The Role of Inflammation in Migraine Headaches: A Review

ABSTRACT

Migraine is a chronic pulsating primary headache affecting billions of individuals worldwide. The condition is associated with neuroinflammation and is listed as the second most common form of headache disorders and the leading cause of disabilities. Migraineurs are susceptible to various pathological conditions ranging from mood and emotional dysregulation to neuronal disorders. Consequently, they often experience a higher rate of depression compared to non‐migraineurs. Some migraineurs do not respond effectively to conventional drugs. As a result, there is a need for more alternative, effective treatment plans. Understanding the role of inflammation in migraine headache conditions could potentially bring solutions. The aim of the review is to outline the role of inflammation, focusing on neuronal excitability, pain, and inflammatory pathways involved in the context of migraine headaches. With the use of various academic and research databases, articles linked to inflammation and neuroinflammation were considered. Data were collected and analyzed surrounding inflammatory biomarkers and their link to migraine pathophysiology and current treatment plans. Studies highlight the impact of inflammatory mediators and neurotransmitters like interleukins (IL‐1β,6,8,10), tumor necrosis factor‐alpha (TNF‐α), transforming growth‐factor‐beta (TNF‐β), glutamate, and chemokines in the onset and severity of migraine headaches with and without aura, eliciting pain and inflammatory responses in the central nervous system. Studies also linked migraines and mood disorders, contributing to the increase in comorbidity prevalence. Further research is needed to address the increasing burden and gaps in existing treatments surrounding the inadequate relief and side effects reported with some migraine treatments. In addition, the use of medicinal plants for inflammation‐targeted therapy needs to be further explored for more viable alternative treatments.

Inflammation plays a crucial role in the onset and intensity of both migraine headache symptoms and attacks. Pro‐inflammatory neurotransmitters and mediators released from neural cells and tissues that contributes to increase in nitric oxide, increase in glutamate, alterations in serotonin and dopamine levels and pain perception are involved in migraine headache developments and problems. Common neurotransmitters and mediators include IL‐1β, TNF‐α, IL‐6, CGRP, substance P and glutamate.

1. Introduction

Migraine headaches are a type of intracranial headache resulting from abnormal vascular phenomena, characterized by severe throbbing pain often with prodromal sensations that include nausea, vomiting, and sensitivity to sound and light, as well as loss of vision and other types of sensory hallucinations [1]. The exact mechanism of this kind of intracranial headache is not known or fully understood [1]. Headache disorders affect billions of individuals worldwide and are prevalent in approximately 52% of the population, with migraine reporting at 14% among various types of headaches contributing to the high levels of ill health and disability [2, 3]. According to research, migraine was found to hold the title of the world's second largest contributor to the disability‐adjusted‐life‐years (DALYs) lost due to the prevalence of neurological disorders in 2016 [4].

Depressive disorders are another attributable factor impacting the rate of DALYs among a broad spectrum of populations worldwide, with an estimated increase of 27.6% in major depressive disorders due to the COVID‐19 pandemic [5]. Overall, older adults depicted an estimated prevalence of 35.1% of depressive disorders, while the depression rates among young children and adolescents, ranked second and fifth in young females and young males, respectively [6, 7]. Based on a 2022 study, the probable prevalence of depression across South Africa varied from 14.7% to 38.8%, indicating that both mood disorders, depression and anxiety had a higher frequency among retired and older adults above 65 years, along with social, psychosocial, and economic stressors [8]. Moreover, a systematic and meta‐analysis review study undertaken in 2023 reported that children, under the age of 19 years and adolescents who suffer from migraines often experience a higher rate of depression compared to non‐migraineurs, indicating a prevalence of depression from approximately 20%–50% [9]. This comorbidity indicates that migraineurs may have an increased likelihood of developing depressive symptoms due to the biological and neurological mechanisms shared between depression and migraine headaches [9]. These biological mechanisms can interplay with the onset of depression in migraine headaches and vice versa. Common biological mechanisms involve neurotransmitter dysfunction, cortical hyperexcitability, and inflammatory responses that can alter dopamine and serotonin levels, including increased sensitivity that increases the chances of predisposition to mood disorders, as well as exacerbating migraine episodes, which is a contributing factor to depressive symptoms [9]. Neuroinflammation is described as an inflammatory response within the nervous system, affecting the brain and spinal cord [10]. Various inflammatory stimuli and mediators play a significant role in this inflammatory response, which includes the production of cytokines, reactive oxygen species (ROS), chemokines, and secondary messengers [10]. The progression and severity of inflammation in the nervous system are influenced by the above factors mentioned, in addition to underlying neuronal disorders [11]. As described by Hall [1], headaches are a form of neuroinflammation characterized as a type of pain experienced at the surface of the head from deep cranial structures, either pain stimuli arising from the inside (intracranial) or outside of the cranium (extracranial).

The current treatment and management of migraine headaches range from lifestyle and diet modifications to drug therapy. There are three categories of drug therapy: first‐, second‐, and third‐line medications used to reduce and prevent migraine attacks, including enhancing the quality of life in conjunction with diet and lifestyle changes [12]. The common first‐, second‐, and third‐line treatment includes nonsteroidal anti‐inflammatory drugs (NSAIDs), triptans, ergots, and ditans [12]. Medicinal or plant‐derived therapy has also shown great potential in alleviating the inflammatory effects involved in migraine headaches that include Tanacetum parthenium (Feverfew) and Curcuma longa (Turmeric) for its traditional use in preventing the onset of migraine headaches, as well as the hot‐water psilocybin mushroom extracts depicting anti‐inflammatory effects against lipopolysaccharide (LPS)‐induced COX‐2 and proinflammatory cytokine levels, which in turn can potentially target inflammatory‐induced conditions [13, 14, 15].

Despite advancements in medical literature pertaining to migraine pathophysiology and treatments, many patients continue to experience inadequate or insufficient relief from this neurological disorder, resulting from existing treatment and conventional treatment that pose undesirable side effects [16]. The gaps and efficacy among individual variability need to be addressed in focusing on tailored therapies that can be just as effective for comorbid and genetically influenced conditions [16]. Overuse of medication can result in mood and depressive disorders as well as migraine development from antidepressants contributing to the increase in comorbidity prevalence [17]. The interconnection of inflammation and neuroinflammation poses significant challenges in research in creating efficacious targeted therapy for optimal relief and treatment in migraine headaches. Furthermore, glutamate is one of the most crucial excitatory neurotransmitters in migraine pathophysiology; its complexities with various subtypes and triggers pose a challenge in establishing treatment success and hence targeting glutamate therapies were found to be beneficial in migraine treatment [18, 19]. Understanding the role of inflammation and its effect on the key neurotransmitters could potentially address the unmet medical needs for patients suffering from migraine headaches, both acute and chronic.

