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How many isomers of THC are in cannabis and beyond?

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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 identified in cannabis extract for the first time. But, how many different variations and isomers of THC are truly in cannabis, and how many more can exist if we go beyond the realm of quantitative data?

A 2D depiction of D9-THC, top left, is next to a 3D image of an identical isomer of THC. A different isomer of the same molecule will possess a different atomic arrangement, such as a shifted double-bond. Whereas, a different stereoisomer of THC will have a different three-dimensional position. (The two red molecules in the 3D image are oxygens).

Seven double-bond isomers

There is a ring on one side of the THC molecule that contains a single double-bond – atoms that are bonded with two pairs of electrons. The position of this double-bond in the ring depicts the Delta-‘number’ of each THC isomer. There are seven possible double-bond isomers in THC, and each one has several potential spatial orientations (stereoisomers). There are even THC isomers with an enantiomer (a molecule that mirrors another).

I did manage to briefly cover several isomers of THC in a 45-minute phone call with Dr. Markus Roggen – the founder of the Health Canada licensed cannabis and psilocybin research lab, Complex Biotech Discovery Ventures (CBDV), and CLN’s contributing scientist. But, we will stick with the basics for now and explore different THC isomers with greater detail in future releases.

Delta-9-THC

D9 is the common form of intoxicating THC that everyone talks about in the cannabis space. 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 is less intoxicating, with a lighter cerebral high since it only activates the CB1 receptor. Pure D8 should be a clear and very thick oil, and cannot be pink without impurities, (saline for example)!

The plant does produce small amounts of natural D8-THC. Alternatively, this form of THC is legal in the USA as long it’s derived from hemp. This is often achieved semi-synthetically by converting CBD with strong acids; a clay leached with sulphuric acid, known as C-bleach or T-41, is common in the industry. Normally, the plant transfers CBD (or CBG) into D8 and D9-THC with natural enzymes. A future installment will explore Delta-8-THC in further detail.

Delta-10

Delta-8’s double-bond is one position to the left of Delta-9’s. If we instead move the double-bond to the right of Delta-9-THC, it will land on the tenth position of the cyclohexene ring. This cannabinoid is known as Delta-10 THC. (3)

Delta-10 THC is currently available to labs in the United States, but not yet in Canada. It is not naturally produced by cannabis and is therefore produced exclusively via (semi-)synthesis.

Delta 6a(10a)-THC

This isomer of THC is produced by further isomerizing Delta-10-THC with specific catalysts, which swings the ring one more position towards the center of the molecule.

Isomerization of THC from D9 to D6a(10a)

…the double-bond is between the two bridging bonds that basically make-up the middle ring of THC.

Dr. Roggen.

Another variant of D6a(10a)-THC was administered to humans in 1972. (4) There are (R) and (S) forms (enantiomers) of this cannabinoid‘s pure structure as well. (5) Another study on humans, published in 1987, determined that the (R) variant is non-intoxicating and much less active at CB2 and CB1 receptors compared to D9. Whereas the (S) variant of D6a(10a) was reported to be intoxicating, but with a third of THC’s potency. (6)

Delta-7-THC and D6a(7)-THC

Each position on the cyclohexene ring can hold THC’s double-bond, but each time this bond changes so does the molecule’s arrangement. We have so far gone around from D8 to D6a(10a) and covered four isomers of THC in cannabis and beyond natural sources. But, the ring has six positions, so there are still at least two isomers of THC left to discuss.

D7 and Delta-6a(7)-THC are theoretically possible but we have so far not found any evidence that they exist [in nature].

Dr. Roggen

D7-THC supposedly facilitates no activity. (3, 7) Although, a synthetic epimer of D7 did show some activity in animals, according to the limited data that exists on this elusive THC isomer. (8) Less excitably, D6a(7) was synthesized in 1975, but it did not possess any cannabimimetic activity. (9)

Exo-THC versus 11-OH-THC, isomers versus hydroxylates

So, we have covered all of the isomers of THC – inside the cyclohexene ring. But, we can’t stop here. There is still one more position the double-bond can move and that is up and outside of the molecule. In this configuration, there is a double-bond at the methyl group on the eleventh position situated above the conjunction between the eighth and ninth positions. This isomer is sometimes known as D(9)11-THC, but a more common name in the industry is exo-THC.

An isomer of THC and hydroxylated D9
11-hydroxyl-THC, top left, is a more well-known version of THC that is created in the liver after digestion. This is not its own isomer of THC, but rather a hydroxylated version of D9-THC with a hydroxyl group at the eleventh position. Conversely, Exo-THC, bottom right, is simply a different isomer with a double-bond at the methylated group on the eleventh position.

