Conversion of CBD to THC explained

Cannabidiol (CBD) can be chemically converted into tetrahydrocannabinol (THC) via a ring-closing reaction.^{[1] [2] [3]} This cyclization can be acid-catalyzed or brought about by heating.^{[4] [5] [6] [7] [8] [9] [10]}

Known methods

Plant cannabinoids 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 THCA to psychoactive cannabinoid 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 begin to form with degradation (the loss is greatly reduced in the absence of oxygen).

• "...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

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.^[22]
• Lewis acids.^[23] - a continuous rather than batch implementation with similar materials
• Catalytic acid solution in 5 minutes in a microwave with a 40% Δ9 and 35% Δ8 yield^[24]
• (−)-Δ8-THC, which can be converted to trans-(−)-Δ9-THC by addition of HCl followed by dehydrochlorination^{[25] [26] [27]}
• Treatment of the purified Δ8 -THC with hydrogen chloride in the presence of zinc chloride gives the chloro compound which is isolated and subsequently treated with potassium tert-amylate to yield the desired (-)-6a,10 a-trans-Δ9 -tetrahydrocannabinol. 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.^[28]
• Gaoni and Mechoulam^[29] also described a method for converting CBD to Δ9-THC comprising boiling a mixture of CBD in ethanol containing 0.05% hydrogen chloride for 2 hours. Percentage yield of Δ9-THC (Δ1-THC) was 2%.^[30] Using boron trifluoride, the yield was 70%^[31] although purity was not given.^[32]

With zeolite

Methods have been claimed for converting CBD to a mixture of Δ8-THC and Δ9-THC using "Zeolites selected from the group consisting of analcime, chabazite, clinoptilolite, erionite, mordenite, phillipsite, and ferrierite."^[33]

In vivo

There is a debated hypothesis that oral CBD could be converted into THC under acidic conditions in the stomach and then absorbed into the blood stream. However, neither THC nor any of its active metabolites have been detected in blood in animals or humans after ingesting CBD.^[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]