2. Methods

2.1. Literature Screening

With the use of various academic databases, including PubMed, Google Scholar, ScienceDirect, and Unisa Library, articles related to the topic have been screened. Narrative, systematic, and meta‐analysis articles have been considered with keywords “neuroinflammation,” “migraine headaches,” “anti‐inflammatory,” and “medicinal plants” used. Over 90 articles have been selected and used as sources of information in this review.

2.2. Selection Criteria and Data Collection

2.2.1. Inclusion Criteria

Reviews (both primary and secondary) ranging from 2015 to 2024; articles performed both globally and in South Africa, primary sources (original authors and published articles); secondary sources (systematic and meta‐analysis reviews); in vitro and in vivo studies; articles related to the aim and context of the study.

2.2.2. Exclusion Criteria

Articles older than a decade (10 years); non‐scholarly sources (non‐peer‐reviewed sources that include editorials, magazines, or internet sources such as websites and webpages), duplicate studies (articles reporting the same study results), and non‐English literature (any articles that are not published in the English language).

3. Literature Review

Migraine headaches are one of the primary headaches prevalent in neuroinflammation and are listed as the second most common form of headache disorders and the leading cause of disabilities [20]. Based on a report by Tucker [21], it is projected that 20% (over 11.8 million) of the population in South Africa will experience migraine at some point in their lives, irrespective of their race, location, life, or income [21]. There is a predisposition among migraineurs and those who suffer from mood disorders such as depression. Various studies have shown a link between depression and migraine chronicity due to their shared risk factors and biological mechanisms that can account for their co‐occurrence [22]. Research indicates the complexity and clinical implications surrounding the genetic predisposition involved in migraine headaches, giving insight into certain genes and polygenic influences associated with increased risk and heritability [23, 24]. Various studies have found that genetic factors among siblings and twins may be influential in the development of depression in migraineurs [25].

Migraineurs who suffer from chronic or episodic migraines have shown an increased likelihood of exhibiting depressive symptoms or episodes and vice versa, with a global prevalence of depression among migraineurs ranging from 8.6% to 47.9% [22, 26]. Depression is considered a risk factor for chronic migraines in migraineurs, including an impact on the quality of life, suicidal behavior linked to psychosocial impairment, therapy resistance, and misuse of treatment drugs [27]. Lifestyle changes that include sleep and eating disorders may be a contributing factor to migraine development due to alterations in normal cognitive and sleep function that can influence neurotransmitter distribution and that include, but are not limited to, serotonin, dopamine, glutamate, and proinflammatory cytokines [27, 28]. These various neurotransmitters differentiate and are linked to their sites of release from the brainstem, hypothalamus, and peripheral sites [28]. This comorbidity highlights the shared intricacies in brain alterations supported by numerous neuroimaging studies noted for abnormal function in specific brain regions, which suggests that these affected regions may contribute to depressive symptoms in migraine without aura [22, 26].

Overuse of antidepressants and opioids has been reported to increase the likelihood of migraine attacks and migraine development [18, 29]. The shared etiology between migraine and depression highlights this comorbidity as similar neurochemical key players and pathways are affected. Neuroinflammation is commonly used to describe abnormalities or pathologies in the central nervous system (CNS), giving rise to various neurological disorders [30]. Headaches are one of the most common and prevalent conditions associated with neuroinflammation, affecting billions of individuals worldwide, with an estimated high prevalence of 52% of active headache disorder in 2022, resulting from 357 publications [2]. Based on a study assessing the impact and prevalence of headaches across the Middle East, Asia, and Africa, it was reported that 23.4% of individuals suffer from primary headache disorders, with prevalence of headaches reported to be 53.29%, around 27.44%, and 30.52%, respectively [31].

Studies have shown that neuroinflammation and its inflammatory response within the CNS is primarily driven by peripheral immune cells, endothelial cells, and glia or neuroglia cells, which are key players in the release of neurotransmitters and inflammatory mediators that include glutamate, dopamine, gamma‐aminobutyric acid (GABA), interleukins (IL‐1α, IL‐1β, and IL‐16), tumor necrosis factor (TNF‐α), transforming growth‐factor‐beta (TNF‐β), chemokines (CCL2) and complement components (C1q) [10, 30]. Cytokines can act as a double‐edged sword, either being pro‐ or anti‐inflammatory in nature, that can either exacerbate or modulate the inflammatory response [30]. Antagonistic and agonistic therapies are common practices in alleviating the symptoms associated with migraine headaches, influenced by the neurotransmitters and cytokines mentioned above [19]. These therapies involve suppression of inflammatory and pain pathways that include calcitonin gene‐related peptide (CGRP), serotonin receptors (5‐HT) and cytokines [32]. The common treatment plans reported are triptans, nonsteroidal anti‐inflammatory drugs (NSAIDS) and Ergots [19]. Findings from this study will uncap the potential therapeutic effects of current treatments and its efficacy in its treatment capacity used in treating neurological problems associated with migraine headaches.

3.1. Headaches

Headaches are a universal ailment, accounting for 96% of benign cases with 3% reported as emergency department chief complaints [33]. The subtypes of headaches can be primary or secondary, each varying in its severity and prevalence. According to the International Classification of Headache Disorders (ICHD‐III), headaches are classified as primary (migraine, tension type and any trigeminal autonomic cephalalgies) having no origin from prior disorders, while secondary (traumatic brain injury, cranial and/or cervical vascular disorders, non‐vascular intracranial disorders, cranial neuropathies: trigeminal neuralgia) is classified as a new occurring headache present in temporal association with another disorder recognized of being a result from the causative disorder [34]. Primary headache disorders are highly prevalent and disabling epidemiological stressors that are continuously challenging among many individuals globally, with a shared concern surrounding medication‐overuse headaches [with three common primary headaches mentioned above] [35]. The epidemiology of headaches is an emerging and relatively new discipline in research with variation among its prevalence, population, country, methodologies, and research studies [2]. The absence of the nociceptors of the brain parenchyma may indicate that headache is an outcome of pain originating in surrounding structures, including blood vessels, meninges, facial structures, muscle fibers, and cranial or spinal nerves [33].

