SoP


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THE HEMP ASSOCIATION


Statement of Principles:  Cannabidiol (CBD) / Δ9-Tetrahydrocannabinol (THC)

 

Compiled & Authored by: Patrick Jones, Executive Director, The Hemp Association, [email protected]

 

ABSTRACT:  Despite what most researchers believe, the fresh Cannabis plant does not contain any THC molecules.  Further, Cannabis CANNOT produce, NOR synthesize THC.  “Statement of Principles: Cannabidiol (CBD) / Δ9-Tetrahydrocannabinol (THC)” (SoP) intends evidence the Genetic and Scientific tests and proof and/or citations that DOCUMENT that NEITHER Cannabis, NOR Hemp can produce CBD.  NEITHER Cannabis, NOR Hemp can synthesize CBD.

Therefore, Laws, Debate, or Discussion of CBN, THC, and/or CBD are not only premature, but the existing protocol for testing CREATES THE THC and this makes Prohibition a Human Rights violation.

 

DEFINITIONS:

Cannabigerolic Acid (CBGA):  Enzymatic Precursor Acid to THCA, or CBDA.

delta-1-Tetrahydrocannabinolic Acid Synthase (THCAS):  Product of Cannabis.

delta-1-Tetrahydrocannabiolic Acid (THCA):  Enzymatic Synthetic of THCAS and CBGA.

delta-9-Tetrahydrocannabiol (THC):  Non-Enzymatic Synthetic of THCA.

Cannabidiolic Acid Synthase (CBDAS):  Product of Hemp.

Cannabidiolic Acid (CBDA):  Enzymatic Synthetic of CBDAS and CBGA.

Cannabidiol (CBD):  Non-Enzymatic Synthetic of CBDA.

 

Introduction:  This Statement of Principles (SoP) is written at the request of Mr. Chris Woodney, New Zealand Hemp Industries Association.  Chris requested I & I write a response to:  “Relationship between Cannabidiol and THC” by Dennis Page dated 24-03-2015.  In this paper, Mr. Page presents a relationship between Cannabinol (CBN), Δ9-Tetrahydrocannabinol (THC), and Cannabidiol (CBD) whereby

Mr. Page states a “simple acidic mediation could facilitate ring closure of the bottom structure (CBD) to give the middle structure (THC) with no overall gain or loss of hydrogen (or any other atoms).”

Mr. Page states in the next paragraph “The first principles definition of an isomer is ‘compounds with the same formula but different chemical structures.’ This definition allows for functional group isomerism of the type discussed above as well as the more familiar geometric isomerism about double bonds (cis-/trans-) or diastereoisomers and enantiomers (different 3D spatial orientations of functional groups). Therefore, clause 2 of B1 could adequately capture CBD under the isomer provision and it could be considered in the broad sense as ‘any tetrahydrocannabinol.’ In addition, under part 2, ‘Interpretation,’ the definition of a controlled drug includes any analogue and the definition of a controlled drug analogue under the same part includes ‘any substance… that has a structure substantially similar to that of any controlled drug.’ I have already described the similarities between the two structures and given only one bond is cleaved/formed between the two of them, would consider them substantially similar in the chemical sense.”

HOWEVER, Mr. Page’s assertion is one that is predicated upon the presence of Cannabidiol (CBD).

 

PRINCIPLES:

  • Cannabis CANNOT produce, NOR synthesize Δ9-Tetrahydrocannabinol (THC) (Fig. 1).
  • Hemp CANNOT produce NOR synthesize Cannabidiol – (CBD) (Fig. 2).
  • The “Product” of Cannabis is THCAS (Fig. 1).
  • The “Enzymatic Synthetic” of Cannabis is THCA (Fig. 3).
  • The “Product” of Hemp is CBDAS (Fig. 2).
  • The “Enzymatic Synthetic” of Hemp is CBDA (Fig. 3).
  • “Marijuana” TESTING PROTOCOL creates THC, and CBD as the Non-Enzymatic Decarboxylated “by-product” of the Synthesis of the Product of Cannabis, and/or the Non-Enzymatic Decarboxylated “by-product” of the Synthesis of the Product of Hemp.

In fact – THC, and/or CBD are three chemical steps removed from the Plant’s Genetic production.

