Combined effects of cannabidiol and Δ9-tetrahydrocannabinol alleviate migraine-like symptoms in mice

Erik Zorrilla; Georgii Krivoshein; Adisa Kuburas; Maarten Schenke; Cassandra L Piña; Sandra H van Heiningen; Jayme S Waite; Anisa Dehghani; William C Castonguay; Harold C Flinn; Arn M J M van den Maagdenberg; Andrew F Russo; Else A Tolner; Anne-Sophie Wattiez

doi:10.1177/03331024251314487

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Combined effects of cannabidiol and Δ9-tetrahydrocannabinol alleviate migraine-like symptoms in mice

Journal article

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Combined effects of cannabidiol and Δ9-tetrahydrocannabinol alleviate migraine-like symptoms in mice

Erik Zorrilla, Georgii Krivoshein, Adisa Kuburas, Maarten Schenke, Cassandra L Piña, Sandra H van Heiningen, Jayme S Waite, Anisa Dehghani, William C Castonguay, Harold C Flinn, …

Cephalalgia, Vol.45(2), pp.1-21

02/2025

DOI: 10.1177/03331024251314487

PMCID: PMC12269478

PMID: 39988876

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Abstract

The therapeutic use of cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC) to treat migraine has been understudied. Using three mouse models, we examined the impact of CBD and THC on migraine-relevant behaviors triggered by: 1) calcitonin gene-related peptide (CGRP), 2) sodium nitroprusside (SNP), and 3) cortical spreading depolarization (CSD). Both male and female CD1 mice were treated with CBD (100 mg/kg) or THC (1 mg/kg) alone or in combinations of CBD (1, 30 or 100 mg/kg) and THC (1 mg/kg) prior to injection of CGRP or SNP. The mice were assessed for light aversion (photophobia), squint (non-evoked pain), and periorbital tactile hypersensitivity, as well as possible adverse effects. In a separate set of experiments, CSD events were optogenetically induced in familial hemiplegic migraine 1 (FHM1) mutant and wildtype littermates (WT) mice (C57BL/6 background), followed by grimace and motor assessments with and without combinations of CBD (30 or 100 mg/kg) and THC (1 mg/kg). In CD1 mice, a 100:1 CBD:THC combination mitigated light aversion induced by CGRP and SNP in males and females. Rescue of CGRP- and SNP-induced squint was observed only in male mice with 100:1 CBD:THC. None of the treatments rescued periorbital tactile hypersensitivity in either sex. In FHM1 mutant and WT mice, the 100:1 CBD:THC ratio did not affect CSD characteristics but did reduce CSD-induced grimace features (i.e., head pain mimic). No adverse effects of any of the cannabinoid treatments were observed using cognitive, emotional, or motor tests. A 100:1 ratio of CBD:THC has a beneficial effect on some of the most bothersome migraine-related symptoms in three mouse models. Our findings support a potential therapeutic efficacy of combined CBD and THC treatments.

Animals

Cannabidiol - pharmacology

Disease Models, Animal

Dronabinol - pharmacology

Drug Therapy, Combination

Female

Male

Mice

Mice, Inbred C57BL

Migraine Disorders - drug therapy

Details

Title: Subtitle: Combined effects of cannabidiol and Δ9-tetrahydrocannabinol alleviate migraine-like symptoms in mice
Creators: Erik Zorrilla - University of Iowa
Georgii Krivoshein - Leiden University Medical Center
Adisa Kuburas - University of Iowa
Maarten Schenke - Leiden University Medical Center
Cassandra L Piña - Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, IA, USA
Sandra H van Heiningen - Leiden University Medical Center
Jayme S Waite - University of Iowa
Anisa Dehghani - Leiden University Medical Center
William C Castonguay - University of Iowa
Harold C Flinn - University of Iowa, Molecular Physiology and Biophysics
Arn M J M van den Maagdenberg - Leiden University Medical Center
Andrew F Russo - University of Iowa
Else A Tolner - Leiden University Medical Center
Anne-Sophie Wattiez - Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, IA, USA
Resource Type: Journal article
Publication Details: Cephalalgia, Vol.45(2), pp.1-21
DOI: 10.1177/03331024251314487
PMID: 39988876
PMCID: PMC12269478
NLM abbreviation: Cephalalgia
ISSN: 0333-1024
eISSN: 1468-2982
Publisher: SAGE PUBLICATIONS LTD
Grant note: Delphian Therapeutics (Schedule 1 Therapeutics)
We thank Michelle van de Brug for help with the four-limb hanging test experiments. Panels featuring experimental designs were created with BioRender.com.
Language: English
Date published: 02/2025
Academic Unit: Neurology; Molecular Physiology and Biophysics; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Craniofacial Anomalies Research Center
Record Identifier: 9984795374302771

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