CBD Primer

Cannabidiol (CBD)- A Primer 

A) The Cannabinoids and Cannabidiol (CBD)

Cannabis contains over 113 cannabinoids- the most widely known of the cannabinoids being Tetradhydrocannabinol (THC) and Cannabidiol (CBD). 

A cannabinoid is one of a class of diverse chemical compounds that acts on two kinds of cannabinoid receptors (CB1 or CB2) found in the central and peripheral nervous system altering neurotransmitter release.  Several types of cannabinoids bind to cannabinoid receptor proteins including the (a) endocannabinoids (produced ‘endogenously’ or naturally within the body), (b) phytocannabinoids (‘phyto’ meaning produced by plants including cannabis and hemp), and (c) synthetic cannabinoids (manufactured artificially).  

Cannabinoid research is a relatively recent phenomenon given the largely prohibited status of cannabis throughout most the 20th century.  In 1964, Raphael Mechoulam, now considered the “Father of Cannabis”, along with his colleague Yehiel Gaoni, identified and synthesized the phytocannabinoid- THC.  THC’s notoriety stems from it being the only psychoactive cannabinoid derived from cannabis and THC is intimately associated with its medical and recreational use.  In 1988, University of St. Louis researchers Allyn Howlett and William Devane discovered THC’s primary target- CB1 cannabinoid receptors in the central nervous system. The discovery of CB2 receptors shortly followed being prevalent throughout both the peripheral nervous and immune systems. CB2 receptors are present in the gut, spleen, liver, heart, kidneys, bones, blood vessels, lymph cells, endocrine glands and reproductive organs. In 1992, Mechaloum and Devane discovered the endocannabinoid neurotransmitter “anandamide”- named after the Sanskrit word for “bliss” and, in 1995, the group discovered yet another major endocannabinoid- 2-arachidonoylglycerol, or “2-AG”.   Cannabinoid research and its physiological effects have continued unabated since.

Although CBD’s discovery by Roger Adams at the University of Illinois predates THC by over 20 years, this cannabinoid has only recently garnered widespread interest for its potential health effects and non-psychoactive properties.  Cannabidiol, like all molecules, is defined by its physical structure and exerts the same effect whether it is produced by the human body, plants, or synthetically.  The early CBD market attributes most of its growth to medical use as many countries and healthcare companies are adopting CBD oils to treat medical conditions based upon anecdotal evidence and largely “anti-inflammatory” properties.  CBD is thought to attenuate the effects of THC.

2012. Lee, MA.  “The Discovery of the Endocannabinoid System”::  The Prop 215 Era O’Shaughnessy’s. https://www.beyondthc.com/wp-content/uploads/2012/07/eCBSystemLee.pdf

---

B) Sources of CBD (Hemp, Cannabis, or Synthetic) and the Future Market

Cannabidiol is typically extracted in oil form from either cannabis or hemp.  Cannabis and hemp are very similar to each other.  Both are typically of the Sativa species of the Cannabis Genera and they differ only in the percentage THC that they contain- hemp typically containing <0.3% THC.   

Although the current and future source of CBD (cannabis, hemp, or synthetic) is hotly debated, it would appear that CBD is increasingly being extracted from hemp given its more favourable legal and economic status throughout the world.  Cannabis-derived CBD is largely illegal around the globe and hemp-derived CBD is often considered a nutritional supplement. While the hemp-derived CBD market appears to be the most viable on the wider world stage, this is in opposition to the US experience (at least observed prior to passing of the Dec 2018 US Farm Bill) that demonstrated, where states embraced cannabis-derived CBD, consumers moved toward this option from hemp-derived products.  The current US preference for cannabis-derived CBD may be explained by (a) the only-recent passing of the Dec 2018 US Farm Bill regulating hemp production and (b) the early US use of CBD is likely limited to medical/recreational purposes versus the emerging and likely much larger use of CBD as an ingredient in traditional consumer and over-the-counter products (i.e. food, beverage, animal health, cosmetic etc.)