3.2. Migraine Headaches

Migraine headaches are one of the two most prevalent headache disorders and can occur with or without aura and are accompanied by pulsating or unilateral pain of the head [36]. Migraine without aura or common migraine is characterized by moderate or severe headache pain lasting up to 4 to 72 h and often accompanied by nausea, vomiting, photophobia (sensitivity to light), or hyperacusis (sensitivity to sound) without warning symptoms [32]. On the contrary, migraine with aura affects 8% of the general population and is characterized by completely reversible visual, sensory, or language disturbances that usually occur 30–60 min before the onset of headache pain [37]. The most common disturbances were reported to be visual aura symptoms occurring in 98%–99% of migraine auras, while disturbances of sensation and language were reported to occur in 36% and 10% of auras, respectively [37, 38]. The pathophysiology of migraine with and without aura shares similarities and differences in their biomarkers, neurotransmitters, and mechanisms. This primary headache consists of five stages, namely, prodrome, aura, headache, postdrome, and interictal, with symptoms and severity varying in each stage. It is important to note that every migraine attack does not progress through all stages [39]. Migraine headaches can be triggered through various mechanisms and the interplay between receptors and neurotransmitters, including active molecules that include catecholamines [32]. This form of headache is also influenced by psychosocial factors and pain modulation affecting the normal serotonergic and glutamatergic systems [28, 29]. These triggers can cause disruption in the hypothalamus, brain stem, and limbic system, which can result in mood changes, sensitivity to light and sound, as well as yawning and fatigue [39].

During a migraine attack, the trigeminal nerve (cranial nerve V) becomes activated, causing the release of neuropeptides in cranial nerve V that include vasoactive inhibitory peptide (VIP), substance P, and CGRP [10]. These neurotransmitters result in painful neurogenic inflammation in the meningeal vasculature, causing mast cell degranulation, plasma protein extravasation, basal dilation, and activation of nociceptors [10, 28]. All these contribute to migraine headache, and these neurotransmitters play a role in trigeminal vascular pain transmission in migraine headaches [10, 29]. A purinergic receptor family member, the P2X7 receptor, has been reported to be involved in the pathogenesis and progression of migraine headaches with elevated levels in migraine patients [40, 41, 42].

This neurological disorder affects millions of people worldwide, contributing to substantial personal impairment which further impacts the quality of life and, in addition, contributes to the increase in economic costs [43]. Based on research and patient comfort and adherence, there are some individuals suffering from chronic migraine who do not respond effectively to conventional drugs, highlighting the need for more alternative, effective treatment plans [43]. The interplay between inflammation, neuroinflammation, and pain pathways remains a challenge in providing sufficient knowledge in migraine and inflammation pathophysiology.

3.3. Migraine Headaches and Depression

Mental health disorders, especially depression, continue to be a growing global problem and the leading cause of the health‐related burden worldwide [44]. According to the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019, the two most disabling mental disorders worldwide were found to be depressive and anxiety disorders. These two disorders were also found to rank among the top 25 leading causes of burden worldwide in 2019 [45]. Previous etiology and cohort studies cited in de Vries et al. have demonstrated that patients who suffered from migraine headaches are three to six times more prone and at risk of suffering from depression in comparison to the persons without a history of severe headaches, which were used as controls [46, 47, 48]. Moreover, research also demonstrated a bidirectional comorbidity relationship between migraine and depression, indicating a shared genetic background for both diseases [47]. In a cohort study of persons aged 25–55 years with migraine cited in Wang et al. depicted that migraine increased the risk for major depression while major depression was found to increase the risk for migraine, however, it was also interesting to note this bidirectional association was not observed with other severe headaches. As a result, findings from the study indicated that migraine increased the risk for major depression and major depression increased the risk for migraine, suggesting shared overlapping biological mechanisms [47, 48].

Mood disorders such as depression and anxiety are mental health conditions characterized by persistent feelings of sadness, hopelessness, or fear that significantly impact a person's daily life [49]. The pathophysiology of these disorders involves complex interactions between genetic, environmental, and neurobiological factors. Although depression was mainly believed to involve central mechanisms and migraine to involve peripheral alterations, such as sensitized perivascular trigeminal nociceptors, recent studies depicted in Viudez‐Martínez et al. review have shown that migraineurs were also found to feature abnormal cortical sensory processing and altered central modulation [50]. As a result, linking neurotransmitters such as serotonin, hormones, and neuropeptides, including functional brain alterations, with migraine. In depression, there is dysregulation of neurotransmitters such as serotonin, dopamine, and norepinephrine, which play a crucial role in regulating mood and emotions. Chronic stress and inflammation can also contribute to changes in brain structure and function, affecting areas involved in emotional processing and stress response. Studies have shown how both depression and headaches that include migraine can influence the onset of each condition or exist as a comorbidity due to their closely linked neurological pathways [51].

3.4. Inflammation and Neuroinflammation

Inflammation is the body's natural response to injury that involves immune system to heal damage and regulate homeostasis. Just in the same way as the body's natural defense system, neuroinflammation involves the activation of glial cells and the release of proinflammatory cytokines that play a protective role against injury to the CNS [36]. However, when there is a fluctuation, excessive or minimal levels of catecholamines, or dysregulation in any integral part of the brain, neurological disorders become apparent. This highlights inflammation and the inflammatory response's dual role in both health and disease [36].

Like many other chronic and acute pain disorder conditions, studies have reported that neurogenic inflammation and neuroinflammation were both implicated in the mechanisms of attacks of both migraine with and without aura, along with chronic migraine [52, 53]. Chronic migraine is demarcated as having a headache for 15 or more days per month for a period of about 3 months, experiencing migrainous features for about 8 days per month [52]. Neurogenic inflammation is referred to as an acute sterile inflammation that is not induced by pathogenic microorganisms; instead, it is triggered by the peripheral release of neural mediators, especially neuropeptides, from nociceptive fibers leading to vasodilatation and plasma protein outburst [11, 53]. Consequently, neurogenic inflammation occurs after activation of the trigeminovascular system in the dura mater due to chemical or electrical stimulation, or local activation of dural mast cells and dendritic cells following the release of proinflammatory cytokines and other inflammatory mediators, as shown in Figure 1 [54, 55].

FIGURE 1.

Various cells involved in neuroinflammation [image generated from Canva using shapes, brain image from Patrick J Lynch (medical illustrator) @ Wikipedia “Skull and brain normal human diagram,” 2006].

On the other hand, neuroinflammation refers to inflammatory processes happening in the CNS in relation to the stimulation of the innate immune cells of the central nervous system, microglia, and astrocytes. As a result, neuroinflammatory responses are therefore mediated by proinflammatory cytokines, chemokines, secondary messengers, and ROS released by these activated cells [11]. We will be focusing in this review on the role of neuroinflammation in migraine headaches, looking at the emergence of CGRP in migraine headache pathophysiology, and the biomarkers of inflammation such as nitric oxide, cytokines and oxidative stress, glutamate, and chemokine's role in migraine headaches.

Under inflammatory conditions, various chemokines and chemical messengers along with ROS and secondary messengers are generated by various cells to generate balance within the body [10]. Findings from both clinical and pre‐clinical studies has reported that any maladaptive or prolonged neuroinflammation acts as a catalyst in the various neurological conditions [10].

