Palmitoylethanolamide in Autism Spectrum Disorder: History
View Latest Version
Please note this is an old version of this entry, which may differ significantly from the current revision.
Subjects: Nutrition & Dietetics
Contributor:
Marco Colizzi

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.

  • neurodevelopment
  • pervasive developmental disorder
  • cannabinoids
  • acylethanolamines
  • immune response
  • glutamate
  • inflammation
  • peroxisome proliferator-activated receptor-α
  • child and adolescent neuropsychiatry

1. Introduction

Autism spectrum disorder (ASD) is a complex and multifactorial neurodevelopmental condition affecting those who suffer from it at different levels. Difficulties in social communication and associated tendency to have restrictive interests and repetitive and stereotyped activities are considered the core aspects of the disorder [1], allowing clinicians to make a diagnosis of ASD based on behavioral assessment [2]. However, converging research evidence supports the presence of altered neurobiological parameters such as functional and structural brain abnormalities [3][4], by which gene variants or epigenetic marks lead to the neurocognitive and biobehavioral symptoms consistently reported in ASD [5][6]. It is noteworthy that, even though the pathophysiology of ASD is not completely understood, studies conducted over the last two decades have helped clarify some of the mechanisms of disease progression. In particular, altered inflammatory response [7] and disrupted glutamate signaling [8][9][10] have been reported, leading the way to the investigation of the effect of molecules targeting the immune-glutamatergic system in improving clinical severity in ASD [11].

Growing evidence indicates that one of the major physiological functions of the cannabinoid signaling system is the modulation of neuroinflammation [12] and glutamate neurotransmission [13]. Both exogenous cannabinoids (e.g., plant-derived cannabinoids Δ9-tetrahydrocannabinol, Δ9-THC, and cannabidiol, CBD) and their endogenous counterparts (e.g., endocannabinoids anandamide and 2-arachidonoylglycerol, 2-AG) interact with the endocannabinoid system, with implications for health and disease [14][15]. Despite promising evidence on the efficacy of Δ9-THC- and CBD-based treatments in the management of ASD-related behavioral problems, it is still limited and requires further investigation [16]. Anandamide (arachidonoylethanolamide) and 2-AG are both derivatives of arachidonic acid, a polyunsaturated fatty acid well known as the precursor of bioactive prostaglandins and other eicosanoids, with anandamide specifically being its ethanolamine [17].

Other ethanolamines of various long-chain fatty acids also naturally occur, and along with anandamide they are collectively referred to as N-acylethanolamines. However, they are more abundant than anandamide in the body and do not bind to cannabinoid receptors, while exerting most of their biological effects by activating the peroxisome proliferator-activated receptor-α (PPAR-α), a nuclear receptor, and PPAR-α-independent pathways involving other receptors such as Transient Receptor Potential Vanilloid 1 (TRPV1) and GPR55 [17][18]. Research evidence suggests that such specific mechanisms of action would account for their anti-inflammatory, analgesic, anticonvulsant, and neuroprotective properties [17][18]. Palmitoylethanolamide (PEA, N-hexadecanoylethanolamide), in particular, is a saturated N-acylethanolamine which has been suggested to be effective in the control of inflammatory responses [19][20], depressive symptoms [21], epilepsy [22], and pain [23], possibly through a neuroprotective role against glutamate toxicity [17].

2. Development and Findings

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 [24]. 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][28][29] as well as in modulating a number of neurobiological processes including neuroinflammation [26], neurotrophy [28], apoptosis [26], neurogenesis [26], neuroplasticity [26], neurodegeneration [29][30], mitochondrial function [28], and microbiota activity [28]. Importantly, PEA administration resulted in an activation of the peroxisome proliferator activated receptor-α (PPAR-α) [28], 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 [31]. 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 [32]. 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 [33].

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 [34]. 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 [35], altered expression and activity of the enzymes responsible for the synthesis and catalysis of ECBs/AEs [35][36], and downregulation of PPAR-α [35][36] and the cannabinoid receptor target GPR55 mRNA expression in the brain [35]. 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 [37].

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 [38], 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.

3. Conclusions

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.

