Abstract
Purpose
The recent release of a medical cannabis strain has given a new impulse for the study of cannabis in Italy. The National Health Service advises to consume medical cannabis by vaporizing, in decoction or oil form. This is the first study that explores the pharmacokinetics and tolerability of a single oral dose of cannabis as decoction (200 ml) or in olive oil (1 ml), as a first step to improve the prescriptive recommendations.
Methods
This is a single-center, open-label, two-period crossover study designed to assess the pharmacokinetics and tolerability of oral cannabis administered to 13 patients with medication overuse headache (MOH). A liquid chromatography tandem-mass spectrometry (LC-MS/MS) method was conducted for the quantification of THC, CBD, 11-OH-THC, THC-COOH, THC-COOH-glucuronide, THCA-A, and CBDA. Blood pressure, heart rate, and a short list of symptoms by numerical rating scale (NRS) were assessed.
Results
Decoctions of cannabis showed high variability in cannabinoids content, compared to cannabis oil. For both preparations, THCA-A and CBDA were the most widely absorbed cannabinoids, while THC and CBD were less absorbed. The most important differences concern the bioavailability of THC, higher in oil (AUC0–24 7.44, 95% CI 5.19, 9.68) than in decoction (AUC0–24 3.34, 95% CI 2.07, 4.60), and the bioavailability of CBDA. No serious adverse events were reported.
Conclusions
Cannabis decoction and cannabis oil showed different pharmacokinetic properties, as well as distinct consequences on patients. This study was performed in a limited number of patients; future studies should be performed to investigate the clinical efficacy in larger populations.
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References
Baron EP (2015) Comprehensive review of medicinal marijuana, cannabinoids, and therapeutic implications in medicine and headache: what a long strange trip it’s been …. Headache 55:885–916
Russo E, Guy GW (2006) A tale of two cannabinoids: the therapeutic rationale for combining tetrahydrocannabinol and cannabidiol. Med Hypotheses 66:234–246
Whiting PF, Wolff RF, Deshpande S et al (2015) Cannabinoids for medical use: a systematic review and meta-analysis. JAMA 357:2456–2473
Grotenhermen F (2003) Pharmacokinetics and pharmacodynamics of cannabinoids. Clin Pharmacokinet 42:327–360
Andrade C (2016) Cannabis and neuropsychiatry, 2: the longitudinal risk of psychosis as an adverse outcome. J Clin Psychiatry 77:e739–e742
Salomonsen-Sautel S, Min SJ, Sakai JT, Thurstone C, Hopfer C (2014) Trends in fatal motor vehicle crashes before and after marijuana commercialization in Colorado. Drug Alcohol Depend 140:137–144
Grella CE, Rodriguez L, Kim T (2014) Patterns of medical marijuana use among individuals sampled from medical marijuana dispensaries in Los Angeles. J Psychoactive Drugs 46:263–272
Harvey DJ (1991) Metabolism and pharmacokinetics of the cannabinoids. In: Watson RR (ed) Biochemistry and physiology of substance abuse, Vol III. CRC Press, Boca Raton, pp 279–365
Wall ME, Sadler BM, Brine D, Taylor H, Perez-Reyes M (1983) Metabolism, disposition, and kinetics of delta-9-tetrahydrocannabinol, in men and women. Clin Pharmacol Ther 34:352–363
Ohlsson A, Lindgren JE, Wahlen A, Agurell S, Hollister LE, Gillespie HK (1980) Plasma delta-9 tetrahydrocannabinol concentrations and clinical effects after oral and intravenous administration and smoking. Clin Pharmacol Ther 28:409–416
Huestis MA (2007) Human cannabinoid pharmacokinetics. Chem Biodivers 4:1770–1804
Harvey DJ, Mechoulam R (1990) Metabolites of cannabidiol identified in human urine. Xenobiotica 20:303–320
Jung J, Meyer MR, Maurer HH, Neusüss C, Weinmann W, Auwärter V (2009) Studies on the metabolism of the Delta9-tetrahydrocannabinol precursor Delta9-tetrahydrocannabinolic acid A (Delta9-THCA-A) in rat using LC-MS/MS, LC-QTOF MS and GC-MS techniques. J Mass Spectrom 44:1423–1433
Dussy FE, Hamberg C, Luginbühl M, Schwerzmann T, Briellmann TA (2005) Isolation of Delta9-THCA-A from hemp and analytical aspects concerning the determination of Delta9-THC in cannabis products. Forensic Sci Int 149:3–10
Jung J, Kempf J, Mahler H, Weinmann W (2007) Detection of Delta9-tetrahydrocannabinolic acid A in human urine and blood serum by LC-MS/MS. J Mass Spectrom 42:354–360
Website: Decreto 9 Novembre 2015: Funzioni di Organismo statale per la cannabis previsto dagli articoli 23 e 28 della convenzione unica sugli stupefacenti del 1961, come modificata nel 1972. Available at: http://www.gazzettaufficiale.it/eli/id/2015/11/30/15A08888/sg;jsessionid=p1rnwNujUKlqQ5azhAQ95A__.NTC-AS3-GURI2A. Accessed 30 Dec 2017
Website: Attuazione della legge regionale n. 11 del 17 luglio 2014 e del Decreto Ministeriale 9 novembre 2015 inerenti l’uso medico dei preparati vegetali a base di cannabis sativa. Available at: http://salute.regione.emilia-romagna.it/documentazione/leggi/regionali/dgr-2127-2016/dgr-1250-2016/at_download/file/dgr-1250-2016-cannabis.pdf. