A century ago cannabis was respected but not well understood in the scientific literature. The intoxicating ingredient THC was officially isolated in 1964. (1) After 56 years, an isomer of THC, delta-10-THC, was first identified in cannabis extract. But how many different variations and isomers of THC are really in cannabis, and how many more can exist if we go beyond the realm of quantitative data?
A 2D image of D9-THC in the upper left is next to a 3D image of an identical THC isomer. Another isomer of the same molecule has a different atomic arrangement, such as a displaced double bond. While another stereoisomer of THC will have a different three-dimensional position. (The two red molecules in the 3D image are oxygen).
Seven double bond isomers
On one side of the THC molecule is a ring that contains a single double bond – atoms linked by two pairs of electrons. The position of this double bond in the ring shows the delta number of each THC isomer. There are seven possible double bond isomers in THC, and each has several possible spatial orientations (stereoisomers). There are even THC isomers with one enantiomer (one molecule that mirrors another).
I managed to get in touch with Dr. Markus Roggen, the founder of Health Canada Licensed Cannabis and Psilocybin Research Laboratory, Complex Biotech Discovery Ventures (CBDV), and CLN’s contributing scientist, briefly discuss some isomers of THC. We’ll stick to the basics for now, however, and dig deeper into various THC isomers in future releases.
D9 is the common form of intoxicating THC that everyone in the cannabis room is talking about. It is a colorless and viscous oil. This is a partial agonist at both CB1 and CB2 receptors and is most commonly used as an antiemetic in clinical settings. (2)
Delta-8: a natural and synthetic isomer of THC
D8-THC is the second most common known isomer of THC. It’s less intoxicating, with an easier brain high, as it only activates the CB1 receptor. Pure D8 should be a clear and very thick oil and cannot be pink without impurities (e.g. saline solution)!
The plant produces small amounts of natural D8-THC. Alternatively, this form of THC is legal in the US as long as it is made from hemp. This is often achieved semi-synthetically by converting CBD with strong acids; A sulfuric acid leached clay known as C bleach or T-41 is common in the industry. Usually the plant transfers CBD (or CBG) with natural enzymes in D8 and D9-THC. Delta-8-THC will be examined in more detail in a future episode.
The double bond of delta-8 is one position to the left of that of delta-9. If we shift the double bond to the right of delta-9-THC instead, it ends up in the tenth position on the cyclohexene ring. This cannabinoid is known as Delta-10 THC. (3)
Delta-10 THC is currently available to laboratories in the US, but not yet in Canada. It is not made naturally from cannabis and is therefore made exclusively via (semi) synthesis.
Delta 6a (10a) -THC
This isomer of THC is made by further isomerizing delta-10 THC with specific catalysts, causing the ring to pivot one more position towards the center of the molecule.
… The double bond lies between the two bridge bonds that basically make up the middle ring of THC.
Another variant of D6a (10a) -THC was administered to humans in 1972. (4) There are also (R) and (S) forms (enantiomers) of the pure structure of this cannabinoid. (5) Another human study published in 1987 found that the (R) variant was non-intoxicating and much less active at CB2 and CB1 receptors compared to D9. While the (S) variant of D6a (10a) was intoxicating, but with a third the potency of THC. (6)
Delta-7-THC and D6a (7) -THC
Any position on the cyclohexene ring can hold the double bond of THC, but every time that bond changes, the order of the molecule changes too. So far we’ve gone from D8 to D6a (10a) and covered four isomers of THC in cannabis and beyond natural sources. However, the ring has six positions, so at least two isomers of THC remain to be discussed.
D7 and Delta-6a (7) -THC are theoretically possible, but we have not yet found any evidence that they exist [in nature].
D7-THC supposedly does not facilitate activity. (3, 7) Although a synthetic epimer of D7 has shown some activity in animals, according to the limited data available for this elusive THC isomer. (8) Less excitable, D6a (7) was synthesized in 1975, but had no cannabimimetic activity. (9)
Exo-THC versus 11-OH-THC, isomers versus hydroxylates
So we’ve covered all of the isomers of THC – within the cyclohexene ring. But we can’t stop there. There is still one position for the double bond to move, above and outside the molecule. In this configuration there is a double bond on the methyl group at the eleventh position above the conjunction between the eighth and ninth positions. This isomer is sometimes referred to as D (9) 11-THC, but a more common name in the industry is Exo-THC.
11-Hydroxyl-THC, top left, is a more familiar version of THC that is made in the liver after digestion. This is not a separate isomer of THC, but a hydroxylated version of D9-THC with a hydroxyl group in the eleventh position. Conversely, exo-THC at the bottom right is simply another isomer with a double bond on the methylated group in the eleventh position.
In the current literature, few methods for the synthesis of exo-THC are known in which the double bond is pushed into this upper position. However, it has been reported that after treatment with gaseous hydrochloric acid, D8-THC becomes the exo-isomer of THC in several other crucial and highly technical steps. (10, 11) However, some D8 are also converted to D9 in this process.
