Benefit of Dietary Supplementation of Nutraceuticals as an Integrative Approach for Management of Migraine: Evidence From Preclinical and Clinical Studies

Abstract

Purpose of Review

To provide information from preclinical and clinical studies on the biological activity and health benefits of dietary inclusion of nutraceuticals as a safe, effective, non-pharmacological approach for the treatment of migraine.

Recent Findings

There is emerging evidence of the therapeutic benefit of nutraceuticals to inhibit oxidative stress, suppress inflammation, and prevent changes in the normal gut microbiome, which are implicated in migraine pathology. Nutraceuticals can be enriched in polyphenols, which act as molecular scavengers to reduce the harmful effects of reactive oxygen species and phytosterols that suppress inflammation. Nutraceuticals also function to inhibit dysbiosis and to maintain the commensal intestinal bacteria that produce anti-inflammatory molecules including short-chain fatty acids that can act systemically to maintain a healthy nervous system.

Summary

Dietary inclusion of nutraceuticals that exhibit antioxidant, anti-inflammatory, and anti-nociceptive properties and maintain the gut microbiota provides a complementary and integrative therapeutic strategy for migraine.

Introduction

Migraine is a debilitating, painful neurological condition that affects roughly 15% of the global population [1]. According to the International Classification of Headache Disorders, episodic migraine can be characterized by acute episodic headaches experienced during 14 days or less of the month, whereas chronic migraines are defined as 15 or more days with a headache in a single month [2]. These migraine attacks are characterized by intense, throbbing pain in the head and face region and can be accompanied by an aversion to light (photophobia) and sound (phonophobia). Approximately 20–25% of people with migraines experience some sort of visual disturbance, called aura, before a migraine attack during the prodrome phase. Hours later, the migraine attack occurs with accompanying pain, throbbing, nausea, and sensitivity to environmental stimuli [3, 4]. This lasts 4–72 h before the pain subsides, and the person enters a postdrome phase that often involves fatigue and brain fog. The pain associated with migraine involves sensitization and activation of the peripheral and central nervous systems [5]. Sensitization in the central nervous system lowers the activation threshold for neurons to respond to stimulatory molecules released from neurons in the peripheral nervous system. Peripheral nervous system sensitization causes a heightened allodynic state of sensitivity to stimuli that would not normally cause a response, leading to hyperexcitable neurons both peripherally and centrally. Currently used anti-migraine therapeutics including triptans, gepants, ditans, OnabotulinumtoxinA, and monoclonal antibodies to calcitonin gene-related peptide (CGRP) or its receptor modulate neuronal and glial cell activities to suppress cellular and molecular events that promote inflammation and pain signaling [6–8]. However, the efficacy and safety of these agents in the treatment of migraine in children and adolescents, which can cause significant disability and is becoming more prevalent, is not well established [9]. Hence, there are relatively limited evidence-based treatment options available for this migraine population when compared to therapeutic options for adult migraineurs [10].

While migraine symptoms are primarily managed with the use of pharmaceuticals and biologics, there is a continued and growing interest in the use of safe and effective complementary and alternative therapies for the management of migraine. These interventions, which include lifestyle, behavioral, and dietary changes, are pursued in addition or to reduce or avoid the use of medications. It is estimated that greater than 40% of the U.S. population utilizes some kind of alternative therapy including dietary supplements [11]. One important class of dietary supplements is nutraceuticals, which should be included in the discussion of migraine management. Nutraceuticals are often consumed as dietary supplements to help preserve, maintain, or restore health by individuals suffering from persistent headaches and migraine [12, 13•].

By definition, a nutraceutical is a food-derived molecule that provides medical or health benefits beyond its basic nutritional role, including the prevention and treatment of a disease and its associated symptoms [14]. The beneficial effects of nutraceuticals have been reported for cardiovascular disease, inflammatory bowel disease, diabetes, obesity, and neurological diseases such as Alzheimer’s and Parkinson’s [15–18]. Importantly, nutraceuticals can modulate the cellular function of neurons and glial cells by inhibiting oxidative stress and prostaglandin synthesis and suppressing signaling pathways implicated in pain and inflammation [19]. Given the low nutritional value provided by the Standard American Diet (SAD), which consists primarily of ultra-processed foods, added sugar, fat, and sodium, it is important to consider the inclusion of nutraceuticals as a supplement to meet our body’s daily nutritional needs, maintain one’s health, and to minimize disease risk. There are many health benefits attributed to nutraceuticals including their potent antioxidant effects, anti-inflammatory effects, and their ability to enhance the uptake of essential nutrients. Nutraceuticals have also been reported to play an important role in maintaining a healthy digestive system by promoting proper digestion, assisting in the absorption of vitamins and minerals to prevent their deficiency, and sustaining a diverse gut microbiota [20, 21•].

