Herpes as Root Cause of Migraine

Despite much research and knowledge that has been gleaned over the years about migraine, it is still a stubborn and formidable beast of a condition that confounds many of medicine’s best practitioners.  Managing symptoms seems to be the name of the game, yet the root cause of migraine remains elusive.

Because migraine headaches are a manifestation of a serious chronic systemic inflammatory process affecting every major organ of the body, there are infinite angles and lenses through which we can try to understand migraine. Migraine is associated with:

  • food sensitivities and digestive problems
  • environmental chemical sensitivities
  • reduced thyroid function (hypothyroid)
  • congested liver and gallbladder
  • adrenal/pituitary axis imbalances and kidney problems
  • neurotransmitter imbalances with attendant mood “disorders” such as anxiety and depression
  • cranial nerve activation and cortical spreading depression
  • hormonal imbalances (low progesterone to estrogen ratios)
  • low antioxidant status (especially glutathione)
  • electrolyte and consequent blood pressure imbalances (caused mostly by compromised kidney function)
  • dehydration
  • beta-amyloid plaque/lesions
  • low blood pressure
  • blood sugar imbalances
  • blood platelet aggregation (“sticky blood”)
  • lymphatic congestion
  • compromised mitochondrial function
  • peripheral neuropathies
  • increased risk of stroke
  • hypermobile joints and lax connective tissue around blood vessels (Ehlers Danlos Syndrome)
  • TMJ
  • Light sensitivities
  • neck and muscular tension
  • insomnia
  • unresolved trauma
  • chronic stress
  • Chronic viral and fungal infections
  • Comorbities like cataracts and arthritis
  • And the list goes on and on

What could possibly explain this wide range of problems?  Where would we even start to find the root cause of migraine?

If you ask the experts, you’ll see that they are still debating whether migraine starts in the gut as a digestive and enzymatic problem, is caused by circulatory issues (dilated or constricted blood vessels), or originates in the brain itself (cortical spreading depression).

Let’s not lose sight of the fact that it’s all one integrated system. Since the vagus nerve connecting gut and brain is a two-way circuit (with 80% of the nerve transmission going from gut to head), I’m not sure why these differing perspectives on the root cause are seen as mutually exclusive. What if ALL of these perspectives are right? And what if, despite being right, these experts are overlooking something crucial?

No matter what the experts say about migraine starting in the brain, we know that migraine in a large number of people is triggered by foods and improved when these foods are eliminated.  We also know that other factors like sleep deprivation and stress can cause migraine without a food trigger. These are not incompatible viewpoints (or even different types of migraine, necessarily) because as we know, migraine is a systemic inflammatory condition. In a constant state of inflammation, triggers can and do come from any number of directions and reinforce each other through infinite nonlinear feedback loops.

There does seem to be quite a bit of agreement that alterations in the microbiome play a big role in not only migraine but most chronic inflammatory diseases.  The problem is that so much of the research has been exclusively focused on the gut microbiome, and that is what comes to mind when someone says “microbiome”. As it turns out, every individual part of our body has a microbiome – and that includes our blood and our brain.

Our Microbiome Includes Viruses

Awhile back, I used to think primarily of bacteria when I considered that people who have had antibiotics have an altered microbiome.  I focused on the problem that many bacteria produce histamine and glutamate, two molecules that, when present in excess, can overwhelm a person’s body with inflammation and pain.  These bacteria can even get infected by viruses, which also make up the microbiome.

New viruses in the human microbiome are being discovered in droves as we speak.

 . . . [W]e cannot study human chronic inflammatory disease without understanding that viruses we have not yet identified may play a role in many human disease processes. To do so would be like going to the rainforest, studying only 2% of the animals, and coming to conclusions about how the entire rainforest functions off that information alone.

Despite this fact many doctors have been taught to test for only 10-20 well-known viruses in their human patients. If these viruses are not identified in the patient, it is assumed that a virus (or group of viruses) cannot be driving or contributing to the patient’s disease. We must work hard to change this assumption, because it greatly prevents the medical/research communities from looking at a much broader picture of what might be going on. (Source)

Researchers at Harvard Medical School have found that:

. . . even “non-sick” humans harbor over 200 organisms in the brain. Those numbers don’t even include the virome (viruses). And we know that a bunch of herpes viruses can also survive in the brain . . . the gut microbiome and the brain microbiome communicate a lot via the vagus nerve. There’s lots of traffic, with bacteria in the brain/gut talking to one another via this highway all the time. Some products of gut fermentation like Short Chain Fatty Acids (SCFAs) literally travel the Vagus Nerve (physical translocation). . . . Conversely, certain bacteria in the gut live exclusively off chemicals generated in the brain that are transported to the gut (Source).

If you’re like me, you probably read that statement and thought about what an amazing organism the body is to be able to communicate between different systems so well – and marvel at the fact that bacteria and viruses live in the brain.  But if you’re like me (especially if you don’t have active herpes infections or any history of that) you probably didn’t really make much of the fact that herpes viruses live in our brains, or wonder if they could be the cause of your migraine headache.

OR, maybe you are someone like the many chronic migraine sufferers I see who “just happen” to also deal with chronic recurring herpes infections, from blisters on your mouth to your butt.  If so, you may have had a little aha moment reading that statement above, and wondered if having herpes in your brain might be related to your migraines.