This entry is adapted from the peer-reviewed paper 10.3390/nu13041346

References

  1. Saghazadeh, A.; Ahangari, N.; Hendi, K.; Saleh, F.; Rezaei, N. Status of essential elements in autism spectrum disorder: Systematic review and meta-analysis. Rev. Neurosci. 2017, 28, 783–809.
  2. First, M.B.; Williams, J.B.W.; Karg, R.S.; Spitzer, R.L. Structured Clinical Interview for DSM-5 Disorders, Clinician Version (SCID-5-CV); American Psychiatric Association: Arlington, VA, USA, 2015.
  3. Zeng, K.; Kang, J.; Ouyang, G.; Li, J.; Han, J.; Wang, Y.; Sokhadze, E.M.; Casanova, M.F.; Li, X. Disrupted Brain Network in Children with Autism Spectrum Disorder. Sci. Rep. 2017, 7, 1–12.
  4. Kern, J.K.; Geier, D.A.; King, P.G.; Sykes, L.K.; Mehta, J.A.; Geier, M.R. Shared Brain Connectivity Issues, Symptoms, and Comorbidities in Autism Spectrum Disorder, Attention Deficit/Hyperactivity Disorder, and Tourette Syndrome. Brain Connect. 2015, 5, 321–335.
  5. Lukito, S.; Norman, L.; Carlisi, C.; Radua, J.; Hart, H.; Simonoff, E.; Rubia, K. Comparative meta-analyses of brain structural and functional abnormalities during cognitive control in attention-deficit/hyperactivity disorder and autism spectrum disorder. Psychol. Med. 2020, 50, 894–919.
  6. Dewey, D. What Is Comorbidity and Why Does It Matter in Neurodevelopmental Disorders? Curr. Dev. Disord. Rep. 2018, 5, 235–242.
  7. Masi, A.; Quintana, D.S.; Glozier, N.; Lloyd, A.R.; Hickie, I.B.; Guastella, A.J. Cytokine aberrations in autism spectrum disorder: A systematic review and meta-analysis. Mol. Psychiatry 2014, 20, 440–446.
  8. Purcell, A.E.; Jeon, O.H.; Zimmerman, A.W.; Blue, M.E.; Pevsner, J. Postmortem brain abnormalities of the glutamate neurotransmitter system in autism. Neurology 2001, 57, 1618–1628.
  9. Shimmura, C.; Suda, S.; Tsuchiya, K.J.; Hashimoto, K.; Ohno, K.; Matsuzaki, H.; Iwata, K.; Matsumoto, K.; Wakuda, T.; Kameno, Y.; et al. Alteration of Plasma Glutamate and Glutamine Levels in Children with High-Functioning Autism. PLoS ONE 2011, 6, e25340.
  10. Shinohe, A.; Hashimoto, K.; Nakamura, K.; Tsujii, M.; Iwata, Y.; Tsuchiya, K.J.; Sekine, Y.; Suda, S.; Suzuki, K.; Sugihara, G.-I.; et al. Increased serum levels of glutamate in adult patients with autism. Prog. Neuro Psychopharmacol. Biol. Psychiatry 2006, 30, 1472–1477.
  11. Blaylock, R.L.; Strunecka, A. Immune-glutamatergic dysfunction as a central mechanism of the autism spectrum disorders. Curr. Med. Chem. 2009, 16, 157–170.
  12. Walter, L.; Stella, N. Cannabinoids and neuroinflammation. Br. J. Pharmacol. 2004, 141, 775–785.
  13. Colizzi, M.; McGuire, P.; Pertwee, R.G.; Bhattacharyya, S. Effect of cannabis on glutamate signalling in the brain: A systematic review of human and animal evidence. Neurosci. Biobehav. Rev. 2016, 64, 359–381.
  14. Colizzi, M.; Ruggeri, M.; Bhattacharyya, S. Unraveling the Intoxicating and Therapeutic Effects of Cannabis Ingredients on Psychosis and Cognition. Front. Psychol. 2020, 11, 833.
