Δ9-Tetrahydrocannabinolic acid A (Δ9-THCA-A) is the biosynthetic precursor of Δ9-tetrahydrocannabinol (Δ9-THC) in plant material of cannabis sativa, without having psychoactive effects . Δ9-THCA-A is not contained in pharmaceutical Δ9-THC formulations. Thus, Δ9-THCA-A can serve as a marker for differentiating between the consumption of illegal cannabis products and legal fully synthetic Δ9-THC

Chatzinikolaou, Fotios

Goulas, Antonios

Koutsoukis, Dimitrios

Kyriazou, Angeliki

Raikos, Nikolaos

Sidiras, Georgios

English

Aristotle University of Thessaloniki: Open Journals / ΑΡΙΣΤΟΤΕΛΕΙΟ ΠΑΝΕΠΙΣΤΗΜΙΟ ΘΕΣΣΑΛΟΝΙΚΗΣ

_____________________________________________________________________________________________________ BRIEF REPORT Δ9-tetrahydrocannabinolic acid A: a reliable marker for differentiating between the consumption of illegal cannabis products and legal, medical Δ9-THC  Angeliki Kyriazou1, Fotios Chatzinikolaou1, Dimitrios Koutsoukis1, Antonios Goulas2, Georgios Sidiras 1, Nikolaos Raikos 1*  1Laboratory of Forensic Medicine and Toxicology, Medical School, Aristotle University, 54124 Thessaloniki, Greece 2Department of Pharmacology, Medical School, Aristotle University of Thessaloniki  ABSTRACT:  Δ9-Tetrahydrocannabinolic acid A (Δ9-THCA-A) is the biosynthetic precursor of Δ9-tetrahydrocannabinol (Δ9-THC) in plant material of cannabis sativa, without having psychoactive effects . Δ9-THCA-A is not contained in pharmaceutical Δ9-THC formulations. Thus, Δ9-THCA-A can serve as a marker for differentiating between the consumption of illegal cannabis products and legal fully synthetic Δ9-THC.  Key Words: Cannabis, Δ9- tetrahydrocannabinol, Δ9- tetrahydrocannabinolic acid  Cannabis is the most popular recreational drug globally 1. The resin of Cannabis plant contains more than 84 chemical compounds with psychoactive effects, known as cannabinoids, the most efficacious of which is Δ9-tetrahydrocannabinol (Δ9-THC)2. The biogenesis of Δ9-THC starts with olivetolic acid, that is produced in the plant from the condensation of hexanoyl-CoA with three molecules of malonyl-CoA. In the next step, olivetolic acid is alkylated to cannabigerolic acid, which is then converted to cannabinolic acid. Cannabinolic acid is the precursor of Δ9-tetrahydrocannabinolic acid A (Δ9-THCA-A or Δ9-THCA). Δ9-THCA-A is a non-psychoactive substance that is decarboxylated to Δ9-THC via heating, when cannabis products are smoked 3.  The therapeutic effects of Δ9-THC have been known since ancient times,  when cannabis was used as a medicine for many different pathological conditions such as insomnia, headaches, gastrointestinal disorders and pain 4. Nowadays the cultivation,  possession and transfer of cannabis is illegal in most of the European countries and is convicted by law. On the other hand, medical Δ9-THC is provided, mainly in the U.S, to treat a range of diseases and the ensuing symptoms. Marinol® (U.S, Canada) is an oral drug containing fully synthetic  Δ9-THC, known as dronabinol and is used to treat anorexia in people suffering from AIDS, and also to minimize nausea and vomiting associated with cancer therapy5.  Another popular pharmaceutical compound, used to treat spasticity and neuropathic pain associated with multiple schlerosis, is Sativex® (U.S, Europe, New Zealand). Sativex® is an oromucosal spray which contains nabiximols, a mixture of compounds derived from cannabis plant. The principal cannabinoid components of the drug are synthetic Δ9-THC and cannabidiol 6.   The high popularity of illegal cannabis and the use of legal fully synthetic Δ9-THC in recent years, demonstrated the need to find reliable markers in biological samples for differentiating between the consumption of illegal cannabis products and legal medication containing fully synthetic Δ9-THC.  