Like most people (at least, “older” people who grew up prior to the chicken-pox vaccine), I got chicken pox as a kid and mono as a teenager.  It wasn’t until I was in my late twenties, having experienced the negative effects of industrial medicine and antibiotics, that my microbiome started to get seriously out of whack.  The c-section operation that I had with the birth of my first son tipped me over into migraine hell. Five years later now I believe the sheer stress of that event, coupled with the mineral deficiencies that resulted from it, triggered latent herpes virus to get a stronghold in my brain (and perhaps my gut and sinus).

Two and a half years after that c-section operation (after suffering from about 3 migraines per week and other countless headaches during that time), I found a way to manage my symtoms wih what I now call the SimplyWell Protocol.  As elated as I was to have a clear brain again, I was also puzzled by the fact that the migraines would return when I stopped the Protocol. I was also mystified as to why it was that after I was able to eat every other food that had previously triggered me, I could not eat even the slightest amount of spicy chilli food without getting some kind of brain fog or headache.

Even after five years of researching migraine, I didn’t think herpes played a role in migraine pathology – until I set out to answer a simple question that kept bugging me. I realized there was a clue here that could potentially hack the mystery of migraine headaches if I could unravel why capsaicin was such a trigger.

Why is it that capsaicin in chilli remains my only food trigger for headache after years on my Protocol which otherwise works to allow me to eat hard cheese, wine, chocolate, beer, etc without any problems?

Little did I know this question would lead me to believe that herpes virus infection is the underlying root cause of most migraine headaches.

How Nutrient Deficiencies Contribute to Viral Overload

As you may know from my last blog post, “Bioavailable Copper for Healing Migraine, Histamine, Herpes, and Hormones (Video)“, I’ve been obsessed with copper recently.

I’ve been studying Morley Robbin’s Root Cause Protocol, a series of steps designed to help copper become bioavailable and thereby able to perform its numerous critical enzymatic functions (including the breakdown of histamine by DAO).

Ceruloplasm is a protein made in the liver that transports copper making it bioavailable, and requires vitamin A and C and some other nutrients. Incidentally, ceruloplasm also helps carry iron to the cells. Without it, these metals in unbound form accumulate in organs and tissues, including the brain but also the liver.  Iron buildup is a key feature of amyloid plaque present in migraineurs. And heavy metal toxicity in general is a known comorbidity in those with migraine. As it turns out, viral infections get triggered by heavy metal toxicity – yet very few people believe that migraine is caused by a virus (or two, or more).  Viruses thrive in the lowered acidic pH caused by metals especially iron.

Harvard neurologist Robert Moir stated in an interview that herpes virus was discovered in amyloid plaque of many people beyond those with Alzheimers – and that (contrary to what was previously assumed), amyloid-beta plaque may serve an intelligent adaptive function  . . . “our studies have found that amyloid-beta has strong antimicrobial activity against the herpes viruses and these viruses are linked to increased plaque deposition.” (Source).  Other researchers have found confirmation that “infection of cultured neuronal and glial cells with HSV1 leads to a dramatic increase in the intracellular levels of beta-amyloid (Abeta) 1-40 and 1-42 . . . “ (Source).

There are 9 herpes virus types that infect humans: herpes simplex viruses 1 and 2; varicella-zoster virus, Epstein–Barr virus, human cytomegalovirus, human herpesvirus 6A and 6B, human herpesvirus 7, and Kaposi’s sarcoma-associated herpesvirus.

Another 130 herpes types infect other animal species – such as ocean turtles, who develop tumors when their herpes virus gets out of control because of exposure to excessive nitrogen compounds in the ocean (hmmmm, migraines get triggered with nitrogen too!).

Knowing that a mineral imbalance of copper would contribute to heavy metal buildup and opportunistic infection of herpes (and other) viruses in the brain, I started to wonder how capsaicin (my one remaining trigger for headache) might affect herpes.  This single question has led me down a path of many questions as I cross-check the validity of the idea that capsaicin is a potent trigger for migraine because it is actually triggering herpes.

Some Research Notes

I have found plenty of evidence to support the hypothesis that what many people believe is migraine may instead be a type of herpesvirus meningoencephalitis. I am not sure which herpes viruses are implicated though it appears different types trigger encephalitis.  I also found out that excess sulfur in the body (which causes sulfur sensitivity issues in many with migraine) robs the body of copper, further exacerbating the problem.

The inquiry and research notes I found along the way looked something like what is outlined below.

I wonder if a connection between herpes and migraine has already been proposed or established?  Looks like it has, with the majority of the evidence summarized by NaPier and Morimoto in their 2018 paper “Migraine Headache Treated with Famciclovir and Celecoxib: A Case Report”:   

“A previously healthy 21-year-old white woman presented with a severe headache and was diagnosed with severe migraine headache disorder. She initially was treated with standard migraine headache medications without symptomatic improvement. She was then given famciclovir and celecoxib. The patient fully recovered within days and continues to enjoy significant reduction in severity and frequency of symptoms. Famciclovir and celecoxib may work synergistically against HSV. The virus may play a role in the pathophysiology of migraine headaches, and this is the first case report of successful migraine headache treatment with these medications. . . It appears that a triggering event in a genetically predisposed patient can initiate a cascade resulting in the headache experience.1 Specifically, trigeminal ganglion activation seems to be a common early observation among patients with migraine.. Herpes simplex virus (HSV) has been known to reside within the trigeminal ganglion and is speculated to play a role in migraine headache pathophysiology. Treatments to target HSV infection may be important in migraine headache management. . . .

