This is the first systematic review of all studies exploring the biobehavioral correlates of palmitoylethanolamide (PEA) in autism spectrum disorder (ASD) in humans and animals. Previous reviews have mainly addressed the potential role of neuroinflammation and altered glutamate signaling in ASD etiopathogenesis, indicating that, in subjects with genetic predispositions, atypical neurodevelopment may arise from a complex interplay between (neuro)inflammatory processes, mitochondrial dysfunction, oxidative stress and altered expression of glutamate signaling [35]. Interestingly, research evidence converges on the crucial role of exogenous cannabinoids and endocannabinoids in modulating such neurobiological systems, including neuroinflammation [12] and glutamate neurotransmission [13]. Overall, this review demonstrates that PEA may be involved in ASD, as indicated by interventional studies of the positive biobehavioral effects of PEA supplementation in both humans and animals as well as observational studies reporting aberrancies in the PEA signaling pathway at different levels.

PEA supplementation in humans as both monotherapy [25,26] and add-on therapy to antipsychotic medication [27] has been shown to reduce overall autism severity [25,26] by improving both expressive language (what the child says) [25] and inappropriate speech (how the child says it) [27], as well as modulating atypical behavior [25,26,27] and immune response [25]. Similarly, PEA supplementation in different animal models of autism and related conditions has been suggested to be effective in improving social and nonsocial behaviors [26,29,30] as well as in modulating a number of neurobiological processes including neuroinflammation [26], neurotrophy [29], apoptosis [26], neurogenesis [26], neuroplasticity [26], neurodegeneration [30,31], mitochondrial function [29], and microbiota activity [29]. Importantly, PEA administration resulted in an activation of the peroxisome proliferator activated receptor-α (PPAR-α) [29], whose downregulation may decrease antioxidative and anti-inflammatory processes, also altering energy homeostasis, mitochondrial fatty acid metabolism, and regulation of genes coding proteins that are involved in glutamate homeostasis and cholinergic/dopaminergic signaling in the brain, with implications for neurodevelopmental conditions [36]. The hippocampus is one of the brain areas where such modulatory effects of PEA are mostly reported. Further studies are needed to investigate the role of the PEA-induced modulation of the hippocampal system in improving the brain spatiotemporal framework within which sensory, emotional, and cognitive aspects of an experience are processed in ASD, with implications for comprehension and language production [37]. This is of paramount importance, as structural, functional, and neurochemical alterations in the hippocampus have been suggested as candidate biomarkers for the diagnosis of ASD in childhood [38].

Another line of research identified lower serum levels of PEA and other endocannabinoids (ECBs)/acylethanolamines (AEs) in humans suffering from ASD, independently of sociodemographic and clinical characteristics [28]. Similarly, studies performed in animal models of autism and related conditions suggested an altered response of the PEA signaling in the face of social exposure [32], altered expression and activity of the enzymes responsible for the synthesis and catalysis of ECBs/AEs [32,33], and downregulation of PPAR-α [32,33] and the cannabinoid receptor target GPR55 mRNA expression in the brain [32]. Interestingly, animals exposed to stress and administered with exogenous cannabinoids showed variations in their ECB/AE levels and expression of genes implied in neuropsychiatric disorders [34].

The findings of this systematic review have to be seen in light of some limitations. Research in the field is still too limited, especially in humans (2 of the 4 human studies are case reports, leaving a single experimental study conducted in a youth population with ASD), and further studies are needed to fully address the relevance of PEA for the different clinical phenotypes of ASD and whether the potentially beneficial effects of PEA are mediated by a protective role of the compound against altered neuroinflammatory responses and glutamate toxicity, which have been suggested to be involved in the pathophysiology of ASD [7,8,9,10]. Additionally, whether the PEA concentration profile can be used as a biomarker for ASD remains to be tested, and future longitudinal studies will have to investigate its clinical utility in monitoring response to treatment. Moreover, as the available evidence does not allow excluding a placebo effect [39], further clinical trials in larger samples are needed to fully explore the efficacy and tolerability of PEA supplementation in ASD. Finally, even though the systematic review followed the PRISMA statement, no review protocol was registered.

PEA may be useful in improving language difficulties and stereotypic behavior as well as in controlling hyperactivity and irritability which co-occur frequently in ASD. Notably, no serious adverse effects were observed with the administration of the compound in all human studies reviewed here, making PEA supplementation a potentially valid and reasonably safe therapeutic intervention in ASD.