Estimation of the future size of the CBD market varies widely and, unfortunately, appears limited to projections of the  medical/recreational market.  For example, in 2015, the US market for consumer sales of hemp-derived CBD products was $90 million, plus another $112 million in cannabis-derived 

CBD products that were sold through dispensaries.  In 2016, there were 15 states that allow CBD only -- this is in addition to the 28 states plus DC that have legalized medical cannabis.

In 2017, the CBD industry grew by 40% and hit $367 million in sales. 25,500 acres of land were devoted to growing hemp in 2017. The hemp was grown in 19 states and the majority, 70%, was devoted to CBD.  For the first time, hemp-derived CBD surged ahead of cannabis-derived CBD. New Frontier expects to see continued changes as the pharmaceutical-derived sector officially opens in 2018.  By 2022, hemp-derived CBD, cannabis-derived CBD, and pharmaceutical CBD will account for approximately one-third of the $1.9 billion total market," said Giadha Aguirre de Carcer, CEO of New Frontier Data. The Hemp Business Journal estimated that the CBD market will grow to a $2.1 billion market in consumer sales by 2020 with $450 million of those sales coming from hemp-based sources. Matt Karnes of Greenwave Advisors is even more optimistic about the growth of the CBD market saying, “In terms of the CBD market size, I estimate an almost $3 billion market by 2021

Such figures could dramatically underestimate future demand.  According to cannabis industry analysts The Brightfield Group, the Canadian hemp CBD market could be generating $22 billion a year by 2022. If the latter projection were true, the hemp CBD market would be double the $8-10B recreational and medical cannabis demand in the first year of legalization according to Canadian government estimates. 

2016 Dec 12, Borchardt, D. https://www.forbes.com/sites/debraborchardt/2016/12/12/the-cannabis-market-that-could-grow-700-by-2020/#3c532f9b4be1 
2018 Aug 15, Ross, K. https://www.thestreet.com/markets/cbd-industry-expected-to-hit-2-billion-by-2022-14683940 
2018 May 30, https://www.bmmagazine.co.uk/in-business/how-much-is-the-cbd-oil-industry-worth/

---

C) Differentiating CBD Oil from Hemp Oil or Hemp Seed Oil

CBD oil, hemp oil, and hemp seed oil are related products which can be produced from the Hemp plan, Cannabis Sativa. However, consumers and health professionals are often confused by the differences between the different products.

i) Hemp Oil
Hemp oil is the oil expressed or mechanically pressed or extracted from the hemp plant itself – typically from the flowering heads but also from left over seeds, stems, stalk etc. According to data compiled by Transparency Market Research, the global CBD hemp oil market is projected to grow from USD 950 Million in 2017 to USD 2.5 Billion by 2026. The market is also expected to grow at a CAGR of 11%

ii) Hemp Seed Oil
Hemp Seed Oil is the food or industrial product mechanically pressed or extracted from seeds of the hemp plant. The oil is extracted, typically mechanically to produce a clear golden oil with a nutty flavour and highly regarded fatty acid profile.

iii) CBD Oil – Concentrated CBD through Extraction and Distillation
CBD oil is hemp oil rich in CBD. Most hemp has low levels of cannabinoids and terpenes, often less than 5% along with many other impurities. Therefore, in order to obtain CBD, large volumes of hemp must be processed through an extraction process.  The best varieties of high CBD hemp have higher CBD content (10% to 15% CBD), with rich terpene profiles. These are the best choice for hemp oil extraction and will produce an oil with 50% to 80% CBD after extraction.

The oil may be further refined by distillation to produce a high CBD distillate containing 75% to 95% CBD.
While most CBD oil in North America is currently derived from high CBD medicinal cannabis, in Europe most CBD oil is produced from industrial hemp with low CBD levels as a byproduct of medical cannabis production.

2018 Sep 29, McMillan. https://rhizosciences.co/cbd-oil-vs-hemp-oil-vs-hemp-seed-oil-whats-the-difference/

---

D) CBD Oil Production- Extraction followed by Distillation

CBD is concentrated in oil by two successive processes:

1. an Extraction process that produces refined oil from the dried plant followed by  
2. a Distillation process that feeds the refined oil into a heated system under a vacuum.   A distillate of the desired compound, in this case- CBD, results.  Several passes of the distillation process may be required to improve purity of the CBD concentrate.