There has been much speculation about the relationship between migraine headaches and HSV, which already has been implicated in some forms of cranial nerve (CN) disorders. In 1991, Adour demonstrated that patients with acute herpes labialis also exhibited [Cranial Nerve] deficiencies involving [Cranial Nerves] V, VII, IX, and X. This phenomenon was termed HSV-related polyganglionitis. In 2003, Thiel et al examined the presence of HSV in postmortem ganglions. By using a specific immunostaining technique, the investigators revealed that HSV-1 and HSV-3 latently resided in the [Cranial Nerve] V (trigeminal) ganglions. It was then speculated that chronic infection and inflammation of the ganglion by [Herpes Simplex Virus] were present in many patients. In 2013, VanElzakker hypothesized that pathologically activated glial cells in the vagal sensory ganglia could cause an exaggerated sickness response that is found in chronic fatigue syndrome. If VanElzakker’s hypothesis is true, then we must ask whether glial cells in the intracranial trigeminal ganglia, pathologically activated by [Herpes Simplex Virus], could initiate migraine.” (Source)

Here is another single case report:

“. . . A 49-year-old lady presents with a 3-year history of a constant 24/7 headache in the right frontal-temporal area of her head and deep behind her eyes. This headache is severe, constant and requires daily analgesics, which have caused a fatty liver. She is overweight and extremely tired.

“She has been told by a neurologist that it is a migraine, which does not make sense, as migraines are episodic headaches and come and go. Her headaches do not respond to drugs that suppress migraines and the neurologist has not been able to help her. She continues to suffer and sees a gynecologist, who tells her that she has headaches due to menopause! Strange, as headaches are not a symptom of menopause and hormone therapy does not help her headaches.

“The clue is that over the previous 3 years she has had an episode of shingles affecting the right forehead and right eye, which was treated with anti-viral medications. Notwithstanding treatment the constant headache remains. Other causes of her headaches are excluded including high blood pressure, sinus infection and brain tumors, and extensive investigations reveal no cause for her headaches. I deduce that she has the herpes virus active in her brain, trigeminal nerve and possibly her optic nerves, which is causing the inflammation and thus the pain.

“I prescribe a detox for her liver and nutritional supplements to fight the herpes virus and reduce brain inflammation. Her headaches gradually lessen and she starts to have headache free days.” (Source)

Interesting.  So infection with herpes viruses has been proposed as causative for migraine, and antiviral herpes medication to migraine presumably caused by herpes has had mixed results.  

Looks like a number of different herpes virus strains are implicated in encephalopathy (brain inflammation and swelling).  Migraine is a form of encephalopathy.

“There is evidence that aberrant inflammation triggered by herpes simplex can result in granulomatous inflammation in the brain, which responds to steroids.  While the herpes virus can be spread, encephalitis itself is not infectious. Other viruses can cause similar symptoms of encephalitis, though usually milder (Herpesvirus 6, varicella zoster virus, Epstein-Barr, cytomegalovirus, coxsackievirus, etc).” (Source)

What further evidence is there to show that herpes causes infection in the cranial nerves?

“Evidence suggests that many cranial nerve syndromes, such as migraine headache, acute vestibular neuronitis, globus hystericus, carotidynia, acute facial paralysis (Bell’s palsy), and Meniere’s disease, are caused by the neurotropic herpes simplex virus (HSV). Because transitory cranial nerve dysfunction during acute HSV infection can be asymptomatic but often occurs in conjunction with mucocutaneous vesicles, we tested five subjects with herpes labialis for cranial nerve dysfunction. . . . Similar findings of an acute, transitory nature should suggest to the clinician a viral polyganglionitis caused by HSV infection.” (Source)

Well, a lot of my migraine clients have active infections of herpes, but I wonder about all the others who don’t.  Could herpes still be playing a role in their migraines?

“Upon primary infection of the oronasal mucosa, herpes simplex virus type 1 (HSV-1) rapidly reaches the ganglia of the peripheral nervous system via axonal transport and establishes lifelong latency in surviving neurons. Central to the establishment of latency is the ability of HSV-1 to reliably switch from productive, lytic spread in epithelia to nonproductive, latent infection in sensory neurons. It is not fully understood what specifically disposes incoming particles of a highly cytopathogenic, fast-replicating alphaherpesvirus to nonproductive, latent infection in sensory neurons.” (Source)

75% of all people with Chronic Fatigue Syndrome (CFS) get migraine.  I wonder if herpes infection plays a role in CFS?

“The vagus nerve infection hypothesis of CFS contends that CFS symptoms are a pathologically exaggerated version of normal sickness behavior that can occur when sensory vagal ganglia or paraganglia are themselves infected with any virus or bacteria. . . . pathogen-activated glial cells can bombard the sensory vagus nerve with proinflammatory cytokines and other neuroexcitatory substances, initiating an exaggerated and intractable sickness behavior signal. According to this hypothesis, any pathogenic infection of the vagus nerve can cause CFS, which resolves the ongoing controversy about finding a single pathogen.” (Source)

So it seems plausible that herpes (or other) viruses, even while latent, could be causing inflammation and migraine (along with a host of other pathological symptoms) through sensitization of multiple cranial nerves.

Spicy food containing capsaicin is such a huge trigger for brain fog, headache, and migraine. I wonder what effect capsaicin has on herpes viruses?

