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Cannabinoids: acid form versus non—acid form

acid form versus non—acid form

acid form versus non—acid form

Cannabinoids present in hemp plants occur mainly in their acidic form. This means that an acid group is attached to each cannabinoid molecule. The plants naturally synthesize them this way. Inside living plants or well preserved dried material, usually more than 90 % of the cannabinoids are in their acid form.
Cannabinoids can undergo a reaction called decarboxylation, where they lose this acid group. This reaction occurs slowly with time, but can be dramatically accelerated by heat. This is for instance what happens when a cannabis product is smoked, or cooked for a sufficient time.

Figure 1: reaction of decarboyclation of CBDA to CBD

Figure 1: reaction of decarboyclation of CBDA to CBD

The regulated Δ9-THC molecule has been demonstrated to be more active in its non-acidic form (REF). The regulations, thus, implies determining and expressing the total cannabinoids content in hemp derived products as the non-acid form (REF).
Besides THC, more than 130 cannabinoids can be found in hemp. In the followings, cannabinoids are referred to in their decarboxylated (non-acid) form for more clarity.

Cannabinoids
CBD: Cannabidiol

Figure 2: CBDA and CBD molecules.

Figure 2: CBDA and CBD molecules.

CBD is, along with Δ9-THC, one of the two major cannabinoids generally produced by hemp. It was first isolated and identified in 1940 by the American chemist Roger Adams and his co-workers (Adams et al., 1940)
Contrary to Δ9-THC, CBD has no psychotropic potency (Pisanti et al., 2017). Moreover, if present in sufficient proportion, CBD can mitigate or even supress psychotropic potency of Δ9-THC (Niesink and van Laar, 2013; Schubart et al., 2011).

Δ9-THC: delta-9-tetrahydrocannabinol

 

Figure 3: Δ9-THCA and Δ9-THC molecules.

Figure 3: Δ9-THCA and Δ9-THC molecules.

Δ9-THC is, along with Δ9-THC, one of the two major cannabinoids generally produced by hemp. It was first isolated and identified in 1964 by the Israeli Dr. Yechiel Gaoni and Prof. Raphel Mechoulam (Gaoni and Mechoulam, 1964).
Δ9-THC has a high psychotropic potency and is for this reason classified as controlled substance by many national and international regulations. In Switzerland, two main ordinances from the Swiss Federal Office of Public Health (SFOPH) indicate what the legal Δ9-THC limit depending on the designation of the product:

– 1% in non-edible hemp products (e.g. tobacco substitute) according to ordinance 812.121.11

– 0.00002 to 0.003% in edible products (depending on product type) according to ordinance 817.022.15.

CBC: cannabichromene

Figure 4: CBCA and CBC molecules.

Figure 4: CBCA and CBC molecules.

CBC is a common cannabinoid found in hemp. It is largely considered as non-psychotropic cannabinoid (Russo, 2011; Turner et al., 1980).
CBC is generally present in same quantity as THC in indoor grown hemp, but can reach notably higher content (up to 5 times that of THC) in outdoor grown hemp.

CBG: cannabigerol

Figure 5: CBGA and CBG molecules.

Figure 5: CBGA and CBG molecules.

CBG is considered as the “parent” cannabinoids that is produced at first by hemp plants, and further metabolized to other cannabinoids such as CBD or Δ9-THC.

Δ8-THC: delta-8-tetrahydrocannabinol

Figure 6: Δ8-THCA and Δ8-THC molecules.

Figure 6: Δ8-THCA and Δ8-THC molecules.

Δ8-THC has a molecular structure very close to Δ9-THC, buts is rather known to expose a notably lower psychotropic potency (as reported by the American National Health Institute https://www.cancer.gov/publications/dictionaries/cancer-drug/def/delta-8-tetrahydrocannabinol).
It is generally present in CBD rich hemp as a product of CBD degradation, usually in amount equivalent to 1- 2% of the total CBD content.

CBN: cannabinol

Figure 7: CBN and CBNA molecules.

Figure 7: CBN and CBNA molecules.

CBN is the product of Δ9-THC degradation.

CBL: cannabicyclol

Figure 8: CBLA and CBL molecules.

Figure 8: CBLA and CBL molecules.

CBL is the product of CBC degradation.

 

CBDv, THCv, CBCv etc..: the cannabinoid-varine groupe

Figure 9: CBD, 9-THC, CBDv and Δ9-THCv molecules.

Figure 9: CBD, 9-THC, CBDv and Δ9-THCv molecules.

