Co-ultramicronized palmitoylethanolamide/luteolin normalizes GABAB-ergic activity and cortical plasticity in long COVID-19 syndrome

Abstract

Objective: Transcranial magnetic stimulation (TMS) studies showed that patients with cognitive dysfunction and fatigue after COVID-19 exhibit impaired cortical GABAB-ergic activity, as revealed by reduced long-interval intracortical inhibition (LICI). Aim of this study was to test the effects of co-ultramicronized palmitoylethanolamide/luteolin (PEA-LUT), an endocannabinoid-like mediator able to enhance GABA-ergic transmission and to reduce neuroinflammation, on LICI. Methods: Thirty-nine patients (26 females, mean age 49.9 ± 11.4 years, mean time from infection 296.7 ± 112.3 days) suffering from persistent cognitive difficulties and fatigue after mild COVID-19 were randomly assigned to receive either PEA-LUT 700 mg + 70 mg or PLACEBO, administered orally bid for eight weeks. The day before (PRE) and at the end of the treatment (POST), they underwent TMS protocols to assess LICI. We further evaluate short-latency afferent inhibition (SAI) and long-term potentiation (LTP)-like cortical plasticity. Results: Patients treated with PEA-LUT but not with PLACEBO showed a significant increase of LICI and LTP-like cortical plasticity. SAI remained unaffected. Conclusions: Eight weeks of treatment with PEA-LUT restore GABAB activity and cortical plasticity in long Covid patients. Significance: This study confirms altered physiology of the motor cortex in long COVID-19 syndrome and indicates PEA-LUT as a candidate for the treatment of this post-viral condition.