Phytocannabinoids exist like precursors to their pharmacologically active counterparts.[11][12] At least three independent methods have successfully converted CBD to THC.
Despite the CBD and THC having the same molecular weight, multiple analytical methods are able to differentiate them.[11]
"on the recovery of both THC (86.7−90.0%) and CBD (92.3−95.6%). The slightly lower recovery of THC can be explained by the fact that THC is less polar than CBD and more likely to remain in the nonpolar sunflower oil."[11]
By heat
CBD heated to 175,[13] or 250–300 °C may partially be converted into THC.[14] Even at room temperature, trace amounts of THC can be formed as a contaminant in CBD stored for long periods in the presence of moisture and carbon dioxide in the air, with storage under inert gas required to maintain analytically pure CBD.[15]
Heat is required to decarboxylate the non-psychoactive phytocannabinoid THCA to its psychoactive form, THC. Likewise, CBDA turns into CBD.
From hemp plant material in an oven, cannabinoid concentration plots (time/temp) show THC:[16]
STP 0 minutes 0.20mg/g
140-160C 20 minutes 0.27mg/g
140-160C 60 minutes 0.05-0.15mg/g
120C 45 minutes 0.27mg/g
120C 90 minutes 0.20mg/g
100C 90 minutes 0.25mg/g
80C 120 minutes 0.24mg/g
Multiple oxidation products form during degradation in the presence of oxygen, a process known as thermolysis In contrast, the absence of oxygen leads to a process called pyrolysis which significantly reduces the loss.
"...the boiling point for THC has been determined at 157 °C, and the boiling point range for CBD sits between 160 and 180 °C."[16]
With acid
Mechanism of the acid catalyzed conversion of CBD into THC
CBD converts to various isomers of THC with catalysts in acidic environments.[17] A wide variety of acids can be used, though different conditions result in varying yield and formation of characteristic impurities.[18][19][20][21]
Adding protons until the CBD sterically-hindered alcohol functional group cyclises to the pyran ring of THC.[23]
Lewis acids.[24] - a continuous rather than batch implementation with similar materials[8]
Gaoni and Mechoulam[25] also described a method for converting CBD to Δ9-THC comprising refluxing a mixture of CBD in ethanol containing 0.05% hydrogen chloride for 2 hours. Percentage yield of Δ9-THC (Δ1-THC) was 2%.[26][27] Using boron trifluoride, the yield was 70%[28] although purity was not given.[29]
When CBD is treated with acid, Δ-8-Tetrahydrocannabinol may form as an impurity.[22] Nevertheless, Δ-8-Tetrahydrocannabinol can be isolated and subsequently converted into THC.
Treatment of the purified Δ8 -THC under Lucas' reagent gives the chloro compound. Following treatment with potassium tert-amylate, the desired (-)-6a,10 a-trans-Δ9 -tetrahydrocannabinol is yielded. The Mechoulam and Petrzilka methods require three steps and involve at least two careful chromatographic separations to obtain (-)-6a,10 a-trans-Δ9 -tetrahydrocannabinol of high purity.[33]
In vivo
Oral
There is a debated hypothesis that oral CBD could be metabolized into THC under acidic conditions in the stomach and then absorbed into the bloodstream. However, neither THC nor any of its active metabolites have been detected in blood in animals or humans after ingesting CBD.[21][11] There is no direct evidence of the conversion of CBD to THC in the human gut; both CBD and THC are excreted unchanged within human feces.[20]
History
The conversion of CBD to THC by an acid based cyclization reaction was first patented by Roger Adams in the 1940s.[34]
^Adams R, Baker BR (September 1940). "Structure of Cannabidiol. VII. A Method of Synthesis of a Tetrahydrocannabinol which Possesses Marihuana Activity". Journal of the American Chemical Society. 62 (9): 2405–2408. doi:10.1021/ja01866a041.
^Adams R, Pease DC, Cain CK, Clark JH (September 1940). "Structure of cannabidiol. VI. Isomerization of cannabidiol to tetrahydrocannabinol, a physiologically active product. Conversion of cannabidiol to cannabinol". Journal of the American Chemical Society. 62 (9): 2402–2405. doi:10.1021/ja01866a040.
^Adams R, Pease DC, Cain CK, Baker BR, Clark JH, Wolff H, et al. (August 1940). "Conversion of cannabidiol to a product with marihuana activity. A type reaction for synthesis of analogous substances. Conversion of cannabidiol to cannabinol". Journal of the American Chemical Society. 62 (8): 2245–2246. doi:10.1021/ja01865a508.