“Herpes simplex virus type 1 (HSV-1) produces a life-long latent infection in neurons of the peripheral nervous system, primarily in the trigeminal and dorsal root ganglia. Neurons of these ganglia express high levels of the capsaicin receptor, also known as the vanilloid receptor-1 (VR-1). VR-1 is a non-selective ion channel, found on sensory neurons, that primarily fluxes Ca(2+) ions in response to various stimuli, including physiologically acidic conditions, heat greater than 45 degrees C and noxious compounds such as capsaicin. Using an in vitro neuronal model to study HSV-1 latency and reactivation, we found that agonists of the VR-1 channel – capsaicin and heat – resulted in reactivation of latent HSV-1. . . .  Taken together, these results suggest that activation of the VR-1 channel, often associated with increases in intracellular calcium, results in HSV-1 reactivation in sensory neurons.” (Source)

“Capsaicin activates the heat and pH-sensitive ion channel Transient Receptor Potential Vanilloid 1 (TRPV1), which seems to be involved in the pathophysiology of migraine. TRPV1 is expressed on trigeminal nociceptors, which innervate the dura mater and the meningeal vascular system. Activation of TRPV1 causes release of CGRP from trigeminal nerve terminals and neurogenic inflammation within the meninges, possibly initiating migraine attacks. Accordingly, the anti-migraine drug sumatriptan was recently shown to block trigeminal TRPV1 channels . . Injection of capsaicin into the carotid artery caused a significant increase in jugular CGRP levels that was sustained for 15 min.” (Source)

Fascinating – not only does capsaicin trigger herpes viruses, it causes reactivation by affecting the capsaicin-vallinoid receptor of the Transient Receptor Potential channels (TRPV1):

“The family of receptors called TRPs drive sensations that allow us to navigate the world, especially our interactions with plants that we encounter or eat. They are responsible for diverse responses like coolness, heat, pain, taste, itch, nausea and drive local protective responses in our barriers like skin, gut and lungs. They are portals that allow us to make choices that are desirable and warn us of danger. They provide flavor to food and form a chemical radar for our wellbeing.” (Source)

Even more interesting is that BOTH herpes and capsaicin increase CGRP levels.  CGRP is a neuropeptide in the brain that causes blood vessel dilation and migraine at elevated levels.  The new CGRP receptor antagonist drugs aim to blunt the receptivity of the neurons to this peptide. With all the new CGRP drugs coming out, I wonder what other evidence exists that herpes raises CGRP levels?

“At all times after infection, equal numbers of CGRP-positive neurons were seen in infected and uninfected ganglia and in sham-operated mice. These results show that [Herpes Simplex Virus -2] infection differentially affects host neuropeptide production and that nervous system effects are not restricted to the acute stage of infection. These events are consistent with those seen in other injury/regeneration paradigms.” (Source)

“In this study, the effects of neuropeptides substance P (SP) and calcitonin gene-related peptide (CGRP) on production of pro-inflammatory cytokines TNF and IL-1 beta by macrophages were considered. Mouse peritoneal macrophages were infected with herpes simplex virus type-1 (HSV-1), or remained unstimulated, and cytokine assays were performed after 12 h. . .  It was concluded that the macrophage-mediated inflammatory response to HSV-1 is enhanced in the presence of these neuropeptides.” (Source)

“In vivo, we further identified a specific subset of NefH+ neurons which co-expressed Calcitonin Gene Related Peptide α (NefH+ CGRP+) as the sensory neuron subpopulation with the highest LAT promoter activity following HSV-1 infection. Finally, an early-phase reactivation assay showed HSV-1 reactivating in NefH+ CGRP+ neurons, although other sensory neuron subpopulations were also involved.” (Source)

Free radical damage (from reactive oxygen species such as peroxynitrite and Nitrogen Oxide, or NO) are also implicated in migraine:

“Besides mitochondrial dysfunction, migraineurs also have higher levels of NO products in their blood during the inter-episodic period. This can be related to the higher basal activity of the L-arginine/NO pathway, especially in patients of migraine with aura and without aura. These products react with superoxide to form peroxynitrite.” (Source)

“M[agnesium] and vit.B6 modulate the level of NO in the cell, both of which are deficient in migraineurs. Due to deficiency of Mg the trapped NO within the cell is not removed which combines with superoxide in the cell and generates peroxynitrite which is a potent free radical resulting in myelin degeneration at specific areas denuding hypersensitive neurons inducing migraines. . . . Both iron and copper are transition metals which become free and stored in deep areas of the brain and peripheral nervous tissue where these ions catalyse the oxidation of catecholamines and produce highly reactive radicals which also cause neurodegeneration, lipid-peroxidation and demyelination exposing hypersensitive neurons inducing migraines.” (Source)

I wonder if herpes virus causes the formation of any free radicals (such as peroxynitrite), adding to the overall load of free radicals compounds associated with migraine?

“Published studies have shown that, like other inflammatory mediators, reactive oxygen species (ROS) are generated during viral brain infection. It is increasingly clear that ROS are responsible for facilitating secondary tissue damage during central nervous system infection and may contribute to neurotoxicity associated with herpes encephalitis.” (Source)

Okay.  So herpes virus infection in the brain, sometimes triggered by capsaicin, increases CGRP, Nitric Oxide, and free radical damage by peroxynitrite. I wonder if herpes virus infection increases glutamate load, which is also a feature of migraine?

“This study demonstrated that herpesvirus 6 (which everyone has been exposed to in childhood as roseola) decreases glutamate transporters (which would in turn increase glutamate): “We infected astrocyte cultures in vitro with HHV-6 and found a marked decrease in glutamate transporter EAAT-2 expression” (Source).

