Thebaine (paramorphine), also known ascodeine methyl enol ether, is anopiatealkaloid, its name coming from theGreek Θῆβαι,Thēbai (Thebes), an ancient city inUpper Egypt. A minor constituent ofopium, thebaine is chemically similar to bothmorphine andcodeine, but has stimulatory rather than depressant effects. At high doses, it causes convulsions similar tostrychnine poisoning. The syntheticenantiomer (+)-thebaine does show analgesic effects apparently mediated through opioid receptors, unlike the inactive natural enantiomer (−)-thebaine.[3] While thebaine is not used therapeutically, it is the main alkaloid extracted fromPapaver bracteatum (Iranian opium / Persian poppy) and can be converted industrially into a variety of compounds that do have medicinal value, includinghydrocodone,hydromorphone,oxycodone,oxymorphone,nalbuphine,naloxone,naltrexone,buprenorphine,butorphanol andetorphine.[4]
Thebaine is controlled under international law, is listed as a Class A drug under theMisuse of Drugs Act 1971 in the United Kingdom, is controlled as an analog of a Schedule II drug per theAnalog Act in the United States, and is controlled with its derivatives and salts, as a Schedule I substance of theControlled Drugs and Substances Act in Canada.[5] The 2013 USDrug Enforcement Administration (DEA) aggregate manufacturing quota for thebaine (ACSCN 9333) was unchanged from the previous year at 145 metric tons.
In 2012, 146,000 kilograms of thebaine were produced.[6] In 2013, Australia was the main producer ofpoppy straw rich in thebaine, followed by Spain and then France. By 2017, worldwide thebaine production dropped to 2,008 kg.[7] Together, those three countries accounted for about 99 per cent of global production of such poppy straw. The seed capsules ofPapaver bracteatum are the primary source of thebaine, with the stem additionally yielding a significant amount.[8][9]
The Canberra Times of 16 November 2022[10] reported that four batches of Hoyts brandpoppy seeds were being recalled due to unusually high levels of thebaine, and that at least twelve people inNew South Wales had required medical attention after ingesting them. As of 15 November 2022,Food Standards Australia New Zealand (FSANZ) is coordinating a national recall of a number of poppy seed products due to the potential presence of thebaine.[11]
The biosynthesis of thebaine starts with the amino acidtyrosine and proceeds viareticuline in a pathway leading to manybenzylisoquinoline alkaloids.[12][13] The final step is catalysed by the enzymethebaine synthase, which forms a2,3-dihydrofuran ring with loss of a molecule of acetic acid from 7-O-acetylsalutaridinol.[14] The reaction occurs spontaneously in alkali but requires catalysis to occur rapidly under physiological conditions near pH 7.[15][16]
The alkaloid product of the reaction, neopinone, can spontaneouslyisomerise to the next intermediate, codeinone, in the pathway to morphine viacodeine but this step is catalysed in opium poppy by the enzymeneopinone isomerase (NISO).[18][13][16]
^Mikus, G.; Somogyi, A. A.; Bochner, F.; Eichelbaum, M. (1991). "Thebaine O-demethylation to oripavine: Genetic differences between two rat strains".Xenobiotica.21 (11):1501–9.doi:10.3109/00498259109044400.PMID1763524.
^Aceto, M. D.; Harris, L. S.; Abood, M. E.; Rice, K. C. (1999). "Stereoselective μ- and δ-opioid receptor-related antinociception and binding with (+)-thebaine".European Journal of Pharmacology.365 (2–3):143–7.doi:10.1016/S0014-2999(98)00862-0.PMID9988096.
^"National Recall of Poppy Seeds".Food Standards Australia New Zealand. Food Standards Australia New Zealand (FSANZ). Archived fromthe original on 24 November 2022. Retrieved21 November 2022.
^abMascavage, Linda M.; Jasmin, Serge; Sonnet, Philip E.; Wilson, Michael; Dalton, David R. (2010). "Alkaloids".Ullmann's Encyclopedia of Industrial Chemistry. pp. 46–54.doi:10.1002/14356007.a01_353.pub2.ISBN978-3-527-30385-4.
^Dastmalchi, Mehran; Chen, Xue; Hagel, Jillian M.; Chang, Limei; Chen, Rongji; Ramasamy, Sukanya; Yeaman, Sam; Facchini, Peter J. (2019). "Neopinone isomerase is involved in codeine and morphine biosynthesis in opium poppy".Nature Chemical Biology.15 (4):384–390.doi:10.1038/S41589-019-0247-0.PMID30886433.