The cannabinoid-varine group includes a series of cannabinoids with very similar structure as the above listed ones (CBD, THC, CBD etc.), but with a shorter alkyl chain (like a shorter “tail”, as shown in the above illustration).
These cannabinoids are usually less concentrated in hemp than the other ones.
Terpenes and terpenoids
Terpenes form an important family of chemical compounds produced by hemp, and also by many other plants and animals. These are the aromatic molecules which give to the various variety of hemp their particular scents and tastes. More than 200 different terpenes have been identified in hemp.
These molecules are hydrocarbons, all built from the same basic unit: isoprene.

Figure 10: isoprene, the basic unit of all terpennes.

Figure 10: isoprene, the basic unit of all terpennes.

Depending on the number of isoprene units which are assembled, several sub-groups are further distinguished: monoterpenes (2 units), sesquiterpenes (3 units), diterpennes (4 units) etc.

Figure 11: example of monoterpenes

Figure 11: example of monoterpenes

 

Figure 12: example of sesquiterpenes

Figure 12: example of sesquiterpenes

Hemp also produces a large series of compounds called terpenoids. These are in fact similar hydrocarbons with functional groups, usually containing oxygen (e.g. alcool, acids, cetones, esters..). These are often referred to as “oxygenated terpenes”. Cannabinoids are in fact diterpenoids (i.e. based on 4 isoprene units with additional functional groups).

Figure 13: example of terpenoids

Figure 13: example of terpenoids

Amongst all those various terpenoids, some are considered as are key precursor for all the other terpenes, terpenoids, and, thus, cannabinoids. This means that hemp first produces these parent molecules, and further transforms them to produce the other above described compounds (see next section).

 

Synthesis of cannabinoid

The precursor Geranyl pyrophosphate (GP) is considered as the parent of all the other terpenes. Hemp also procures two other precursors, olivetolic acid (OA) and divarolinic acid (DA), which are then reacted with GP to produce CBG and CBGv respectively. These two “parent cannabinoids” are then further transformed to produce all the other cannabinoids found in hemp.

Figure 14: synthesis pathways of terpenes and cannabinoids in hemp.

Figure 14: synthesis pathways of terpenes and cannabinoids in hemp.

 

Cannabinoids ratio

The ratio between the different cannabinoids contents is primarily determined by genetics, and further influenced by environment. This is especially the case by dealing with the CBD: Δ9-THC ratio, which falls within pretty narrow range of value.

Three main groups of hemp can be identified:
–          The CBD-dominant strains with a CBD:THC ratio generally between 20:1 and 32:1. Some varieties can have a ratio as low as 15:1, but are rarely encountered.
–          the balanced strains with a CBD:THC ratio falling between 1:1 and 4:1
–          the THC-dominant strains with a CBD:THC well below 1:50, down to 1:200
Only CBD-dominant strains are likely to contain low enough THC content to be considered legal. Since the CBD:THC of the CBD dominant strains is fixed by the genetic and pretty distinct from the two other types, it can be predicted by analysing young plants. It falls in a pretty narrow range, as outlined by the following diagram:

figure-15

figure-15

Copyright by Alplant GmbH Dr. Jebril Hadi

References

Adams, R., Hunt, M. & Clark, J.H. (1940). Structure of Cannabidiol, a Product Isolated from the Marihuana Extract of Minnesota Wild Hemp. I. Journal of the American Chemical Society 62, 196-200.
Gaoni, Y. & Mechoulam, R. (1964). Isolation, Structure, and Partial Synthesis of an Active Constituent of Hashish. Journal of the American Chemical Society 86, 1646-1647.
Niesink, R.J.M. & van Laar, M.W. (2013). Does Cannabidiol Protect Against Adverse Psychological Effects of THC? Frontiers in psychiatry 4, 130-130.
Pisanti, S., Malfitano, A.M., Ciaglia, E., Lamberti, A., Ranieri, R., Cuomo, G., Abate, M., Faggiana, G., Proto, M.C., Fiore, D., Laezza, C. & Bifulco, M. (2017). Cannabidiol: State of the art and new challenges for therapeutic applications. Pharmacology & Therapeutics 175, 133-150.
Russo, E.B. (2011). Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects. British Journal of Pharmacology 163, 1344-1364.
Schubart, C.D., Sommer, I.E.C., van Gastel, W.A., Goetgebuer, R.L., Kahn, R.S. & Boks, M.P.M. (2011). Cannabis with high cannabidiol content is associated with fewer psychotic experiences. Schizophrenia Research 130, 216-221.
Turner, C.E., Elsohly, M.A. & Boeren, E.G. (1980). Constituents of Cannabis sativa L. XVII. A review of the natural constituents. Journal of Natural Products 43, 169-234.