The acid and enzymes in your gut are more likely to convert D8 and D9 into corresponding hydroxylated forms, 11-hydroxyl-THC, with a double bond in the same eighth or ninth position. In this case, the methyl group is replaced by a hydroxyl group. Hydroxylation strictly refers to the addition of a hydroxyl group (OH) to any molecule, while isomerization instead refers to a rearrangement of the atomic structure of the same molecule.
Isomers of THC over the limit
Complex Biotech Discovery Ventures, CBDV (soon to be Delic Labs), a licensed cannabis and psilocybin research laboratory in British Columbia, Canada, can track most of these THC isomers. And they’re set up to identify anyone else who might appear next on our radar. In summary, there are three main double bond isomers of THC that can be easily quantified: D8, D9, and exo-THC. For the others, more advanced tricks must be used. (12)
However, these are the only isomers of THC that have been administered to humans – with the recent addition of D10. And I’m sure it’s only a matter of time before Delta-10 reference standards are available in Canada for processors to further explore the secrets in their snippets.
look at that episode from #AskAnExpert for a visual guide to the different stereoisomers, trans and cis-THC, while Dr. Markus synthesized the cannabinoid from his molecule kit. And we stayed tuned as we took a deep dive into the highly processed cannabinoid Delta-8-THC.
Photo of a cannabis plant from Fairy God Mother courtesy of Cannabis Promoter, Pixabay.
- Y. Gaoni and R. Mechoulam. 1964. Isolation, structure and partial synthesis of an active ingredient in hashish. Journal of the American Chemical Society. 86 (8), 1646- 1647. DOI: 10.1021 / ja01062a046
- Russo EB (2011). Taming THC: Potential Cannabis Synergy and Phytocannabinoid Terpenoid Entourage Effects. British Journal of Pharmacology, 163 (7), 1344-1364. https://doi.org/10.1111/j.1476-5381.2011.01238.x
- T. Jarbe, A. Hiltunen, R. Mechoulam, M. Srebnik, A. Breuer, Separation of the discriminative irritative effects of stereoisomers of Δ2- and Δ3-tetrahydrocannabinols in pigeons, European Journal of Pharmacology 156 (3) (1988) 361-366 .
- Sidell, FB, Pless, JE, Neitlich, H., Sussman, P., Copelan, HW & Sim, VM (1973). Dimethylheptyl-Delta 6a-10a-Tetrahydrocannabinol: Effects after parenteral administration to humans. Procedure of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine (New York, NY), 142 (3), 867-873. https://doi.org/10.3181/00379727-142-37134
- Hollister LE (1970). Tetrahydrocannabinol isomers and homologues: contrasting effects of smoking. Nature, 227 (5261): 968-969. https://doi.org/10.1038/227968a0
- Hollister, LE, Gillespie, HK, Mechoulam, R. et al. Human pharmacology of 1S and 1R enantiomers of delta-3-tetrahydrocannabinol. Psychopharmacology 92, 505-507 (1987). https://doi.org/10.1007/BF00176485
- R. Mechoulam, Z. Ben-Zvi, H. Varconi, Y. Samuelov, Cannabinoid Rearrangements: Synthesis of 5-Tetrahydrocannabinol, Tetrahedron, Volume 29, Issue 11, 1973, Pages 1615-1619, ISSN 0040-4020, https: //doi.org/10.1016/S0040-4020 (01) 83406-2.
- John W. Huffman, W. Kenneth Banner, Grace K. Zoorob, H. Howard Joyner, Patricia H. Reggio, Billy R. Martin, David R. Compton, Stereoselective Synthesis of the Epimeric 7-Tetrahydrocannabinols, Tetrahedron, Volume 51, Issue 4 , 1995, pages 1017-1032, ISSN 0040-4020, https://doi.org/10.1016/0040-
- A. Arnone, L. Merlini, S. Servi. Hashish: synthesis of (+) -? 4-Tetrahydrocannabinol, Tetrahedron, Volume 31, Issue 24, 1975, pages 3093-3096, ISSN.
- AR Banijamali, CJ Van Der Schyf, A. Makriyannis, Addition and Elimination of HCl to Tetrahydrocannabinol Isomers. A method for making stereospecifically 2H-labeled cannabinoids, Journal of Labeled Compounds and Radiopharmaceuticals 41 (2) (1998) 121-130.
- JW Wildes, NH Martin, CG Pitt & ME Wall (1971). The synthesis of (-) – Delta-9 (11) -trans-tetrahydrocannabinol. The Journal of Organic Chemistry, 36 (5), 721-723. https://doi.org/10.1021/jo00804a024
- Berman, P .; Futoran, K .; Lewitus, GM; Mukha, D .; Benami, M .; Shlomi, T .; Meiri, D. A New ESI-LC / MS Approach for Comprehensive Metabolic Profiling of Phytocannabinoids in Cannabis. Sci rep-uk20188 (1), 14280. https://doi.org/10.1038/s41598-018-32651-4