Science for product makers: How hemp cannabinoids are produced

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As hemp beverages gain more exposure to the mainstream marketplace, discussion about the origin of hemp cannabinoids is taking center stage among distributors, regulators and brands. It seems necessary to educate and align the community on:

1. The number of ways hemp cannabinoids are currently produced
2. How each hemp cannabinoid is produced
3. Why each production method is chosen for each hemp cannabinoid

There are two main categories of methods to produce hemp cannabinoids: naturally extracted and chemically modified. While the hemp plant naturally expresses over 100 cannabinoids, only a few can be extracted based on the high level of expressions by certain hemp cultivars. On the other hand, most of the rare cannabinoids are only expressed in trace amounts by the hemp plant, which makes it economically challenging to obtain through natural extraction. This is where chemical modifications come in.

Chemical modification includes three main methods: chemical conversion, chemical synthesis and bio-synthesis. Below are the definitions of each method and consideration behind why they are deployed:

1. If the target cannabinoid can be chemically converted from another cannabinoid, which was extracted from a hemp plant, then chemical conversion may be a viable production method. Its success depends a lot on the yield ratio between target cannabinoid vs reaction by-products. Excessive purification may be needed to reach high purity of target cannabinoid. Examples here are CBN, D8-THC and D9-THC, which can all be chemically converted from hemp extracted CBD isolate.
2. In some situations, it can be challenging to obtain the first base cannabinoid from hemp extraction. For example, THCv can be converted from CBDv in theory. However, it is uncommon to obtain high purity CBDv from hemp extraction, this is why most of the THCv was chemically synthesized from other food grade molecules. In some other situations — CBC, for example — there is not a viable path to chemically convert any cannabinoid to the target cannabinoid. This is why CBC is mostly chemically synthesized from other molecules.
3. If the target cannabinoid can be produced by bio-organisms, such as yeast, under certain fermentation conditions, then it can be bio-synthesized. This path is valid at a small scale, but we have yet to see its commercialization. The main reason is the high cost associated with the scaling up.
4. Another important factor is crystallization, which is when the same target molecules aggregate with each other and fall out of solution. Some cannabinoids (CBD, CBG and CBN) can be crystallized, which makes it easier to obtain high purity isolates, sometimes over 98% purity. Other cannabinoids (CBC, D8-THC, D9-THC and THCv) can not be crystallized, which leads to distillation to obtain relatively high purity (85-95%). The graph below illustrates the major production routes.
   

Now, let’s take a look at the 9 most applied hemp cannabinoids, how they are produced currently, and the reasons behind their production methods.

CBD & CBG (naturally extracted)

Certain hemp cultivars express high amounts of CBDa and CBGa, which can both be crystallized. Those features make it relatively easy to obtain CBD and CBG isolates from natural extraction at high purity. It is not uncommon to see CBD and CBG isolates at purity above 98%.

CBN (chemically converted)

Currently, CBN cannot be expressed by any cultivars at a high enough concentration to justify natural extraction. However, it can be chemically converted from CBD. There are potential by-products from the conversion, but due to CBN’s crystallization nature, high purity CBN isolate can be efficiently purified from those byproducts. This is why its price is reasonable for many brands.

CBC (chemically synthesized)

Currently, CBC cannot be expressed by any cultivars at a high enough concentration to justify natural extraction — and it isn’t easy to convert CBC from other cannabinoids. But CBC can be produced from chemical synthesis using other food molecules (source). The chemical structure of CBC does not allow for crystallization, which makes distillation the main purification method. We can usually get over 95% pure CBC from this synthesis route.

D8-THC (chemically converted)

D8-THC can be found only at trace levels in the hemp plant, making natural extraction not an ideal path. However, it can be converted from CBD under an acid catalysis reaction.

D9-THC (naturally extracted or chemically converted)

This is the most popular cannabinoid in the current hemp beverage market. There are two main routes to obtain D9-THC from hemp:

• Route 1: natural extraction from “Mother Liquor”, which is the leftover material after CBD is isolated from the hemp biomass. An enrichment and distillation process is required to obtain the distillate.

• Route 2: chemical conversion from CBD through an acid catalysis reaction, similar to the D8-THC conversion process.

D9-THCv (mostly chemically synthesized)

D9-THCv could be a very interesting cannabinoid for future beverage brands to leverage. There are several ways to obtain it, but some factors may currently prove to be prohibitive.

• Natural extraction: D9-THCv exists only in trace amounts in most hemp cultivars, but there are special cultivars that can express higher D9-THCv. However, those cultivars usually contain > 0.3% THC, making it non-compliance with hemp regulations. Furthermore, the distillate will always contain a decent amount of THC. This could be an issue for brands who need to formulate with pure THCv input
• Chemical conversion: THCv can be chemically converted from CBDv, but it is not common to obtain high purity CBDv from the hemp plant. More work is needed to make this path viable.

• Chemical synthesis: This is the main method for producing THCv in the current market. The starting materials are usually divarinol and menthadienol (Source).

THCa and CBDa (naturally extracted)

Both of the acidic forms of THC and CBD exist at high concentrations in the hemp plant. They can both be crystalized, which makes it easy to obtain from natural extraction at large scale.

The future of cannabinoid production will only continue to iterate as new technology emerges

The table below summarizes the current production method for the major hemp cannabinoids as of Q1 2024. Our industry is never lacking in innovation and new production routes will continue to emerge. As we welcome new technologies, we need to pay close attention to the quality of the chemically modified cannabinoids, where undesired byproducts often co-exist.

BUT we should also not demonize chemically modified cannabinoids, because many food ingredients can be chemically produced with high quality. An industrial standard that regulates chemically modified cannabinoids is necessary to set this industry up for success.

Dr. Harold Han — the “Happy Chemist” — combines his storied background in emulsion chemistry and science with curiosity and fascination in the rapidly growing cannabis industry. Developing nano and micro emulsions his entire career, Harold holds a Ph.D in Surface Chemistry from NYU and is the holder of multiple patents for his inventions in emulsion chemistry.

As the Chief Science Officer at Vertosa, Harold spearheads the company’s development of industry-leading and customized active ingredients for infused product makers, offering pre-suspended aqueous solutions to create incredibly homogenous and stable products while maximizing bioavailability, clarity, and taste.

To learn more about the science of cannabis, make sure to follow Harold on LinkedIn and check out his Happy Chemist videos.