vittorio Frasca, Marco Ceccanti, et al

Short-Term Ultramicronized Palmitoylethanolamide Therapy in Patients with Myasthenia Gravis: a Pilot Study to Possible Future Implications of Treatment.

Studyn = 22Physical Performance

This open pilot study investigated the effects of ultramicronized-palmitoylethanolamide (μm-PEA) on muscular fatigue and neurophysiological changes in 22 patients with myasthenia gravis over a three-week period. PEA significantly improved the quantitative MG score and reduced decremental muscle response, although antibody titers did not change significantly.

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