In response to muscle damage induced by intense exercise, the body initiates an acute inflammatory response that can lead to delayed onset muscle soreness (DOMS) and reduced muscle performance. Much research has focused on the effect of inflammatory cytokines in this process, but the body also produces special fat-derived compounds called bioactive lipid mediators that are implicated in this inflammation.
New data published in Pflugers Archiv – European Journal of Physiology indicate that palmitoylethanolamide (PEA) supplementation may help support levels of these bioactive lipid mediators, compared to placebo.
“This study provides novel insights into the lipid mediator profile of skeletal muscle tissue following an acute bout of MDE [muscle damaging exercise], and how this response is modulated by PEA supplementation,” wrote scientists from KU Leuven in Belgium.
“Most lipid mediators decreased below baseline levels 48 h post-exercise, whereas PEA supplementation attenuated or counteracted this decline.
PEA
Interest in the endocannabinoid system has grown significantly in recent years. For companies seeking to influence this system beyond CBD and hemp, one promising option is PEA. Discovered in 1957 during research into the anti-inflammatory properties of egg yolk, PEA is also produced by the body as a first responder to pain, stress and inflammation and is used up locally in all tissues.
PEA has been reported to confer anti-inflammatory and immune health benefits.
The new study used Levagen+ from Gencor Pacific Limited, which is described as a specialized form of PEA formulated using a proprietary delivery system (LipiSperse, Pharmako Biotechnologies) that has been shown in previous studies to significantly increase PEA bioavailability.
Study details
Ten health men were recruited to participate in the placebo-controlled, double-blind crossover study. The men were randomly assigned to receive either placebo or PEA (Levagen+, 350 mg in the morning and evening) for six days prior to muscle damaging exercise. This was followed by a three-week washout period and then the men crossed over to the other intervention. Muscle biopsies, obtained before the start of the intervention and again 48 hours after the exercise.
The results showed that, while many lipid mediators decreased 48 hours after exercise in the placebo group, levels were either unchanged or elevated in the PEA group.
“Interestingly, results of the current study showed that PEA supplementation diminished or counteracted the effect of MDE on the abundance of lipid mediators,” wrote the researchers. “More specifically, PEA supplementation either increased or stabilized levels of pro-inflammatory lipid mediators in response to MDE, as opposed to the decrease observed in PLA.”
These results contradict findings from previous studies, they added, where PEA was reported to reduce the expression and activity of pro-inflammatory enzymes COX2 and LOX5.
On the other hand, PEA was also associated with increased or stabilized levels of pro-resolving/anti-inflammatory lipid mediators in response to intense exercise, while levels dropped in the placebo group, and the researchers recorded increases in one specific metabolite that is implicated in tissue regeneration and accelerated muscle recovery.
“PEA administration did not result in differences in functional outcomes including muscle strength, explosivity, pain or muscle damage markers,” they added. “This suggests that, in the context of acute exercise-induced inflammation, modulation of the bioactive lipid profile alone may have limited clinical relevance. However, PEA may still be of value in conditions characterized by chronic or prolonged muscle inflammation, where sustained inflammatory dysregulation may increase the physiological relevance of these biochemical effects.”
The researchers call for future studies to elucidate the mechanisms of action and to determine if these effects translate into physiologically relevant impacts on performance.
Source: Pflugers Archiv – European Journal of Physiology, 2026, 478, 77, doi: 10.1007/s00424-026-03208-6. “Palmitoylethanolamide supplementation partly modulates eccentric exercise-induced changes in the bioactive lipid profile of skeletal muscle tissue.” Authors: M. Schouten, et al.