Notes and References

1. Adams R, Baker BR . Structure of Cannabidiol. VII. A Method of Synthesis of a Tetrahydrocannabinol which Possesses Marihuana Activity. . Journal of the American Chemical Society . September 1940 . 62 . 9 . 2405–2408 . 10.1021/ja01866a041 .
2. 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 cannabinol. . Journal of the American Chemical Society . September 1940 . 62 . 9 . 2402–2405 . 10.1021/ja01866a040 .
3. Adams R, Pease DC, Cain CK, Baker BR, Clark JH, Wolff H, Wearn RB . 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 . August 1940 . 62 . 8 . 2245–2246 . 10.1021/ja01865a508 .
4. Book: Razdan RK . The Total Synthesis of Cannabinoids. . Total Synthesis of Natural Products . ApSimon J . John Wiley & Sons. January 1981 . 4 . 185–262 . 978-0-470-12953-1 . 10.1002/9780470129678.ch2 .
5. Bloemendal VR, van Hest JC, Rutjes FP . Synthetic pathways to tetrahydrocannabinol (THC): an overview. . Organic & Biomolecular Chemistry . 2020 . 18 . 3203–3215 . 3203–3215 . 10.1039/D0OB00464B . 32259175 . 2066/218829 . free .
6. Bloemendal VR, Spierenburg B, Boltje TJ, van Hest JC, Rutjes FP . One-flow synthesis of tetrahydrocannabinol and cannabidiol using homo-and heterogeneous Lewis acids. . Journal of Flow Chemistry . June 2021 . 11 . 2 . 99–105 . 10.1007/s41981-020-00133-2 . free .
7. Hurrle T, Gläser F, Bröhmer MC, Nieger M, Bräse S . The Diels-Alder Approach towards Cannabinoid Derivatives and Formal Synthesis of Tetrahydrocannabinol (THC) . ChemistryOpen . 10 . 5 . 587–592 . May 2021 . 33988908 . 8121136 . 10.1002/open.202000343 .
8. Bassetti B, Hone CA, Kappe CO . Continuous-Flow Synthesis of Δ9-Tetrahydrocannabinol and Δ8-Tetrahydrocannabinol from Cannabidiol . The Journal of Organic Chemistry . 88 . 9 . 6227–6231 . May 2023 . 37014222 . 10167683 . 10.1021/acs.joc.3c00300 .
9. Ujváry I . Hexahydrocannabinol and closely related semi-synthetic cannabinoids: A comprehensive review . Drug Testing and Analysis . 16 . 2 . 127–161 . February 2024 . 37269160 . 10.1002/dta.3519 .
10. Capucciati A, Casali E, Bini A, Doria F, Merli D, Porta A . Easy and Accessible Synthesis of Cannabinoids from CBD . Journal of Natural Products . 87 . 4 . 869–875 . April 2024 . 38427968 . 10.1021/acs.jnatprod.3c01117 .
11. Huang S, Claassen FW, van Beek TA, Chen B, Zeng J, Zuilhof H, Salentijn GI . Rapid Distinction and Semiquantitative Analysis of THC and CBD by Silver-Impregnated Paper Spray Mass Spectrometry . Analytical Chemistry . 93 . 8 . 3794–3802 . March 2021 . 33576613 . 8023514 . 10.1021/acs.analchem.0c04270 .
12. Caprari C, Ferri E, Vandelli MA, Citti C, Cannazza G . An emerging trend in Novel Psychoactive Substances (NPSs): designer THC . Journal of Cannabis Research . 6 . 1 . 21 . May 2024 . 38702834 . 11067227 . 10.1186/s42238-024-00226-y . free .
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14. Czégény Z, Nagy G, Babinszki B, Bajtel Á, Sebestyén Z, Kiss T, Csupor-Löffler B, Tóth B, Csupor D . CBD, a precursor of THC in e-cigarettes . Scientific Reports . 11 . 1 . 8951 . April 2021 . 33903673 . 8076212 . 10.1038/s41598-021-88389-z . 2021NatSR..11.8951C .
15. Citti C, Russo F, Linciano P, Strallhofer SS, Tolomeo F, Forni F, Vandelli MA, Gigli G, Cannazza G . Origin of Δ9-Tetrahydrocannabinol Impurity in Synthetic Cannabidiol . Cannabis and Cannabinoid Research . 6 . 1 . 28–39 . 2021 . 33614950 . 7891213 . 10.1089/can.2020.0021 .
16. ((Moreno, T.)), ((Dyer, P.)), ((Tallon, S.)) . Industrial & Engineering Chemistry Research . Cannabinoid Decarboxylation: A Comparative Kinetic Study . 59 . 46 . 20307–20315 . 18 November 2020 . 0888-5885 . 10.1021/acs.iecr.0c03791 . 17 May 2024.
17. Mechoulam R, Hanus L . Cannabidiol: an overview of some chemical and pharmacological aspects. Part I: chemical aspects . Chemistry and Physics of Lipids . 121 . 1–2 . 35–43 . December 2002 . 12505688 . 10.1016/s0009-3084(02)00144-5 .
