A New High

Cannabis consumers are becoming increasingly sophisticated and are seeking new experiences from novel cannabinoids. Much of the often-touted safety of cannabis and cannabis extracts comes from their balance of cannabinoids, terpenes, and other lesser known but potentially active ingredients, such as flavonoids, alkaloids, spiroindans, dihyrostilbenes, dihydrophenanthrenes, and lignanamides.

However, some cannabis consumers are more interested in the effects of purified and concentrated cannabinoids like cannabinol (CBN), cannabigerol (CBG), cannabichromene (CBC), or tetrahydrocannabivarin (THCV). These purified isolates (usually about 99% purity) do not benefit from the chemical balance in the plant or in whole plant extracts, so we are learning in real time about the potential health benefits—and risks—of purified, isolated cannabinoids.

The newest extension of this trend seems to be the isolation of (or isomerization to create) novel, rare isomers of tetrahydrocannabinol (THC) for inclusion in new consumer products. While delta-9 THC has been widely studied, the other much rarer isomers such as delta-8 THC, delta-10 THC, and delta-6 THC have not.

Scientists and growers know that cannabis and hemp are really just different varieties of the same plant, Cannabis sativa. However, U.S. legislators have created two legally distinct market opportunities by defining hemp as cannabis or cannabis extracts with less than 0.3% delta-9 THC.

Because delta-8 THC product manufacturers start with CBD from hemp, these products are more widely available than delta-9 THC products, due to delta-9’s status as a Schedule I drug at the federal level.

Hemp and hemp-derived products are protected under the 2018 Farm Bill, so when delta-8 products hit the market, they were legal for sale across state lines until specific, new legislation was passed to restrict their sales within a state or prevent importation and exportation across state lines. More than a dozen states have now enacted specific laws restricting or outlawing delta-8 products, but the newer isomers like delta-10 and delta-6 are likely not on legislators’ radar.

Plant-Derived Cannabinoids

Almost all cannabinoids in the intact cannabis plant are stored in their cannabinoid acid forms, i.e., tetrahydrocannabinolic acid (THCA), cannabidiolic acid (CBDA), cannabigerolic acid (CBGA), etc. Heat and light will remove the carboxylic acid group from the cannabinoid acid through a decarboxylation reaction, which is why most raw flower is smoked or vaped to release the cannabinoids (THC, CBD, CBG, etc.).

Cannabis product manufacturers usually decarboxylate the cannabinoid acids to produce cannabinoids for prepared cannabis extracts and processed consumer products like tinctures, edibles, or beverages. Decarboxylation of THCA to produce delta-9 THC can happen spontaneously or over time in raw flower due to sunlight or heat; however, naturally occurring levels of delta-9 THC usually measure only 1% to 3%, even in flower with high THCA concentrations, and the levels of delta-8, delta-10, and delta-6 may not be detectable or may be very near the limit of detection, depending on the method of detection.

So how are these rare isomers of THC being produced?

New Market Opportunities

The rarity of delta-8, delta-10 and delta-6 THC in the cannabis plant make purifying them from plant extracts very cost prohibitive, even if the plant extract is fully decarboxylated. Therefore, manufacturers are using multistep chemical processes to create these rare isomers in greater quantities.

In 2020, delta-8 THC became more widely available in consumer products as manufacturers began converting CBD derived from hemp into delta-8 THC through a process called isomerization. Isomerization involves rearranging the molecules in one compound to form another compound with the same starting molecules through the formation of new chemical bonds. The nomenclature used to describe the isomers of THC denotes the position of the carbon with the double bond. For example, delta-9 THC has the double bond at the 9th carbon, while delta-8 THC has the double bond at the 8th carbon, delta-10 THC has the double bond at the 10th carbon, and delta-6 THC has the double bond at the 6th carbon.

Because of the distinct and arbitrary markets for cannabis products, there is a lot of gray area in the market as hemp-derived cannabinoids can be isomerized to create THC isomers not considered by the Farm Bill. Now U.S. states are scrambling to keep pace with new regulations for THC isomers, and they do not have the benefit of the extensive scientific research that exists for delta-9 THC. However, the research conducted so far suggests both potential benefits and risks to consumers.

