What the Cannabis Industry Needs to Know About Novel Synthetic Cannabinoids
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Delta-8-THC does occur naturally in cannabis, but only in trace levels. To get substantial quantities of the compound, it must be synthesized via a semi-synthetic isomerization process from cheap and readily available CBD.
But such synthetic processes pose a number of important questions for the industry. Firstly, is this process legal? And, if so, is the process safe?
This is exactly what Chris Hudalla, president and chief scientific officer at ProVerde Laboratories, explored in his latest webinar for Analytical Cannabis, “Changing potency landscapes: Emergence of synthetic cannabinoids”.
Hudalla discussed the reaction pathways used in these synthetic processes, highlighted the complexity of analyzing the resultant synthetic product mixtures, and discussed how these synthetic cannabinoids are already impacting the commercial landscape.
Semi-synthetic cannabinoids: a legal gray area
The Agricultural Improvement Act of 2018, also known as the Farm Bill, effectively legalized the production of industrial hemp as well as “any part of that plant, including the seeds thereof and all derivatives, extracts, cannabinoids, isomers, acids, salts, and salts of isomers” so long as the total THC content of the plant is less than 0.3% by dry weight.
Whether it was the intent of the lawmakers or not, the inclusion of the words “derivatives” and “isomers” has so-far allowed some in the cannabis industry to increase their scope and begin producing semi-synthetically derived products, such as delta-8 THC.
Delta-8 THC has become a popular trend recently as the cannabinoid is moderately intoxicating but exists in this legal gray area.
“The industry thought process is that hemp is legal under the Farm Bill, [so] CBD extracted from hemp is natural and, therefore, legal; trace levels of delta-8 THC have been observed in [hemp] biomass and, therefore, is a natural product. And since delta-8 is naturally occurring, a derivative pathway from CBD [to delta-8 THC] for production should be illegal,” Hudalla said.
“The problem with that thought process is that conversion of CBD into delta-8 THC is not a natural process,” he continues. “Many isomers are formed that are not naturally occurring. And so there are both legal and consumer safety issues that arise from some of these unknown isomers and contaminants.”
What risks might synthetic cannabinoids pose?
The FDA and CDC have both issued warnings to consumers and retailers on the potential dangers of delta-8 THC products.
“In each of these regulatory statements, it’s clear that the delta-8 is not necessarily the culprit of concern,” Hudalla said. “It’s more the production in an unregulated environment, and the fact that these contaminants exist that very little information is available for.”
The latest FDA release reminds consumers that delta-8 THC products have not been approved or evaluated by the FDA for safe use. Additionally, the FDA highlights that the making of these products can involve the use of harmful chemicals, with the potential for other compounds of unknown safety to be generated during the synthetic process.
“These products are produced without regulatory oversight. In the process, many identified contaminants are observed in these products, and no efficacy or toxicity information is available for most of these contaminants,” Hudalla said. “The CDC has recorded over 600 adverse events associated with these products.”
Delta-8 THC and other minor cannabinoids are produced by the cannabis plant in a very selective manner. However, in a synthetic process, it becomes much harder to control the stereochemistry of the compounds being produced. As a result, the synthetic/semi-synthetic production of delta-8 THC and other minor cannabinoids opens the door to lesser-known isomers also being made.
To understand the potential dangers of this uncontrolled stereochemistry, Hudalla points to the thalidomide disaster of the 1950s and 60s. Thalidomide was a drug used widely for treating nausea during pregnancy. But the drug had an enantiomer that could cause birth defects. Thalidomide was quickly taken off of the market once these health risks were realized. The thalidomide story has since become an important lesson in the importance of evaluating isomers and enantiomers in drug development.
Synthetic cannabinoids can be challenging to analyze
There are around 30 unique THC isomers, most of which do not exist in nature and have not been studied for safety. There are also many THC-like compounds that vary in terms of their carbon “tail” length, and these can each have distinct properties. For example, delta-9 tetrahydrocannabiphorol (THCP), which features a heptyl chain in place of delta-9 THC’s usual pentyl chain, is approximately 30 times more active than delta-9 THC when comparing binding activities.
Possible products of the CBD to THC conversion. (Source: Chris Hudalla/ProVerde Laboratories).
As Hudalla highlights, it is important to consider all these possibilities for synthetic or semi-synthetic processes, such as converting CBD into delta-8 THC.
But this can be difficult when it comes to analysis. Chromatography techniques are the standard in many cannabis analysis laboratories, but these compounds will have similar retention times to delta-9 THC and so their signals may be obscured by larger peaks.
“To help us identify some of these [compounds], or at least pull these [chromatogram peaks] apart, we started a collaboration with Waters Corporation using cyclic ion mobility mass spectrometry,” Hudalla said.
“It’s like a traditional time-of-flight chromatographic system, with the exception that in the middle there is a ring or a ‘racetrack’ in which the ions that are created are diverted to go around that racetrack. During that trip around the racetrack, depending on the speed, which is based on ion mobility, these ions can separate further almost into a second dimension.”
Currently, most labs are not focused on such complex synthetic mixtures, and so when delta-8 THC products or products with similar synthetic origins arrive for testing, it is likely that they are simply not being detected and reported. This is something that more attention and increased regulatory oversight could address, so that certificates of analysis are not inadvertently inaccurate by omission.
Tackling misinformation in the industry
Synthetic and semi-synthetic cannabinoid products have already hit the open market. Analysis by ProVerde Laboratories has found mixtures of synthetic cannabinoids – including hexahydrocannabinol (HHC), hexahydrocannabiphorol (HHCP), and delta-8 THCP – in gummies and vape cartridges sold online.
As an example, Hudalla shows a product claiming to be “100% organic” gummies, containing more than 3000 milligrams of delta-8 THC per package.
“Delta-8 THC only occurs in trace levels in cannabis. It would actually require approximately 55,000 kilos of hemp biomass to produce one kilo of natural delta-8 THC extract,” Hudalla explained.
“If we do a little bit of math on that $400 per kilo for the biomass, the raw plant material alone would be about $22 million to produce that kilo of delta-8 extract. So if somebody’s telling you that they’re selling you natural delta-8, I would be a little bit skeptical.”
It is also possible to find cannabis flower being sold on the market that is marketed as belonging to some special high delta-8 THC strain. Such products are frequently just regular cannabis flower that has been sprayed with a diluted delta-8 THC extract, Hudalla said, and so it comes with the same questionable safety risks.
Transparency and accurate labeling is critically important in the cannabis industry; consumers deserve to know what they are putting in their bodies. But through deliberately misleading product marketing and/or unsatisfactory testing methods that are not designed to handle these complex synthetic products, this is currently not guaranteed.
“Currently these synthetic products are synthesized in a completely unregulated environment, giving rise to multiple contaminants of concern. Many of these contaminants have not been identified and most laboratories ignore their presence, making most laboratory COAs unreliable when it comes to these synthetics,” Hudalla said. “More research is absolutely required to understand these products and those potential contaminants.”