3.5. The Role of Inflammatory Cytokines in Migraine Headaches

The biomarkers of inflammation and oxidative stress have been associated with migraine headaches in various studies, as indicated in Figure 1 [16]. Cytokines are released predominantly by immune cells, including macrophages and dendritic cells as well as non‐immune cells such as endothelial cells and fibroblasts. In the context of migraine, cytokines and chemokines are released through the activation of the microglia, activation of the NOD‐like receptor pyrin domain‐containing‐3 (NLRP3) inflammasome as well as the cyclooxygenase‐2 (COX‐2) activity with microglial cells sharing a common origin with peripheral macrophages [50, 56]. Common cytokines and chemokines released involve interleukins (−1β, −6), tumor necrosis factor‐α (TNF‐α), inducible nitric oxide (iNOS), cyclooxygenase (COX), and matrix metalloproteinase [57, 58]. Migraine without aura is characterized by unilateral pulsating headache often accompanied by nausea, sensitivity to light and sound [10]. In contrast, migraine with aura involves visual or sensory disturbances prior to the headache and is associated with cortical spreading depression (CSD), whereby cytokines play a role in the phenomenon of CSD [10]. Increase in parasympathetic activity has been linked to the activation of meningeal nociceptors, facilitating symptoms from the premonitory to the prodrome phase that may include mood changes, nasal congestion, nausea, and vomiting [58].

Proinflammatory cytokines such as interleukin (IL)‐1 and IL‐6 have been found at the onset and duration of migraines, with high levels of IL‐1α present in the blood of children experiencing migraine with aura and similarly, elevated levels of IL‐1β were found in adults during both headache‐free periods and the early onset of migraine attacks without aura, Figure 1 [16]. Additionally, levels of IL‐6 are elevated during the first 2 h of attack, including elevated levels of IL‐10, IL‐8, and TNF‐α [16]. Serum levels of homocysteine (Hcy) and metalloproteinase‐9 (MMP‐9) are also elevated during migraine attacks, with studies hypothesizing that there is a correlation between elevated Hcy levels and the frequency and severity of migraine [16]. Both the inflammatory and pain pathways involved in migraine are attributed to the metabolism and imbalance of the neurotransmitter and neuromodulator levels within the trigeminovascular system (TVS) [16].

Based on the review from [36], the main putative neuroinflammatory pathogenetic mechanisms of primary headaches involve hypothalamic activation, stimulation of trigeminal ganglion (TG) causing the release of CGRP from trigeminal endings of TG, and lastly the activation of dural mast cells influenced by the release of CGRP. These main pathophysiological mechanisms induce release of inflammatory mediators that include histamine, serotonin, proteases, nitric oxide (NO), and proinflammatory cytokines such as IL‐1β, TNF‐α, and IL‐16 [36]. The release of proinflammatory cytokines and influx of calcium ions (Ca2+) at the synaptic terminal may have an influence on the cyclooxygenase‐2 (COX‐2) activity, further heightening the inflammatory response [59]. Proinflammatory cytokines IL‐β and IL‐8 has shown the interplay between microglia and astrocytes may result in microgliosis and astrogliosis in the dorsal horn of the medulla, causing migraine‐like behavior and inflammatory soup (IS) stimulation. Subsequently, repeated stimulation of the inflammatory soup stimulated upregulation of the purinergic receptor P2X7 and activation of NLRP3 inflammasome, contributing to migraine induction and changes in peripheral cortex regulation [56]. Prior studies have suggested that the transcription factor involved in gene regulation, primarily in stimulating an inflammatory response known as the nuclear factor‐kappa beta (NF‐κβ), acts as a mediator in neurochemical cascade pathways that lead to migraine attacks [60]. This transcription factor and tumor necrosis factor‐alpha (TNF‐α), known pain and inflammatory markers, contribute to neurogenic inflammation and central sensitization [60].

Proinflammatory cytokines can enhance nociceptive signaling in the TVS, central to migraine pathophysiology, and may sensitize nociceptive neurons, resulting in increased pain perception in the periorbital, occipital, and cervical‐neck regions [58, 61]. Stimulation of intracellular signaling molecules associated with pain that include mitogen‐activated protein kinase (MAPK) p38, cyclic adenosine monophosphate (cAMP), cAMP‐response element binding protein (CREB), and the extracellular signal‐regulated kinase has been associated with both peripheral and central sensitization of trigeminal pathways [62]. This also increases the susceptibility of developing chronic migraine [60]. Fluctuations in cytokine levels may play a role in the onset or exacerbation of cortical excitability, and with increased release of these cytokines, neurogenic inflammation may impact both the aura and headache phases [60]. As a result, the continual rise and fluctuation in cytokine levels can impact both episodic and chronic migraine headaches by increasing the risk of chronic migraine development, and on the other hand, can contribute to ongoing pain sensitivity and central sensitization in chronic migraineurs [28, 61].

3.6. The Role of Nitric Oxide in Migraine Headaches

Nitric oxide (NO) is an essential signaling molecule known to act as a double‐edge sword, depending on its derivative, either modulating and facilitating inflammatory responses, aiding immunity, and healing [63, 64]. On the contrary, when inflammatory responses are chronic and facilitate pain with alterations in sensory and neurotransmitter signaling, inflammatory conditions such as migraines are prevalent [64]. The pro‐ or anti‐inflammatory responses exhibited by this signaling molecule are influenced by its concentration and location in the central and peripheral nervous systems, in addition to their impact on pain pathways involved in the TG [64]. There are various nitric oxide synthases (NOS) involved in inflammatory responses within the peripheral and central nervous systems; the three predominantly NOS isoforms that will be discussed are inducible NOS (iNOS), endothelial NOS (eNOS), and neuronal NOS (nNOS) [65].

Under normal physiological conditions, low levels of nitric oxide (NO) are responsible for vasodilation and increased blood flow to inflamed tissues, with endothelial nitric oxide (eNOS) mainly found in endothelial cells involved in the regulation of vascular homeostasis by producing NO, essential for vasodilation and inhibition of platelet aggregation [65]. eNOS also aids in the delivery of immune cells to the site of injury, enhancing the inflammatory response while preventing excessive leukocyte adhesion to the endothelium under normal conditions [65]. nNOS, mainly found in neurons, plays a role in neuronal signaling, protection, and coupling of neurovascular components, essential for modulation of synaptic transmission and maintenance of neuronal survival. nNOS is less involved in the inflammatory response; however, this synthase isoform can modulate local blood flow in response to neuronal activity and provide a protective role [61, 65]. On the other hand, iNOS is expressed in various cell types, including macrophages, and is not calcium dependent. This type of isoform is not normally expressed under normal conditions, as it is induced under inflammatory stimuli, producing large quantities of NO that exhibit antimicrobial properties, which play a role in host defense and tissue protection [63, 64]. Both nNOS and eNOS are activated by the influx of calcium ions (Ca2+) in response to shear stress from blood flow and various signaling molecules [63].

