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

Abstract

Cognitive decline is believed to be associated with neurodegenerative processes involving excitotoxicity, oxidative damage, inflammation, and microvascular and blood-brain barrier dysfunction. Interestingly, research evidence suggests upregulated synthesis of lipid signaling molecules as an endogenous attempt to contrast such neurodegeneration-related pathophysiological mechanisms, restore homeostatic balance, and prevent further damage. Among these naturally occurring molecules, palmitoylethanolamide (PEA) has been independently associated with neuroprotective and anti-inflammatory properties, raising interest into the possibility that its supplementation might represent a novel therapeutic approach in supporting the body-own regulation of many pathophysiological processes potentially contributing to neurocognitive disorders. Here, we systematically reviewed all human and animal studies examining PEA and its biobehavioral correlates in neurocognitive disorders, finding 33 eligible outputs. Studies conducted in animal models of neurodegeneration indicate that PEA improves neurobehavioral functions, including memory and learning, by reducing oxidative stress and pro-inflammatory and astrocyte marker expression as well as rebalancing glutamatergic transmission. PEA was found to promote neurogenesis, especially in the hippocampus, neuronal viability and survival, and microtubule-associated protein 2 and brain-derived neurotrophic factor expression, while inhibiting mast cell infiltration/degranulation and astrocyte activation. It also demonstrated to mitigate β-amyloid-induced astrogliosis, by modulating lipid peroxidation, protein nytrosylation, inducible nitric oxide synthase induction, reactive oxygen species production, caspase3 activation, amyloidogenesis, and tau protein hyperphosphorylation. Such effects were related to PEA ability to indirectly activate cannabinoid receptors and modulate proliferator-activated receptor-α (PPAR-α) activity. Importantly, preclinical evidence suggests that PEA may act as a disease-modifying-drug in the early stage of a neurocognitive disorder, while its protective effect in the frank disorder may be less relevant. Limited human research suggests that PEA supplementation reduces fatigue and cognitive impairment, the latter being also meta-analytically confirmed in 3 eligible studies. PEA improved global executive function, working memory, language deficits, daily living activities, possibly by modulating cortical oscillatory activity and GABAergic transmission. There is currently no established cure for neurocognitive disorders but only treatments to temporarily reduce symptom severity. In the search for compounds able to protect against the pathophysiological mechanisms leading to neurocognitive disorders, PEA may represent a valid therapeutic option to prevent neurodegeneration and support endogenous repair processes against disease progression.

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

“…Moreover, our observations support prior research examining the effects of various anti-inflammatory nutraceuticals on BDNF levels. Investigations into anti-inflammatory compounds such as curcumin [ 51 ], zinc [ 52 ], probiotics [ 53 ], polyphenols [ 54 ], and carotenoids [ 55 ] have provided valuable insights into the potential influence of diverse dietary interventions on BDNF. A systematic review of 48 recent human interventions has reported mixed outcomes on BDNF concentrations for the various dietary interventions [ 56 ].…”

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

“…This is the first systematic review of all evidence exploring the biobehavioral correlates of palmitoylethanolamide (PEA) in psychosis across human and animal studies. Unlike previous research in this field ( 38 – 40 ), the greatest majority of records included consisted of human studies. Existing reviews focusing on the role of the major phytocannabinoid cannabidiol (CBD) as a potential treatment for schizophrenia (SCZ) patients ( 20 , 56 , 57 ) gathered still preliminary evidence supporting its antipsychotic (AP) efficacy, while highlighting its advantageous side effect profile and good tolerability.…”

“…In light of the methodological heterogeneity of collected evidence, quality of studies assessment was conducted in accordance to an adapted and suitably flexible set of criteria suggested by the Agency for Healthcare Research and Quality (AHRQ) guidance ( 42 ), in line with previous research in the field ( 38 – 40 ). Risk of systematic bias across human studies was ruled out by screening all papers for potential confounding factors (e.g., gender, age, smoking status, level of education).…”

“…Due to the shared pharmacodynamic properties, PEA is considered as the endogenous equivalent of CBD ( 36 , 37 ). A growing body of literature has confirmed the role of PEA in most neurobiological mechanisms underpinning several neuropsychiatric conditions both in clinical and preclinical settings ( 38 – 40 ).…”

The Endocannabinoid Activity Remodulation for psychosis Liability in Youth (EARLY) Study: An Open-Label Feasibility Trial of Palmitoylethanolamide Oral Supplementation in Clinical High-Risk State for Psychosis

“…To this extent, growing research is focusing on the role of the eCB-like compound Palmitoylethanolamide (PEA) as a potential therapeutic agent in the context of several neuropsychiatric conditions (17,18,19).…”