Investigating Neuropharmacological Features of the Cortical Activity of Cannabidiol GWP42003 P-A Phase 1 Clinical Trial
Viviana Santoro 1 2, Po-Yu Fong 2 3 4 5, Andrea Biondi 1, Isabella Premoli 1 6, Harry Clark 1 7, Lorenzo Rocchi 1 8, Mark P Richardson 1
- 1Department of Basic and Clinical Neuroscience, Institute of Psychiatry Psychology and Neuroscience (IoPPN), King’s College London, London WC2R 2LS, UK.
- 2Headache Group, Wolfson SPaRC, Institute of Psychiatry Psychology and Neuroscience (IoPPN), King’s College London, London WC2R 2LS, UK.
- 3Division of Movement Disorders, Department of Neurology and Neuroscience Research Centre, Chang Gung Memorial Hospital at Linkou, Taoyuan City 33305, Taiwan.
- 4Medical School, College of Medicine, Chang Gung University, Taoyuan City 33302, Taiwan.
- 5Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, University College London, London WC1E 6BT, UK.
- 6Saniona A/S, Murervangen 42, 2600 Albertslund, Denmark.
- 7Centre for Cognitive Neuroimaging, School of Psychology and Neuroscience, University of Glasgow, Glasgow G12 8QQ, UK.
- 8Department of Medical Sciences and Public Health, University of Cagliari, 09124 Cagliari, Italy.
Affiliationer
Background/Objectives: Despite the clinical efficacy of cannabidiol (CBD) in treating certain epilepsies, its in vivo neuropharmacological mechanisms remain incompletely understood. This Phase 1 clinical trial aimed to evaluate the acute effects of a single oral dose of highly purified CBD (GWP42003-P) on cortical excitability. Transcranial magnetic stimulation combined with electroencephalography (TMS-EEG) and electromyography (TMS-EMG) were utilized as assessment tools. Methods: In a randomized, double-blind, placebo-controlled crossover trial, 15 healthy male participants received a single 1500 mg dose of GWP42003-P or placebo. Cortical activity metrics, including resting and active motor thresholds (RMT, AMT), short intracortical inhibition (SICI), TMS-evoked potentials (TEPs), TMS-related spectral perturbations (TRSP), and inter-trial phase clustering (ITPC), were recorded pre-dose and at 1, 4, and 6 h post-dose. Results: RMT and AMT significantly decreased over time following CBD administration, though without a significant Condition × Time interaction. While primary analyses showed no condition-driven alterations for SICI, TEPs, or TRSP, secondary longitudinal modeling revealed a transient reduction in beta-band desynchronization 1 h post-dose, aligning with peak plasma concentration. The drug condition also exhibited a qualitative, non-significant trend toward increased alpha ITPC and decreased delta ITPC at 4 and 6 h post-dose compared to placebo. Conclusions: A single acute 1500 mg dose of GWP42003-P did not produce statistically significant alterations in widespread cortical excitability in healthy adult males. However, the transient blunting of beta desynchronization at peak concentration may reflect CBD’s distinct, non-classical neuromodulatory profile. Overall, these largely null findings suggest that acute CBD administration lacks a robust, direct modulatory effect on cortical networks. Capturing its precise neuropharmacological mechanisms will likely require future investigations utilizing chronic dosing paradigms or clinical patient populations.
Keywords: GABA receptors; TMS-EEG; anti-seizure medications; cannabidiol; cortical excitability; electroencephalography; electromyography; epilepsy; neural synchronization; transcranial magnetic stimulation.
