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

Abstract

Autism spectrum disorder (ASD) pathophysiology is not completely understood; however, altered inflammatory response and glutamate signaling have been reported, leading to the investigation of molecules targeting the immune-glutamatergic system in ASD treatment. Palmitoylethanolamide (PEA) is a naturally occurring saturated N-acylethanolamine that has proven to be effective in controlling inflammation, depression, epilepsy, and pain, possibly through a neuroprotective role against glutamate toxicity. Here, we systematically reviewed all human and animal studies examining PEA and its biobehavioral correlates in ASD. Studies indicate altered serum/brain levels of PEA and other endocannabinoids (ECBs)/acylethanolamines (AEs) in ASD. Altered PEA signaling response to social exposure and altered expression/activity of enzymes responsible for the synthesis and catalysis of ECBs/AEs, as well as downregulation of the peroxisome proliferator activated receptor-α (PPAR-α) and cannabinoid receptor target GPR55 mRNA brain expression, have been reported. Stress and exposure to exogenous cannabinoids may modulate ECBs/AEs levels and expression of candidate genes for neuropsychiatric disorders, with implications for ASD. Limited research suggests that PEA supplementation reduces overall autism severity by improving language and social and nonsocial behaviors. Potential neurobiological underpinnings include modulation of immune response, neuroinflammation, neurotrophy, apoptosis, neurogenesis, neuroplasticity, neurodegeneration, mitochondrial function, and microbiota activity, possibly through peroxisome proliferator-activated receptor-α (PPAR-α) activation.

Utilizing Genomically Targeted Molecular Data to Improve Patient-Specific Outcomes in Autism Spectrum Disorder

“…Palmitoylethanolamide (PEA) was chosen for this patient, as a targeted intervention for decreasing CCL2. This particular intervention was chosen because of the published studies noting benefits in children with ASD [49]. The patient's genomic results also reinforced what was seen in the labs regarding other specific nutritional deficiencies.…”

Is It Time to Test the Antiseizure Potential of Palmitoylethanolamide in Human Studies? A Systematic Review of Preclinical Evidence

“…In the absence of human studies, no conclusions can be drawn about the relevance of PEA for the different clinical phenotypes of epilepsy. While limited evidence supports a neuroprotective effect of PEA against neuroinflammation and glutamate toxicity in the context of different neuropsychiatric conditions [ 13 ], studies are needed to elucidate the exact mechanism of action of PEA in epilepsy. Caution is needed about the finding of reduced PEA tone in epilepsy.…”

“…It is an endogenous fatty acid amide, which exerts its biological effects through the activation of peroxisome proliferator-activated receptor-α (PPAR-α) and its related independent pathways, including ion channels involved in neuronal firing and the Transient Receptor Potential Vanilloid 1 (TRPV1) receptor [ 8 ], whose role is considered crucial in the fulfilment of neuroprotective, anti-inflammatory, and analgesic properties [ 9 ]. PEA has been suggested as an effective treatment for inflammatory disorders and pain [ 10 , 11 ], together with possible therapeutic implications in depressive symptoms and autism spectrum disorder [ 12 , 13 ].…”

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

“…Due to the methodological heterogeneity of the studies ( Table 1 ) included in this review, risk of bias and study quality assessments were conducted with a reasonably inclusive and flexible approach, in line with previous research in the field ( 15 , 53 ). To this extent, interventional and observational studies in humans were evaluated through an adapted set of criteria suggested by the Agency for Healthcare Research and Quality (AHRQ) guidance ( 54 ), and risk of systematic bias across human studies was further ruled out by screening all papers for potential confounding variables, such as patients' age and educational level ( Table 2 ).…”