“Studying epilepsy (not migraine) caused by herpes, researchers found that “[herpes] infected brain tissue didn’t produce very much of a chemical that transports the key neurotransmitter glutamate across the brain. . . If it doesn’t get transported properly, it ‘hangs around’, and because glutamate tends to make brain cells more active, too much could lead to overactivity . . .In the lab, they discovered that herpes slowed the creation of the transporter chemical for glutamate, providing strong evidence for the link.” (Source)

As you can probably tell, there are countless questions we could (and should) ask to try to cross-check this idea with various features of migraine. For example, how does citrus affect herpes?  Does blue light trigger herpes? Etc. etc. But I hope this little clustering of research is enough to make you intrigued about a possible, or actual, connection between herpes virus and migraine.


Bioavailable Copper for Healing Migraine, Histamine, Herpes, and Hormones (Video)

This past week was a goldmine for me connecting dots in my ever-deepening understanding of migraine pathology. I’ve been dancing with joy because what I’ve discovered explains a LOT about the root cause of migraine.  And it all has to do with having sufficient bioavailable copper to heal your migraines.

As you know, I’ve been looking for that root cause in earnest because while my beloved Protocol does prevent me and others from having migraine, it clearly hasn’t solved the underlying cause since the migraines return when it is stopped.

I’m in the middle of selling my house and buying a new one so haven’t had time to write blog posts, but I was so excited about this information I decided to make a video for you to summarize what I’ve been learning. I don’t have time to write a transcript so I hope you can watch or listen to the video to get the full download.

In this video, you will learn about the importance of bioavailable copper and zinc and what that has to do with histamine, herpes, and hormones.  I’d also like to share my pate recipe here for those of you adventurous enough to incorporate it into your diet.

Natural, Plant-based CGRP Receptor Antagonists for Migraine Relief

CGRP receptor antagonist

Drug companies are making their first pharmaceutical medications that are actually geared towards treating migraine directly.

Until recently, meds prescribed for migraine have been developed for other conditions but used by migraineurs with varying degrees of success.  Now, new injectable migraine drugs slated to come out in 2017 or 2018 aim to reduce migraine symptoms by inhibiting CGRP or acting as CGRP receptor antagonists. These new generation pharmaceuticals appear to be quite effective and for many migraineurs who have been suffering for decades without truly effective medications, their availability will come as a relief – until they get the sticker shocker.  These drugs will cost anywhere from $12,00-50,000 a year.  Like Botox injections, they may not be covered by insurance providers.  These CGRP receptor antagonists will also be made using genetic engineering, specifically through monoclonal antibodies.

Monoclonal antibodies are designed to bind to a specific substance. They can detect or purify that substance. CGRP monoclonal antibodies bind to CGRP to prevent the activation and sensitisation of trigeminal nerves. CGRP monoclonal antibodies prevent migraine by: binding with the CGRP released from trigeminal sensory nerve fiber; preventing activation of trigeminal nerves; preventing attacks in migraine susceptible individuals (Source)

The pharmaceutical family of triptans work as serotonin receptor agonists (increasing serotonin uptake); they also work via influence of CGRP levels by initially decreasing them.  The bad news is that eventually circulating CGRP levels actually increase with chronic exposure, leading to MOH (migraine overuse headache).  So triptans cause chronic migraine when stopped, which leads to dangerous dependency and overuse – since continual use may be the only way to stave off the rebound headache.

Sumatriptan, a pharmaceutical intervention used to abort migraine, has been shown to decrease CGRP levels concomitant with symptom relief. Sumatriptan is primarily classified as a 5-HT1 (serotonin) receptor agonist, but has also demonstrated inhibition of action potential signaling by inhibiting [calcium] channels in CGRP fibers. Calcium influx upon depolarization is a fundamental signaling mechanism which, among a host of other functions, stimulates the release of CGRP. (Source).

It becomes relevant to ask (as a promoter of Folk Medicine) whether Mother Nature has already provided us with natural, safe, gentle, affordable, and effective CGRP receptor antagonists in food or plant form?  As it turns out there are many plants that contain CGRP receptor antagonists or prevent levels of CGRP from escalating.  No surprises there!  The question is to what extent these plants may actually be comparably helpful and effective for migraine.  That’s a question that I pose here without a known answer, but which seems eminently practical to ask, given the unknown effects of emerging technologies such as genetically-engineered medications and the longer track record for safe use of plants such as those outlined in this article. But first . . .

What is CGRP?

CGRP stands for calcitonin gene-related peptide. CGRP is a neuropeptide – a molecule made up of 2-50 amino acids (as distinguished from a protein, which contains 50 amino acids or more).  Amino acids transport and store nutrients. One route through which food substances may impact CGRP secretion is through interruption of calcium signaling, which can trigger CGRP release. CGRP levels have been detected in the serum of migraineurs, with elevated levels in individuals with chronic migraine headache as compared to those with episodic migraine.

When CGRP is injected via IV it delivers a migraine attack in migraineurs – so researchers in phase 2 trials of the injectable medication now in development wanted to find out if inhibiting CGRP levels would have the opposite effect and prevent a migraine attack. It did – but there was also a strong placebo effect (15% of placebo had no migraines whilst 26% with the treatment experienced no migraines during this period).

It’s interesting to note that the brain itself can’t feel pain – the sensation of pain is triggered when CGRP is released, binding to receptors in the trigeminal nerve and causing vasodilation in blood vessels lining the meninges (the membrane which covers the brain).

