Fibromyalgia, Migraines & The Science Of Clinical A theoretical syndrome, clinical endocannabinoid deficiency, could provide new insight. Foremost among these are migraine, fibromyalgia, and irritable bowel syndrome, The theory of clinical endocannabinoid deficiency (CED) was .. in-depth historical and scientific review of cannabis in migraine treatment. Migraine, Fibromyalgia, Irritable Bowel Syndrome and other. Treatment-Resistant underlying clinical endocannabinoid deficiency that may be suitably treated available science at the twilight of the 19th century was.
Endocannabinoid Clinical Migraines Deficiency Fibromyalgia, Science Of The &
However, studies have found that some people have lower endocannabinoid levels than others, which brings about health complications. There is an increasing body of clinical research which shows anxiety to be associated with reduced anandamide levels, and major depression to be linked with reduced 2-AG levels.
When the body is unable to produce endocannabinoids in the concentrations required, chemical imbalances occur, which leads to illness.
Cannabinoid receptors interact with both endocannabinoids and cannabinoids, with the plant-derived compounds able to mimic endocannabinoids or otherwise influence them for ECS regulation.
Therefore, it is logical that a cannabinoid treatment could effectively remedy CECD. This followed an earlier release. Medical researchers have been unable to come up with a definite cause for fibromyalgia.
Patients suffer from an array of debilitating symptoms that have a significant effect on quality of life. According to the Anxiety and Depression Association of America, 20 percent of fibromyalgia patients experience one of or both of these mental health disorders. Typically, this is a result of the pain and fatigue caused by the condition. In , a study found that CBD could reduce anxiety beyond placebo levels , with patients given a mg dose administered via CBD capsules.
Moreover, several symptoms of fibromyalgia are indicative of ECS dysregulation — for instance, inflammatory conditions occur due to problems with immune system response, which is modulated by the ECS and specifically the CB2 receptor. Around 39 million Americans are affected by migraines, according to the Migraine Research Foundation.
Migraines can cause dizziness, nausea, numbness or tingling in the face and other unpleasant symptoms. Russo found that endocannabinoid system changes could help to alleviate migraines in his research.
This could help with treating acute migraines and as a preventative treatment. Furthermore, the results showed that several cannabinoids exhibited anti-inflammatory properties and dopamine-blocking effects. The light and sound sensitivity that results from migraines may be due to an overactive nervous system. The ECS is renowned for regulating such imbalances Russo, Some have suggested that the root cause of migraines can be traced back to the trigeminovascular system, which brings blood to the brain.
Studies have shown that endocannabinoids can influence this system. Migraines and cluster headaches may be best managed with a treatment that is an agonist of the CB1 receptor. In the case of migraines, one study found that while a CBD and THC treatment was not necessarily more effective than existing anti-migraine treatments, the side effects were significantly reduced. Fascinatingly, cannabis was a common treatment for migraines in Europe and North America from the mids until the s, a time when the herb was being prohibited around the globe.
As governments all over the world look into the benefits of medical cannabis, the number of high-quality studies being carried out in clinical settings is sure to increase.
With time, we should get an in-depth look at the potential of cannabinoids as a treatment for fibromyalgia, migraines and other illnesses. Sensitized nerve fibers, via activation of certain subtypes of sodium channels Nav , generate nociceptive firing nociceptive spikes propagated to the brainstem and, later, to the higher pain centers where this nociceptive traffic is perceived as migraine pain. The anti-nociceptive effect of eCBs depends on their local concentrations, determined by the balance between the synthesis and degradation as well as availability and subtypes of their target receptors.
At peripheral site in meninges, CB1 receptors expressed in peripheral trigeminal nerve endings can contribute to anti-nociception by reducing probability of spike generation and reducing release of CGRP. Cannabinoid receptor type 1 CB1 in the CNS is mainly expressed in neurons with predominant presynaptic location providing the inhibitory action of glutamate release in the brainstem.
CB1 subtype is also expressed in astrocytes Metna-Laurent and Marsicano, Cannabinoid receptor type 2 CB2 and GPR55 are primarily expressed in cells of immune origin such as peripheral MC or T-cells as well as in microglial cells in the brain. Recent data also suggest heteromerization of CB1 and CB2 receptors in activated microglia.
Notably, microglia are much more efficient than astrocytes and neurons Walter et al. The ECS signals are relayed primarily by two receptors: The mechanism of action is less clear for CBD, which has been reported to affect more than 65 discrete molecular targets and to have varied effects outside of ECS Bih et al.