 

EVIDENCE:

  • Cannabis CANNOT produce, NOR synthesize Δ9-Tetrahydrocannabinol (THC). & 3.)  The “Product” of Cannabis is THCAS (Fig. 1).

cannabis-genetic-pathway

Fig. 2 (SOURCE: http://genome.ccbr.utoronto.ca/cgi-bin/hgGateway, Page et al 2011, MedicinalGenomics.com)

  • Hemp CANNOT produce NOR synthesize Cannabidiol – (CBD). & 5.) The “Product” of Hemp is CBDAS (Fig. 2).

hemp-genetic-pathway

 

Fig. 2 (SOURCE: http://genome.ccbr.utoronto.ca/cgi-bin/hgGateway,  Page et al 2011, MedicinalGenomics.com)

 

4.) The “Enzymatic Synthetic” of Cannabis is THCA (Fig. 3).  &  6.)  The “Enzymatic Synthetic” of Hemp is CBDA (Fig. 3).

cannabinoid-pathway1

Fig. 3 (SOURCE: Page et al 2011, http://genome.ccbr.utoronto.ca/images/cannabinoid-pathway.png MedicinalGenomics.com)

 

7.)  “Marijuana” TESTING PROTOCOL creates THC, and CBD as the Non-Enzymatic Decarboxylated “by-product” of the Synthesis of the Product of Cannabis, and/or the Non-Enzymatic Decarboxylated “by-product” of the Synthesis of the Product of Hemp.

United Nations TESTING PROTOCOL creates THC and CBD by means of Decarboxylation.

(SOURCE:  https://www.unodc.org/documents/scientific/ST-NAR-40-Ebook.pdf)

Actual test results show only 0.5% THC is Non-Enzymatically Decarboxylated from the Fresh Form of Cannabis:

“Quantitative analysis using gas chromatography coupled with mass spectrometry made it possible to determine the average delta-9-THC content of cannabis in fresh form (0.5 percent), its dry form (2.21 percent), and its powdered form (8.3 percent)”

(SOURCE:  Cultivation of Cannabis Sativa.L in Northern Morocco: Stambouli, et al 2005)

Above we see that even AFTER Non-Enzymatically Decarboxylation the fresh form STILL ONLY HAS 0.5 percent of THC.  This means 0.0 Percent THC is present in fresh form.

Then we look at:

Cannabidiolic-acid synthase, the chemotype-determining enzyme in the fiber-type Cannabis sativa (Taura et al., 2007) where we find:

(Fig. 1, Source: Taura et al)

“Thus, THC and CBD are derived artificially from their acidic precursors tetrahydrocannabinolic-acid (THCA) and cannabidiolic acid (CBDA) (Fig. 1) by nonenzymatic decarboxylation (Fig. 2). With respect to the biosynthesis of cannabinoids (Fig. 3), we have previously reported the identification and purification of novel enzymes, THCA synthase and CBDA synthase (Fig. 1), which are specifically expressed in respective drug-type (THCA-rich) and fiber-type (CBDA-rich) chemical phenotypes of C. sativa [10,11]. These enzymes are the first cannabinoid synthases to be studied, and potentially attractive targets for various biotechnological applications as they produce the direct precursors of pharmacologically active cannabinoids. In addition, these enzymes catalyze an unique biosynthetic reaction, the stereospecific oxidative cyclization of the geranyl group of cannabigerolic-acid (CBGA) (Fig. 1), for which no equivalent reaction has been reported to date.”

ENZYMATIC SYNTHESIS

cannabidiol_and_thc_biosynthesis

vs.

NON-ENZYMATIC DECARBOXYLATION

non-ezymatic-decarboxylation

(Fig. 2, Source: Taura et al)

[1] Yamauchi, T., Shoyama, Y., Aramaki, H., Azuma, T. and Nishioka, I. (1967) Tetrahydrocannabinolic acid, a genuine substance of tetrahydrocannabinol. Chem. Pharm. Bull. 15, 1075–1076.

[2] Kimura, M. and Okamoto, K. (1970) Distribution of tetrahydrocannabinolic acid in fresh wild Cannabis. Experientia 26, 819– 820.

[3] Taura, F., Morimoto, S., Shoyama, Y. and Mechoulam, R. (1995) First direct evidence for the mechanism of D1 -tetrahydrocannabinolic acid biosynthesis. J. Am. Chem. Soc. 117, 9766–9767.

[4] Taura, F., Morimoto, S. and Shoyama, Y. (1996) Purification and characterization of cannabidiolic-acid synthase from Cannabis sativa L. Biochemical analysis of a novel enzyme that catalyzes the oxidocyclization of cannabigerolic acid to cannabidiolic acid. J. Biol. Chem. 271, 17411–17416.

Taura, et al have shown above Cannabis is determined to produce THCA-Synthase, and Hemp is determined to produce CBDA-Synthase.

Then we look to the study of Cannabis/Hemp and we find the procedure, protocol and testing processes for seventy-five years, Dequesnois-Levine Test (DLT) uses chemical reagents that react with THCA Synthase/THCA to produce THC.