So, which Specific Plants Naturally Reduce CGRP Levels?

The two most promising plants featured below (Sangre de Grado and grape pomace) are very high in proanthocyanidins, a powerful flavonoid that has been shown to play a role in boosting serotonin (5-HT) levels in the brain (not just the gut) of mice.  Essentially, proanthocyanidins seem to act as MAO inhibitors (meaning that they increase serotonin by way of inhibiting the enzyme that breaks them down).  When serotonin levels increase, CGRP levels decrease.

“. . . proanthocyanidin produced a marked increase of 5-HT levels at 25 and 50mg/kg in three brain regions, the frontal cortex, hippocampus and hypothalamus. Noradrenaline and dopamine levels were also increased when higher dose of proanthocyanidin (50mg/kg) administration both in the frontal cortex and hippocampus. These effects were similar to those observed for the classical antidepressant imipramine (10mg/kg, i.p.). Moreover, Our study suggested that proanthocyanidin (12.5, 25 and 50mg/kg) dose dependently inhibited monoamine oxidase-A (MAO-A) activity, while MAO-B inhibitory activity was also found at higher doses (25 and 50mg/kg) after 7days administration. MAO-A selective inhibitor, moclobemide (20mg/kg, i.g.) produced MAO-A inhibition of 70.5% in the mouse brain. These findings suggest that the antidepressant-like effects of proanthocyanidin may involve the central monoaminergic neurotransmitter systems.”

As it turns out, some plants work to slow activation of CGRP in the first place (grape pomace, ginger, butterbur), while others work at the level of the receptor sites (ie, as a CGRP receptor antagonist) – or both (Sangre de Grado).  It’s very likely that there are many many compounds in plants that play a role in CGRP levels.  I will add to this list as I do more research, but below are the most exciting plants I’ve found so far in this inquiry.

Sangre De Grado (aka Dragon’s Blood, Sangre de Drago, Croton lechleri)

Sangre de Drago, aka Dragon’s Blood, is a viscous, red tree sap that has been used by indigenous cultures of the Amazon River basin for thousands of years in their ethno-medicine. Most of the sap is harvested from the upper jungle of Peru and Ecuador, although the plant is common throughout the Amazon.  The plant that we are referring to here is in the Croton species (and not from species Dracaena, Daemonorops, Calamus rotang and Pterocarpus).

Sangre de Grado is a powerful antibiotic, antiviral, antiseptic, antifungal, antihemorrhagic, analgesic, and antioxidant. An article published in the Nutrition Journal in 2010 testing 3100 foods, beverages, spices and herbs worldwide found that Sange de Grado had the highest antioxidant content of the 59 herbal products tested in the database at 2897.1 mmol/100 g – much higher than the next highest herb formula Triphala at 706.25 mmol/100 g.

While Sangre de Grado has been used effectively for thousands of years in Amazonian medicine for skin wounds, gum health, gastrointestinal problems, ulcers, hemorrhage and bacterial and viral infections (especially Hep B and C), our primary interest in this article is how it affects CGRP levels and what the implications for that effect are.

It’s encouraging that blood engorgement, edema, and excessive sensitivity to pain were all reduced with administration of Sangre de Grado at a 1:10,000 dilution, in a study titled “Inhibition of Neurogenic Inflammation by the Amazonian Herbal Medicine Sangre de Grado”.  The researchers concluded that:

Sangre de Grado is a potent inhibitor of sensory afferent nerve mechanisms and supports its ethnomedical use for disorders characterized by neurogenic inflammation. . . . [Sangre de Grado’s] applications in Amazonia are not limited to cutaneous disorders. [Sangre de Grado] is also taken orally, in dilute form, for severe gastrointestinal distress. . . Despite the widespread use of [Sangre de Grado] in Amazonia as an analgesic, antidiarrheal, and wound-healing agent few in the Western world are aware of its existence and little is known about how it achieves these therapeutic benefits. We postulated that these benefits may result from a suppression of sensory afferent nerve activation and the present results support this conclusion. This hypothesis was generated from experience and the knowledge that sensory afferent nerves serve as broad-based sentinels in the skin, gut, and lung, and that the rapidity by which [Sangre de Grado] relieved pain . . .  was consistent with a neurogenic mechanism. In addition, the serendipitous personal observation by an author that [Sangre de Grado] relieved the symptoms of cutaneous capsaicin (sensations associated with an overly spicy meal) focused our attention to sensory afferent nerve mechanisms. [Sangre de Grado] appears to suppress the activation of sensory afferent nerves at a prejunctional level, in addition to inhibiting the tissue responses to CGRP, a primary neurotransmitter of sensory afferent nerves. (Source)

This report makes it clear that Sangre de Grado is good at alleviating many issues associated with migraine, including loose stool and sensitivity to chilli (which contains capsaisin, a known CGRP activator and trigger of histamine overload). Since we know that migraines have a digestive component as well as a neurological component involving blood vessel dilation, the ability of Sangre de Grado to calm digestion, constrict blood vessels, and reduce pain from nerve inflammation would make it very attractive as an experimental treatment.  The fact that it may be providing these benefits by way of inhibiting tissue responses to CGRP is even more exciting.

