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New potent THCo and CBDo ents were created with cannabis terpenes

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New marvel cannabinoids have been discovered within cannabis decades after Dr. Roger Adams first found CBD in 1942 and then later synthesized THC from CBD. (1) So, wonderous discoveries into new phytocannabinoids clearly take numerous steps to achieve. And thankfully, new potent forms of THCo and CBDo ents, have now been created from dirt-cheap and natural terpenes that are derived from the essential oils of cannabis. (2)

This means that, as a step in the process, synthetic cannabinoids can be used as reference tools for breeders. This can unlock higher evolutions of natural cannabis plants. These novel cannabinoids are also useful reference bases for clinicians formulating viable cannabimimetic solutions for pain, epilepsy, cancer, and many other ailments. (3)

Roger Adams and Dean R. D.
Carmichael with the electron
super microscope, June 1941. (4)

New novel cannabinoids from NMSU

New research from Maio Laboratories in New Mexico State University elucidated octo-CBD. Their team also focused on CBD variants that are a thousand percent stronger than regular CBD at cannabinoid receptor sites. (2) But, potency (affinity) does not translate to what happens when a cannabinoid binds to a receptor (efficacy). In other words, we still don’t know what these cannabinoids do to the body. (5)

What are ent and octo-cannabinoids?

Pentyl-CBD has a five-carbon chain and is simply referred to as CBD since it is the common variation. Phorol THC (THCp) has a seven-carbon side chain and is thirty times stronger than THC (affinity).

Octyl instead regards the eight-carbon side-chain group of cannabinoids. To extend their definition, all of the aforementioned cannabinoids have regarded different homologues of the D9 isomer.

Enantiomers of different cannabinoids are also possible, which we explained for the THC molecule in a previous document. Ent simply stands for enantiomer, which is a chiral (mirror) of an identical molecule. The potent enantiomer, (+)-ent-CBD, does exist within natural strains of cannabis plants. And, most of the ingredients for octo-cannabinoids can also be derived from the plant. This means that highly potent THCo and CBDo, and other ents, might be natural substances we have yet to find in the wild.

Professor William Maio courtesy of NMSU.

Maio Lab’s plans to assess ent-octo-CBD on Epilepsy

Conventional synthesis of CBD ents by Professor Mecheloum in 2005 used synthetic and expensive starting agents. (6) Professor Maio from New Mexico State University (NMSU) recently found a novel route to these variations of CBD by oxidizing and modifying an organic terpene product, carvone. His team’s achievement ultimately circumvented the need for more costly artificial compounds priced at $1000 per gram.

Dr. William Maio is an Associate Professor at NMSU with a Ph.D. in organic chemistry from John Hopkins and the lead of Maio Labs. His lab will be exploring effects within their growing catalogue of different CBD molecules in greater detail.

I sent Professor Maio an email and asked if he was willing to leave any further comments for publication, to which he happily replied.

We are hopeful that our improved synthesis of enantiomers of CBD, which can also be applied to the synthesis of the natural stereoisomers of CBD simply by switching the enantiomer of carvone (which is a terpene natural product) that you use as starting material, will lead to the increased synthesis of novel derivatives. As an example, our laboratory is already preparing another library of derivatives. 

In terms of future plans, we have already tested our derivatives into a mouse model for epilepsy and the results have been exciting! We submitted these preliminary findings to the NIH and recently received funding for that part of the project. We hope to publish some of these results later this year. While I can’t disclose specifics at this time, the ent-CBD-oct is a clear winner. 

Professor William Maio

How terpenes make carvone and novel CBD molecules

In nature, carvone is an oxidation product of the cannabis terpene, limonene. It is otherwise extracted from caraway oil and costs 0.15/g USD. During CBDo synthesis, carvone is intricately oxidized even further into an intermediate terpenoid. This resulting intermediate (hydrazone) can be transformed into specific orientations of itself (an enantioselective reaction). 

The reaction from carvone to the intermediate terpenoid is partially initiated with acetic acid, which is the main ingredient in tabletop vinegar. The modified terpenoid then completes the four technical steps required to build minor forms of CBD that are found in cannabis plants from a natural terpene. Otherwise, the team found a means to use carvone to create other novel cannabinoids, including a few non-natural variations.

What do potent new THCo and CBDo mean for the future?

Higher side-chain groups (homologues) such as the natural octyl cannabinoids are known to possess stronger affinities towards cannabinoid receptors. This occurs for CBDo, so perhaps THC-oct is even stronger than the super-potent new cannabinoid, THCp. Enantiomers (ents) are also known to possess high affinities than their standard cannabinoid counterpart.

New Mexico State University campus. Courtesy of NMSU.

We asked Dr. Maio if he is interested in discovering more about unusual forms of THC.

While we are able to work with CBD derivatives here at NMSU, we are not permitted to work on THC derivatives at this time. So, we have no plans to prepare these derivatives… Using our method it is indeed possible to synthesize the ent-THC-oct, simply by modifying the reaction conditions slightly. 