There is accumulating evidence to support the importance of maintaining a diverse, commensal population of bacteria and other microorganisms in the digestive tract, which is referred to as the gut microbiota, for maintaining human health and preventing disease [22, 23]. Importantly, dysbiosis, which is associated with changes in the microbiota that cause a shift in the normal balance of key microorganisms, is implicated in chronic inflammatory and painful conditions including neurological diseases like migraine [24, 25]. The notion that a healthy gut promotes a healthy brain and vice versa has become an active area of study since there is a clear association of headache disorders and gastrointestinal dysfunction [25, 26]. Commensal microorganisms in the gut synthesize signaling molecules that regulate localized inflammation and systemically modulate chronic pain pathways to inhibit cellular processes that mediate peripheral and central sensitization via modulation of receptors and ion channels. The microbiota-synthesized signaling molecules include neurotransmitters such as GABA and 5-HT, neuropeptides, and metabolites such as short-chain fatty acids. In contrast, gut dysbiosis is associated with the development and maintenance of chronic neuropathic pain, inflammatory pain, fibromyalgia, and migraine [27, 28]. Daily consumption of nutraceuticals can provide a means to restore and maintain a diverse gut microbiota, which will promote both gut and brain health.

Many plant-based nutraceuticals are enriched in polyphenols. Polyphenols are secondary plant molecules that act as molecular scavengers like vitamin C and E to reduce the harmful effects of reactive oxygen species (ROS). Elevated levels of ROS, which are implicated in migraine pathology, are associated with oxidative stress, can cause DNA damage and are reported as pronociceptive in the meninges via involvement of TRPA1 receptors [29]. Other types of nutraceutical plant products are enriched in phytosterols such as β-sitosterol that bind and activate the glucocorticoid receptor to suppress inflammation [30]. Activation of the glucocorticoid receptor leads to an upregulation of the anti-inflammatory protein MKP-1 [31, 32] that inhibits the stimulatory effect of the pro-inflammatory MAP kinase signaling pathways. In addition, when consumed in their native form, many plants provide natural fiber that promotes and maintains the commensal gut bacteria responsible for the production of anti-inflammatory molecules including short-chain fatty acids, GABA, and 5-HT [33]. These molecules can enter the bloodstream and exert beneficial effects on all major physiological systems including the nervous system [34]. A summary of preclinical and clinical studies that demonstrate the health benefits of nutraceuticals with the corresponding PMID is provided in Table 1.

Table 1.

Preclinical and clinical evidence of the benefit of nutraceuticals to reduce oxidative stress, suppress inflammation, and promote a healthy gut microbiome

Nutraceutical	Study	Physiological benefit	PMID
Grape seed extract	Chronic temporomandibular disorder model in rat	Anti-nociceptive	32531825
			33544064
	Episodic migraine model	Anti-nociceptive	35295808
	Chronic temporomandibular disorder model in rat	Anti-inflammatory	21143976
	Primary cultures of trigeminal ganglion	Anti-inflammatory	36093283
	Rat model of obesity	Anti-obesity effect on microbiome	35794638
	Colitis mouse model	Antioxidant	32808642
		Anti-inflammatory
		Restored intestinal barrier
Cocoa	Primary cultures of trigeminal ganglion, and temporomandibular joint disorder rat model	Anti-inflammatory	17997062
	Temporomandibular joint disorder rat model	Anti-inflammatory	20138852
		Anti-nociceptive
	Temporomandibular joint disorder rat model	Anti-inflammatory	23576361
	Acute neurogenic inflammation in rats	Anti-nociceptive	28643911
	Mouse model of obesity	Anti-inflammatory	35934271
		Reduced F/B ratio in microbiome
	Zucker diabetic fatty rats	Anti-obesity	32331673
	Healthy adult humans	Mood boosting	34530112
		Greater gut microbial diversity
Chicken bone broth	Temporomandibular joint disorder rat model	Anti-nociceptive	29509826
		Anti-inflammatory
	Episodic migraine rat model	Anti-nociceptive	32326809
Vitamin D + topiramate	Pediatric migraine	Anti-nociceptive	35733373
Coenzyme Q10 + amitriptyline	Pediatric migraine	Anti-nociceptive	35814300
Riboflavin	Pediatric migraine	Anti-nociceptive	32336482
Folic acid + pyridoxine	Migraine with aura	Anti-nociceptive	28526386
Alpha-lipoic acid	Adolescent migraine	Anti-nociceptive	37563914
		Anti-inflammatory
		Antioxidant
Omega-3 fatty acids	Episodic migraine	Anti-inflammatory	37954068
			37126739