In laboratory tests, Dr. John Wallace of the University of Calgary’s Faculty of Medicine research team has demonstrated that Sangre de Grado blocks the activation of nerve fibers that relay pain signals to the brain, therefore functioning as a broad-acting pain killer. Wallace states that:

Not only does Sangre de Grado prevent pain sensation, it also blocks the tissue response to a chemical released by nerves that promotes inflammation. There is currently no other substance that we know of that shares these same activities. (Source)

It could also be that topical application of Sangre de Grado in the neck and base of the skull (where cranial nerves including the trigeminal nerver are located) could also help with inflammation associated with migraine. The authors point out that:

. . . [Sangre de Grado] was an effective analgesic and anti-inflammatory agent when applied topically, even when the hyperalgesic [pain] stimuli were applied by intradermal injection. This suggests that active components have sufficient lipophilicity to readily cross the skin. . . . this transcutaneous absorption appears to be rapid. (Source)

What are the compounds that make Sangre de Grado so medicinal?  As with most plants used as medicine in whole form, it’s likely a specific combination of compounds all working together, but what is clear is that proanthocyandins account for 90% of Sangre de Grado’s chemical composition. Proanthocyandins can be found in many plants including red grapes (as discussed in the next section). Proanthocyanidins inhibit enzymes that produce histamine, and have been shown to have protective effects on gastric mucosa in experiments on rats via their anti-histamine effects. Proanthocyanidins also inhibit the same class of prostaglandins (PGE2) that are associated with migraine.

Botanist Dr. James Duke points out that,

. . . in addition to the proanthocyanadins (including Pycnogenol) and taspine, there’s another active ingredient – dimethylcedrusine. While each of these alone – dimethylcedrusine, pycnogenol and taspine – was shown to effectively heal wounded rats (with squares of skin exfoliated, i.e., peeled off) by European scientists, the whole dragon’s blood was shown to speed healing four times faster. The whole was better than the sum of its parts. Synergy makes the whole herb stronger; diversity makes the rainforest stronger. (Source)

Various online sources that I’ve seen have reported relief from arthritis, IBS, psoriasis, ulcers, cancer, and many other inflammatory conditions through the use of 10-15 drops of Sangre de Grado taken internally per day.  Amazonian Shaman Don Jose Campos mentions in his book that Sangre de Grado is one of the most powerful and effective medicines for a wide variety of health problems, but that it’s important to never exceed 20 drops per day as a dose.

It’s unclear whether Sangre de Grado used over the course of weeks could eventually heal the underlying pathology of migraine headache including its digestive component, or would best be used as a temporary way to avert an oncoming migraine. Given that this medicine has been used safely by many people at doses mentioned above for other conditions, it would seem to be a simple enough experiment to try at modest doses and gradually build up to 15 drops a day until an effect or benefit is noticed. (As always, if you are on medication, check with your physician first for any contraindications).

Sangre de Grado is the most promising of the plants I’ve researched because it acts BOTH to prevent release of CGRP as well as to block CGRP receptors (ie, it is both a CGRP inhibitor and receptor antagonist). Sangre de Grado seems to be an overlooked medicinal resource from the rain forests of the Amazon that may offer useful therapeutic advantages over pharmaceutical migraine medications.

Note: It’s important to get Sangre De Grado from a source that uses sustainable harvesting methods. I get my Sangre de Grado from Whole World Botanicals. (I have no personal relationship or financial interests in this company).  Also, make sure to get the sap straight, NOT in an alcohol based tincture, since alcohol can trigger migraines.

Grape Pomace

Grape pomace is the remaining skin and seed byproduct leftover after grapes are pressed. This waste product is often thrown away or put back into the soil, or sometimes given to animals in their feed to improve their health, as it is a potent antioxidant.  Occasionally it is used for resale as a nutritional supplement.  It appears that few have explored its potential for use with migraine headache, although this company (Two Willows Farm) is selling grape seed and skins with or without pine bark (which has also been effective in alleviating migraines).

As it turns out, grape pomace also contains proanthocyandins, (the main constituent of Sangre de Grado), although it is unclear whether it is due to proanthocyandins that it affects CGRP levels. As mentioned in the section above on Sangre de Grado, proanthocyandins – specifically, those from grape seed – inhibit proinflammatory prostaglandin E associated with migraine.

Grape pomace is also high in the flavonoid quercetin, which is a known mast-cell stabilizer (and therefore reduces histamine levels).

Brain mast cells can also secrete pro-inflammatory and vasodilatory molecules such as interleukin-6 (IL-6) and vascular endothelial growth factor (VEGF), selectively in response to corticotropin-releasing hormone (CRH), a mediator of stress which is known to precipitate or exacerbate migraines. (Source)

In Italy, researchers found melatonin or melatonin-like stubstances in different grape varieties.  Low melatonin levels are associated with migraine.  As it turns out, melatonin also inhibits CGRP levels (at least in rats).  (Low melatonin is also associated with adrenal insufficiency, so presumable, improved melatonin levels would help with kidney/adrenal health as well).

Concentration-dependent dilation of the rat middle cerebral artery produced by CGRP . . . was significantly inhibited in the presence of . . . melatonin. . . In addition, CGRP-mediated increase in adenylate cyclase activity was also significantly attenuated by the receptor mediated action of melatonin. These results indicate that melatonin may interact with CGRP to regulate cerebral arterial tone. (Source).

A study at George Mason University (Effect of Grape Pomace Extract on In Vitro CGRP Secretion as a Proxy for Migraine) concluded that “Results from the study provide evidence that chemicals in grape pomace extract reduce the levels of CGRP secreted.”  In other words, they don’t work as CGRP receptor antagonists, but rather prevent the secretion of CGRP in the first place. Another set of rats orally fed grape seed extract for 14 days had lower basal expression of CGRP in the neurons and microglia of the trigeminal nucleus caudalis than control rats.