  15. Freitas, H.R.; Isaac, A.R.; Malcher-Lopes, R.; Diaz, B.L.; Trevenzoli, I.H.; Reis, R.A.D.M. Polyunsaturated fatty acids and endocannabinoids in health and disease. Nutr. Neurosci. 2017, 21, 695–714.
  16. Aran, A.; Harel, M.; Cassuto, H.; Polyansky, L.; Schnapp, A.; Wattad, N.; Shmueli, D.; Golan, D.; Castellanos, F.X. Cannabinoid treatment for autism: A proof-of-concept randomized trial. Mol. Autism 2021, 12, 1–11.
  17. Tsuboi, K.; Uyama, T.; Okamoto, Y.; Ueda, N. Endocannabinoids and related N-acylethanolamines: Biological activities and metabolism. Inflamm. Regen. 2018, 38, 1–10.
  18. Rankin, L.; Fowler, C.J. The basal pharmacology of palmitoylethanolamide. Int. J. Mol. Sci. 2020, 21, 7942.
  19. Solorzano, C.; Zhu, C.; Battista, N.; Astarita, G.; Lodola, A.; Rivara, S.; Mor, M.; Russo, R.; Maccarrone, M.; Antonietti, F.; et al. Selective N-acylethanolamine-hydrolyzing acid amidase inhibition reveals a key role for endogenous palmitoylethanolamide in inflammation. Proc. Natl. Acad. Sci. USA 2009, 106, 20966–20971.
  20. Verme, J.L.; Fu, J.; Astarita, G.; La Rana, G.; Russo, R.; Calignano, A.; Piomelli, D. The nuclear receptor peroxisome proliferator-activated receptor-α mediates the anti-inflammatory actions of palmitoylethanolamide. Mol. Pharmacol. 2005, 67, 15–19.
  21. Yu, H.-L.; Deng, X.-Q.; Li, Y.-J.; Quan, Z.-S.; Sun, X.-Y.; Li, Y.-C. Short communication–N-palmitoylethanolamide, an endocannabinoid, exhibits antidepressant effects in the forced swim test and the tail suspension test in mice. Pharmacol. Rep. 2011, 63, 834–839.
  22. Lambert, D.M.; Vandevoorde, S.; Diependaele, G.; Govaerts, S.J.; Robert, A.R. Anticonvulsant activity of N-palmitoylethanolamide, a putative endocannabinoid, in mice. Epilepsia 2002, 42, 321–327.
  23. Jaggar, S.I.; Hasnie, F.S.; Sellaturay, S.; Rice, A.S. The anti-hyperalgesic actions of the cannabinoid anandamide and the putative CB2 receptor agonist palmitoylethanolamide in visceral and somatic inflammatory pain. Pain 1998, 76, 189–199.
  24. Savino, R.; Carotenuto, M.; Polito, A.N.; Di Noia, S.; Albenzio, M.; Scarinci, A.; Ambrosi, A.; Sessa, F.; Tartaglia, N.; Messina, G. Analyzing the Potential Biological Determinants of Autism Spectrum Disorder: From Neuroinflammation to the Kynurenine Pathway. Brain Sci. 2020, 10, 631.
  25. Antonucci, N.; Cirillo, A.; Siniscalco, D. Beneficial Effects of Palmitoylethanolamide on Expressive Language, Cognition, and Behaviors in Autism: A Report of Two Cases. Case Rep. Psychiatry 2015, 2015, 1–6.
  26. Bertolino, B.; Crupi, R.; Impellizzeri, D.; Bruschetta, G.; Cordaro, M.; Siracusa, R.; Esposito, E.; Cuzzocrea, S. Beneficial Effects of Co-Ultramicronized Palmitoylethanolamide/Luteolin in a Mouse Model of Autism and in a Case Report of Autism. CNS Neurosci. Ther. 2016, 23, 87–98.
  27. Khalaj, M.; Saghazadeh, A.; Shirazi, E.; Shalbafan, M.-R.; Alavi, K.; Shooshtari, M.H.; Laksari, F.Y.; Hosseini, M.; Mohammadi, M.-R.; Akhondzadeh, S. Palmitoylethanolamide as adjunctive therapy for autism: Efficacy and safety results from a randomized controlled trial. J. Psychiatr. Res. 2018, 103, 104–111.
