Care and Feeding of the Endocannabinoid System

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GW Pharmaceuticals Investigates Care And Feeding Of The Endocannabinoid System

One of the greatest advantages for publicly traded companies is their ability to raise capital in public markets. Capital can be used to fund research and development (R&D), fund capital expenditure, or even be used to pay off existing debt.

This advantage is even more crucial for small biotechnology companies. Because of long lead times, extremely high R&D costs, and very little to no revenue in the years of development, many biotech companies must rely on a steady stream of invested capital in order to survive and fund operations. Not surprisingly, even with promising drugs in the pipeline, many biotech companies fail because of undercapitalization due to their inability to access external finance.

In the case of British biopharmaceutical company GW Pharmaceuticals (NASDAQ:GWPH), they’ve raised over £472.78 million over the last three years – giving them a nice cushion to fund R&D and Capex. Today, even though they’ve been operating at a loss (for the 12 months ended September 30, 2016, the company lost £63.66 million), the company is valued at over £2.03 billion ($2.61 billion).

So why the lofty valuation?

GW Pharmaceuticals is the global leader in the development of cannabinoid-based medicines. They commercialized the world’s first plant-derived cannabinoid prescription drug, Sativex® (nabiximols), which is approved for the treatment of spasticity due to multiple sclerosis. In addition to Sativex, their lead cannabinoid product candidate is Epidiolex® which is a liquid formulation of pure plant-derived cannabidiol (CBD). This product is in development for the treatment of rare, treatment-resistant epilepsy conditions where there are limited or in some cases, no approved treatment options. These include Dravet Syndrome (phase 3 clinical trials), Lennox-Gastaut Syndrome (phase 3 clinical trials), tuberous sclerosis (phase 3 clinical trials), and infantile spasms (phase 2 clinical trials). If approved, Epidiolex would be a game-changer for rare childhood-onset epilepsy disorders.

GW Pharmaceuticals is also heavily involved in research that explores the potential therapeutic applications of cannabinoids across a broad range of disease areas and also in the endocannabinoid system (ECS) itself. One particular area of interest is in ways to enhance the ECS – especially when there’s an endocannabinoid deficiency (associated with conditions like migraine, fibromyalgia, irritable bowel syndrome, psychological disorders, and others).

 

Care and Feeding of the Endocannabinoid System: A Systematic Review of Potential Clinical Interventions that Upregulate the Endocannabinoid System

The “classic” ECS includes the cannabinoid receptors CB1 and CB2, the endocannabinoid ligands anandamide (AEA) and 2-arachidonoylglycerol (2-AG), and their metabolic enzymes. But because there is growing literature on endocannabinoid deficiency and its links to a variety of conditions, researchers are now investigating possible clinical interventions that correct endocannabinoid deficiency and enhance the ECS. The three main molecular mechanisms are to upregulate cannabinoid receptors, increase ligand synthesis, or inhibit ligand degradation.

In a 2014 article published in PLOS One and partly funded by GW Pharmaceuticals, John McPartland from the U.K. teamed up with Geoffrey Guy from the U.S. and Vincenzo DiMarzo from Italy to perform a systematic review of clinical interventions that enhanced the ECS. John McPartland has received research grants from GW Pharmaceuticals and serves on its scientific advisory board. Geoffrey Guy is the CEO of GW Pharmaceuticals, and Vincenzo DiMarzo has received research grants from GW Pharmaceuticals and serves as a research consultant.

The study reviewed 184 in vitro studies, 102 in vivo animal studies, and 36 human studies.

Many randomized controlled trials identified in the review were conducted on lifestyle modifications and complementary and alternative medicine (CAM) interventions. The authors found that clinical interventions characterized as CAM upregulated the ECS. These included massage and manipulation, acupuncture, dietary supplements, and herbal medicines. Lifestyle modifications (diet, weight control, exercise, and the use of psychoactive substances—alcohol, tobacco, coffee, cannabis) also modulated the ECS as well. They concluded that these were sensible methods of enhancing the ECS.

The study also identified several classes of pharmaceuticals that upregulated the ECS. These included antidepressants, antipsychotics, anxiolytics, anticonvulsants, and analgesics (acetaminophen, non-steroidal anti-inflammatory drugs, opioids, glucocorticoids).

However, although some prescription drugs in the preclinical studies (such as certain antidepressants, anxiolytics, antipsychotics, and anticonvulsants) were identified as useful, they were not recommended.

According to the authors:

“These drugs are generally administered in a chronic fashion, and this comes with a caveat: generating chronic elevations in AEA and 2-AG may be counterproductive. Faced with constant activation by agonists, CB1 and CB2 desensitize and downregulate. A desensitized receptor drives less receptor-mediated signal transduction, and develops cross-tolerance to all agonists—eCBs and phytocannabinoids alike. A downregulated receptor is not functional—either it does not bind ligand or has internalized away from the cell membrane.”

Other drugs identified in preclinical trials that upregulated the ECS included corticosteroids, opioids, and nicotine. However, these drugs were found to have side effects that were too severe to warrant their use.

Finally, preclinical studies suggested that a number of over-the-counter medications, such as analgesics, seemed to act through endocannabinoid-mediated mechanisms. The authors concluded that clinical trials were warranted, although over-the-counter medications lacked patent protection, so expensive clinical trials seemed unlikely.

 

Conclusion

As this study showed, there are several ways in which the ECS in our bodies can be enhanced. Its findings provide a great base for further research into how to combat endocannabinoid deficiency and its associated conditions.

However, it’s important to note that this study was only made possible by capital raised in the public markets. The groundbreaking cannabis research being conducted by GW Pharmaceuticals is being funded by investors who believe in the company’s mission to explore the potential therapeutic applications of cannabinoids to treat diseases. As a result, this company has made great strides in developing cannabinoid-based medicines and continues to raise the bar in cannabis-based research and development.

Of course, this is in stark contrast to the heavily-biased, government-funded studies by agencies like the National Institute of Drug Abuse (NIDA) and the U.S. Food and Drug Administration (FDA). Most of their studies focus on the harmful effects of cannabis and often try to blame cannabis use as the root cause of many health conditions.

Fortunately, people are beginning to realize that the bulk of these studies are biased and fail to establish causality. In fact, government agencies – facing mounting pressure from the pro-cannabis movement – have begun to change their tone on cannabis research and are beginning to fund studies on its therapeutic potential.

Let’s hope this trend continues.

 

https://www.dallasnews.com/opinion/commentary/2014/09/11/why-research-is-biased-against-pot-to-focus-on-its-harm-and-not-its-benefits

http://www.hemplandusa.com

https://www.gwpharm.com/about-us

https://www.google.com/finance?q=NASDAQ%3AGWPH&fstype=ii&authuser=0&ei=1GsqWam9A4im0gSDuovIBw

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3951193/

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