Grape Seed Extract

The potential benefit of daily supplementation with a polyphenol-enriched grape seed extract has been demonstrated in preclinical models of migraine and the comorbid orofacial pain condition of temporomandibular joint disorder [35–37]. In a seminal study, rats receiving grape seed extract for 14 days exhibited higher levels of the anti-inflammatory protein MKP-1 in neuronal and glial cells in the trigeminal ganglion and trigeminal nucleus caudalis, and lower basal levels of CGRP in the spinal cord [38]. Dietary inclusion of grape seed extract also increased the level of the glutamate aspartate transporter in the spinal glia that functions to suppress the development of central sensitization by removal of the excitatory neurotransmitter glutamate. In addition, grape seed extract was shown to inhibit the stimulated expression of pro-inflammatory and pronociceptive proteins in spinal cord neurons and glial cells. In another preclinical study, dietary supplementation with grape seed extract at 0.5% in the drinking water was found to inhibit sensitization and activation of trigeminal neurons in both male and female animals [35]. The inhibitory effect of grape seed extract on trigeminal nociception involved activation of 5-HT3/7 and GABAB receptors to enhance central descending inhibitory pain pathways and suppress ongoing trigeminal nociception [37]. More recently, grape seed extract supplementation was shown to inhibit nociception in a preclinical model of episodic migraine [36]. In this model, hyperalgesic priming of female and male rats was induced by restraint stress and trigeminal activation initiated by exposure to the pungent odors from a bay leaf oil extract that contained the compound umbellulone. Importantly, the nocifensive response in both the orofacial region and hind paw was significantly suppressed in animals receiving grape seed extract via the drinking water prior to restraint stress. The anti-nociceptive effect of GSE involved activation of the CB1 and CB2 cannabinoid receptors, which are implicated in descending inhibitory pain pathways in the upper spinal cord. Recent findings from a study using primary cultures of trigeminal ganglia provided evidence that grape seed extract can significantly inhibit basal CGRP secretion [39]. Grape seed extract also stimulated neuronal expression of the enzymes GAD 65 and 67, which synthesize the inhibitory neurotransmitter GABA that functions to suppress neuronal and glial cell sensitization and activation [40]. In addition, grape seed extract increased the expression of the GABAB receptors in trigeminal neurons and glia that couple to intracellular pathways known to suppress activation. Taken together, these findings support the notion that dietary supplementation with grape seed extract would be beneficial in the management of patients with migraine, and possibly other orofacial pain conditions, by suppressing neuronal and glial excitability in the trigeminal ganglion and spinal cord and inhibiting development of peripheral and central sensitization.

The benefits of an extract of grape skin and seed were demonstrated in a preclinical model of obesity [41], which is a condition associated with increased risk of migraine [42]. In that study [41], supplementation with the extract decreased weight of adipose tissue, improved serum levels of molecules implicated in cardiovascular disease, improved gut dysbiosis, and helped to maintain commensal bacteria. In agreement, results from a preclinical study of colitis that involved dietary supplementation with a grape seed extract enriched in the polyphenol proanthocyanidin provided evidence of the protective and restorative effect on the gut microbiota [43]. Consumption of grape seed extract in the drinking water prior to induction of experimental colitis was shown to decrease disease index, pathological scores, and oxidative stress. Supplementation was also associated with suppression of colitis-associated inflammation and downregulation of pro-inflammatory cytokines in colon tissues including TNF-α and IL-1β, which are implicated in peripheral and central sensitization [44]. Furthermore, the dysbiosis observed in this model was suppressed and the microbiota balance was maintained by the inclusion of grape seed extract [43]. These results demonstrate that an advantage of nutraceuticals provided in the diet is that they can function systemically to improve and maintain the health of multiple systems including the digestive and nervous systems.