Definitions:
An extract is considered “a preparation containing the active ingredient of a substance in concentrated form”
A distillate is simply an oil produced by distillation.  Distillation is the “act of purifying a liquid through successive evaporation and condensation”.

In the Extraction Process, the purity of an oil is dependent upon the extent of its refinement

The purity of an oil extract falls on a spectrum between ‘crude’ whole-plant extractions and higher-purity refined oils.  The difference between the ‘crude’ extract and a refined one is that the crude extract contains a mix of fats, waxes, terpenes and other plant chemicals in addition to the desired cannabinoids. This is akin to the difference between crude petroleum and gasoline. Crude petroleum is extracted from the ground, containing hundreds of different chemicals. This crude petrol then must go through a refining process to eliminate unwanted chemicals to produce the more usable gasoline. A similar process must be conducted on Hemp and Cannabis extracts. The initial product that will be produced contains a lot of extraneous material that needs to be removed to get to the much more usable refined CBD Oil, which can be used as a raw material to produce products.

Extracts of any given purity can then be diluted using a ‘carrier oil’  (i.e. sunflower oil) to form a consumable product.   Typically, carrier oils dilute the refined oil in a ratio between 5:1 and 10:1.  This is similar to how water is used to dilute alcohol.

CBD Distillation to produce a CBD isolate 
Taking the refining process a step further, the individual chemical compounds of an oil can be separated to produce a highly refined ‘isolate’ – an oil consisting almost entirely of CBD (97.0%+ purity) which can then be powderized through an encapsulation process. This powderized CBD is an ideal form of CBD for inclusion into pharmaceuticals, natural health products and other tightly controlled dosage forms due to the high purity and lack of extraneous, non-CBD impurities.  CBD isolate powder will be an optimal form for use in products, due to the specificity and purity of the material, as well as the ability to modify it’s chemical and physical characteristics to enhance stability, shelf-life, efficacy as well as water- solubility. 

---

E) CBD Use- Medical Evidence 

The rise in popularity of CBD Oil for sale has gone hand in hand with anecdotal accounts and some research evidence that it may well have a beneficial impact on a variety of health conditions. That includes helping to reduce pain, stop seizures for epileptics, and generally improving health and wellbeing.  

A 2017 Review of the Health Effects of Cannabis by the US National Academies of Science, Engineering, and Medicine determined that there is sufficient and conclusive evidence to suggest cannabis is of benefit in chronic pain, as an anti-emetic in chemotherapy, and to address spasticity associated with multiple sclerosis.  The report indicates that other disease states may hold promise such as glaucoma, anxiety, depression, PTSD, epilepsy, and movement disorders like Parkinson’s, Huntingdon, and dystonia, but, to date, there remains insufficient evidence to draw conclusions.  The report suggests the need for understanding and improvement in quality research, health policy and economics, public health and safety, surveillance capacity, and to address historical research barriers like access to quality cannabis and funding.  It is only a matter of time before research confirms or refutes anecdotal reports of benefit and patients, consumers, industry, and governments stand to benefit.

A 2018 review by the WHO demonstrated that “For most indications, there is only pre-clinical evidence, while for some there is a combination of pre-clinical and limited clinical evidence.  The range of conditions for which CBD has been assessed is diverse, consistent with its neuroprotective, antiepileptic, hypoxia-ischemia, anxiolytic, antipsychotic, analgesic, anti-inflammatory, anti-asthmatic, and antitumor properties.” 

CBD has been touted for a wide variety of health issues, but the strongest scientific evidence is for its effectiveness in treating severe childhood epilepsy syndromes, such as Dravet syndrome and Lennox-Gastaut syndrome (LGS), which typically don’t respond to antiseizure medications. In numerous studies, CBD was able to reduce the number of seizures, and in some cases it was able to stop them altogether. Videos of the effects of CBD on these children and their seizures are readily available on the Internet for viewing, and they are quite striking. Recently the FDA approved the first ever cannabis-derived medicine for these conditions, Epidiolex, which contains CBD.

CBD is commonly used to address anxiety, and for patients who suffer through the misery of insomnia, studies suggest that CBD may help with both falling asleep and staying asleep.

