Micro-LC-MS/MS Links 2-AG to Depression, Not Migraine

Scientists have suspected that problems with the body's endocannabinoid system, a network involved in regulating things like mood and pain, might play a role in both migraines and depression, two conditions that often occur together in the same patients. However, there isn't much solid evidence to back this idea up yet. This led a research team to investigate whether this system is disrupted in migraine patients during the periods between attacks, and whether other factors might be muddying the picture. To find out, they measured levels of two natural endocannabinoid compounds (called AEA and 2-AG) along with a related molecule (called DHEA) in cerebrospinal fluid (CSF) samples using micro-liquid chromatography-tandem mass spectrometry (micro-LC-MS/MS). These samples came from 194 people who experience migraines with distinct attack episodes (split evenly between those who get migraines with aura and those who don't), as well as 94 healthy volunteers for comparison. A paper based on this work was published in the journal Cephalalgia.¹

Why Might Studying the Endocannabinoid System in Migraine Patients Help Explain What Causes Migraines?

Migraine is a common and often debilitating brain condition that causes attacks of intense headaches along with other symptoms. Depression and anxiety frequently occur alongside migraine as well.^2-4 Studying brain chemistry in people with migraine during the times between attacks could help scientists better understand what is driving the condition and potentially point to new treatment options. Since migraine attacks happen repeatedly over time, it's likely that there are underlying differences between people with migraine and those without, whether these differences are a root cause of the condition or simply a result of experiencing so many attacks. One possible factor that could make someone more prone to migraine attacks is changes in the endocannabinoid system, a network that plays a major role in how brain cells communicate with each other, as well as in hormone regulation and immune function in the brain,^5-7all of which being factors in migraine pathophysiology.^8,9

Did the Study Find Differences in Endocannabinoid Levels Between Migraine Patients and Healthy Controls?

The researchers made sure the groups being compared were similar in age and sex, and they followed a strict, consistent process for collecting and handling the samples so results would be comparable across participants. To compare the groups statistically, they used a method that could account for other factors that might influence the results, such as sex, age, body weight, substance use, and symptoms of depression.¹

The results showed no meaningful differences between people with migraine (with or without aura) and healthy volunteers in terms of the levels of the three compounds measured in spinal fluid. However, one of the compounds, 2-AG, was found to be higher in people with more depressive symptoms, suggesting a possible connection between this compound and depression, even though it didn't seem to be linked to migraines specifically.¹

CSF endocannabinoids such as AEA, 2-AG, and DHEA “may not serve as effective biomarkers for distinguishing interictal episodic migraine patients from controls,” write the authors of the paper.¹ “Instead, CSF levels of 2-AG are linked to depressive symptoms, shedding further light on the relevance of endocannabinoids in patients with migraine and depression. This study highlights the intricate nature of the endocannabinoid system concerning episodic migraine and confounding factors.”

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References

1. Harder, A. V. E.; Di, X.; Winter, W. M. et al. Endocannabinoid Cerebrospinal Fluid Levels in Migraine and Its Relation to Symptoms of Depression. Cephalalgia 2026, 46 (7), 3331024261451250. DOI: 10.1177/03331024261451250
2. Headache Classification Committee of the International Headache Society (IHS) The International Classification of Headache Disorders, 3rd edition. Cephalalgia 2018, 38 (1), 1-211. DOI: 10.1177/0333102417738202
3. Louter, M. A.; Pijpers, J. A.; Wardenaar, K. J. et al. Symptom Dimensions of Affective Disorders in Migraine Patients. J Psychosom Res. 2015, 79 (5), 458-463. DOI: 10.1016/j.jpsychores.2015.09.014
4. Breslau, N.; Lipton, R. B.; Stewart, W. F. et al. Comorbidity of Migraine and Depression: Investigating Potential Etiology and Prognosis. Neurology 2003, 60 (8), 1308-1312. DOI: 10.1212/01.wnl.0000058907.41080.54
5. Hillard, C. J.; Beatka. M.; Sarvaideo, J. Endocannabinoid Signaling and the Hypothalamic-Pituitary-Adrenal Axis. Compr Physiol. 2016, 7 (1), 1-15. DOI: 10.1002/cphy.c160005
6. Pandey, R.; Mousawy, K.; Nagarkatti, M. et al. Endocannabinoids and Immune Regulation. Pharmacol Res. 2009, 60 (2), 85-92. DOI: 10.1016/j.phrs.2009.03.019
7. Szabo, B.; Schlicker, E. Effects of Cannabinoids on Neurotransmission. Handb Exp Pharmacol 2005, 168, 327–365. DOI: 10.1007/3-540-26573-2_11
8. Goadsby, P. J.; Holland, P. R.; Martins-Oliveira, M. et al. Pathophysiology of Migraine: A Disorder of Sensory Processing. Physiol Rev. 2017, 97 (2), 553-622. DOI: 10.1152/physrev.00034.2015
9. Bruno, P. P.; Carpino, F.; Carpino, G. et al. An Overview on Immune System and Migraine. Eur Rev Med Pharmacol Sci. 2007, 11 (4), 245-248.