At high levels, particularly from iNOS as shown in Figure 2, induced NO production can lead to oxidative stress, promoting further inflammation and affecting neighboring tissues [64]. As in the context of migraine headaches, iNOS found in central and peripheral tissues can affect cranial vessels and tissue, causing them to be inflamed, resulting in pain associated with headaches [63]. As indicated also in Figure 2, iNOS is in response to proinflammatory mediators typically found in immune cells and is responsible for the large amounts of NO produced [63, 65]. The increased activity of iNOS is influenced by other inflammatory constituents that include cyclooxygenase (COX), tumor necrosis factor‐α (TNF‐α), lipopolysaccharide, interferon‐γ and interleukin‐1β [62, 65]. Elevated NO cause dilation of cranial vessels, accounting for the onset of migraine development. In addition, NO signaling can exacerbate trigeminal nociceptive pathways, resulting in heightened pain and sensory perception [63, 65]. Nitroglycerin (NTG), an NO donor, a vasodilator implicated in pain processing, can induce migraine‐like headaches due to its ability to produce NO, and this vasodilator has been associated with activation of purinergic receptors, particularly P2X, contributing to NTG‐induced migraine symptoms and headache development [56, 63]. NLRP3 inflammasome is responsible for the influx of potassium (K+) ions in the peripheral TG response to intracranial pain [56]. It is also worth noting that nNOS‐derived NO from the brain is important for mood regulation and neurotransmission. A shift in the normal biological pathways and levels results in an increase in nNOS, and this isoform is associated with depressive symptoms, usually associated or co‐occurring with migraine attacks and headaches [63, 64, 65]. At the onset and duration of migraine symptoms and attacks, there is a default in the biological negative feedback loop (failure in inhibitory processes) in which normal levels of NO are not reached but rather facilitate symptoms of cranial pain and synaptic changes reported in migraine headaches [56, 59]. An explanatory example would be the failure of inhibitory processes such as inhibiting the influx of calcium ions during high levels of nitric oxide, which under normal conditions would counteract the high levels of NO produced. Chronic exposure to high levels of NO may induce neuronal damage and change neuroplasticity, which is strongly linked to depressive disorders [63, 64, 65].

FIGURE 2.

Nitric oxide synthase and its various isoforms.

3.7. The Role of Glutamate Release in Migraine Headaches

One integral and complex excitatory neurotransmitter, glutamate, has been found to be widely distributed in the CNS and plays a crucial role in migraine pathophysiology [39]. This neurotransmitter is often associated with excitatory signaling and affects both presynaptic and postsynaptic neurons, influencing various receptors that include N‐methyl‐D‐aspartate (NMDA) and $\alpha$‐amino‐3‐hydroxy‐5‐methyl‐4‐isoaxzolepropionic acid (AMPA) receptors [39]. This in turn affect pain modulation within the CNS. It has also been reported that glutamate may alter peripheral circulation in migraineurs, altering the blood levels of kynurenines along with facilitating CSD, central sensitization, and pain transmission in migraine aura and headache [39]. Glutamate exerts its effects through several receptor types, primarily NMDA, AMPA, and kainate receptors, which all facilitate calcium influx into neurons, essential for excitatory signaling.

The microglia are the primary housing for neural immune cells and are significant contributors to the neurological response present in various conditions ranging from acute to chronic neuroinflammation or disorders associated with neuroinflammation such as migraine headaches [66, 67]. During migraine attacks, increased levels of glutamate are released, which can lead to excitotoxicity as a result when excessive glutamate overstimulates neurons, subsequently causing inflammation and damage to neurons [66]. The release of glutamate is influenced by the influx of calcium (Ca2+) ions at the presynaptic terminal caused by an action potential. Astrocytes, such as glial cells, play a significant role in the delivery of glucose and glutamine to neurons, which are precursors of the metabolism of glutamate [51]. In addition, astrocytes can uptake an excessive amount of glutamate from the synaptic cleft, converting it to glutamine, which is then reused by neurons, thereby regulating glutamate levels [51]. These glial cells also contribute to the integrity of the blood–brain barrier (BBB) [51]. Pathophysiology of migraine starts with trigger, central sensitization, and then neuroinflammation.

Glutamate can cause microglia activation, leading to the production of inflammatory cytokines and signaling molecules, which can increase or heighten sensitivity of pain pathways [66, 68]. Glutamate signaling and microglia activation prompt a neuroinflammatory response characterized by the release of proinflammatory cytokines and signaling molecules, and this is what is associated with migraine attacks or the pathophysiology of migraines. The interplay between inflammatory responses and microglia activation can lead to sensitization of pain pathways, particularly those involved in the central neural pathways. This may cause a lower threshold for pain perception, increasing the susceptibility to migraine triggers and symptomatic responses [66, 69]. Magnesium deficiency is associated with migraine attacks, as magnesium (Mg2+) levels are decreased during attacks, which are related to the control of the NMDA glutamate receptors [69]. NMDA receptors play a pivotal role in the regulation of pain transmission and cerebral blood flow, including the phenomenon of CSD, briefly described as a wave of neuronal depolarization followed by a period of inhibition [10, 69].

The excessive excitatory input during migraine attack can contribute to central sensitization, in which the CNS becomes hyperresponsive to sensory stimuli, further impacting pain perceptions, which can intensify headache symptoms and attacks [28, 60]. Activation of microglia can further release of proinflammatory markers, further intensifying the headache and pain perception and migraines from episodic to chronic [28, 60]. In chronic migraine, the sustained presence of cytokines can increase or contrive ongoing pain sensitivity and central sensitization [28, 60]. Glutamate levels are dysregulated in depressive episodes and increase release of glutamate in predominantly glutamatergic areas, reported to be the prefrontal cortex, amygdala, and hippocampus, can lead to excitotoxicity, which may alter neuronal function and mood regulation [70]. Excessive levels of glutamate can result in the increase of calcium ions and oxidative stress, in turn contributing to the onset and progression of migraine attacks [32, 70].

3.8. Emerging Role of CGRP in the Pathophysiology of Migraine Headaches

CGRP, a 37‐amino acid vasoactive and neuro endocrine peptide expressed in the peripheral ganglia and CNS [50]. This peptide from the calcitonin family, both of its isoforms CGRP‐α and CGRP‐β, play a role in peripheral and central sensitization [50]. During a migraine attack, CGRP is released from the afferent trigeminal ganglia, causing dilation of the cortical pial arteries, arterioles, and the middle meningeal artery, as depicted in Figure 3 [10, 50]. This in turn elevated local cortical cerebral blood flow, shown to induce migraine‐like symptoms in previous in vivo studies [28, 50]. Onset of depression and chronicity of migraine attack could also be influenced by the CGRP, in which studies have reported an increase in premonitory, depressive‐like symptoms and a common acute symptom (photophobia) in migraine depicted in mice models after the central administration of the isothermal CGRP‐α [28]. An increased expression of the human receptor activity‐modifying protein 1 (RAMP‐1) is reported, which is a critical need for the subunit of the CGRP receptor [29].