Polyphenols

A diet enriched in phytochemicals and polyphenols (especially flavanones and lignans) is associated with low migraine severity while lower intake of phenols and flavonoids from vegetable oil, olive oil, fruits, and vegetables was associated with more severe migraine attacks [45••]. Based on their findings, it was proposed that examination of migraine characteristics and dietary pattern together with phytochemical and polyphenol intake should guide the development of dietary strategies to be used in patients with migraine. In particular, diets enriched in antioxidants may be a useful strategy since migraine, similar to other inflammatory neurological diseases, is associated with higher levels of oxidative stress and reactive oxygen species that exceed cellular capacity and cause pathological changes to neurons and glia [46]. Dietary inclusion of foods that contain higher levels of vitamins, polyphenols, carotenoids, and anthocyanins that are known to reduce the harmful effects of oxidative stress are likely to be beneficial to patients with migraine given the pro-inflammatory nature of the standard American diet.

Cocoa

The consumption of dark chocolate enriched in cocoa is now thought to be a craving for some patients with migraine during the premonitory phase [47]. Different anti-inflammatory and anti-nociceptive effects have been attributed to compounds isolated from cocoa [48, 49]. Evidence that cocoa contains biologically active compounds that can modulate the activity of trigeminal ganglion neurons has been demonstrated in multiple preclinical studies. In a study utilizing primary cultures of trigeminal ganglion, a methanol extract from Theobroma cacao L. beans enriched for polyphenols was shown to cause hyperpolarization of trigeminal neurons via modulation of calcium channels to suppress stimulated CGRP secretion [50]. In addition, when injected in the joint capsule, the extract repressed CGRP expression in the trigeminal ganglion in a preclinical model of TMD. Findings from an in vivo study provided the first evidence that inclusion of cocoa powder as a dietary supplement could upregulate the expression of the anti-inflammatory proteins MKP-1 and MKP-3 and suppress stimulated expression of pro-inflammatory signaling proteins in trigeminal ganglion neurons [51]. Dietary cocoa powder also significantly suppressed trigeminal neuron expression of CGRP and stimulated levels of the inducible form of nitric oxide synthase (iNOS), which are proteins implicated in the underlying pathology of migraine. Results from another study provided evidence that the inclusion of cocoa powder in the food suppressed basal expression of CGRP in the spinal trigeminal nucleus and stimulated basal expression of two proteins, GLAST and MKP-1, that help to regulate neuronal excitability of spinal cord neurons [52]. Supplementation with cocoa powder also inhibited stimulated expression of protein kinase A, P2X3, P-p38, GFAP, and OX-42, whose elevated levels in the spinal cord are implicated in central sensitization and suppressed elevated levels of pro-inflammatory cytokines in the spinal cord. Furthermore, results from a study assessing operant pain behavior using the Orofacial Pain Assessment Device demonstrated that inclusion of cocoa powder as a dietary supplement was effective in inhibiting neurogenic inflammatory pain in rats [53]. Interestingly, the most biologically active purified fraction of cocoa that upregulated MKP-1 expression in trigeminal neurons contained the phytosterol β-sitosterol, which has a similar chemical structure to the drug dexamethasone [30]. This finding may help to explain one of the potential mechanisms by which cocoa exerts its anti-inflammatory and anti-nociceptive effects by inducing MKP-1 expression in trigeminal neurons. Thus, inclusion of cocoa or dark chocolate as a dietary supplement may help to suppress sensitization and activation of trigeminal neurons which is implicated in migraine pathology.