CBD may offer an option for treating different types of chronic pain. A study from the European Journal of Pain showed, using an animal model, CBD applied on the skin could help lower pain and inflammation due to arthritis. Another study demonstrated the mechanism by which CBD inhibits inflammatory and neuropathic pain, two of the most difficult types of chronic pain to treat. More study in humans is needed in this area to substantiate the claims of CBD proponents about pain control.

Safety
CBD is non-psychoactive, safe, and well tolerated.  Well-controlled human studies show no evidence of abuse, dependence.  Side effects of CBD include nausea, fatigue and irritability. CBD can increase the level in your blood of the blood thinner coumadin, and it can raise levels of certain other medications in your blood by the exact same mechanism that grapefruit juice does. A significant safety concern with CBD is that it is primarily marketed and sold as a supplement, not a medication. Currently, the FDA does not regulate the safety and purity of dietary supplements. So you cannot know for sure that the product you buy has active ingredients at the dose listed on the label. In addition, the product may contain other (unknown) elements. We also don’t know the most effective therapeutic dose of CBD for any particular medical condition.

2017 https://www.nap.edu/catalog/24625/the-health-effects-of-cannabis-and-cannabinoids-the-current-state 
2018 Jun, WHO CBD Critical Report, https://www.who.int/medicines/access/controlled-substances/CannabidiolCriticalReview.pdf 
2018 Aug 24, Grinspoon.  https://www.health.harvard.edu/blog/cannabidiol-cbd-what-we-know-and-what-we-dont-2018082414476

---

F) CBD Use in Other Industries
Cannabis producers have recognized that CBD may serve as ingredients in all types of industries- food, beverage, cosmetics, animal health, medicine, pharmacy- in several delivery forms.  

As the first G7 nation to legalize cannabis, Canada is a bellwether market for the future use of cannabis.  Numerous supply contracts have already been signed by traditional industry.  Constellation Brands, the owner of Corona Beer, was the first to enter the cannabis market with a 10% stake in and partnership with Canopy Growth Inc.  Says Chris Burrgraeve, former chief marketing officer for Anheuser-Busch InBev NV, the brewer of Budweiser beer, “Ignore it (cannabis) at your peril”.   To date, Weston Foods’ subsidiary Shoppers Drug Mart, the largest pharmacy chain in Canada, has established long-term contracts with 4 licensed producers.  Provincial government wholesalers are quickly securing supply in advance of recreational cannabis legalization. Most recently, Novartis Pharmaceutical’s generic subsidiary, Sandoz, has partnered with BC licensed producer Tilray.   Anecdotally, pet owners are using cannabis to treat their pets for a host of conditions.  Health Canada has indeed met with the Canadian Veterinary 

Medicine Association and there now exists a Canadian Association of Veterinary Cannabinoid Medicine.  It is not difficult to imagine forthcoming announcements from other food, cosmetics, and animal health companies.

CBD oil usage is also growing in the beauty and wellness industry. According to a research published by Cutis, CBD is being used to treat skin disorders such as atopic dermatitis, psoriasis and acne. Claudia Mata, Co-Founder of Vertly, says that CBD is beneficial due to its anti-inflammatory properties, vitamins A, D, and E, and essential fatty acids it makes it a popular product within the beauty and wellness market

According to Headset Research data, in Washington state alone there are over 800 CBD products in the marketplace. This makes it difficult for consumers to know what is what when they are trying to buy CBD products. In addition, CBD products, although suggested to improve a variety of health problems, can't actually make those claims. So most labels on these products are intentionally light on details and this can make it pretty difficult for a shopper to know what to buy.

2016 Dec 12, Borchardt, D. https://www.forbes.com/sites/debraborchardt/2016/12/12/the-cannabis-market-that-could-grow-700-by-2020/#3c532f9b4be1 
2018 Jun, WHO CBD Critical Report  https://www.who.int/medicines/access/controlled-substances/CannabidiolCriticalReview.pdf 
2018 Dec 17, https://www.prnewswire.com/news-releases/data-projects-the-global-cbd-based-oil-market-will-continue-its-growth-852730975.html