^Razdan RK (January 1981). "The Total Synthesis of Cannabinoids.". In ApSimon J (ed.). Total Synthesis of Natural Products. Vol. 4. John Wiley & Sons. pp. 185–262. doi:10.1002/9780470129678.ch2. ISBN978-0-470-12953-1.
^Bloemendal VR, van Hest JC, Rutjes FP (2020). "Synthetic pathways to tetrahydrocannabinol (THC): an overview". Organic & Biomolecular Chemistry. 18 (3203–3215): 3203–3215. doi:10.1039/D0OB00464B. hdl:2066/218829. PMID32259175.
^Ujváry I (February 2024). "Hexahydrocannabinol and closely related semi-synthetic cannabinoids: A comprehensive review". Drug Testing and Analysis. 16 (2): 127–161. doi:10.1002/dta.3519. PMID37269160.
^Capucciati A, Casali E, Bini A, Doria F, Merli D, Porta A (April 2024). "Easy and Accessible Synthesis of Cannabinoids from CBD". Journal of Natural Products. 87 (4): 869–875. doi:10.1021/acs.jnatprod.3c01117. PMID38427968.
^Mechoulam R, Hanus L (December 2002). "Cannabidiol: an overview of some chemical and pharmacological aspects. Part I: chemical aspects". Chemistry and Physics of Lipids. 121 (1–2): 35–43. doi:10.1016/s0009-3084(02)00144-5. PMID12505688.
^Gaoni Y, Mechoulam R (January 1966). "Hashish—VII: The isomerization of cannabidiol to tetrahydrocannabinols". Tetrahedron. 22 (4): 1481–1488. doi:10.1016/S0040-4020(01)99446-3.
^Kiselak TD, Koerber R, Verbeck GF (March 2020). "Synthetic route sourcing of illicit at home cannabidiol (CBD) isomerization to psychoactive cannabinoids using ion mobility-coupled-LC-MS/MS". Forensic Science International. 308: 110173. doi:10.1016/j.forsciint.2020.110173. PMID32028121.
^Peng H, Shahidi F (February 2021). "Cannabis and Cannabis Edibles: A Review". Journal of Agricultural and Food Chemistry. 69 (6): 1751–1774. doi:10.1021/acs.jafc.0c07472. PMID33555188.
^Gaoni Y, Mechoulam R (April 1964). "Isolation, structure, and partial synthesis of an active constituent of hashish". Journal of the American Chemical Society. 86 (8): 1646–1647. doi:10.1021/ja01062a046.
^ abMechoulam R, Braun P, Gaoni Y (August 1972). "Syntheses of 1 -tetrahydrocannabinol and related cannabinoids". Journal of the American Chemical Society. 94 (17): 6159–65. doi:10.1021/ja00772a038. PMID5054408.
^Mechoulam R, Gaoni Y (July 1965). "A total synthesis of dl-Δ1-tetrahydrocannabinol, the active constituent of hashish". Journal of the American Chemical Society. 87 (14): 3273–5. doi:10.1021/ja01092a065. PMID14324315.
^Gaoni Y, Mechoulam R (January 1971). "The isolation and structure of delta-1-tetrahydrocannabinol and other neutral cannabinoids from hashish". Journal of the American Chemical Society. 93 (1): 217–24. doi:10.1021/ja00730a036. PMID5538858.
^US 20040143126, Webster GR, Sarna L, Mechoulam R, "Conversion of CBD to delta8-THC and delta9-THC", issued 15 July 2008, assigned to Full Spectrum Laboratories Ltd.
^US 11352337B1, Gindelberger D, "Zeolite catalyst and method for preparation of aromatic tricyclic pyrans", issued 7 June 2022, assigned to Acid Neutral Alkaline Laboratory.
^Mechoulam R, Braun P, Gaoni Y (August 1967). "A stereospecific synthesis of (-)-delta 1- and (-)-delta 1(6)-tetrahydrocannabinols". Journal of the American Chemical Society. 89 (17): 4552–4. doi:10.1021/ja00993a072. PMID6046550.
^US Abandoned 20160199344, Gutman AL, Etinger M, Fedotev I, Khanolkar R, Nisnevich G, Pertsikov B, Rukhman I, Tishin B, "Methods for purifying trans-(-)-δ9-tetrahydrocannabinol and trans-(+)-δ9 tetrahydrocannabinol", published 14 July 2016, assigned to SVC Pharma LP
^US 4025516, Razdan RK, Dalzell HC, "Process for the preparation of (-)-6a,10a-trans-6a,7,8,10a-tetrahydrodibenzo[b,d]-pyrans", issued 24 May 1977, assigned to Application filed by Sheehan John C Institute for Research Inc.