Next:  IDENTIFICATION AND CHARACTARIZATION OF SPECIAL TYPES OF HERBAL CANNABIS (Trofin et al., 2012) to find where THC and CBD come from.

U.P.B. Sci Bull, Series B, Vol. 74, Iss. 1, 2012

“Samples Preparation   The preparation of cannabis samples in order to be analyzed in terms of their major cannabinoids: Δ9-Tetrahydrocannabinol (THC). Cannabidiol – (CBD), Cannabinol (CBN), Cannabigerol (CBG), Cannabichrome (CBC), Δ9-Tetrahydrocannabivarin (THCV) and Δ8-Tetrahydrocannbinol (Δ8-THC) is briefly described in the following.  Thus, 0.2g of dryed, homogenized and grinded herbal cannabis was extracted with 20Ml of methanols for 15 minutes in an ultrasonic bath.  An extract aliquot was then transferred into a 2ml GC vial.  After this, the vial was put into a heating unit at 150C for 12 minutes in order to evaporate the solvent and decarboxylate the tetrahydrocannabinolic acid (THCA).  The obtained residue was extracted in methanol and then the resulted solution was analyzed by GC-MS (Gas Chromagraphy-Mass Spectrometry) and GC-FID (Gas Chromatography-Flame Ionization Detector.)”   Here we see the process for testing heats the samples to 150C and NON-ENZYMATICALLY DECARBOXYLATES any THCA into THC.”

Finally we see the Seven (7) Steps to Isomerize CBD into THC which Mr. Page has asserted as a “simple acidic mediation”:

U.S. Patent No. 7399872

CLAIMS:

  1. A method of converting cannabidiol (CBD) to Δ9-tetrahydrocannabinol (Δ9-THC) comprising:

providing a reaction mixture comprising CBD in dry methylene chloride;

adding BF3Et2O to the reaction mixture;

stirring the ice cold reaction mixture under a nitrogen atmosphere;

adding NaHCOto the reaction mixture;

allowing the mixture to separate into an aqueous phase and an organic phase;

removing the organic phase;

washing the organic layer with water; and

eluting Δ9-THC from the organic phase, purity of the eluted Δ9-THC being greater than 97%.

  1. The method according to claim 1 including stirring the reaction mixture for approximately 1 hour.
  2. The method according to claim 1 including drying the organic phase over MgSOand evaporating the organic phase following washing.
  3. The method according to claim 1 including eluting the organic phase on an HPLC column.
  4. The method according to claim 4 wherein the Δ9-THC is eluted with ether in petroleum ether following washing the column with petroleum ether.
  5. The method according to claim 5 wherein the ether in petroleum ether is 2 parts ether in 98 parts petroleum ether.
  6. The method according to claim 1 including eluting the organic phase on an RP-HPLC column.

 

CONCLUSION:

As is evidenced in Genetics and Chemical testing above, Cannabis does NOT contain THC, nor CBD, Cannabis does not produce THC, nor CBD, and Cannabis does not Synthesize THC, nor CBD.

THC and CBD are the by-products of United Nations TESTING PROTOCOL which requires Non-Enzymatic Decarboxylation of THCA/CBDA into THC/CBD to determine Total-THC/Total-CBD.

DOWNLOAD: SoP

SoP COVER LETTER:

September 14, 2016

Mr. Chris Woodney

New Zealand Hemp Brokers, LTD.

 

Dear Chris:

It is a pleasure to discuss your concern regarding the continued Prohibition of the Cannabaceae plant family genus: Cannabis/Hemp.

This “Statement of Principles:  Cannabidiol – (CBD) / Δ9-Tetrahydrocannabinol (THC)” is intended to address information presented in the paper:

“Relationship between Cannabidiol and THC, Dennis Page, 24-03-2015”

AND clear up the common misconception that Cannabis and/or Hemp produce and/or synthesize THC and/or Cannabidiol (commonly referred to, and referred in this SoP, as CBD) respectively.

There is a well-established relationship between Cannabidiol (1942 U.S. Patent No. 2304669) and THC (U.S. Patent No. 7399872), and between THC and Cannabinol (CBN).

Further, Mr. Page may be accurate in his chemical description of Cannabidinol (CBN), Cannabidiol (CBD), and delta-9-Tetrahydrocannabinol/delta-9-THC (THC), HOWEVER…, Mr. Page FAILS to mention that Cannabis/Hemp (Cannabis Sativa.L, Cannabis Indica.L, etc.) CANNOT produce, NOR synthesize Cannabidiol (CBD).

In fact, Cannabis CANNOT produce, NOR synthesize delta-9-TetrahydroCannabinol (THC).

