Cannabidiol Exerts Anticonvulsant Effects Alone and in Combination with Δ9-THC through the 5-HT1A Receptor in the Neocortex of Mice

• Published in: Cells (Basel, Switzerland) Vol. 13; no. 6; p. 466
• Main Authors: Javadzadeh, Yasaman, Santos, Alexandra, Aquilino, Mark S., Mylvaganam, Shanthini, Urban, Karolina, Carlen, Peter L.
• Format: Journal Article
• Language: English
• Published: Basel MDPI AG 07.03.2024; MDPI
• Subjects: 5-HT1A receptor; Anticonvulsants; Brain; Brain slice preparation; Cannabidiol; cannabidiol (CBD); Cannabinoids; Clinical trials; Convulsions & seizures; Dosage; Drug resistance; drug resistant epilepsy; electrophysiology; Epilepsy; FDA approval; Marijuana; Neocortex; Pediatrics; Quality of life; Seizures; serotonin; Serotonin S1 receptors; Tetrahydrocannabinol; THC; United States > US
• ISSN: 2073-4409; 2073-4409
• DOI: 10.3390/cells13060466

Cannabinoids have shown potential in drug-resistant epilepsy treatment; however, we lack knowledge on which cannabinoid(s) to use, dosing, and their pharmacological targets. This study investigated (i) the anticonvulsant effect of Cannabidiol (CBD) alone and (ii) in combination with Delta-9 Tetrahydrocannabinol (Δ9-THC), as well as (iii) the serotonin (5-HT)1A receptor’s role in CBD’s mechanism of action. Seizure activity, induced by 4-aminopyridine, was measured by extracellular field recordings in cortex layer 2/3 of mouse brain slices. The anticonvulsant effect of 10, 30, and 100 µM CBD alone and combined with Δ9-THC was evaluated. To examine CBD’s mechanism of action, slices were pre-treated with a 5-HT1A receptor antagonist before CBD’s effect was evaluated. An amount of ≥30 µM CBD alone exerted significant anticonvulsant effects while 10 µM CBD did not. However, 10 µM CBD combined with low-dose Δ9-THC (20:3 ratio) displayed significantly greater anticonvulsant effects than either phytocannabinoid alone. Furthermore, blocking 5-HT1A receptors before CBD application significantly abolished CBD’s effects. Thus, our results demonstrate the efficacy of low-dose CBD and Δ9-THC combined and that CBD exerts its effects, at least in part, through 5-HT1A receptors. These results could address drug-resistance while providing insight into CBD’s mechanism of action, laying the groundwork for further testing of cannabinoids as anticonvulsants.