Synthetic cannabinoids drug profile Synthetic cannabinoids are functionally similar to Δ 9 -tetrahydrocannabinol (THC), the active principle of cannabis. Like THC, they bind to the same CBD can be either natural or synthetic. Here's the difference between the two types and why it matters. 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 cannabinoids drug profile
Synthetic cannabinoids are functionally similar to Δ 9 -tetrahydrocannabinol (THC), the active principle of cannabis. Like THC, they bind to the same cannabinoid receptors in the brain and other organs as the endogenous ligand anandamide. More correctly designated as cannabinoid receptor agonists, they were initially developed over the past 40 years as therapeutic agents, often for the treatment of pain. However, it proved difficult to separate the desired properties from unwanted psychoactive effects.
In late 2008, several cannabinoids were detected in herbal smoking mixtures or so-called incense/room odorisers. Typical of these were Spice Gold, Spice Silver and Yucatan Fire, but many other products later appeared. They do not contain tobacco or cannabis but when smoked, produce effects similar to those of cannabis. These products are typically sold via the Internet and in ‘head shops’.
Although often referred to simply as synthetic cannabinoids, many of the substances are not structurally related to the so-called ‘classical’ cannabinoids, i.e. compounds, like THC, based on dibenzopyran. The cannabinoid receptor agonists form a diverse group, but most are lipid soluble and non-polar, and consist of 22 to 26 carbon atoms; they would therefore be expected to volatilize readily when smoked. A common structural feature is a side-chain, where optimal activity requires more than four and up to nine saturated carbon atoms. The first figure shows the structure of THC, while the others show examples of synthetic cannabinoid receptor agonists, all of which have been found in ‘Spice’ or other smoking mixtures. The synthetic cannabinoids fall into seven major structural groups:
- Naphthoylindoles (e.g. JWH-018, JWH-073 and JWH-398).
- Phenylacetylindoles (i.e. benzoylindoles, e.g. JWH-250).
- Cyclohexylphenols (e.g. CP 47,497 and homologues of CP 47,497).
- Classical cannabinoids (e.g. HU-210).
Other cannabinoid receptor agonists include substances such as oleamide — an endogenous substance that is also used in plastics manufacture — and methanandamide, both of which are structurally related to anandamide. However, the cannabinoid activity of these has been questioned. It is thought that neither methanandamide nor other arachidonyl derivatives related to anandamide would be sufficiently volatile to be smoked. Certain fluorosulfonates exhibit agonist activity at cannabinoid receptors, as does naphthalen-1-yl-(4-pentyloxynaphthalen-1-yl)methanone, but the latter appears not to be psychoactive, at least when administered orally.
Structure of selected synthetic cannabinoids found in ‘Spice’ products, with high affinity for cannabinoid (CB1) receptors
Molecular structure: Δ 9 -THC
Molecular formula: C21H30O2
Molecular weight: 314.4 g/mol
Molecular structure: HU-210
Molecular formula: C25H38O3
Molecular weight: 386.6 g/mol
Molecular structure: CP 47,497
Molecular formula: C21H34O2
Molecular weight: 318.5 g/mol
Molecular structure: JWH-018
Molecular formula: C24H23NO
Molecular weight: 341.5 g/mol
Molecular structure: JWH-250
Molecular formula: C22H25NO2
Molecular weight: 335.4 g/mol
In the pure state, these substances are either solids or oils. Smoking mixtures are usually sold in metal-foil sachets, typically containing 3 g of dried vegetable matter to which one or more of the cannabinoids have been added. Presumably, a solution of the cannabinoids has been sprayed onto the herbal mixture. A number of plants are often listed on the packaging, but it appears that many are not present. However, large amounts of tocopherol (Vitamin E) have been detected, possibly to mask analysis of the active cannabinoids. The presence of several cannabinoids in some samples may also be intended to confound forensic-chemical detection.
The cannabinoid receptor agonists mimic the effects of THC and anandamide by interacting with the CB1 receptor in the brain. In vitro studies have shown that some synthetic compounds bind more strongly to this receptor than THC as measured by the affinity constant Ki. All of the cannabinoids found in smoking mixtures have, like THC (Ki = 10.2nM), high affinity to the CB1 receptor although small variations in Ki values occur between different publications. The substance HU-210 has a particularly low value of Ki (0.06nM), and it binds over 100 times more tightly to the CB1 receptor than THC.