In the study “Impact of Food Components on in vitro Calcitonin Gene-Related Peptide Secretion—A Potential Mechanism for Dietary Influence on Migraine”, impacts of grape pomace, ginger, and S-petasin (a compound found in butterbur) were studied on cell cultures.

Interestingly, grape pomace extracts displayed the strongest ability to inhibit CGRP secretion of any of the tested substances. This is notable not only for the scale of the inhibition, but also because the grape pomace extracts did not significantly inhibit calcium uptake upon stimulation. This suggests that inhibition of CGRP release of grape pomace extracts occurs by a mechanism different from calcium channel inhibition. . . Presumably, as red grapes, both pomace extracts would also contain anthocyanins, procyanidins, flavonols, and catechins. It is reasonable to propose these phenolic acids and polyphenolics may be responsible for the activity witnessed here.(Source)

As with many studies of plant compounds, the conclusions about the role grape pomace plays in CGRP levels were reached based off of analysis of results obtained from studies in cell cultures or animals, and not consumption by human beings.  But there have bee studies of grape pomace’s effects on other health markers in humans.  Grape pomace extracts and procyanidins have been associated with reduced risk of cardiovascular diseases such as atherosclerosis and shown to slow down degradation of skin collagen and elasticity associated with ageing.

Additional research has shown that in ruminants, grape pomace consumption increase sperm motility and improved faecal microflora in lambs.  Grape pomace also was shown to enrich soil phosphorus levels in soils supplemented with grape pomace biochar.  The dietary fiber and phenols in grape phenolic extract (1mg/mL) also induced a “significant biomass increase of L. acidophilus grown in liquid culture media“, which could theoretically translate into improved gut health and microflora when consumed by humans.

Currently, I am in the process of sourcing whole, dried, organic grape pomace in the Columbia Gorge region where I live to feature in my shop. The drying process does reduce the total phenolic content as compared to consumption of fresh grape pomace, but the end product still contains significant beneficial properties. My hope is to find a source in whole dried form that can then be powdered on the spot in a spice grinder for optimal freshness by the migraineur, preventing oxidation that would occur with pre-ground grape pomace powders.

Ginger & Butterbur

As the above cited study states, both ginger and butterbur (in the form of s-petasin) demonstrated “a mild decrease in calcium uptake as well as a mild reduction in CGRP secretion”, which may have been affected by the calcium channel blocking effects of these two plants.

While there may be other properties in both ginger and butterbur that help with migraine through other mechanisms, it appears that neither have such significant effects on lowering CGRP levels on their own as compared to either Sangre de Grado or grape pomace, which do not seem to be calcium channel blockers.  Perhaps a blend of these herbs and foods would have a more positive synergistic effect?

Other Plant Compounds that Affect CGRP Levels

Plants, as a rule, possess dynamic properties – with multiple molecules working together in synergistic (and unpredictable ways).  I wanted to share some notes I’ve taken about different plant compounds and how those compounds may affect CGRP, without concluding that all plants containing these compounds will necessarily help reduce migraines (as indicated by the fact that theobroma cacao lowers CGRP levels but is also a known migraine trigger.  It could be that the tyramine levels in cacao due to fermentation have a stronger physiological effect than the CGRP-inhibitory effect of the theobroma).  Notice that many compounds that inhibit CGRP also happen to reduce glutamate levels and are vasoconstrictive. CGRP and glutamate levels are both affected by calcium channel activation.

Compounds that Lower CGRP (Potentially Helpful in Alleviating Migraine)

  • Piperine – found in black pepper; also vasoconstrictive.
  • L-malate (ie, malic acid) – found in apples and many other tart fruits. It is a precursor to oxaloacetate, which reduces glutamate levels as well.
  • Ferulic acid – found in flax seeds, rice bran, and the Chinese herb Danshen (Salvia miltiorrhiza). Also reduces glutamate leves. Flax seeds also contain prebiotic gums.
  • Caffeic acid – in coffee, danshen and other plants such as celery.
  • Rosmarinic acid, an ester of caffeic acid – found in the herb Danshen and rosemary essential oil; also known to be a vasoconstrictor.
  • Interestingly, theobroma cacao from chocolate (a known migraine trigger) was also shown to decrease CGRP levels (in rats). Perhaps the tyramines overshadow the benefits of reduced cgrp!

Compounds that Raise CGRP (best avoided)

  • Capsaisin – present in chilli.
  • Cannabidiol – in cannabis; also a vasodilator. “the cannabidiol-evoked CGRP release depended on extracellular calcium.”

Stay Tuned for More Info . . .

Stay tuned for future blog posts in which we will explore the role that GABA, Serotonin, gut bacteria, melatonin, and electrolytes play in CGRP levels.

Please note that this information is for educational purposes only and is not intended to diagnose or treat migraines, or act as a replacement for medical care from a medical professional.

[author] [author_image timthumb=’on’]http://www.simplywell.info/wp-content/uploads/2016/04/Marya.jpg[/author_image] [author_info]Marya Gendron is a biodynamic craniosacral therapist, health coach, and wellness researcher. She specializes in chronic migraine headache relief and alleviation of brain fog, indigestion, and histamine intolerance through plant-based solutions.

The SimplyWell Protocol is available here, or you can book a consultation with Marya.
Learn more about Marya’s healing journey here.
[/author_info] [/author]