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Cannabinoids Reduce Behavioral Symptoms in Mouse Model of Migraine

Mice given calcitonin gene-related peptide (CGRP), a trigger for migraine, lost their aversion to light when simultaneously given the two main components of cannabis, tetrahydrocannabinol (THC) and cannabidiol (CBD), according to a study reported at the American Headache Society annual scientific meeting.

At the same time, mice treated with the cannabinoids showed no impairment of their motor function when tested on the rotarod assay.

“Our preclinical studies add to the growing body of supportive literature indicating that cannabinoids may help alleviate migraine symptoms at dosages that are well tolerated," said the senior author of the paper, Andrew F. Russo, PhD, professor in the department of molecular physiology & biophysics and in the department of neurology at the University of Iowa.

“While these results are preliminary and still need to be verified, we believe that our findings warrant further study of these compounds in human trials," Dr. Russo said.

Erik Zorrilla, a graduate student in Dr. Russo's laboratory presented the findings at the meeting.

To conduct their study, the research teams co-administered CGRP at 0.1 mg/kg along with THC, CBD, and combinations of the two. The positive control mice were given only CGRP, and the negative controls were given only the sunflower oil in which the other drugs were administered.

The cannabinoids had no effect on light aversion in mice who were not given CGRP. But when CGRP was given with CBD and THC, their light aversion was “almost completely alleviated...and no longer significantly different from the negative control group."

The mice were placed on a stationary rod for the rotarod assay during three trials of five minutes each, separated by 10 minutes of rest. During each five-minute trial, the rod would begin rotating at a rate of four rotations per minute, eventually increasing to 60 RPM. The investigators then measured how long it took for mice to fall off the rod.

For a positive control, the group used diazepam (5 mg/kg), and for a negative control, they used only sunflower oil.

None of the combinations of cannabinoids impaired the motor function of the mice, they found. “The data showed that at the 100:1 (CBD to THC) ratio, we were able to reverse the light aversive phenotype," Zorilla said.

In an email, Dr. Russo said: “If confirmed in humans, a similar product would have the potential to offer relief to millions of migraine sufferers."

The THC and CBD used in the study were provided by Schedule 1 Therapeutics, and the study was funded by the National Institutes of Health and the Migraine Research Foundation.

While impressed with the mouse model of migraines, a leading migraine specialist said he was concerned that people might take the wrong message from the paper.

“The utility of this paper is not to suggest that migraineurs run out to take THC," said Peter Goadsby, MD, PhD, DSc, professor of neurology at the David Geffen School of Medicine at UCLA and director of the National Institute of Healthcare Research Wellcome Trust at King's College Clinical Research Facility in London. “It's about having a model that is sensitive to pharmacology, using light aversion as a surrogate in an experimental animal."

Dr. Goadsby called Dr. Russo a “pioneer who has championed this model. He's very well respected."  But, Dr. Goadsby said, he worries about the potential ill effects of cannabinoids.

“Cannabinoid receptors sit in the same place in the brain where opioid receptors sit," he said. “What we've learned in the last 50 years is that giving opioids to people with migraine on a regular basis is a spectacularly bad idea. So, it's worth being careful with this type of pharmacology."

 “Cannabinoids at the very least don't help, and in the people I see, they tend to stand in the way of improvement," Dr. Goadsby said.

Zorrilla had no disclosures. Dr. Russo disclosed that he has received funding from the National Institutes of Health, the Veterans Administration Medical Center, Migraine Research Foundation, ​​and Lundbeck, and has consulted for Lundbeck, AbbVie, Eli Lilly, Amgen/Novartis, and Schedule 1 Therapeutics.

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AHS OR-03: Zorrilla E, Kuburas A, Wattiez A, et al. Therapeutic potential of cannabinoids on preclinical migraine models.​​