Dr. Maio

New Mexico passed the Controlled Substances and Therapeutic Research Act in 1978, (7) and yet, Professor Maio is still not permitted to study THC. At the very least, the discovery at Maio Labs will give researchers reference data on CBDo. So, labs can start identifying the substance in cannabis plants and extracts. And, before the breeders succeed in their efforts, clinicians can get a jumpstart on their work by validating some of the cannabinoid’s (like THCo and CBDo) medicinal properties.

A niche need for synthesis in the cannabis space

To prove any viability in epilepsy research for CBDv, we first had to discover the propyl-cannabinoid. Some cannabinoids exist within the plant but they are not yet clinically viable. Even CBD was trapped in an unfunded position before science discovered its importance. Oftentimes, pharmaceutical industries rather fund synthetic cannabinoids to override the need for natural ones – and fail. Does this misguided mindset disvalue the true need for organic synthesis in the cannabis space? (8)

Scientists can find ways to create cannabinoids artificially (like- THCo and CBDo) while respecting the plant’s natural cycle. Much like Professor Maio’s effort to find more organic and cheap methods of building cannabinoids. From here, cannabinoids that are hardly more synthetic than D8-THC can provide data for cultivators, processors, and clinicians studying the plant’s unusual ensemble of natural constituents. Eventually, breeders will find a way to grow octo-CBD, much as they have found a way to breed CBG cultivars with selective techniques.

Mechoulam might have never elucidated THC from a cannabis plant in 1964 without Dr. Adams’ efforts in organic synthesis two decades earlier. Dr. Rogers was limited by technology much as Professor Maio is limited by prohibition. Therefore, the breeders and processors need chemists to be allowed to manipulate chemicals in their beakers. The synthesis of CBD-oct and other enantiomers of CBD is a critical first step to the discovery of new minor cannabinoids in cannabis plants.

A chemist synthesizes THC from a terpene

In the following episode of #AskAnExpert hosted on CLN, Dr. Markus Roggen, a P.h.D. in chemistry, explains how a cannabinoid in the plant is created by wrapping the cannabis terpene, myrcene, around a second moiety. This is thematically representative of the process it takes to transform the terpene, carvone, into novel cannabinoids like CBD-oct and ent-CBD.

Let us know what you think of the novel synthesis of potent new forms of THCo and CBDo for clinical and cultivation research. And, stay tuned to find out if THCp is found in more than one strain bred by the Italian Government and if the cannabinoid is truly hyper-potent.

Show your work

  • Carvone is treated with a Rubottom oxidation to achieve a-hydroxycarvone isomers.
  • The resulting isomers were treated with tosylhydrazone over acetic acid and then reduced to ents of isopiperitenol, a terpenoid, using catecholborane. The acetic acid was precipitated into sodium acetate.
  • Isopiperitenol ents were then buffered to variations of CBD using Professor Mecheloum’s protocol with a Lewis Acid (Boron Trifluoride) over alumina.
  • (+)-ent-THC was formed when the terpenoid, isopiperitenol, was buffered with a Lewis Acid in the absence of alumina.

Sources

  1. Adams R, Pease DC, Cain CK, Clark JH. Structure of cannabidiol. Vi. Isomerization of cannabidiol to tetrahydrocannabinol, a physiologically active product. Conversion of cannabidiol to cannabinol1. J Am Chem Soc. 1940;62(9):2402-2405.
  2. Alexandra E. Golliher, Antonio J. Tenorio, Nina O. Dimauro, Nicolas R. Mairata, F. Omar Holguin, William Maio, Using (+)-carvone to access novel derivatives of (+)-ent-cannabidiol: The first asymmetric syntheses of (+)-ent-CBDP and (+)-ent-CBDV, Tetrahedron Letters, Volume 67, 2021, 152891, ISSN 0040-4039, https://doi.org/10.1016/j.tetlet.2021.152891.
  3. Kamal, B. S., Kamal, F., & Lantela, D. E. (2018). Cannabis and the Anxiety of Fragmentation-A Systems Approach for Finding an Anxiolytic Cannabis Chemotype. Frontiers in neuroscience12, 730. https://doi.org/10.3389/fnins.2018.00730
  4. Ronald E. Doel. 2003. Roger Adams: Linking University Science with Policy on the World Stage. Ch. 9. Pp 124-144.
  5. Ibsen, M. S., Connor, M., & Glass, M. (2017). Cannabinoid CB1 and CB2 Receptor Signaling and Bias. Cannabis and cannabinoid research, 2(1), 48–60. https://doi.org/10.1089/can.2016.0037
  6. Hanus, L. O., Tchilibon, S., Ponde, D. E., Breuer, A., Fride, E., & Mechoulam, R. (2005). Enantiomeric cannabidiol derivatives: synthesis and binding to cannabinoid receptors. Organic & biomolecular chemistry3(6), 1116–1123. https://doi.org/10.1039/b416943c
  7. James E. Smith. 2011. A Memorial Requesting The Department Of Health To Conduct A Study Of The Impact On The State Of The Controlled Substances Therapeutic Research Act And The Lynn And Erin Compassionate Use Act. House Memorial 53. 50th Legislator.
  8. Ethan Russo. 2017. The pharmacology of cannabis cannabinoid and terpenes. CHCE.





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