One important issue remaining unsolved is how exactly eCBs are released from cells. An alternative view suggests that eCBs may be pre-synthesized and stored, much like neurotransmitters Maccarrone et al.
Endocannabinoid system is active in stress-responsive parts of central and peripheral nervous system, functioning to reduce pain and to alleviate neurodegenerative and inflammatory damage Preedy, ; Smith et al. All these mechanisms are linked, directly or indirectly, to the migraine pathology. The importance of the trigeminovascular system TGVS in migraine pathophysiology is widely recognized by experts in the field.
During a migraine attack, prolonged activation of the TGVS — comprising meningeal trigeminal nerves and vessels along with dural mast cells MC Figure 1 — ultimately causes sensitization of higher order neurons in the central nervous system CNS , leading to the persistent nociceptive signaling Burstein et al.
Furthermore, the resulting sensitization has been found to stimulate TGVS activity, creating a positive feedback loop Eroli et al. The main migraine mediator associated with the TGVS system is the neuropeptide calcitonin gene-related peptide CGRP , which promotes vasodilation and contributes to the sterile meningeal inflammation associated with sensitization of nociceptive pathway Giniatullin et al. Several papers from P. In particular serotonin, a major component of mast cell granules, is able to produce a robust activation of trigeminal afferents in meninges Kilinc et al.
It is yet to be studied using migraine models, but similar mast cell stabilizing effect in meninges could potentially contribute to the anti-migraine action of cannabinoids Figure 1.
Both within CNS and peripherally, eCBs act as retrograde messengers or synaptic modulators for their respective target cells Gabral et al. Unlike the selective presynaptic inhibitory effect of adenosine on excitatory glutamatergic terminals Safiulina et al. CB2 receptor, being, like CB1 receptor, highly sensitive to 2-AG, possesses an individual set of expression patterns and characteristic functions.
Thus, CB2 expression is higher in peripheral organs than in the CNS and is mostly restricted to the immune system cells including B and T lymphocytes Figure 1. Endocannabinoid system contributes to both innate and adaptive immune responses, functioning as a preventative force against the onset of pro-inflammatory responses Nagarkatti et al. CB2 receptors are primarily responsible for exerting immunosuppressive effects in the periphery.
During an inflammatory reaction, which is expected in most severe or chronic forms of migraine, more of CB2 receptors are made available for activation Gabral et al.
In our recent study, familial migraine was found to be associated with enhanced concentrations of key inflammatory cytokines detected in blood Khaiboullina et al.
Thus, cannabinoids may act by correcting the dysregulation of cytokine production Nagarkatti et al. Taken together, these studies suggest that the less explored CB2 receptors possessing the anti-inflammatory potential Gabral et al. Besides their independent functions, CB1 and CB2 receptors have been shown to work together by forming hetero-receptor complexes Callen et al. This type of receptor-receptor interaction has been shown recently for brain-residing immune cells such as microglia.
Thus, it has been recently shown that, alongside CB2 receptors, the CB1-CB2 heteroreceptor complexes are expressed in microglia Smith et al. Microglia could play a part in the pathogenesis of migraine with aura, since the cortical spreading depression CSD associated with this type of migraine effectively activates microglia Shibata and Suzuki, Notably, the ability of microglia to secrete 2-AG is about times higher than that of astrocytes and neurons Walter et al.
In view of the recent data, this link appears to be even more intriguing as microglia are essential for initiation of CSD Pusic et al. Consistent with growing interest to the medications targeting receptor heteromers, a study using the bivalent CB1 antagonist specifically affecting dimerized CB1 receptors, showed pain-alleviating effects Zhang et al. In peripheral migraine mechanisms, activation of TRPV1 receptor, a non-selective cation channel expressed in trigeminal nociceptors, leads to massive CGRP release Kageneck et al.
Our and other studies indicate an important contribution of TRPV1 receptors to migraine pathology Zakharov et al. This complexity may explain why increased doses of cannabinoids diminished their analgesic effect Kandasamy et al.
It further creates an incentive for development of new synthetic CBs with minimal activity on TRPV1 receptors, or specific MAGL inhibitors, which, apart from triggering the accumulation of anti-nociceptive 2-AG, can decrease the level of the pro-nociceptive arachidonic acid AA and reduce pain Aaltonen et al.
Disruptions in supply or functionality of eCB ligands have been connected to numerous mental state disturbances and, particularly, to migraine. Migraine, along with comorbid conditions such as fibromyalgia and irritable bowel syndrome, share symptomatic commonalities of hyperalgesia as well as treatment resistance, likely stemming from common pathophysiological phenomenon: The lowered inhibitory activity of eCS in migraine, possibly due to reduced CB1 and CB2 receptor expression, serves as an assertion for the compensatory therapy with exogenous cannabinoids.