FIGURE 3.

CGRP release and its pathophysiological mechanisms.

The onset and pathological mechanisms surrounding neuroinflammation and pain signaling in migraine headaches have been proposed through two theories cited in Dodick [61]. Firstly, meningeal nociceptor activation through elevated parasympathetic tone, and secondly, modulation of nociceptive signals from the trigeminal nucleus caudalis (TNC) to supratentorial structures involved in pain signaling [61]. In short, the onset of migraine attacks is derived from the activation of nociceptors of microglial cells and neurons situated in the meninges, hypothalamus, and TVS, accounting for the premonitory symptoms or prodrome stage [28, 61]. The various cells involved in this inflammatory response, illustrated in Figure 1, play an integral role in the levels of biomarkers involved in migraine headaches facilitated by physiological or pathological stimuli, as illustrated in Figure 3. Physiological and pathological stimuli can be caused by either intrinsic or extrinsic triggers, comprised of exaggerated sensory responses in individuals prone to migraines; hormone fluctuations in response to stress, diet, and mental or mood disorders, climatic factors, and bright lights and loud noises [2, 70]. Firstly, sensory signaling from various cell types alters the level of glutamate, serotonin, dopamine, and NOSs, which facilitates the integrity of the blood–brain‐barrier, peripheral nociception, and sensitization. The activation of the TVS, accounting for the sensory and stimulus processing in the surrounding areas, results in action potentials along axons of the meningeal and neuronal fibers. The presence of action potentials causes an influx of calcium ions, enabling CGRP to be released from the neuron vesicles. Release of calcium ions can be influenced by various inflammatory factors that include increased activity of nNOS, eNOS, and inflammatory mediators (COX, TNF‐α, IL‐1‐β, and interferon‐γ). In turn, this results in dilation of cortical plural arteries, arterioles and middle meninges arteries which causes an increase in cortical cerebral flow. The heightened influx of calcium ions and CGRP can promote inflammation to surrounding tissues including the release of other inflammatory mediators that include interleukins, glutamate, and NLRP3. These neurogenic and nitrosative stress and inflammatory responses can increase cerebral dilation, peripheral nociception, and sensitization, contributing to cranial pain and intensity.

Based on research collected from 2015 to 2024, the mechanisms and pathophysiology of migraine headaches have evolved in receptor identification, structural cells of the brain, neurotransmitters, and influence from other factors that include dietary, physiological, and genetic factors. The pathophysiology of both migraine with and without aura shares similarities and differences in their role of biomarkers, mechanisms, and neurotransmitters present. The phenomenon known as CSD described as a depolarized wave across the cortex following wave inhibition of the cerebral cortex that is influenced by glutamate, glutamine, and CGRP release, led to the understanding of the underlying mechanisms in migraine with aura [19, 32] which is also influenced by the release of CGRP [10]. The NOD‐like receptor pyrin domain‐containing 3 (NLRP3) inflammasome can also be influenced by the release of CGRP associated with the intracranial pain experience in migraine‐like headaches [59]. Purinergic receptors, specifically P2X, have been implicated in the pathophysiology of migraines derived from the release of CGRP from the TG activation [60]. This potent vasodilator contributes to the neurogenic inflammation that occurs in migraine attacks, either being localized or widespread in cranial and peripheral tissues, contributing to the increase in pain perception, therefore facilitating peripheral nociception at the walls of extracerebral vessels and meninges [71]. This chain of events can account for headache intensity and pain perception [71].

3.9. Recent Emerging Role of COVID‐19 Headaches in Migraine Headaches

Recently, COVID‐19 emerged in the past 5 years as a global pandemic that affected an average of 14.28% of the global population with the prevalence of various SARS‐CoV‐2 variants combined [72]. This epidemiological burden accounts for the approximately 778 million cases reported worldwide [73]. One of the most common problems associated with COVID‐19 was the headache, or better known as long COVID‐19 headache, part of the so‐called long COVID‐19 syndrome [74]. Since 2020, the detrimental effects of the COVID‐19 pandemic have remained to be a global concern, and this disease is predominantly associated with the respiratory system. A collective family of viruses known to cause respiratory infections, which may cause illness in animals or humans is known as coronaviruses [75]. This type of respiratory infection can range from the common cold to more severe diseases such as Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS). The most recently discovered coronavirus is COVID‐19 [75].

It is important to note that COVID headaches are diverse and can have a broad spectrum of triggers and key players involved. According to research, long COVID headaches often present a new or worsening of pre‐existing headache conditions and often start during acute infection or post‐delay. These headaches can be migraine‐like or tension type associated with activation of the immune systems and trigeminovascular circuits [74]. A study has hypothesized that long COVID‐19 headaches from pre‐existing or secondary conditions could emerge as a contributor to migraine development [74]. Patients who have been vaccinated also reported migraine as a side effect upon receiving the vaccine. This finding was more prevalent with the use of mRNA‐based COVID‐19 vaccines compared to the SARS‐CoV‐2 vaccines [31]. This can be attributed to the excitability of the trigeminal vascular system, accounting for the inflammatory and sensitization of migraine attacks [67]. The central sensitization of migraine headache has been reported to be influenced by microRNA‐155‐5p that promotes inflammation through modulatory effects of microglia polarization [31, 67].

MicroRNAs (miRNAs) are small, non‐coding, approximately 22‐nucleotide chain RNA molecules that function as post‐transcriptional gene expression regulators, which have gained interest in epigenetic mechanisms in migraine pathophysiology [76, 77, 78, 79]. These post‐transcriptional regulators promote messenger RNA (mRNA) degradation or repression of mRNA translation, which influence gene expression regulation as an effect of environmental factors. Due to its complexity, miRNAs can target hundreds of various mRNAs, accounting for each mRNA undergoing regulation by multiple RNA molecules [80]. Research has reported how miRNAs can influence activation of the microglia and astrocytes including neuroinflammatory processes from immune cells residing in the peripheral immune system [81, 82, 83, 84]. MicroRNA‐155‐5p plays a role in the regulation of immune and inflammatory responses. It has been linked to the modulation of pain pathways, particularly neuropathic pain, which is a potentially contributing factor responsible for headache disorders including its involvement in the endothelium‐dependent vasodilation through regulation of the NOS pathway [31, 74, 85]. In addition, the ability of this RNA molecule to modulate inflammatory mediators including tumor necrosis factor (TNF‐α), interleukin‐1‐beta (IL‐1β), alarmins, nuclear factor erythroid 2‐related factor 2 (NRF2), and toll‐like receptors (TLR) in various cell types [68, 85]. These findings were reported in COVID‐19 patients, and with an increased level of proinflammatory cytokines, microRNA‐1555‐5p could serve as a biomarker for headache symptoms or disorders among infected patients [31, 74]. Vaccines with the presence of microRNA‐155‐5p may be susceptible to facilitating neuroinflammation due to their pathophysiological mechanisms that include pain modulation [73]. A study by Cheng et al. reported increased serum miR‐155 levels in individuals suffering from episodic migraine, highlighting the role of this specific miRNA variant in migraine biology [86].