Δ9-THCA-A could serve as a marker of illegal consumption of cannabis products if the substance is detected in biological samples of cannabis users. Δ9-THCA-A attracted scientists' attention in recent years, as it is the precursor substance of natural Δ9-THC in plant material and is not contained in Marinol® or Sativex®. In 2005, it was shown that during smoking cannabis joint, Δ9-THCA-A is only partially converted to Δ9-THC and therefore it can be taken up by the consumer 7.  In 2007, Jung et al. detected Δ9-THCA-A in the urine and blood serum samples collected from police controls of drivers suspected for driving under the influence of drugs (DUID). Liquid chromatography tandem-mass spectrometry (LC-MS/MS) was used for Δ9-THCA-A determination. Δ9-THCA-A was detected in the urine and blood serum samples of cannabis users in concentrations of up to 10.8 ng/ml in urine and 14.8 ng/ml in serum. The concentration of Δ9-THC was higher than the concentration of Δ9-THCA-A in most serum samples 8. In the above paper, Δ9-THCCOOH-D3 was used as internal standard (IS) because the isotopically labeled Δ9-THCA-A was not commercially available.  In 2012, Roth et al. succeeded to synthesize deuterated Δ9-THCA-A 9. Metabolism studies of Δ9-THCA-A in rats showed that the main metabolites of THCA-A were formed in close analogy to Δ9-THC metabolism and twelve metabolites were identified 10.    In 2013, Brabanter N. et al. developed a fast method for quantification of Δ9-THCA-A in urine using microwave-accelerated derivatization and gas chromatography–triple quadrupole mass spectrometry. Their method could quantify Δ9-THCA-A in 30 min, using only 1 mL of urine 11. In 2013, Raikos N. et al. analyzed fifty eight authentic whole blood and the respective plasma samples collected from drivers suspected for driving under the influence of cannabis, using LC-MS/MS. Δ9-THCA-A concentrations ranged from 1.0 to 496 ng/mL in blood samples and from 1.4 to 824 ng/mL in plasma samples. Δ9-THC was present in all blood samples with levels ranging from 0.7 to 51 ng/mL. The plasma:blood partition coefficient had a mean value of 1.7  12. In 2010, Auwarter et al. concluded that Δ9-THCA-A can  be incorporated in hair only by external contamination e.g. by condensate of smoked cannabis material and not by blood *Corresponding author: Raikos Nikolaos, Laboratory of Forensic Medicine and Toxicology, Medical School, Aristotle University, 54124 Thessaloniki, Tel.:+30 2310 999206, Fax: +30 2310 999216, email: raikos@med.auth.gr Δ9-tetrahydrocannabinolic acid A: a reliable marker for legal or illegal Δ9-THC consumption 21  or sweat and Δ9-THCA-A could be a valuable marker for external cannabinoid contamination of hair 13. In conclusion, Δ9-THCA-A can be detected in blood and urine samples of cannabis consumers and this detection in biological fluids may serve as a marker for differentiating between the intake of legally prescribed Δ9-THC medication and illegal cannabis products. However, the knowledge about its usefulness in forensic cases is very limited and further research is needed.   Δ9-τετραϋδροκανναβινολικό οξύ Α: ένας αξιόπιστος δείκτης για τη διάκριση μεταξύ της χρήσης παράνομων προϊόντων της κάνναβης και της λήψης φαρμακευτικής  Δ9-THC.  Κυριάζου Αγγελική1, Χατζηνικολάου Φώτιος1, Κουτσούκης Δημήτριος1, Γούλας  Αντώνιος2, Σιδηράς  Γεώργιος1, Ράικος Νικόλαος1*  1Εργαστήριο Ιατροδικαστικής και Τοξικολογίας, Ιατρική Σχολή, Α.Π.Θ., 54124 Θεσσαλονίκη 2Εργαστήριο Φαρμακολογίας, Ιατρική Σχολή, Α.Π.