According to the CECD hypothesis, treatment of migraine using exogenous cannabinoids could be achieved with low doses due to predisposition for elevated neuronal excitability. The CECD-causing deficiencies can appear for congenital reasons, or can be acquired. There is a long history of using cannabinoids for effective treatment of pain conditions. Due to their long-standing status of out-lawed substances Baron, , it is worth taking a look at the arguments still standing in the way of legalization.
Overall, targeting ECS with peripherally acting drugs is a promising strategy for development of safe migraine treatments. However, there are still many insufficiently explored issues that may be detrimental for this seemingly harmless treatment. Regularly experiencing chronic migraine pain can have adverse impacts on social relationships and job status which can lead into psychological distress Ramsden et al.
In a study of the cannabis use for self-medication in Germany, Austria and Switzerland, Another group found that the self-treatment outcome was highly variable, with low doses tending to alleviate migraine while higher doses even triggering headaches Lu and Anderson, These findings call for creating a highly specific prescription for individual patients, which would be required for safe and successful treatment plan.
One of the main problems arising from the long-term usage of cannabis is the physical reliance on the pCBs, mainly THC. Moreover, there is evidence that patients can develop tolerance for pCBs Kandasamy et al.
A crucial point when considering cannabinoid treatment is that smoking marijuana is the most common method of pCB self-administration. When self-administering pCBs via smoking, the relief seekers often use marijuana mixed with tobacco leaves. In view of the recently established crosstalk between nicotinic cholinergic and ECS Scherma et al.
Particularly interesting is the ability of the endogenous nicotinic antagonist kynurenic acid to counteract the addictive effects of CBs Justinova et al. Notably, new derivatives of kynurenic acid were suggested recently as promising medicines for migraine Greco et al. Interestingly, the main migraine mediator CGRP can reduce the activity of nicotinic receptors Giniatullin et al.
Cannabidiol CBD , the second most prevalent pCB, should also be explored in relation to migraine treatment. This stands as an important milestone paving the way for possible repurposing of this CBD-based drug for treating migraine, as well as other related neurological conditions. In summary, cannabinoids — due to their anticonvulsive, analgesic, antiemetic, and anti-inflammatory effects — present a promising class of compounds for both acute and prophylactic treatment of migraine pain.
In view of the rapidly unfolding changes in the legal status of cannabis, research on endo cannabinoids has become pertinent once again.
Formal approval of a cannabinoid-based drug for other pathologies opens a possibility for repurposing these agents also to treat migraine. The abundance of CB1 receptors in the brain makes them an attractive target for treatment of migraine via blocking not only peripheral but also the central nociceptive traffic and reducing the pathologically enhanced cortical excitability predisposing to CSD.
CB2 receptors in immune cells can be targeted to reduce the inflammatory component associated with severe forms of migraine. Exogenous compounds lacking the unwanted peripheral pro-nociceptive component or eCBs generated via inhibited degradation pathways and combined with other supportive agents are most desirable for this aim.
Moreover, primary stratification of patients to identify and predict the effectiveness of cannabinoid treatment can greatly improve the efficiency of this approach. RG was supported by the Finnish Academy grant and by the program of competitive growth of Kazan Federal University and the subsidy 6. The other authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Targeting the endocannabinoid system: Cannabinoid CB1 receptor activation inhibits trigeminovascular neurons. Anandamide is able to inhibit trigeminal neurons using an in vivo model of trigeminovascular-mediated nociception. Comprehensive review of medicinal marijuana, cannabinoids, and therapeutic implications in medicine and headache: Molecular targets of cannabidiol in neurological disorders.
On the g-protein-coupled receptor heteromers and their allosteric receptor-receptor interactions in the central nervous system:
Fibromyalgia, Migraines & The Science Of Clinical Endocannabinoid Deficiency
This study examines the concept of clinical endocannabinoid deficiency (CECD), Migraine, fibromyalgia, IBS and related conditions display common clinical, supported by the National Academies of Science, Engineering and Medicine. linked to Clinical Endocannabinoid Deficiency (CED) are migraines, fibromyalgia,  What is the science to support these observations?. ISSUE BRIEF ON CLINICAL ENDOCANNABINOID DEFICIENCY Cannabis Review Panel, and to interested members of the public scientific studies of cannabis evidence of CED: migraine, fibromyalgia, and irritable bowel syndrome.