Potential targets for the anti-nociceptive action of phyto-cannabinoids (marijuana compounds) and eCBs in migraine pain. Migraine-associated pain (pain propagating pathways are marked in brown) is generated in the TGVS comprising meningeal mast cells (MC), dural vessels and nociceptive trigeminal nerve fibers. Activation of pro-nociceptive TRPV1 receptors in sensory neurons which cell bodies are located in the trigeminal ganglion (TG) surrounded by satellite glial cells (SGC), results in release of the migraine mediator CGRP which can degranulate MC, provide a strong vasodilatory effect and target T-cells (TC). Degranulation of MC is associated with release of multiple pro-inflammatory compounds (5-HT, histamine, cytokines) supporting local neuroinflammation and sensitization of nociceptive fibers. 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. eCBs and exocannabinoids (marked in green) including anandamide (AEA) and 2-arachidonoylglycerol (2-AG) as well as their exogenous counterparts THC and CBD, respectively, are promising agents to provide the anti-nociception in migraine. 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. The degradation of 2-AG is controlled by MAGL whereas hydrolysis of AEA is determined by the activity of FAAH. As some eCBs, such as AEA, can also activate TRPV1 receptors, migraine-associated pain is affected by a delicate balance between anti-nociceptive effects of CBs on specific cannabinoid receptors and pro-nociceptive effects on TRPV1 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, 2015). 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., 2003) in producing the major eCB 2-AG which, in a paracrine way, can control neurons and, in autocrine manner, activate microglia.
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 Figure1 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., 2009; Oláh et al., 2017). 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., 2015). In our recent study, familial migraine was found to be associated with enhanced concentrations of key inflammatory cytokines detected in blood (Khaiboullina et al., 2017). Thus, cannabinoids may act by correcting the dysregulation of cytokine production (Nagarkatti et al., 2009). Taken together, these studies suggest that the less explored CB2 receptors possessing the anti-inflammatory potential (Gabral et al., 2015) represent a promising target to counteract migraine (Scherma et al., 2016).
Mapping ECS Effects in Migraine Models – Central Vs. Peripheral
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, 2015), 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.
PRO and Contra of Cannabinoids in Migraine Treatment
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.
Historical Reports of the Use of Cannabis as a Treatment for Headache (19th and Early 20th Century)
The schedule 1 classification of marijuana in 1970 has made rigorous clinical studies on the treatment efficacy of this substance difficult. Currently, there are no placebo-controlled clinical studies examining the use of cannabis for headache; nevertheless, there have been a number of other studies published that give insight into its therapeutic efficacy ( Table 2 ). 19,43–58 However, care should be taken when interpreting the findings from these studies. With one exception, 53 these studies did not include a control group, and given that the placebo effect can be altered by the context of treatment, 59 it is reasonable to expect a significant placebo response given the pre-existing public popularity and notoriety of cannabis. Moreover, self-reports and case studies may have a bias toward immediate improvement without awareness of possible dependence, rebound, or withdrawal responses, which are important concerns in headache treatment. 60 In fact, studies show that headache can be induced in 23.2% patients undergoing cannabis withdrawal. 61
Historical Use of Cannabis for Headache
When cannabis was deemed illegal by the U.S. government, its therapeutic use and research into its medical potential was largely discontinued. To this day, there are few clinical investigations of the use of cannabis for headache; however, the studies that have emerged demonstrate potential efficacy. In addition, numerous pre-clinical investigations 18 have validated the role of endocannabinoids in preventing headache pathophysiology, which suggests a mechanistic role of cannabis in the treatment of these disorders. Although the cannabis plant comprises more than 100 cannabinoids, there has been little study of the individual effects of these cannabinoids on headache disorders; therefore, the present review will focus largely on the clinical potential of the cannabis plant as a whole.
Early reports of cannabis for the treatment of headache appear to be largely positive, with many patients experiencing a decrease in the frequency and intensity of their headache episodes. In some cases, headache was cured entirely even after cannabis discontinuation. 28,32,36–42 Furthermore, these early clinical reports praise the apparent safety of long-term cannabis use, as well as its added benefits of mollifying the nausea and anxiety that often accompany headaches. A common emphasis was placed on the importance of specific purity, preservation, and administration of the cannabis as well as patient adherence in the efficacy of treatment.
Clinical Studies on Cannabis Use for Headache
Nabilone, a synthetic cannabinoid mimicking tetrahydrocannabinol (THC), has been shown to decrease analgesic intake while reducing MOH pain in a double-blind, placebo-controlled trial. 53 In this study, 26 patients with treatment refractory MOH completed a course of either nabilone (0.5 mg) or ibuprofen (400 mg) for 8 weeks, then after a week-long washout period, completed a second 8-week course of the previously excluded medication. Oral cannabinoid administration was chosen over an oromusocal THC spray, both because oral administration avoids the concentration peaks that can lead to euphoric effects and because chronic administration better overcomes individual differences in bioavailability. Although both substances showed improvement from baseline, nabilone was significantly more effective than ibuprofen in reducing pain intensity, analgesic intake, and medication dependence, as well as in improving quality of life. This study also examined the safety of nabilone as a treatment for headache and found that patients only experienced mild adverse effects that disappeared after discontinuation of the medication. The results of this study are significant, especially given that MOH is exacerbated by many pharmacological treatments. This study also highlights the potential value of cannabis in combination therapies, as a supplement to traditional treatments, or as a secondary treatment in refractory cases. Currently, a multicenter, double-blind, placebo-controlled study is being performed to examine the safety and efficacy of a dronabinol, or synthetic THC, metered dose inhaler for the treatment of migraine (clincaltrials.gov, NCT Identifier: <"type":"clinical-trial","attrs":<"text":"NCT00123201","term_id":"NCT00123201">> NCT00123201). When published, this study could give valuable insights into the efficacy and risks of cannabinoids for the treatment of migraines.