New CGRP drugs coming on the market
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).
Important Update: my research since first writing this article has helped me to understand that elevated CGRP levels are a side-effect of hypoxia, or low tissue oxygen. I believe that hypoxia is the root cause of migraine headaches. You can learn how to heal your migraines by addressing hypoxia in my Repattern Migraine Masterclass.
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).
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.”