18. Gaoni Y, Mechoulam R . Hashish—VII: The isomerization of cannabidiol to tetrahydrocannabinols. . Tetrahedron . January 1966 . 22 . 4 . 1481–1488 . 10.1016/S0040-4020(01)99446-3 .
19. Kiselak TD, Koerber R, Verbeck GF . 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 . March 2020 . 32028121 . 10.1016/j.forsciint.2020.110173 .
20. Nelson KM, Bisson J, Singh G, Graham JG, Chen SN, Friesen JB, Dahlin JL, Niemitz M, Walters MA, Pauli GF . The Essential Medicinal Chemistry of Cannabidiol (CBD) . Journal of Medicinal Chemistry . 63 . 21 . 12137–12155 . November 2020 . 32804502 . 10.1021/acs.jmedchem.0c00724 . 7666069 .
21. Golombek P, Müller M, Barthlott I, Sproll C, Lachenmeier DW . Conversion of Cannabidiol (CBD) into Psychotropic Cannabinoids Including Tetrahydrocannabinol (THC): A Controversy in the Scientific Literature . Toxics . 8 . 2 . 41 . June 2020 . 32503116 . 7357058 . 10.3390/toxics8020041 . free .
22. Peng H, Shahidi F . Cannabis and Cannabis Edibles: A Review . Journal of Agricultural and Food Chemistry . 69 . 6 . 1751–1774 . February 2021 . 33555188 . 10.1021/acs.jafc.0c07472 .
23. Marzullo P, Foschi F, Coppini DA, Fanchini F, Magnani L, Rusconi S, Luzzani M, Passarella D . Cannabidiol as the Substrate in Acid-Catalyzed Intramolecular Cyclization . Journal of Natural Products . 83 . 10 . 2894–2901 . October 2020 . 32991167 . 8011986 . 10.1021/acs.jnatprod.0c00436 .
24. Ramirez GA, Tesfatsion TT, Docampo-Palacios ML, Cruces I, Hellmann AJ, Okhovat A, Pittiglio MK, Ray KP, Cruces W . Ultrasonic or Microwave Modified Continuous Flow Chemistry for the Synthesis of Tetrahydrocannabinol: Observing Effects of Various Solvents and Acids . ACS Omega . 9 . 11 . 13191–13199 . March 2024 . 38524441 . 10956408 . 10.1021/acsomega.3c09794 .
25. Mechoulam R, Braun P, Gaoni Y . A stereospecific synthesis of (-)-delta 1- and (-)-delta 1(6)-tetrahydrocannabinols . Journal of the American Chemical Society . 89 . 17 . 4552–4 . August 1967 . 6046550 . 10.1021/ja00993a072 .
26. Mechoulam R, Braun P, Gaoni Y . Syntheses of 1 -tetrahydrocannabinol and related cannabinoids . Journal of the American Chemical Society . 94 . 17 . 6159–65 . August 1972 . 5054408 . 10.1021/ja00772a038 .
27. Methods for purifying trans-(-)-δ9-tetrahydrocannabinol and trans-(+)-δ9 tetrahydrocannabinol . Gutman AL, Etinger M, Fedotev I, Khanolkar R, Nisnevich G, Pertsikov B, Rukhman I, Tishin B . SVC Pharma LP . 14 July 2016 . Abandoned . US . 20160199344 .
28. Process for the preparation of (-)-6a,10a-trans-6a,7,8,10a-tetrahydrodibenzo[b,d]-pyrans ]. Razdan RK, Dalzell HC . Application filed by Sheehan John C Institute for Research Inc. . 24 May 1977 . US . 4025516 .
29. Gaoni Y, Mechoulam R . Isolation, structure, and partial synthesis of an active constituent of hashish. . Journal of the American Chemical Society . April 1964 . 86 . 8 . 1646–1647 . 10.1021/ja01062a046 .
30. Mechoulam R, Gaoni Y . A total synthesis of dl-Δ1-tetrahydrocannabinol, the active constituent of hashish . Journal of the American Chemical Society . 87 . 14. 3273–5 . July 1965 . 14324315 . 10.1021/ja01092a065 .
31. Gaoni Y, Mechoulam R . The isolation and structure of delta-1-tetrahydrocannabinol and other neutral cannabinoids from hashish . Journal of the American Chemical Society . 93 . 1 . 217–24 . January 1971 . 5538858 . 10.1021/ja00730a036 .
32. Conversion of CBD to delta8-THC and delta9-THC . Webster GR, Sarna L, Mechoulam R . Full Spectrum Laboratories Ltd. . 15 July 2008 . US . 20040143126 .
33. Zeolite catalyst and method for preparation of aromatic tricyclic pyrans . US . 11352337B1 . Acid Neutral Alkaline Laboratory. . Gindelberger D . 7 June 2022 .