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This New Study Will Test the Link Between Cannabis and Migraines

By Alexander Beadle

Published: Apr 22, 2022   
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Stress, bright lights, strong smells, and dietary changes can all bring on a migraine. But while experts have identified many common triggers for migraine attacks, the physiological basis for why some people get migraines is still a mystery.

Now, scientists at the University of Arizona Health Sciences Comprehensive Pain and Addiction Center believe that the endocannabinoid system might hold the answers.

After discovering a correlation between endocannabinoid levels and migraines in animal models, one UArizona research group is investigating whether these levels could be manipulated to alleviate migraine and headache pain.

More than a headache

Migraines are the leading cause of disability among the 15 to 49 age group and is estimated to affect three times as many women as men. The condition is a neurological disorder predominantly characterized by intense, unilateral head pain lasting anywhere from 4 to 72 hours if left untreated. Roughly one-third of migraine sufferers will also experience a migraine ‘aura’ before the onset of pain, consisting of additional visual disturbances such as flashing lights or a temporary loss of vision.

“There is clinical evidence that patients who have chronic migraine, defined as 15 or more headache days per month, as well as patients who have medication-overuse headache, have lower circulating plasma levels of endocannabinoids,” Tally Largent-Milnes, an associate professor of pharmacology at the UArizona College of Medicine, Tucson, said in a statement.

“Clinical endocannabinoid deficiency is a common feature between the three major functional pain disorders: migraine, fibromyalgia and irritable bowel,” Largent-Milnes explained.

The two primary endocannabinoids identified by researchers are anandamide and 2-arachidonoylglycerol, or 2-AG. Preliminary research has suggested that blocking the degradation of anandamide could be a possible therapeutic avenue for treating migraine pain, as this would address some of the endocannabinoid imbalance seen in chronic migraine sufferers.

“That line of research came from this idea of clinical endocannabinoid deficiency, and the fact that we can measure anandamide levels in both the central nervous system and the blood plasma,” Largent-Milnes said. “But the 2-AG story has been largely overlooked, and my lab is primarily interested in 2-AG due to its increased endogenous levels.”

CBD and migraines

Largent-Milnes’ group has previously examined whether there is a correlation between 2-AG levels and migraine headaches, finding that 2-AG levels were indeed lower in the migraine model group than the healthy controls.

“We are seeing a variety of changes in the molecular components of migraine – especially in the enzyme activities, receptors and inflammatory markers – that point to this idea that 2-AG is playing a role,” Largent-Milnes said.

“The losses of 2-AG that we see are not due to any changes in how much is being made, but rather how much is being degraded. It really pushes forth this idea that enhanced degradation of 2-AG may be a driving factor for headache.”

In another pre-clinical study, Largent-Milnes’ research group found that both anandamide and 2-AG levels are lower in females than males, particularly in the periaqueductal gray region of the brain. This area is largely responsible for amplifying or dampening stressors, such as pain.

“From the sex difference standpoint, this seems to be a female-mediated system, so it’s likely, at least in part, that a hormone regulation of the endocannabinoid system is what's driving this female susceptibility to headache,” Largent-Milnes suggested.

The Largent-Milnes group is now investigating whether 2-AG levels can be manipulated to tackle migraine pain by inhibiting the enzymes in the body responsible for breaking down 2-AG. If successful, this could lead to the development of therapies that are able to influence the endocannabinoid system and treat migraine without the need for intoxicating cannabis.

Cannabis and migraine

A previous study of medical cannabis symptom tracker app data found that inhaled cannabis reduced the severity of headaches and migraine attacks by nearly 50 percent.

Published in the Journal of Pain, the researchers from Washington State University examined records from more than 1,300 medical cannabis users that had been submitted to the medical cannabis tracker app Strainprint. They found that men reported larger reductions in headache pain than women, and that cannabis concentrate use was associated with larger reductions in headache than flower.

However, the medical cannabis users did tend to use larger amounts of cannabis product as the study period progressed, suggesting the possible build-up of a tolerance to cannabis and a lessening effect on the migraine and headache pain. This is one of the reasons why an alternative drug to cannabis may be required if the endocannabinoid system really is an effective mediator of migraine pain.

Other studies have suggested that migraine sufferers who use cannabis for pain relief may also be at higher odds of developing medication overuse headache (MOH), also known as rebound headaches. Such rebound headaches are normally the result of long-term painkiller or triptan medication use, where a sudden halt in use can trigger headaches as a result of withdrawal.

The research, presented last year at the American Academy of Neurology’s 73rd Annual Meeting, examined medical records from over 360 patients with chronic migraine over the course of a year, concluding that “cannabis use significantly contributes to the prevalence of MOH” in chronic migraine.


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