The endocannabinoid system, which is the body’s system of natural cannabinoids, receptors that metabolize cannabinoids of any source, and enzymes that control that interaction, is one of the few body-wide systems that has direct interaction with both neurological and physiological disorders. A quick review of the Cornerstone blog yields a wealth of evidence of the endocannabinoid system influencing everything from general pain, to sleep, to neurological malfunction, to immune system regulation, psychological health, and much more. In February 2016, specifically, we wrote about the possibility of cannabinoids/cannabis being used to treat migraine headaches:
Anecdotally, this study confirmed that medical cannabis patients experience relief from migraines in a large sample (121 people). However, at the time, little was understood about the potential cause of relief, as well as the ramifications of cannabinoid signaling on other body functions and systems. In July, the International Cannabis Research Symposium Journal published more information shedding light on additional research surrounding cannabinoids and migraines, as well as on the potential interaction with kynurenine, a receptor antagonist (blocker) related to glutamate, one of the main neurotransmitters in the central nervous system, which includes the brain.
To review, migraine headaches affect roughly 16% of the population at different stages of life! This has yielded an estimated 18.4 billion euro cost to European healthcare a year, not to mention extreme decrease in quality of life for patients suffering from migraines. While researchers are still trying to pin down what exactly causes migraines, we can presume from research that migraines are caused by hyperexcitability of the glutamatergic system. In other words, patients suffering from migraines are generally suffering from overactive neurotransmitters, specifically glutamate.
The kynurenine pathway (KP) concerns Trp metabolism, or the metabolism of tryptophan. While the interactions of the entire system go beyond the scope of this article, it is important to note that in individuals suffering from migraines, KP metabolites are generally very different than in healthy patients (reduced). In almost every working animal model of migraine, or artificially induced models used to test migraine-related research hypotheses, KP metabolites are directly or indirectly involved. While again, the specifics remain unknown, and a full discussion is beyond the scope of this article, common sense and a wealth of research would indicate that the kynurenine pathway will be involved in the future cure/remedy of migraines.
Separately, “clinical studies [have] shown that the formation of AEA and 2-AG”, which are the main naturally occurring cannabinoids in the human body, are down-regulated in individuals with migraines, or are produced less frequently. Additionally, researchers have indicated a raised FAAH enzyme level, or a raised level of the enzyme that removes AEA from its receptors as well. This would indicate that in individuals with migraine headaches, the endocannabinoid system is not functioning properly. Lastly, of course, the endocannabinoid system has shown a particular ability to influence pain, to the degree that physicians are currently evaluating the idea of inducting cannabis/cannabinoid-based medicine into the pantheon of modern pain treatment. As we’ve reported previously, cannabinoids show particular strength in inflammation-related pain and neuropathic pain, representing a much safer alternative to health-damaging and physiologically-addictive opioids commonly in use. It is, of course, no stretch to understand how these findings relate to migraine itself, severe headache and neurological pain. Supporting this, cannabis flowers have been incorporated into migraine treatments of numerous civilizations historically, indicating in an anecdotal way, that those societies found cannabis helpful in treatment.
Given that both KP and the endocannabinoid system have proven connections to migraines, the question asked by researchers in “Interactions between the Kynurenine and Endocannabinioid System with Special Emphasis on Migraine” is “how do these systems potentially relate?”.
According to the review, cannabinoid receptors interact with NMDA receptors (N-methyl-D-aspartate receptors). NMDA receptors’ permeability is co-activated in part by glutamate. “The most widely studied and known pathological disorders in which these two [receptors] interact are psychosis, schizophrenia[,] and epilepsy.” In fact, the receptors “have been demonstrated to be…co-localized allowing them to functionally interact in both sides of the synapse”, the transmission gap between brain cells. Specifically, CB1 cannabinoid receptors reduce the activity of NMDA receptors by reducing glutamate release. This is supported by a wealth of research, specifically in the case of epilepsy, which is thought to be caused by over-excitability of NMDA receptors and responds well to cannabis and cannabinoid-based treatments, as covered in other Cornerstone blog articles. Given that glutamate, as discussed, holds some kind of key to the end of migraine headache, while there is no direct research supporting the interaction between the two systems, we do therefore know that they must interact in some indirect manner.
Secondly, the “orphan receptor”, GPR-35 (which you can read about in an earlier Cornerstone blog post found here: The Hunt to Establish New Cannabinoid Receptors: G Protein Pathways, is activated by both KP components and cannabinoids. In fact, the discovery of its activation by the endocannabinoid system was one of the first hints of its use/purpose in the human body. Again, while the potential interaction has not been investigated, common sense would suggest that this could be another potential avenue of interaction if both systems are competing over activation.
For additional technical reading, we would encourage blog followers to visit the ICRSJ website and read the full report, which lists even more specific concepts of interactions between the two systems. However, the real meat of this report is the realization that this may be the actual pathway through which cannabis and cannabinoid based medicines can decrease migraine. While this hypothesis must stand the test of time and aggressive research, we can predict that the scientific community will devote a portion of future endocannabinoid system research to resolving this connection in an attempt to understand and eradicate migraine. In the meantime, if anecdotal evidence is any indication, patients will continue to find relief of migraine through medical cannabis use.
Gabor Nagyj-Grocz, Ferenc Zador, Szabolcs Dvoracsko, et al. “Interactions between the Kynurenine and Endocannabinoid System with Special Emphasis on Migraine”. Interaction Journal of Molecular Sciences