Θ., 54124 Θεσσαλονίκη  ΠΕΡΙΛΗΨΗ: Το Δ9-τετραϋδροκανναβινολικό οξύ Α (Δ9-THCA-A) αποτελεί την πρόδρομη ουσία της Δ9-τετραϋδροκανναβινόλης (Δ9-THC) στο φυτό cannabis sativa,  χωρίς ψυχοδραστικές ιδιότητες. Το Δ9-THCA-A δεν εμπεριέχεται στα φαρμακευτικά προϊόντα που περιέχουν συνθετική Δ9-THC. Συνεπώς το Δ9-THCA-A μπορεί να χρησιμεύσει ως ένας δείκτης για τη διάκριση μεταξύ της χρήσης παράνομων προϊόντων της κάνναβης και της λήψης φαρμακευτικής  Δ9-THC.  Λέξεις Κλειδιά:Κάνναβη,Δ9-τετραϋδροκανναβινόλη, Δ9-τετραϋδροκανναβινολικό οξύ A22 Aristotle University Medical Journal, Vol. 41, Issue 2, June 2014    REFERENCES  1. EMCDDA: “A cannabis reader. Global issues and local experiences: Perspectives on cannabis controversies, treatment and regulation in Europe.” European Monitoring Centre for Drugs and Drug Addiction (2007), Lisbon. 2. Ethan B. Russo: “Cannabis and Cannabinoids: Pharmacology, Toxicology and Therapeutic Potential.” Routledje (2013), 28. 3. Steve J. Gagne, Jake M. Stout, Enwu Liu et al.: “Identification of olivetolic acid cyclase from Cannabis sativa reveals a unique catalytic route to plant polyketides.” PNAS (2012), 109 (31):12811-16. 4. Procon.org “History of Marijuana as Medicine - 2900 BC to Present” http://medicalmarijuana.procon.org/view.timeline.php?timelineID=000026. 5. Product Information of Marinol1, Unimed Pharmaceuticals, Mariette, GA, USA (2006). 6. Wade D, Makela P, House H, Bateman C, Robson P: “Long-term use of a cannabis-based medicine in the treatment of spasticity and other symptoms in multiple sclerosi.” Mult Scler (2006) 12 (5): 639–45. 7. Dussy F.E, Hamberg C, Luginbuhl M, Schwerzmann T, Briellmann T.A: “Isolation of D9-THCA-A from hemp and analytical aspects concerning the determination of D9-THC in cannabis products,” Forensic Sci. Int. (2005), 149:3–10. 8. Jung J, Kempf J, Mahler H, Weinmann W: “Detection of 19-tetrahydrocannabinolic acid A in human urine and blood serum by LC–MS/MS.” J. Mass Spectrom. (2007), 42:354–360. 9. Roth N, Wohlfarth A, Muller M, Auwarter  V: “Regioselective synthesis of isotopically labeled D9-tetrahydrocannabinolic acid A (THCA-A-D3) by reaction of D9-tetrahydrocannabinol-D3 with magnesium methyl carbonate.” Forensic Science International  (2012), 222:368–372. 10. Jung J, Meyer M.R, Maurer H.H, Neususs C, Weinmann W, Auwarter V: “Studies on the metabolism of the D9-tetrahydrocannabinol precursor D9-tetrahydrocannabinolic acid A (D9-THCA-A) in rat using LC–MS/MS, LC–QTOF MS and GC–MS techniques” J. Mass Spectrom  (2007) 44:1423–1433. 11. Brabanter N, Gansbeke W. et al.: “Fast quantification of 11-nor-D9-tetrahydrocannabinol-9-carboxylic acid (THCA) using microwave-accelerated derivatisation and gas chromatography–triple quadrupole mass spectrometry.”  Forensic Science International (2013) 90- 95. 12. Raikos N, Schmid H, Roth N, Auwärter V, Lanz  S, Läng A, König S, Weinmann W: “Determination of delta-9 tetrahydrocannabinolic acid A (delta-9-THCA-A) in whole blood and plasma by LC-MS/MS and application in authentic samples from drivers suspected of driving under the influence of cannabis.” 51st Annual Meeting  of The International Association of Forensic Toxicologists, Poster Session (2013). 13. Auwarter V, Wohlfarth A, Traber J, Thieme D, Weinmann W: “Hair analysis for Δ9-tetrahydrocannabinolic acid A—New insights into the mechanism of drug incorporation of cannabinoids into hair” Forensic Sci. Int. (2010) 196 :10–13.  

Δ9-tetrahydrocannabinolic acid A: a reliable marker for ifferentiating between the consumption of illegal cannabis products and legal, medical Δ9-THC

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Δ9-tetrahydrocannabinolic acid A: a reliable marker for ifferentiating between the consumption of illegal cannabis products and legal, medical Δ9-THC

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Aristotle University of Thessaloniki: Open Journals / ΑΡΙΣΤΟΤΕΛΕΙΟ ΠΑΝΕΠΙΣΤΗΜΙΟ ΘΕΣΣΑΛΟΝΙΚΗΣ