At your request, I have prepared the following “Statement of Principles:  Cannabidiol – (CBD) / Δ9

Tetrahydrocannabinol (THC)” compiled by means of generally-accepted, readily available, and reported information to clarify that Cannabaceae: Cannabis and Hemp Prohibition are UNFOUNDED IN CHEMICAL and GENETIC SCIENCE.

Thank you.

Kind Regards,

 

Patrick Jones

DOWNLOAD: Cover letter

 

This Statement of Principles is in response to the following:

Relationship between Cannabidiol and THC

Dennis Page

24-03-2015

To Sue Wiltshire, Medicines Control,

This document sets out the structural relationship between the compound in question, CBD (cannabidiol), and THC.  The structures are shown in the diagram below (Note; ‘THC’ could represent any structure with the isolated double bond in the top left ring at one of several positions in the ring [see middle structure]; in this case it is shown between positions 9 and 10 as in ∆9-THC [‘delta-9’ THC] since this is the most common active associated with cannabis extracts).

Cannabinol or

6,6,9-trimethyl-3-pentyl-6H-dibenzo[b,d] pyran-1-ol

(-)-∆9-THC or

(-)-(6aR,10aR)-6a,7,8,10atetrahydro-6,6,9-trimethyl-

3-pentyl-6H-dibenzo[b,d] pyran-1-ol

5-pentyl-1,3-benezenediol

The top structure, cannabinol, shows the top left ring fully unsaturated (or benzenoid) in character.  The fused, tricyclic system is known as a dibenzopyran system.  Where I have used the two red arrows, these are used to indicate sites of addition of four hydrogen atoms (i.e. tetrahydro) to show the relationship between cannabinol and ∆9-THC.  You will also see this indicated in the formal CAS name of the second structure; the numbers shown in red are where the hydrogen atoms have been introduced.

In the bottom structure, where cannabidiol (CBD) is concerned, the issue of the ‘missing tetrahydro’ moiety as argued by the applicant is not of concern since it is still possessed by the 2-cyclohexen-1-yl moiety (see red text, bottom structure and also red arrows showing sites of introduction and relationship to top structure).  Some confusion may arise because the formal name has changed as a result of the ether link in the structure (the pyran moiety) being cleaved as one shifts from the THC unit to the CBD unit.  Formal name changes occur because different units take priority in chemical nomenclature as structures are varied (this is usually based on the highest oxidised state of the molecule; in the bottom molecule it is the benzenediol portion that takes priority; in the middle and top molecules it is a dibenzopyran moiety that forms the basis for priority). These facts do not negate the fact that a ‘tetrahydro’ moiety exists in both the middle and bottom structures.

The next question to consider is could the bottom structure ‘CBD’ be considered as a tetrahydrocannabinol?  At first inspection of the middle and bottom structures, the answer, might be ‘no,’ because the ether link in the pyran unit has been cleaved.  However, there is clearly a strong structural relationship between the two bottom structures; they are known as functional group isomers of compounds of the same general formula C21H30O2.  Clearly not all molecules with this empirical formula are going to have the same structural relationship and be classed as cannabinoids, but these two certainly are.  In the bottom structure, I have marked the OH group with an asterisk and the isoprenyl unit with a double asterisk to show that simple acidic mediation could facilitate ring closure of the bottom structure to give the middle structure with no overall gain or loss of hydrogen (or any other atoms).  This is supported by the e-mail communication with ESR (Robyn Somerville; 10-02-2012).  Clause 2 in part B1 is silent with respect to the definition of isomers as to what type of isomerism is allowed or disallowed.

The first principles definition of an isomer is ‘compounds with the same formula but different chemical structures.’  This definition allows for functional group isomerism of the type discussed above as well as the more familiar geometric isomerism about double bonds (cis-/trans-) or diastereoisomers and enantiomers (different 3D spatial orientations of functional groups).  Therefore, clause 2 of B1 could adequately capture CBD under the isomer provision and it could be considered in the broad sense as ‘any tetrahydrocannabinol.’  In addition, under part 2, ‘Interpretation,’ the definition of a controlled drug includes any analogue and the definition of a controlled drug analogue under the same part includes ‘any substance… that has a structure substantially similar to that of any controlled drug.’  I have already described the similarities between the two structures and given only one bond is cleaved/formed between the two of them, would consider them substantially similar in the chemical sense.

I hope this helps to clarify any chemical interpretative aspects of the communication.

I will leave the other hemp versus cannabis interpretations to others in Medicines Control to deal with.  If there are any aspects of the above document that you would like me to clarify, please do not hesitate to get back in touch.

Kind regards

Dennis