However, little is known about the detailed pharmacology and toxicology of the synthetic cannabinoids and few formal human studies have been published. It is possible that, apart from high potency, some cannabinoids could have particularly long half-lives potentially leading to a prolonged psychoactive effect. In addition, there could be considerable inter-and intra-batch variability in smoking mixtures, both in terms of substances present and their quantity. Thus, there is a higher potential for overdose than with cannabis.
Synthesis and precursors
Some cannabinoids are commercially available. Synthetic methods for many others have been published, while the precursor chemicals can often be purchased from retail chemical suppliers. However, synthesis of the naphthoylindoles from available starting materials requires many stages, whereas the preparation of dibenzopyrans is further complicated by the need to isolate the desired enantiomer from the racemic mixture.
Mode of use
Like cannabis, the herbal mixtures containing cannabinoids are most often smoked. However, some user reports also suggest that ‘Spice’ can be ingested as an infusion.
Herbal products containing synthetic cannabinoids have included Spice Gold, Spice Silver, Spice Diamond, Yucatan Fire, Sence, Chill X, Smoke, Genie, Algerian Blend and many others. These products may already be obsolete, since the Internet market is rapidly evolving; the synthetic cannabinoids used in the preparations are also being continuously substituted by ‘legal’ alternatives, in pace with new control measures.
The cannabinoids are readily resolved using gas chromatography, but their identification and quantitative analysis is limited by the availability of pure reference samples. No field tests are known that will detect the majority of synthetic cannabinoids. Methods for the forensic analysis of blood samples for the recent intake detection of synthetic cannabinoids are available in some laboratories. However, the detection of metabolites in urine samples is not yet fully developed.
Few quantitative studies have been carried out to determine the amount of synthetic cannabinoids present in smoking mixtures. Because of the difficulty in making a homogeneous mixture of dried vegetable matter and small quantities of synthetic additives, it is likely that there could be considerable inter-batch differences in the concentration of cannabinoids.
None of the synthetic cannabinoids is under international control by virtue of the UN drug control conventions, but JWH-018, JWH-073, HU-210, and CP 47,497 (together with its C6, C8 and C9 homologues) are scheduled drugs in some Member States.
The following countries control ‘Spice’ and/or other synthetic cannabinoids: Denmark, Germany, Estonia, France, Ireland, Italy, Latvia, Lithuania, Luxembourg, Austria, Poland, Romania, Sweden and UK.
In Poland, JWH-018 and some of the claimed constituents of ‘Spice’ are controlled substances. In Germany, a fast-track regulation controls JWH-018 and CP 47,497. In Austria, Estonia and France, JWH-018, HU-210, and CP 47,497 are scheduled drugs; in addition to those, in Sweden and Lithuania JWH-073 is also classified as a narcotic. Luxembourg seems to have adopted an analogue approach by referring to ‘synthetic agonists of cannabinoid receptors’. The UK has adopted generic definitions and is expected to introduce control measures for a wide range of synthetic cannabinoids. Other Member Sates are also considering control measures.
Little is known about the extent to which smoking mixtures containing synthetic cannabinoids have replaced cannabis.
However, a 2009 survey conducted among 1 463 students aged between 15 and 18 years at schools providing general and vocational training in Frankfurt found that around 6 % of respondents reported having used ‘Spice’ at least once.
Sachets of smoking mixtures (3 g), sufficient for around eight joints, can be purchased for EUR 26 to 30 from Internet sites or specialist shops.
Apart from THC (dronabinol), the only synthetic cannabinoid receptor agonist to have found clinical use is nabilone — a derivative of THC and constituent of the proprietary preparation Cesamet®; it finds limited use for the treatment of nausea in cancer chemotherapy.
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Natural vs. Synthetic CBD: What’s the Difference?
The rise in the popularity of CBD brings an increase in various CBD products that individuals can take.
It can be confusing to distinguish the difference between natural and synthetic CBD. Read on to find out more about the difference between the two and the benefits of each type.
What Is CBD?
