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Randomized Controlled Trial
. 2023 Jan:145:81-88.
doi: 10.1016/j.clinph.2022.10.017. Epub 2022 Nov 11.

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

Viviana Versace  1 , Paola Ortelli  2 , Sabrina Dezi  2 , Davide Ferrazzoli  2 , Alessia Alibardi  2 , Ilenia Bonini  2 , Michael Engl  3 , Roberto Maestri  4 , Martina Assogna  5 , Valentina Ajello  6 , Elke Pucks-Faes  7 , Leopold Saltuari  2 , Luca Sebastianelli  2 , Markus Kofler  7 , Giacomo Koch  8
Affiliations
Randomized Controlled Trial

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

Viviana Versace et al. Clin Neurophysiol. 2023 Jan.

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.

Keywords: LTP-like cortical plasticity; Long Covid; Long-interval intracortical inhibition; Palmitoylethanolamide; Transcranial magnetic stimulation.

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Figures

Fig. 1
Fig. 1
Results of transcranial magnetic stimulation (TMS)-protocols for long-interval intracortical inhibition (LICI) at interstimulus interval (ISI) 100 ms (A) and short-latency afferent inhibition (SAI) at an ISI corresponding to the latency of the N20 component of the ulnar nerve somatosensory evoked potentials (B) in co-ultramicronized palmitoylethanolamide/luteolin (PEA-LUT) and PLACEBO patient groups. The columns represent the amplitude of conditioned motor evoked potentials (MEPs) expressed as percentage of the corresponding mean unconditioned response in PRE and POST conditions. Whiskers represent standard error. ** P = 0.009 in post-hoc testing.
Fig. 2
Fig. 2
The graph represents the mean amplitude of motor evoked potentials (MEPs) at baseline (T0) and after 1, 10 and 20 min (T1, T10, T20) excitatory repetitive transcranial magnetic stimulation given as intermittent theta burst stimulation (iTBS) to the primary motor cortex for 190 s (600 pulses) in co-ultramicronized palmitoylethanolamide/luteolin (PEA-LUT) (red) and PLACEBO (blue) patient groups at PRE (dashed line) and POST (solid line). A significant increase of MEP amplitude was evident 1 and 10 minutes after iTBS in the PEA-LUT group POST-treatment. ** P = 0.0009 and P = 0.01 in PEA-LUT group for T1 and T10 in post-hoc testing, respectively.
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