Cannabidiol Acts at 5-HT1A Receptors in the Human Brain: Relevance for Treating Temporal Lobe Epilepsy

Abstract

Experimental evidence indicates that cannabidiol (CBD) induces anxiolytic and antiepileptic effects through the activation of 5-HT1A receptors. These receptors are coupled to Gi/o proteins and induce inhibitory effects. At present, the interaction of CBD with 5-HT1A receptors in the human brain is unknown. The aim of this study focused on evaluating the interaction between CBD and 5-HT1A receptors in cell membranes obtained from the hippocampus and temporal neocortex of autopsies and patients with drug-resistant mesial temporal lobe epilepsy (DR-MTLE). Cell membranes were isolated from the hippocampus and temporal neocortex of a group of patients with DR-MTLE who were submitted to epilepsy surgery (n = 11) and from a group of autopsies (n = 11). The [3H]-8-OH-DPAT binding assay was used to determine the pharmacological interaction of CBD with 5-HT1A receptors. The [35S]-GTPγS assay was used to investigate the CBD-induced activation of Gi/o proteins through its action on 5-HT1A receptors.The CBD affinity (pKi) for 5-HT1A receptors was similar for autopsies and patients with DR-MTLE (hippocampus: 4.29 and 4.47, respectively; temporal neocortex: 4.67 and 4.74, respectively). Concerning the [35S]-GTPγS assay, no statistically significant changes were observed for both hippocampal and neocortical tissue (p > 0.05) at low CBD concentrations (1 pM to 10 μM). In contrast, at high concentrations (100 μM), CBD reduced the constitutive activity of Gi/o proteins of autopsies and DR-MTLE patients (hippocampus: 39.2% and 39.6%, respectively; temporal neocortex: 35.2% and 24.4%, respectively). These changes were partially reversed in the presence of WAY-100635, an antagonist of 5-HT1A receptors, in the autopsy group (hippocampus, 59.8%, p < 0.0001; temporal neocortex, 71.5%, p < 0.0001) and the group of patients with DR-MTLE (hippocampus, 53.7%, p < 0.0001; temporal neocortex, 68.5%, p < 0.001). Our results show that CBD interacts with human 5-HT1A receptors of the hippocampus and temporal neocortex. At low concentrations, the effect of CBD upon Gi/o protein activation is limited. However, at high concentrations, CBD acts as an inverse agonist of 5-HT1A receptors. This effect could modify neuronal excitation and epileptic seizures in patients with DR-MTLE.

Psychedelic experience dose-dependently modulated by cannabis: results of a prospective online survey

“…Previous animal work reports that CBD facilitates 5-H 1A receptor-mediated neurotransmission (Resstel et al 2009) which can lead to an increase in 5-HT and glutamate levels, which in turn translates to antidepressant-like effects (Linge et al 2016). Recent work in humans corroborates this finding and shows that at high concentrations, CBD acts as an inverse agonist on 5-HT 1A receptors (Martínez-Aguirre et al 2020). Additionally, chronic exposure to THC has also been reported to promote pro-hallucinogenic signalling of 5-HT 2A R in mice; however, this has not yet been studied during acute exposure or in humans (Ibarra-Lecue et al 2018).…”

A narrative review of molecular mechanism and therapeutic effect of cannabidiol (CBD)

“…82 CBD also shows a high affinity towards serotonin receptors (5-HT 1A and 5-HT 2A ). 24,83 These receptors may be involved in epilepsy even though their role is still not entirely clear. 76 In the past few decades, several clinical studies have been conducted to evaluate the safety, tolerability and efficacy of CBD in the treatment of epilepsy.…”

Cannabinoids in Audiogenic Seizures: From Neuronal Networks to Future Perspectives for Epilepsy Treatment

“…Therefore, the exploration of these mechanisms associated with cannabinoids in audiogenic strains is an interesting approach that should be further investigated. Furthermore, recent clinical data indicate that, regardless of the CBD low affinity for 5-HT1A receptors, at high concentration, CBD reduced the constitutive activity of receptors coupled to Gi/o receptors and these effects were reversed in the presence of 5-HT 1A antagonist, suggesting that CBD can act as a 5-HT 1A inverse agonist (Martínez-Aguirre et al, 2020 ). Therefore, the linking behind CBD anticonvulsant effects and the serotonergic system, should be further investigated in audiogenic strains.…”