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Rare THC Isomers: The Potential

Delta-8 THC

Based on consumer reports, delta-8 THC provides a milder high, which can be sedating and may cause an increase in appetite. Delta-8 THC’s reduced potency is likely because the altered double bond in delta-8 THC makes it less efficient than delta-9 THC at binding to cannabinoid-sensitive receptors in the human brain.

There have been a number of studies conducted over the years that suggest delta-8 THC’s potential in several medical applications.

For example, one human trial with eight pediatric cancer patients suggested that delta-8 THC was fairly good at preventing the nausea and vomiting that often accompanies chemotherapy treatments, but the study had only a limited number of participants (Abrahamov et al., 1995).

Animal studies have demonstrated that delta-8 THC relieves pain and inflammation through interactions with cannabinoid receptor 1 (CB1), but not cannabinoid receptor 2 (CB2). These same studies suggested that delta-8 THC likely binds to a few other cannabinoid sensitive receptors because blocking delta-8 THC’s effects with CB1-inhibitors was only partially effective (Thapa et al., 2018).

In rodents, delta-8 THC also reduces the turn-over of hippocampal acetylcholine, an important neurotransmitter for memory functions, which makes it a promising therapeutic ingredient for human patients with dementia and Alzheimer’s disease (Revuelta et al., 1980).

Delta-8 THC was also effective at relieving experimental autoimmune encephalomyelitis (EAE), which is the animal model for multiple sclerosis (MS) in human patients (Wirguin et al., 1994).

Taken together, these experiments support a role for further delta-8 THC research in therapies for pain, inflammation, and neuroprotection.

Delta-10 THC

Consumers report that delta-10 creates a lighter, euphoric high that is uplifting and perfect for daytime use. Delta-10 is reported to enhance focus and creativity.

Delta-10 THC is not naturally occurring; therefore, it is also synthesized from hemp-derived precursors. If delta-10 THC is produced from hemp-derived CBD, it is presumed to be legal under the Farm Act (for now). However, specific legislation may arise to restrict or ban delta-10 THC. Chemically, delta-10 THC can also be isomerized from delta-9 THC from medical cannabis, but this production process would automatically create a Schedule I product because it is derived from cannabis with a THC content greater than 0.3%. The Schedule I designation is less desirable on the market because it restricts sales to states with medical marijuana programs and prevents transportation across state lines.

According to a well-researched blog by ACS Laboratory, preparations of delta-10 THC from hemp-derived precursors often contain significant amounts of delta-8 THC or delta-9 THC along with the harsh reagents used in its isomerization. During the isomerization process for delta-10, there are several competing side reactions that produce delta-8 and delta-9. Of these three isomers, delta-8 THC is the most stable, followed by delta-9 THC, and then delta-10 THC. The secondary purification steps to remove delta-8 THC and delta-9 THC from delta-10 THC can be costly, so not all manufacturers remove them prior to the sale of the delta-10 THC. Consumers should be aware of this and look for testing results.

No randomized, placebo-controlled human trials nor animal trials of delta-10 THC have been reported, so we have a lot to learn about its potential health benefits and risks.

Delta-6 THC

Little is known about how delta-6 THC effects human patients, but it is the very latest in the parade of rare THC isomers being produced from hemp precursors.

One reported animal study of delta-6 THC exposure in mice revealed that this isomer of THC could cause catalepsy, an adverse reaction characterized by a trance or seizure with a loss of sensation and consciousness accompanied by rigidity of the body (Ohlsson et al., 1980). This is just one study, but this kind of potential outcome is not very promising.

Conclusion

Products containing rare THC isomers produced from hemp do not have to be tested and are not regulated as well as the delta-9 THC containing products manufactured in state-licensed facilities. Safety and efficacy studies for these new, rare THC isomers are urgently needed to avoid any unforeseen adverse reactions or issues with harmful contaminants. Products made with these rare THC isomers should also be subject to basic safety (from contaminants and solvents) and purity testing of all the cannabinoids in the products, especially for delta-10 products that often have significant quantities of delta-8 THC or delta-9 THC.