Cannabidiol (CBD) is a naturally occurring compound found in cannabis. While cannabis contains around over 100 different cannabinoids, like tetrahydrocannabinol (THC), and minor cannabinoids, like CBN and CBG, CBD is probably the most well known.
Each cannabinoid has its own features, therapeutic properties, chemical structure, and benefits. CBD is well-known for its versatility and well-tolerated nature, and because of this, it is often isolated and made into CBD-based oils, tinctures, topical creams, and edibles.
All cannabinoids interact with the endocannabinoid system (ECS) to produce therapeutic effects. CBD is no different. The ECS is a complex cell signalling system found within all mammals that consist of endocannabinoids and receptors. These receptors are on the brain, on body tissues, and within the nervous system. The ECS is responsible for regulating many body processes, so when CBD interacts with these receptors, effects are experienced.
What Is Natural CBD?
Before being included in a product, different forms of CBD must go through a specific process of manufacturing and refinement. Natural CBD comes from the cannabis plant (either hemp or marijuana) and is extracted in one of a number of different ways, including ethanol, oil, or CO2 extraction. After the CBD has been successfully extracted, additional processing can be done.
With most extraction methods other cannabinoids are present in the initial extract – these may be retained (full spectrum), selectively removed (broad spectrum) or totally removed (isolate) to produce different forms of CBD suitable for different uses.
Natural forms of CBD can provide wide-ranging benefits that span our mental and physical health.
Chronic pain is one of the most popular reasons for CBD use. CBD not only changes how the brain perceives pain throughout the body but can also decrease inflammation levels. During high inflammation levels, swelling can push against nerve endings, which send pain signals to the brain. CBD has long been associated with its anti-inflammatory properties .
CBD can also interact with receptors in your brain and nervous system to decrease pain perception . Because of this, CBD has emerged as an effective natural alternative to traditional painkillers without any of the nasty side effects.
CBD has emerged as a possible treatment to decrease symptoms of insomnia and sleeplessness. As mentioned earlier, CBD can interact with the ECS and receptors in the brain to promote calm feelings, slow a racing heartbeat, and even slightly decrease blood pressure. All of this can reduce stress and therefore encourage sleep .
CBD can interact with the ECS receptors in the brain and nervous system to promote relaxation . This also comes without adverse side effects often seen in traditional medication.
Anxiety and depression often walk hand in hand. While CBD itself doesn’t directly increase serotonin levels in the body, it can also interact with serotonin receptors to improve serotonin uptake and expression. This means more of the happy hormone, resulting in elevated mood levels, which can improve focus and concentration.
What Is Synthetic CBD?
While natural CBD is produced from hemp or cannabis plants, synthetic varieties of CBD are produced either by chemical synthesis using ingredients like limonene, or by biological synthesis using modified yeast or other bacteria.
High-quality synthetic CBD and natural CBD are considered to be chemically identical to each other, with studies confirming that both types of CBD have identical chemical structures. Synthetic CBD is an appealing alternative for industries requiring strict legal regulations and requirements, like the cosmetic industry. While natural CBD is popular amongst users for its wide-ranging effects, the production of synthetic CBD is a valuable asset for a wide range of consumer applications requiring high yield and consistency.
Natural vs. Synthetic CBD
Natural and synthetic cannabinoids, including CBD, are not very different from each other. However, there are some key differences .
Generally, synthetic CBD is produced to contain more specific yielding pure CBD molecules, while natural CBD extracts often come with other naturally occurring compounds, like cannabinoids, terpenes, and flavonoids.
Because of their composition, which includes other compounds, cannabinoids and terpenes can also bind to one or more cannabinoid receptors. This can therefore alter the therapeutic effect of natural CBD.
Regarding their affinity, synthetic CBD is often designed to have a high affinity for receptors, resulting in lasting effects. In comparison, natural CBD is considered to be more gentle, with a moderate affinity for receptors. This affinity can also be short-lasting and overpowered by other compounds or modulators.
Finally, natural CBD is a popular option as the other naturally occurring compounds can work together to create the entourage effect . This phenomenon amplifies the effects of the individual compounds to create a potent experience for the user.
The Bottom Line
Both natural and synthetic CBD provide therapeutic effects for the user and can be purchased for use in many countries.
Choosing high-quality CBD products from a reputable company is essential, and checking in with your health professional before starting use is recommended.
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.
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.
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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