In addition to the anti-inflammatory and anti-nociceptive effects of cocoa, dietary inclusion of cocoa has been reported to reduce weight gain in female and male mice and to help maintain a proper balance of the gut microbiome [54]. In that study, supplementation with cocoa powder, regardless of whether prepared by a fermentation or roasting protocol, was found to significantly suppress biomarkers of inflammation. In another study involving diabetic rats, inclusion of cocoa was found to maintain the integrity of the gut epithelium and suppress expression of inflammatory cytokines in the colon of diabetic rats [55]. Dietary supplementation of cocoa was associated with greater relative abundance of bacteria that produce short-chain fatty acids, which are important molecules that suppress inflammation in the gut and systemically. Importantly, evidence of the potential benefit of consumption of cocoa powder in dark chocolate was provided in a randomized controlled clinical trial investigating the effects of dark chocolate on one’s mood during everyday life and its effect on the gut microbiome [56]. In that study, healthy adults between the ages of 20–30 consumed either 30 g/d of 85% cocoa chocolate or 70% cocoa chocolate or no chocolate, which served as the control group, for 3 weeks. Daily consumption of the 85% but not 70% dark chocolate was reported to significantly reduce the negative mood effect as assessed using the Positive and Negative Affect Schedule. In agreement, 85% cocoa was associated with greater gut microbial diversity and the observed changes in negative affect scores were negatively correlated with diversity. Findings from that study provide support for the notion that dark chocolate containing at least 85% cocoa functions as a prebiotic to help maintain a healthy gut microbiome and may be beneficial as a dietary supplement to improve a negative emotional state that is often reported by patients with migraine.

Regular dietary inclusion of cocoa and dark chocolate is also reported to help maintain a healthy gut by modulating the intestinal immune system via enhancing bacterial production of short-chain fatty acids (SCFA) [57]. There is emerging evidence of the importance of SCFA to control inflammation and immune responses to maintain intestinal homeostasis. The three main SCFA include acetate, propionate, and butyrate and reduced levels of these SCFA are associated with active irritable bowel disorder (IBD) [58]. Of relevance, migraine is more prevalent in patients with IBD and the odds of developing migraine are significantly higher in those with IBD [59]. In support of the protective effects of SCFA, oral administration of propionate and butyrate decreased hyperalgesia and pain in a mouse model of nitroglycerine-induced migraine [60]. In addition to inhibiting pain signaling, administration of SCFA was associated with reducing intestinal damage, restoring intestinal permeability, and reestablishing the gut microbiome. These findings support the potential benefit of dietary cocoa, which enhances levels of SCFA to suppress central sensitization and maintain a healthy intestinal microbiome.

Chicken Bone Broth

Although soups made with broths have been used for centuries as a remedy for colds and inflammatory respiratory conditions, only recently have results from preclinical studies provided evidence of the potential benefit for migraine and other comorbid orofacial pain conditions like TMD [61, 62]. In a study of a commercially available enriched chicken bone broth product, daily supplementation via the drinking water was shown to inhibit trigeminal nociception in the orofacial region and suppress the stimulated expression of the pro-inflammatory enzyme protein kinase A in the spinal cord [61]. Interestingly, the chicken bone broth greatly reduced enzyme activity of COX-2, which is the key enzyme involved in the synthesis of prostaglandins and the target of selective NSAIDs, while exhibiting no effect on COX-1 activity. Hence, this finding provides evidence that chicken bone broth possesses antioxidant properties that likely can function to reduce sensitization and activation of trigeminal neurons. More recently, daily supplementation with chicken bone broth was reported to inhibit trigeminal nociception in a preclinical model of episodic migraine involving early life stress [62]. In that study, early life stress was found to promote a primed state of trigeminal nociceptors in both male and female animals that could be activated by exposure to a pungent odor. As early life stress is a risk factor for development of migraine [63], findings from this study support the notion that chicken bone broth may be beneficial in a neuroprotective capacity by suppressing the development of a sensitized state of trigeminal neurons associated with migraine pathology. We can only speculate that the physiological effects of chicken bone broth to inhibit trigeminal sensitization and activation is due to its reported benefit in maintaining a healthy gut microbiome and the stimulating production of short chain amino acids, GABA, and 5-HT.

