Mehkri et al. have presented a thorough review of calcitonin-gene related peptide (CGRP) and its relationship with headaches, both primary (e.g., migraine headaches) and secondary headaches (e.g., headaches secondary to subarachnoid hemorrhage (SAH) and traumatic brain injury (TBI)) [1]. They have provided an accurate depiction of the literature and the current knowledge regarding CGRP’s association with neurologic injury, as well as some of the physiologic mechanisms and therapeutic targets. This commentary aims to further discuss the veracity of this article and to add an alternative viewpoint in terms of neuromodulators influencing post-traumatic headaches (PTH).

Regarding PTH, the authors accurately depict a current understanding that is grounded in literature – CGRP’s association with neurologic injury is incompletely understood. Whether it be intracellular signaling leading to a pseudo-inflammatory response or hyperstimulation of the brain, CGRP is known to exacerbate headache symptoms. However, CGRP’s interactions in the setting of secondary headaches, such as those induced by subarachnoid hemorrhage (SAH) or traumatic brain injury (TBI), are variable depending on the timeframe. CGRP is thought to be neuroprotective in the acute setting [2]. Over time, CGRP levels normalize [3,4], and despite low-to-normal CGRP levels, patients with persistent PTH likely remain hypersensitized to CGRP, suggesting that there is reason for more thorough investigation [5]. This is further supported by the fact that monoclonal antibodies against CGRP have shown promise in treating PTH [3].

Existing therapies, such as triptans, gepants, and monoclonal antibodies have mostly been studied in regard to chronic neurologic conditions, where they have demonstrated adequate efficacy in terms of pain relief. While these same medications are often prescribed in the acute setting after trauma, supporting evidence is limited. Long-term, preventative medications used in patients with PTH include tricyclic antidepressants and anti-epileptics, both of which have variable therapeutic efficacy. One potential reason for this discrepancy is that PTH come in different phenotypes. These may often be misdiagnosed for new-onset headache disorder, such as migraine or tension-type headaches, as well as other neurologic conditions. Current thought dictates that in addition to further high-powered clinical trials and a more rigorous classification of PTH, a multi-disciplinary approach is warranted to account for pain and other post-traumatic symptoms such as emotional distress, impaired sleep, physical deconditioning, and autonomic symptoms [6]. Promising interventions focus on antagonizing CGRP in the acute setting before sensitization can occur. However, further studies are needed before clinical trials can take place.

Although CGRP is one of the more commonly studied neurotransmitters for headache pain, there are other potential pathophysiologic mechanisms, and thus chemical mediators, that play a role in the development of PTH. Endocannabinoids (eCB), and the endocannabinoid system (eCBS) in general, have garnered recent attention as a potential therapeutic option for PTH. The two main receptors proposed to be involved include type 1 cannabinoid (CB1) and type 2 cannabinoid (CB2) receptors, which are most commonly found in the stress-responsive locations of the brain and periphery, respectively [7]. The mechanisms behind eCB’s therapeutic effects are broad and include inhibition of afferent trigeminovascular nociceptive inputs, serotonin release from circulating platelets and mast cell degranulation, glutamate signaling, and cranial blood vessel dilatation cause by NO and CGRP [8,9].

Microglia appear to be important mediators of eCB effects in SAH and TBI. CB2 receptors are primarily expressed in immune cells (e.g., mast cells) and microglia, where they function independently or in a receptor complex with CB1. Upon activation (e.g., trauma, hemorrhage, hypoxia), microglia generate neuroinflammation and neuronal cell death through the release of various pro-inflammatory cytokines and reactive oxidative species. Activation of CB2 receptors alters the microglial maturation pathway, shifting microglia from a pro-inflammatory to an anti-inflammatory phenotype [10]. As important contributors in the pathogenesis of PTH and with significant eCBS connections, microglia make an attractive target for headache relief. Pre-clinical studies regarding the efficacy of cannabidiol (CBD) have been promising, with multiple studies demonstrating CBD’s anti-inflammatory and anti-nociceptive effects, which is thought to be attributed to CBD’s inhibition of microglia-induced inflammation [11,12].

Medications associated with the eCBS have long been used for chronic pain conditions. However, due to their historically banned status, there have been few studies assessing the dosing, safety, and efficacy of such therapies. Additionally, much of the existing literature focuses on medical cannabis use, which poses concerns for dependence, rebound, and withdrawal, potentially exacerbating headache symptoms [8]. With that being said, there are promising reports of medical cannabis and CBD being used as efficacious headache therapies. CBD acts as a neuromodulator of the eCBS and, as opposed to tetrahydrocannabinol (THC), has anti-inflammatory, antioxidant, neuroprotective, anticonvulsant, hypnotic, and antiemetic effects without the deleterious psychoactive and dependence-related effects, and has thus been useful in neuropsychiatric, neurodegenerative, post-traumatic stress, and ischemic disorders [13]. Additionally, TBI-induced deficits in behavior, learning, memory, and motor function, as well as psychiatric manifestations and seizures, may also respond to manipulations of the eCBS [14].

In one of the largest reviews of studies regarding eCB’s and the treatment of TBI, Kerger et al. reported mixed findings [15]. Amidst the various studies, medical cannabis use was associated with improved quality of life and cognitive processing speed as well as reduced intake of standard pain medications, depressive symptoms, and impulsivity. In contrast, they found that the use of medical cannabis was associated with impaired neurocognitive function, psychomotor slowing, memory loss, and increased risk of cannabis use disorder. The psychiatric effects of eCB’s are up for debate, with some studies suggesting medical cannabis alleviates and others that it exacerbates symptoms in conditions such as post-traumatic stress disorder, anxiety, and depression. Furthermore, the cognitive effects of medical cannabis may overlap with sequelae of TBI, making post-traumatic evaluations more difficult to track. Current thought suggests that such negative symptoms are induced by THC rather than CBD, and that by utilizing and optimized combination of the two, adverse effects can be minimized without compromising their intended benefits.

Regardless, an overwhelming majority of the scientific community is in agreement that eCB’s can help with pain relief. The majority of studies regarding the eCBS concentrate on migraines, but post-traumatic headaches have become a more popular emphasis as of late. McVige et al. studied medical cannabis for the treatment of post-traumatic concussion in regard to headache, mood, sleep, attention/ concentration, and dizziness and found that medical cannabis use was associated with improved sleep, pain, and mood, reduced opioid use, and improved quality of life. In addition, they found that the best utilization to be 20:1 (THC:CBD) oral tincture for headache prophylaxis and 20:1 vapor inhalation for acute pain [16]. Not only were benefits related to pain control, but Knoller et al. also reported decreased intracranial pressures and improved neurologic outcomes after severe closed head injury in patients given dexanabinol, a type of eCB [17].

Although further studies are needed to properly assess the eCBS and its role in PTH, current literature suggests that eCB’s are an attractive target for further investigation. While the current focus on management of headache secondary to SAH or TBI revolves around CGRP, eCBS present a related and potentially similarly effective alternative. The proposed link between the two, that eCB’s inhibit the effects of CGRP, imply that an ideal drug regimen may include eCB’s and other CGRP inhibitors, which may act harmoniously to inhibit CGRP via different pathways. This synergism could lead to the discovery of a long-awaited cure for PTH and should be investigated further.