3.10. Current Treatment and Management of Migraine Headaches

Management and treatment of migraine headaches with and without aura requires recognition and elimination of specific factors involved in exacerbation as well as custom preventive approaches of acute migraine headaches [39]. Current treatment includes lifestyle and diet modifications to improve the quality of life in conjunction with primarily oral administration first‐, second‐, and third‐line treatments [12]. First‐line medication includes nonsteroidal anti‐inflammatory drugs (NSAIDs) that are effective in reducing mild migraines, in conjunction with non‐prescription analgesics such as acetylsalicylic acid (aspirin) and ibuprofen [12, 16]. In addition, first‐line medications such as diclofenac potassium, neuroleptics, Dopamine D2 receptor antagonists, and triptans are used in reducing the intensity and pain threshold of migraine attacks [16]. Second‐line medication includes primarily the administration of triptans to increase serotonin levels during a mild migraine attack, while third‐line treatment includes ditans or gepants when triptans are ineffective [12].

The recent emergence of non‐oral medication, valproic acid, and plant‐derived treatments has shed light on more alternative and effective plans. Non‐oral treatments such as Zavegepant nasal spray and IV valproic acid have been reported to provide effective relief in acute migraine headaches with a favorable safety profile and a reduction in headache intensity, respectively [87, 88]. A recent study has reported the safety and promising effects of Neurasites, a natural plant extract derived from the genus in the sunflower family, Asteraceae (butterbur), used in the treatment and prevention of migraine attacks [12]. Other studies that investigated medicinal potential include Tanacetum parthenium (Feverfew) and Curcuma longa (Turmeric) for their traditional use in preventing the onset of migraine headaches, including inflammatory pathways during CSD, and their anti‐inflammatory properties on neuroinflammation, which can potentially alleviate migraine headaches, respectively [13, 14].

The potential therapeutic effects of psychedelic drugs are currently at the forefront of drug research and therapeutic interest due to their ability to provide long‐lasting psychological effects [89]. In the study by Nkadimeng et al. promising results were reported on the four hot‐water extracts from the psychedelic type of mushrooms called psilocybin mushrooms, which are also commonly known as magic mushrooms [15]. The four psilocybin mushroom water extracts (Panaeolus (Copelandia) cyanescens, Psilocybe natalensis, Psilocybe cubensis, and Psilocybe cubensis leucistic A+ strain) used in the study showed anti‐inflammatory effects against lipopolysaccharide (LPS)‐induced COX‐2 in human U937 macrophage cells, where the extracts reduced COX‐2 in comparison to the LPS‐induced cells in the study [15]. The mushroom extract from Pilocybe cubensis leucistic A+ strain mushroom extracts significantly reduced COX‐2 levels at its lowest concentration, 25 μg/m. Moreover, the study also reported effective activities on the proinflammatory cytokine levels upon treatment with the mushroom extracts on human U937 macrophage cells [15]. The four mushrooms inhibited both TNF‐α and IL‐1β,‐levels with 25 and 50 μg/mL extract concentrations significantly very close in levels to the positive control quercetin, which is a naturally compound found in fruits and vegetables used in the study and also toward unstimulated control cells which was very interesting [15].

Furthermore, the mushroom extracts also exhibited lowering effects on the proinflammatory cytokine IL‐6 and were significant with Psilocybe natalensis and Psilocybe cubensis mushrooms, with IL‐6 levels nearly identical to the positive control as well [15]. Similar results were also shown by Nkadimeng et al. in vitro in the LPS‐induced mouse macrophage cells upon treatment with Psilocybe natalensis [90]. The similar findings were demonstrated by Zanikov et al. in a neuroinflammation condition where inflammation was induced through the gut‐brain axis, using a colitis mouse model via oral feeding of dextran sulfate sodium (DSS) [91]. The effects of psilocybin in this study was tested in synergy with eugenol (4‐allyl‐2‐methoxyphenol) which is an aromatic compound, commonly found in essential oils of plants such as cloves, bay leaves, and all spice reported to have antioxidant, antibacterial and analgesic, antiseptic, hepatoprotective, properties and inhibitory effects on the expression of tumor necrosis factor‐alpha (TNF‐α) and production of nitrous oxide radicals [92, 93]. It has also been shown to be highly effective in reducing inflammatory markers, including cadmium‐induced inflammation [92]. In this study, the combinations of the two compounds administered at different concentrations revealed that the oral psilocybin and eugenol post‐treatment significantly reduced the expression of proinflammatory cytokines and inflammatory mediators in the brain, including IL‐1β, IL‐6, and COX‐2 [92]. The cytokine effects were more pronounced with the combined treatment on IL‐6 levels when compared to the DSS group [92].

In addition, Gojani et al. study revealed a dose‐dependent inverse correlation between psilocybin exposure and the production of LPS‐induced proinflammatory cytokines and proteins in vitro in THP‐1 human macrophages and concluded that psilocybin likely mediates these responses by influencing key signaling pathways, including NF‐κB, IL‐6/TYK2/STAT3, and TYK2/STAT1 [94]. Many studies showed that the IL‐6/JAK/STAT3 pathway plays a very crucial role in inflammation and hence, has gained significant attention as a potential target for innovative therapeutic strategies in the treatment of diverse inflammatory conditions [94, 95]. With regards to IL‐10 anti‐inflammatory cytokine, the study of Laabi et al. was in agreement with the finding of Nkadimeng' et al. on an increase, although non‐significant in IL‐10 [96]. However, in their study, there was a significant increase in IL‐10, and the significant increase was observed with psilocin, but not psilocybin, in post‐treatment, leading them to conclude that the anti‐inflammatory effects observed on classically activated macrophages was due to psilocin, the active form of psilocybin in their study [96]. With the significant antidepressant effects of the psilocybin and psilocybin mushrooms currently emerging, these potential anti‐inflammatory effects suggest very promising projections of their use in the investigations of their use in the treatment migraine headaches and inflammation associated with the condition.

