Hey Brian,

CGRP has been a hot topic not only in neurology but rheumatology and gastroenterology as well.  Moreover, there are common links...  the pain associated with many of the autoimmune inflammatory disorders and a vitamin D3 deficiency. 

There are 80 of these autoimmune inflammatory disorders so far...  Some of the more common include: rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, celiac sprue disease, psoriasis, inflammatory bowel disease and Graves’ disease.

You can't really talk about CGRP without going deep into the weeds and start talking molecular biology, the immune system, inflammation and genetic expression. 

As the name Calcitonin Gene-Related Peptide (CGRP) implies, we're talking about a peptide, a naturally occurring family (calcitonin) of biological molecules produced within cells by a specific gene on a specific chromosome, primarily in nerve cells within the spine and brain as well as nerve cells in other areas of the body.

For CH'ers and migraineurs, CGRP is likely the primary perpetrator of pain and neurogenic inflammation.  CGRP serum concentrations rise during the pain phase of CH and migraine headaches... and drop to zero when we're pain free.

The leading candidate in explaining how vitamin D3 prevents CH is the mechanism of action by which vitamin D3 down-regulates CGRP production through the process of genetic expression.

Dr. Robert Heaney explains genetic expression best by saying, "vitamin D3 unlocks the cell's genetic library of instructions and the cell starts executing them." 

During genetic expression, the cell starts performing one or more of the following activities:  it replicates, differentiates, starts producing or inhibiting the production of peptides and other active chemicals that signal or control other biological processes within the cell or surrounding cells, or the cell dies.

Research in this area reveals several studies that indicate there are vitamin D3 receptors and the enzymes needed to hydroxylate vitamin D3 to 25(OH)D and 1,25(OH)2D3 found in brain cells throughout the brain.  What is particularly interesting is the highest concentrations of these genetic expression precursors are found in the hypothalamus and trigeminal nerves…  With the hypothalamus involved, we're talking the neurogenic head-waters of CH pathogenesis.

If we follow this confluence of findings and add in calcitonin gene-related peptide (CGRP), which several studies have found is produced in the trigeminal ganglia and elevated in the bloodstream during the pain phase of CH and migraine... we have a possible trigger. 

Adding one more factoid that vitamin D3 has been shown to down regulate/suppress the production of CGRP, (quite possibly through genetic expression), we have a viable candidate mechanism of action for vitamin D3's capacity to prevent CH.

I say possible candidate, as a 2010 study identified 2776 genomic positions occupied by the VDR and 229 genes with significant changes in expression in response to vitamin D3...  Accordingly, there are thousands of other candidates for genetic expression made possible by vitamin D3... and any one or more of them could easily play a role in a mechanism of action inhibiting CH pathogenesis...

That said, I'll stick with the CGRP gambit for now as there is corroborating evidence provided by none other than the good Dr. Peter Goadsby and Dr. David Dodick.  These two neurologist tag teamed on a pair of phase 2 RCTs in 2013 involving the use of two monoclonal antibodies, ALD403 (Alder BioPharmaceuticals Inc) and LY2951742 (Eli Lilly and Company), both with an appetite for CGRP... to prevent migraine headaches... 

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They reported their findings on these two RCTs during the 2014 Annual Meeting of the American Academy of Neurology, where I made a poster presentation on the results of our online survey of CH'ers taking the anti-inflammatory regimen with 10,000 IU/day vitamin D3 to prevent their CH.

Given there is sufficient overlap in the pathophysiology of CH and migraine and that CGRP is a common component in both headache disorders, I commented in June of 2014 that it wasn't unreasonable to expect one or both of these two MABs would eventually find its way into an RCT preventative treatment for CH...  That has already happened.

At an estimated cost of $3000 to $5000 per treatment...  either of these two MABs is likely going to be expensive.  As a comparative cost gauge, Humira, (Adalimumab), runs $3099 for two subcutaneous injections.

Unfortunately, all biologics/MABs carry a long list of side effects that range in order from nasty to down-right onerous including: compromised immune system, life threatening infections like tuberculosis and pneumonia, fungal infections and a growing list of cancers.  Watch the TV ads for Humira and you'll get an even longer list of adverse side effects.

Having taken one of the MABs, daclizumab, (a potent immunosuppressant used following kidney transplants to prevent rejection), during one of the clinical trials at NIH... I experienced squamous cell carcinoma and eosinophilic meningitis within two months after starting it... 

Accordingly, I'll stick with the anti-inflammatory regimen with 10,000 IU/day vitamin D3 and the cofactors... at ~ 40 cents/day to prevent my CH... and keep me in better health in the process.

If any of you decide to participate in this RCT... read the study consent form very carefully before you sign it...

Take care,

V/R, Batch