  28. Cristiano, C.; Pirozzi, C.; Coretti, L.; Cavaliere, G.; Lama, A.; Russo, R.; Lembo, F.; Mollica, M.P.; Meli, R.; Calignano, A.; et al. Palmitoylethanolamide counteracts autistic-like behaviours in BTBR T+tf/J mice: Contribution of central and peripheral mechanisms. Brain Behav. Immun. 2018, 74, 166–175.
  29. Herrera, M.I.; Udovin, L.D.; Toro-Urrego, N.; Kusnier, C.F.; Luaces, J.P.; Capani, F. Palmitoylethanolamide Ameliorates Hippocampal Damage and Behavioral Dysfunction After Perinatal Asphyxia in the Immature Rat Brain. Front. Neurosci. 2018, 12, 145.
  30. Udovin, L.D.; Kobiec, T.; Herrera, M.I.; Toro-Urrego, N.; Kusnier, C.F.; Kölliker-Frers, R.A.; Ramos-Hryb, A.B.; Luaces, J.P.; Otero-Losada, M.; Capani, F. Partial Reversal of Striatal Damage by Palmitoylethanolamide Administration Following Perinatal Asphyxia. Front. Neurosci. 2020, 13, 1345.
  31. Wójtowicz, S.; Strosznajder, J.B.; Jeżyna, M. The Novel Role of PPAR Alpha in the Brain: Promising Target in Therapy of Alzheimer’s Disease and Other Neurodegenerative Disorders. Neurochem. Res. 2020, 45, 972–988.
  32. Hay, I.; Hynes, K.L.; Burgess, J.R. Mild-to-Moderate Gestational Iodine Deficiency Processing Disorder. Nutrients 2019, 11, 1974.
  33. Li, D.; Karnath, H.-O.; Xu, X. Candidate Biomarkers in Children with Autism Spectrum Disorder: A Review of MRI Studies. Neurosci. Bull. 2017, 33, 219–237.
  34. Aran, A.; Eylon, M.; Harel, M.; Polianski, L.; Nemirovski, A.; Tepper, S.; Schnapp, A.; Cassuto, H.; Wattad, N.; Tam, J. Lower circulating endocannabinoid levels in children with autism spectrum disorder. Mol. Autism 2019, 10, 1–11.
  35. Kerr, D.; Downey, L.; Conboy, M.; Finn, D.; Roche, M. Alterations in the endocannabinoid system in the rat valproic acid model of autism. Behav. Brain Res. 2013, 249, 124–132.
  36. Blanco, E.; Galeano, P.; Holubiec, M.I.; Romero, J.I.; Logica, T.; Rivera, P.; Pavón, F.J.; Suarez, J.; Capani, F.; De Fonseca, F.R. Perinatal asphyxia results in altered expression of the hippocampal acylethanolamide/endocannabinoid signaling system associated to memory impairments in postweaned rats. Front. Neuroanat. 2015, 9, 141.
  37. Tomas-Roig, J.; Piscitelli, F.; Gil, V.; Quintana, E.; Ramió-Torrentà, L.L.; Del Río, J.A.; Moore, T.P.; Agbemenyah, H.; Salinas, G.; Pommerenke, C.; et al. Effects of repeated long-term psychosocial stress and acute cannabinoid exposure on mouse corticostriatal circuitries: Implications for neuropsychiatric disorders. CNS Neurosci. Ther. 2018, 24, 528–538.
  38. Siafis, S.; Çıray, O.; Schneider-Thoma, J.; Bighelli, I.; Krause, M.; Rodolico, A.; Ceraso, A.; Deste, G.; Huhn, M.; Fraguas, D.; et al. Placebo response in pharmacological and dietary supplement trials of autism spectrum disorder (ASD): Systematic review and meta-regression analysis. Mol. Autism 2020, 11, 1–19.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license; additional terms may apply. By using this site, you agree to the Terms and Conditions and Privacy Policy.
This entry is offline, you can click here to edit this entry!
ScholarVision Creations
Feedback