Current treatments of migraine often rely on medications that are not specifically targeted for everyone's unique symptoms and triggers, and while short‐term relief is established, their effectiveness for long‐term relief may not be well established. With the above literature, there is growing interest in herbal medication and treatment plans. The active compound in magic mushrooms, psilocybin, has been found to contain anti‐inflammatory constituents that may be relevant to migraine pathophysiology through its interaction with serotonin systems as well as targeting specific inflammatory mediators. Psilocybin mushrooms can potentially act as a targeted‐inflammatory therapeutic agent through their reported action on the COX‐2 inflammatory pathway, affecting the levels of TNF‐α, IL‐6, and IL‐1β, which are the common biomarkers in migraine pathophysiology [15]. Psilocybin acts on 5‐HT2A serotonin receptor, and since serotonin levels are abnormal in migraine headaches resulting in inflammation, the modulation of the serotonin receptor by psilocybin was shown to exert strong anti‐inflammatory effects through inhibition of inflammatory‐induced proinflammatory, TNF‐α [15, 97].

4. Discussion

As mentioned, pathological inflammation remains a problem in migraine headaches and a potential target in its treatment. Inflammation is a natural response to injury and contributes to the healing process to maintain homeostasis [10]. However, with chronic inflammatory and pain responses in migraine attacks, abnormalities arise in the normal serotonergic and glutamatergic systems, resulting in imbalances of neurotransmitter and cytokine levels, subsequently predisposing individuals to symptoms of mood disorders [12, 28, 29]. At the onset and duration of migraine attacks, the TVS is activated, causing activation of meningeal nerves, particularly the trigeminal nerve, which triggers the release of CGRP and substance P. As shown in Figures 1 and 2, the activation and release of these neurotransmitters result in blood vessel dilation around the brain and surrounding tissues [28, 29]. Important key players are various interleukins and chemokines reported in various studies, which contributes to the phenomenon known as neurogenic inflammation [10]. IL‐1β, IL‐6, IL‐8, IL‐10, and TNF‐α were reported to increase in concentration and accounting to the pain and intensity experienced [10].

The neuropeptide CGRP and neurotransmitter glutamate have also evolved as one of the most critical key players involved in both the pathophysiology and treatment of migraine headaches. It has been reported that excessive ROS production is prevalent in migraine headaches, and there are numerous medications targeted at preventing and diminishing the effects of these mediators, along with the interleukins mentioned. In fighting the burdens of migraine headaches currently, the first‐line medications include NSAIDs (acetylsalicylic acid, ibuprofen) and triptans that target inflammatory and pain pathways through COX‐2 inhibition and serotonin‐targeted therapy through inhibition of neurotransmitter release that is reported to reduce the intensity of migraine headaches [12]. Second‐line medications include primarily ergots (ergotamine and dihydroergotamine), CGRP antagonists that target serotonin receptors and the CGRP pathway that reduces the severity and frequency of migraine attacks [12]. Ergots are serotonin receptor agonists, particularly binding to subtypes serotonin 5‐1HT‐1B and 5‐HT‐1D that stimulate these receptors to facilitate vasoconstriction, which counteracts the vasodilation that occurs in migraine attacks [12]. In addition, these serotonin receptor agonists inhibit the release of CGRP and substance P, known proinflammatory cytokines involved in migraine attacks; in contrast, CGRP antagonists inhibit the activation of CGRP release by blocking the activation of CGRP receptors, primarily preventing the effects of this neuropeptide [12]. The main function of second‐line medications is to target inflammatory and pain signaling pathways to reduce overall inflammation and pain as a result of serotonin fluctuations and the release of CGRP in migraine attacks. Third‐line medications, on the other hand, are set to counteract the pain and inflammatory pathways when patients are not responsive to the first and second lines of treatment. In this scenario, antidepressants are utilized in providing long‐term relief and reducing the severity of migraine attacks [12].

Despite advances in targeted inflammation and neuroinflammation, more research still needs to be done in expanding the literature surrounding the use of medicinal plants as alternative treatment plans. In older and recent studies, the evolution of turmeric, psilocybin mushrooms, and butterbur has been reported to contain active and anti‐inflammatory constituents that can promote inflammatory relief, targeting mediators that include IL‐6, IL‐8, and TNF, along with inhibition of the COX‐2 pathway. These findings are very crucial as these targeted mediators' pathways are pathways that have also been found to be dominant in migraine neuroinflammation and involved in the progression of the condition. The key biomarkers, IL‐1β, IL‐6, IL‐8, IL‐10, CCL2, CGRP, NO, TNF‐α and serotonin (5‐HT) are commonly prevalent in the role of both forms of migraine headaches, with and without aura.

5. Conclusion

Migraine headaches are one of the prevalent and complex neurological disorders characterized by intense head pain influenced by the activation of inflammatory and pain pathways that impact the surrounding brain structures, located inside and outside the cranium. The study concludes that the interplay between the neurogenic inflammatory response, release, and dysregulation of neurotransmitters that include CGRP, glutamate, substance P, tumor necrosis factors, and interleukins, among many, contributes to the onset and intensity of migraine headaches. With the availability and evolution of first‐, second‐, and third‐line medications, specific neuronal pathways are targeted to provide effective relief from pain and inflammation involved in migraine attacks. Alternative medication that includes herbal and plant‐based remedies has also shown potential in targeting key players involved in migraine pathophysiology and inflammatory pathways known to elicit both acute and chronic inflammatory responses prevalent in migraine studies. With the challenges of the biomarkers in migraine headaches and the limited knowledge in understanding their intricacies and complexities, there is a need for more focus and research to generate more effective and targeted therapies that will benefit the various forms and effects associated with migraine headaches. Additionally, the role of medicinal plants and natural remedies can potentially offer a holistic approach in targeting and treating migraine headaches.

Understanding the role of inflammation and its effect on the key neurotransmitter, glutamate, and neuropeptide CGRP could potentially address the unmet medical needs for patients suffering from migraine headaches, both acute and chronic. Study recommends effective complementary and alternative treatment plans that can both prevent and reduce the severity and frequency of migraine headaches and address the continual rise in migraine prevalence that places a concerning burden on the socioeconomic status and epidemiological status worldwide. This review has outlined the importance of inflammation in migraine headaches and the need to address the pathological inflammation in migraine headaches as a target in the treatment and control of migraine headache problems.

Author Contributions

Sanah M. Nkadimeng: conceptualization and supervision; Caryn T. Morgan: writing – original draft; Caryn T. Morgan and Sanah M. Nkadimeng: writing – review and editing. All authors have read and agreed to the published version of the manuscript.

Conflicts of Interest

The authors declare no conflicts of interest.

Morgan C. T. and Nkadimeng S. M., “The Role of Inflammation in Migraine Headaches: A Review,” FASEB BioAdvances 7, no. 7 (2025): e70033, 10.1096/fba.2024-00188.

Data Availability Statement

Included in the article. The data that support the findings of this study are available in the sections and references of this article.