Assessing the role of serotonergic receptors in cannabidiol's anticonvulsant efficacy

Epilepsy Behav. 2017 Aug;73:111-118. doi: 10.1016/j.yebeh.2017.04.045. Epub 2017 Jun 16.


Cannabidiol (CBD) is a phytocannabinoid that has demonstrated anticonvulsant efficacy in several animal models of seizure. The current experiment validated CBD's anticonvulsant effect using the acute pentylenetetrazol (PTZ) model. Furthermore, it tested whether CBD reduces seizure activity by interacting with either the serotonergic 5HT1A or 5HT2A receptor. 120 male adolescent Wistar-Kyoto rats were randomly assigned to 8 treatment groups in two consecutive experiments. In both experiments, subjects received either CBD (100mg/kg) or vehicle 60min prior to seizure testing. In Experiment 1, subjects received either WAY-100635 (1mg/kg), a 5HT1A antagonist, or saline vehicle injection 80min prior to seizure testing. In Experiment 2, subjects received either MDL-100907 (0.3mg/kg), a specific 5HT2A antagonist, or 40% DMSO vehicle 80min prior to seizure testing. 85mg/kg of PTZ was administered to induce seizure, and behavior was recorded for 30min. Seizure behaviors were subsequently coded using a 5-point scale of severity. Across both experiments, subjects in the vehicle control groups exhibited high levels of seizure activity and mortality. In both experiments, CBD treatment significantly attenuated seizure activity. Pre-treatment with either WAY-100635 or MDL-100907 did not block CBD's anticonvulsant effect. WAY-100635 administration, by itself, also led to a significant attenuation of seizure activity. These results do not support the hypothesis that CBD attenuates seizure activity through activation of the 5HT1A or 5HT2A receptor. While this work further confirms the anticonvulsant efficacy of CBD and supports its application in the treatment of human seizure disorders, additional research on CBD's mechanism of action must be conducted.

Keywords: 5HT1A; 5HT2A; Anticonvulsant; Cannabidiol; Seizure; Serotonin.

MeSH terms

  • Animals
  • Anticonvulsants / therapeutic use*
  • Cannabidiol / therapeutic use*
  • Fluorobenzenes / pharmacology
  • Male
  • Pentylenetetrazole / toxicity
  • Piperazines / pharmacology
  • Piperidines / pharmacology
  • Pyridines / pharmacology
  • Rats
  • Rats, Inbred WKY
  • Receptor, Serotonin, 5-HT1A / physiology*
  • Receptor, Serotonin, 5-HT2A / physiology*
  • Seizures / chemically induced
  • Seizures / drug therapy*
  • Seizures / metabolism
  • Serotonin 5-HT1 Receptor Antagonists / pharmacology
  • Serotonin 5-HT2 Receptor Antagonists / pharmacology
  • Treatment Outcome


  • Anticonvulsants
  • Fluorobenzenes
  • Piperazines
  • Piperidines
  • Pyridines
  • Receptor, Serotonin, 5-HT2A
  • Serotonin 5-HT1 Receptor Antagonists
  • Serotonin 5-HT2 Receptor Antagonists
  • Receptor, Serotonin, 5-HT1A
  • Cannabidiol
  • N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide
  • volinanserin
  • Pentylenetetrazole