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The non-psychoactive component of Cannabis Sativa, cannabidiol (CBD), has centered the attention of a large body of research in the last years. Recent clinical trials have led to the FDA approval of CBD for the treatment of children with drug-resistant epilepsy. Even though it is not yet in clinical … As the industry matures and as increasingly savvy consumers begin to demand higher quality at a lower cost, the future of cannabinoid manufacture lies not in natural plants but in chemical synthesis

Synthetic and Natural Derivatives of Cannabidiol

The non-psychoactive component of Cannabis Sativa, cannabidiol (CBD), has centered the attention of a large body of research in the last years. Recent clinical trials have led to the FDA approval of CBD for the treatment of children with drug-resistant epilepsy. Even though it is not yet in clinical phases, its use in sleep-wake pathological alterations has been widely demonstrated.Despite the outstanding current knowledge on CBD therapeutic effects in numerous in vitro and in vivo disease models, diverse questions still arise from its molecular pharmacology. CBD has been shown to modulate a wide variety of targets including the cannabinoid receptors, orphan GPCRs such as GPR55 and GPR18, serotonin, adenosine, and opioid receptors as well as ligand-gated ion channels among others. Its pharmacology is rather puzzling and needs to be further explored in the disease context.Also, the metabolism and interactions of this phytocannabinoid with other commercialized drugs need to be further considered to elucidate its clinical potential for the treatment of specific pathologies.Besides CBD, natural and synthetic derivatives of this chemotype have also been reported exhibiting diverse functional profiles and providing a deeper understanding of the potential of this scaffold.In this chapter, we analyze the knowledge gained so far on CBD and its analogs specially focusing on its molecular targets and metabolic implications. Phytogenic and synthetic CBD derivatives may provide novel approaches to improve the therapeutic prospects offered by this promising chemotype.

Keywords: Cannabidiol; Cannabidiol analog; Cannabidiol derivative; Cannabinoid; Sleep; Synthetic cannabidiol.

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What’s the Deal with Synthetic CBD?

As scientists, you’ll likely be aware that your morning vitamin C tablet does not originate from a lemon grove on some sunny Sicilian hillside. But what about consumers? Do they know that their “natural” supplements come from a chemical plant and not an actual plant? And, if it’s efficacious, safe, and cheap, do they care? The industrialized reality is that many naturally-occurring chemical compounds, including ascorbic acid, can be produced far more efficiently (and at potentially lower cost) than their natural equivalents.

And few (naturally-occurring) compounds have generated as much interest – or shown as much therapeutic promise – as the cannabinoid CBD. So it should come as no surprise that CBD is the next “supplement” set to be overtaken by a synthetic revolution.

Some surveys estimate that one in three people in the US have tried CBD and up to six million people in the UK are self-medicating with CBD products to help with diverse problems, including anxiety, insomnia. and chronic pain. And yet the quality and content of cannabis-based products are often unknown – and some products are even illegal or potentially dangerous. Why? Because plant-derived products are impure by their very nature, containing contaminants, such as pesticides, and other (unwanted) cannabinoids, such as THC, and even unnatural cannabinoid degradents, depending on the extraction process.

Growing Cannabis at scale is more an agricultural than a scientific endeavor; small environmental variations can lead to large differences in plant quality, purity, and cannabinoid yield – this is not news to the industry. Cannabis is also particularly effective at absorbing lead, cadmium, and nickel from the soil, which is great for environmental remediation, but certainly not when it comes to selling food and cosmetic products.

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Synthesis is currently the only way to meet strict (albeit unenforced) European requirements on cosmetics ingredients (which do not permit origin material that is illegal in any member state) or to meet specific institutional requirements, such as those from the World Anti-Doping Agency (which prohibits all cannabinoids except CBD, in any amount).

Referred as bio-identical or nature identical, depending on the market, synthetic CBD is now the dominant base material against which naturally occurring CBD purity is tested.

Following these trends, and as quality and safety regulations for the CBD industry are further developed and implemented for the consumer market, synthetic CBD is becoming an increasingly appealing alternative. I’d like to reiterate an important point: high-quality synthetic CBD is chemically identical to naturally-occurring CBD. Referred as bio-identical or nature identical, depending on the market, synthetic CBD is now the dominant base material against which naturally occurring CBD purity is tested.

Why the need for reiteration? Unfortunately, synthetic cannabinoids have garnered a great deal of bad press thanks to synthetic analogues (think: “spice”!) that act upon the same receptor but do not occur in nature. Thankfully, (known) cannabinoid analogues are illegal, but their existence has given the synthetic CBD sector somewhat of a marketing headache.

But where does synthetic CBD come from? Well, in the case of biotechnology company PureForm Global, the starting base material is actually a citrus terpene, while high-flying Cellular Goods are touting future commercialization of CBD via a biosynthetic route (a form of fermentation).

Though pathways in CBD synthesis vary and other cannabinoids (including THC) can be accidentally produced, a number of manufacturers are now producing CBD without any detectable unwanted cannabinoids. Such purity is better for consumers (especially those subject to professional testing) and for formulators, who can put greater amounts of CBD in products without risk of exceeding the assumed limit of 1 mg per container.

For many people, words like “plant/herbal extract” and “natural origin” sound better or safer – for humans and the environment – than “chemical synthesis.” But the synthetic route – at least for CBD – actually uses fewer chemicals than solvent and gas extraction, making it more eco friendly. There is also no need for fertilizers or pesticides – and thus no risk of residues. And there is no risk of dangerous, potentially cancer causing mycotoxins, which is an ongoing challenge for cannabis growers everywhere. All good for humans. In addition to being purer, each batch is consistent, free from pesticides, and traceable.

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Right now, despite the advantages of synthetic CBD, the vast majority of products contain plant-derived CBD – and, especially for those stated to be “broad spectrum,” these are highly likely to contain THC in trace or greater amounts (not to mention the other known and unknown impurities). In my view, if we’re thinking about CBD as a health and wellness product, this needs to change.

My view is clearly shared by the EU, who have already rejected multiple Novel Food applications from hemp growers (the application deadline for CBD brands looking to gain Novel Food certification was March 31, 2021). And though products with an application submitted were allowed to remain on sale from April 1, who knows how many of these products will meet the Food Standard Authority’s (FSA) strict requirements? It is Biosportart’s view that synthetic producers of CBD that follow clear manufacturing and testing protocols, such as PureForm Global, have a serious upper hand when it comes to achieving full Novel Food status from the FSA.

As we begin to understand the benefits and side effects of individual cannabinoids, the industry must evolve and mature.

Don’t get me wrong, Cannabis sativa is an amazing plant. It has co-evolved with mammals for millions of years and contains a whole suite of interesting, interacting chemicals – the full potential of which we are just beginning to understand. Indeed, we are only now emerging from what could be described as the “dark ages” of Cannabis; for so many years, social stigma and a strict legal environment have prevented the plant’s incredible benefits from being extracted, researched, and applied.

But as we begin to understand the benefits and side effects of individual cannabinoids, the industry must evolve and mature. In my view, CBD synthesis solves many challenges and provides the means to achieve purity, consistency, and yields at a scale that allows adoption of CBD for a wider variety of consumer and medical applications, unlocking just one beneficial aspect of this incredible plant.

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