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

Abstract

Antiseizure medications are the cornerstone pharmacotherapy for epilepsy. They are not devoid of side effects. In search for better-tolerated antiseizure agents, cannabinoid compounds and other N-acylethanolamines not directly binding cannabinoid receptors have drawn significant attention. Among these, palmitoylethanolamide (PEA) has shown neuroprotective, anti-inflammatory, and analgesic properties. All studies examining PEA’s role in epilepsy and acute seizures were systematically reviewed. Preclinical studies indicated a systematically reduced PEA tone accompanied by alterations of endocannabinoid levels. PEA supplementation reduced seizure frequency and severity in animal models of epilepsy and acute seizures, in some cases, similarly to available antiseizure medications but with a better safety profile. The peripheral-brain immune system seemed to be more effectively modulated by subchronic pretreatment with PEA, with positive consequences in terms of better responding to subsequent epileptogenic insults. PEA treatment restored the endocannabinoid level changes that occur in a seizure episode, with potential preventive implications in terms of neural damage. Neurobiological mechanisms for PEA antiseizure effect seemed to include the activation of the endocannabinoid system and the modulation of neuroinflammation and excitotoxicity. Although no human study was identified, there is ground for testing the antiseizure potential of PEA and its safety profile in human studies of epilepsy.

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

“…However, growing evidence indicates a crucial role for neuroinflammation in neurodegeneration ( 8 ) and a potential therapeutic effect of neuroinflammation modulation in contrasting neurodegeneration at both the neurobiological and behavioral level ( 11 ). In this regard, recent research highlights the importance that cannabinoid-related compounds, whose actions depend on the interaction with non-CB receptors, may have in terms of anti-inflammatory properties ( 16 – 18 ), in turn accounting for their ability to mitigate biological mechanisms involved in neurodevelopmental disorders ( 53 ), epilepsy ( 15 ), and neurodegeneration ( 12 ).…”

“…First, NCDs represent the group of conditions where the use of PEA seems to be the most supported by research studies, with an overwhelming convergence of evidence toward a therapeutic effect on core cognitive symptoms and underlying neurobiological underpinnings. Also, compared to other conditions, such as autism spectrum disorders ( 53 ) or epilepsy ( 15 ), where the evidence for a therapeutic potential of PEA is robust, but very limited ( 53 ) or absent ( 15 ) in humans, the present review identified 7 studies performed in humans. Such studies were either in vivo, in vitro , or observational studies, and a preliminary meta-analysis of studies assessing cognition before and after PEA administration ( 24 , 27 , 28 ) revealed an effect of PEA in partially reversing cognitive decline.…”

“…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 ).…”

“…Instead, it activates the peroxisome proliferator-activated receptor-α (PPAR-α) as well as its associated independent pathways, including ion channels involved in neuronal firing and the Transient Receptor Potential Vanilloid 1 (TRPV1) receptor (14). Such peculiar activity is believed to explain PEA potential anti-inflammatory, analgesic, and anti-epileptic effects (15)(16)(17)(18). Interestingly, several PEAcontaining products are licensed as nutraceuticals or food supplements for human use in different countries, at a recommended dose of 600-1,200 mg/day (19).…”

Cannabis Use in Autism: Reasons for Concern about Risk for Psychosis

“…To date, the FDA has approved purified cannabidiol (CBD), nabiximols, dronabinol, and nabilone with indications for treatment in very specific neuropsychiatric conditions [ 32 ]. In parallel, great interest has been aroused regarding the therapeutic potential of terpenoids and endocannabinoid-like compounds [ 33 , 34 ].…”