The entropic anarchy of the endocannabinoid system
I was thinking of visiting PorcFest this year but when I was asked to present a personalized medicine paper at the ICRS 2014 meeting I jumped at the opportunity. Hence, I spent the last week at the International Cannabinoid Research Society in Baveno Italy. This meeting was a collection of 350 cannabinoid researchers gathered to better the understanding of the symphony of lipids that influence our metabolism, our immunity and our consciousness. This was 100 more people than attended last year and the industry presence was pleasantly diversified.
For starters, it was held in a remarkable venue at Hotel Dino on Lake Maggiore near the Italian-Swiss border. It also had a blow out list of presentations that really stretched the simple model on cannabinoids touching 2 receptors (CNR1 and CNR2 are the most written about). The abstract program is on line and is an interesting read.
What is clear from these presentations is that FDA model of approving drugs is simply unfit to manage the science that is coming. The conventional concept of one drug targeting one receptor is all that model can approve. The Pharma industry is thus hyper focused on the path the central planners laid out. I believe this simple failed framework (more so than any DEA/NIDA conspiracy) is more responsible for the failure of cannabinoid based medicines to make it past regulatory hurdles and back into widespread use seen in the 1860s.
There is certainly merit to the concern that we have government funded ‘Scientific’ Institutions with titles that are in and of themselves a confirmation bias like ‘National Institute on drug abuse‘ as opposed to ‘drug outcomes or drug benefits‘ and scientists who accept this funding seemed to have well funded but poorly laid out study design that received a lot of consternation amongst the community uninfluenced by this institution of confirmation bias. I will provide a few examples in a later post but felt it was more important to focus on the exciting work that is making their model obsolete.
First, the complexity of 88 Phytocannabinoids is awe inspiring. Take just one of the diverse compounds and measure where it ‘hits’ in the human body and you don’t have a finger playing one note on an instrument, but instead you have a 10 handed hydra playing a soft and subtle symphony on over 50 receptors and peptides. This entails 2 of the most prevalent GPCRs in the human body (CNR1 and CNR2) and 6 TRPV receptors (temperature gated and often Capsaicin triggered), 6 different lipid rafts (Fatty Acid Binding Proteins interestingly enough being study at Stony Brook NY) that shuttle cannabinoids between aqueous and lipid compartments in the body, 3 receptors of unknown function (GPR55, GPR119, GPR18) that communicate with LPI (lysophosphatidylinositol) and at least 6 different endocannabinoids (AEA, 2-AG, NADA, NAGly,OEA, LPI) all influenced by dozens of enzymes which metabolize them (DAGLa, DAGLb, MAGL, ABHD6, ABHD12, FAAH). This is one cannabinoid and the plants often have half a dozen to dozen dominant cannabinoids based on their genetics.
Next, layer in the terpenes. The plant has 100s of these but usually 2 dozen that are uniquely dominant per plant. These are all pharmacologically active but the route of administration alters these a bit more than the cannabinoids. Generally smaller volatile organic compounds or VOCs, these VOCs can vaporize off at different temperatures and be present in different concentrations based the preparations people use. This link showcases some excellent work done by Bedrocan in attempt to chart the differences in Indica vs Sativa cannabis plants. You can see the terpene profiles are wildly different and it can be difficult to segregate the two subspecies with Chemotype alone. Genetics of the plant may aid this.
Now try to understand this complexity in light of each patient having 4 million changes in their genome. The impact of any one cannabinoid is very likely dependent on the array of variation present in a given patient and their ~50 critical genes mentioned above. Now the FDA wants to squeeze this complexity into 1 compound against 1 target. To GW Pharma’s credit, they are getting the FDA to accept botanical extracts (not approved yet but under study) as long as they can show efficacy in a given population but until this population is genetically stratified it will still be a hit or miss game in application of a symphony easily placed an octave off. They are showing success in Epilepsy but at a 44% response rate in a subclass of genetically well defined epilepsies (80% of Dravet syndrome is SCN1A variant). Cannabidiol is the most exciting drug to come to Epilepsy! There is limited debate on this point in the field. Why the other 56% don’t respond isn’t yet clear. We are hoping to help resolve this conundrum (See video below) by applying a CLIA and CAP certified sequencing test covering over 500 genes known to be involved in Epilepsy and as many of the endocannabinoid genes as possible.
Its not clear if the GW Pharma approach is more efficacious than the dispensary model showcased by Realm of Caring and GW Pharma will have the FDA trial cost overhead likely increasing the cost of the drug 5 fold over dispensary material. I expect demand for both markets to flourish despite all of this added cost for safety appearing terribly moot (given governments don’t decide to regulate the dispensaries out of CBD). The cannabis plant (as diverse as it is) has very few reported fatalities if any but applying the right plant to the right patient is what will determine if the plant is helping or worsening the disease.
This is where personalized medicine comes in and attempts to tailor this information for a given individual. We are witnessing a great convergence in technology that puts more power in the hands of the people. This presentation demonstrates the use of iPhone based ECGs and personalized genome sequencing guided cannabinoid selection for treating Atrial Fibrillation. In many ways this spontaneously ordered itself because we were most vested in finding a solution. We are not experts at making ECG, nor do have a clue how the iPhone operates. We understand a small slice of the genome and how to read it but in a highly networked world the i Pencil story is getting more and more powerful.
This would have cost over $1B and 10 years if done with the central planner model of FDA approval. Granted our story isn’t complete and ready for blind one size fits all application to a population. We hope this aids in underscoring the need for a creative destruction in how we apply drugs to individuals. The intersections of these vectors of convergence will create rapid wealth and tremendous health. Jeff Berwick likes to reference the “3 killer B’s” radically altering the economy as being Bullion, Bitcoin, and Buds. I agree with him but believe bullion to be redundant to bitcoin and the 3rd B is really Big Biology manifested in personalized medicine. The paper I gave provides an early glimpse of this. It can be seen at this link:
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