Vitamins and Minerals

There are guidelines for daily amounts of vitamins and minerals that are recommended to maintain human health, yet many people do not achieve those levels on a regular basis. For example, patients with migraine have been reported to have lower than normal serum levels of magnesium and vitamin D [64–66]. Results from a double-blinded prospective clinical study of the potential benefit of combining vitamin D with topiramate in a pediatric population reported that combination reduced the frequency of monthly migraines and disability score [67]. These responses were significantly better than placebo and a lower percentage of side effects was reported. The authors concluded that vitamin D3 supplementation may be beneficial in pediatric migraine prophylaxis since it appears to be a well-tolerated, safe, and effective strategy. Similarly, in a randomized clinical trial the effectiveness of coenzyme Q10 was found to cause comparable therapeutic benefit as amitriptyline in children after 3 months but with fewer reported side effects [68]. In another study involving pediatric migraine [69], the frequency of migraine episodes was significantly lower in patients that had received 10 mg/day or 40 mg/day riboflavin for 3 months. Results from their analysis provide evidence that low doses of riboflavin are safe and modestly effective for migraine in general, but more so in children without other comorbid types of headaches. Results from several clinical studies have demonstrated the therapeutic benefit of folic acid as a dietary supplement for migraine. It is worth noting that pediatric patients with migraine are reported to have significantly lower serum levels of folic acid and B12 [70] and thus may benefit from supplementation. In support of this notion, results from a study of women experiencing migraine with aura reported that there was a significant inverse correlation between folic acid consumption and migraine frequency [71]. Another nutraceutical shown to be beneficial as a migraine therapeutic is alpha-lipoic acid, which is a potent antioxidant that is made naturally in the body. In an open-label, add-on clinical trial with adolescent migraineurs randomized to receive flunarizine or flunarizine with add-on alpha-lipoic acid, the frequency of acute attacks was significantly reduced with the combination therapy at 12 weeks [72]. In addition, the responder rate was reported to be significantly higher in the test group than the control group; disability as measured by the Pediatric Migraine Disability Assessment Scale (PedMIDAS) scores were significantly improved, and the severity of the acute migraine attacks was significantly decreased when compared to control group. Further, serum levels of CGRP were reported to be significantly reduced with the adjunctive alpha-lipoic acid therapy. Taken together, these findings support the add-on of alpha-lipoic acid with flunarizine, which is a medication used as a prophylactic agent for migraine [73], to improve clinical outcomes in adolescents with migraine.

Therapeutic benefit has also been reported in response to supplementation of omega-3 for 2 months in individuals experiencing episodic migraine when compared to those on a control diet [74]. Improvements in stress perception, sleep quality, and perceived health were reported as well as substantially improved Migraine Disability Assessment Scale (MIDAS) scores and Patient-Reported Outcomes Measurement Information System (PROMIS)^© measures such as pain interference and pain intensity, which mirrored improvements in non-headache pain as well as physical and psychological function. Further support for the benefit of omega-3 was provided in a randomized, double-blind, placebo-controlled trial involving patients experiencing episodic migraines that received omega-3 or placebo for 2 months [75]. A significant increase in the serum concentration of the anti-inflammatory cytokine IL-4 was reported with omega-3 supplementation, while causing a significant decrease in the level of the pro-inflammatory cytokine IFN-γ.

Conclusions

In conclusion, natural products and nutraceuticals represent an underutilized resource in the pursuit of safe and effective ways to treat inflammatory diseases such as migraine by modulating the level of proteins implicated in peripheral and central sensitization. Furthermore, the reported benefit of nutraceuticals that includes their antioxidant, anti-inflammatory, and anti-nociceptive cellular properties and ability to maintain a healthy gut microbiome provides a complementary and integrative therapeutic strategy for migraine. Since nutraceuticals modulate cellular functions via similar pathways as pharmaceuticals but with fewer reported side effects, their inclusion as dietary supplements may be prudent as a therapeutic for pediatric and adolescent migraine to reduce the dependency on pharmaceutical treatments. Furthermore, nutraceuticals may be beneficial in patients with refractory migraine, which is characterized by migraine that has become chronic and resistant to standard medications and are extremely difficult to treat effectively [76]. While there is emerging evidence of the numerous health benefits of nutraceuticals, there remains a need for additional well-designed preclinical and clinical studies to provide more specific information to guide their use as a migraine therapeutic.

Data Availability

No datasets were generated or analysed during the current study.