Seldom few methods to synthesize exo-THC are known in the current literature, which involves pushing the double-bond into that upper position. Although, it has been reported that D8-THC will turn into the exo isomer of THC after it is treated with gaseous hydrochloride acid upon a few other crucial and highly technical steps. (10, 11) Some D8 will also convert to D9 in this process, though.

The acid and enzymes in your gut rather convert D8 and D9 into respective hydroxylated forms, 11-hydroxyl-THC, with a double bond in the same eighth or ninth position. In this incidence, the methyl group is replaced with a hydroxyl group. Hydroxylation refers strictly to the addition of a hydroxyl group (OH) on any molecule, whereas isomerization instead refers to a rearrangement of the same molecule’s atomic structure.

Isomers of THC over the border

Complex Biotech Discovery Ventures, CBDV, (soon to be Delic Labs) an approved cannabis and psilocybin research lab in British Columbia, Canada can track most of these THC isomers. And they are set up to identify any others that might appear on our radar next. In conclusion, 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 have to be used. (12)

However, these are the only isomers of THC that have been given to humans – with the addition of D10 more recently. And, I am sure it is only a matter of time until Delta-10 reference standards are in Canada, allowing processors to further explore mysteries in their extracts.

Watch this episode of #AskAnExpert for a visual guide on the different stereoisomers, trans and cis-THC, as Dr. Markus synthesizes the cannabinoid from his molecule kit. And, stayed tuned as we dive deep into the highly processed cannabinoid, delta-8-THC.

Photo of a Fairy God Mother cannabis plant courtesy of Cannabis Promoter, Pixabay.

Sources

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  2. Russo E. B. (2011). Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects. British journal of pharmacology163(7), 1344–1364. https://doi.org/10.1111/j.1476-5381.2011.01238.x
  3. T. Jarbe, A. Hiltunen, R. Mechoulam, M. Srebnik, A. Breuer, Separation of the discriminative stimulus effects of stereoisomers of Δ2 and Δ3-tetrahydrocannabinols in pigeons, European Journal of Pharmacology 156(3) (1988) 361-366.
  4. Sidell, F. B., Pless, J. E., Neitlich, H., Sussman, P., Copelan, H. W., & Sim, V. M. (1973). Dimethylheptyl-delta 6a-10a-tetrahydrocannabinol: effects after parenteral administration to man. Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine (New York, N.Y.)142(3), 867–873. https://doi.org/10.3181/00379727-142-37134
  5. Hollister L. E. (1970). Tetrahydrocannabinol isomers and homologues: contrasted effects of smokingNature227(5261), 968–969. https://doi.org/10.1038/227968a0
  6. Hollister, L.E., Gillespie, H.K., 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
  7. R. Mechoulam, Z. Ben-Zvi, H. Varconi, Y. Samuelov, Cannabinoid rearrangements: Synthesis of Δ5-tetrahydrocannabinol, Tetrahedron, Volume 29, Issue 11, 1973, Pages 1615-1619, ISSN 0040-4020, https://doi.org/10.1016/S0040-4020(01)83406-2.
  8. 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 Δ7-tetrahydrocannabinols, Tetrahedron, Volume 51, Issue 4, 1995, Pages 1017-1032, ISSN 0040-4020, https://doi.org/10.1016/0040-
  9. A. Arnone, L. Merlini, S. Servi. Hashish: Synthesis of (+)-Δ4-tetrahydrocannabinol, Tetrahedron, Volume 31, Issue 24, 1975, Pages 3093-3096, ISSN.
  10. A.R. Banijamali, C.J. Van Der Schyf, A. Makriyannis, Addition and elimination of HCl to tetrahydrocannabinol isomers. A method for the preparation of stereospecifically 2H-labeled cannabinoids, Journal of Labelled Compounds and Radiopharmaceuticals 41(2) (1998) 121-130.
  11. Wildes, J. W., Martin, N. H., Pitt, C. G., & Wall, M. E. (1971). The synthesis of (-)-delta-9(11)-trans-tetrahydrocannabinol. The Journal of organic chemistry36(5), 721–723. https://doi.org/10.1021/jo00804a024
  12. Berman, P.; Futoran, K.; Lewitus, G. M.; 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

Footnote(s)

https://www.pixabay.com/photos/fairy-godmother-cannabis-marijuana-2756580/





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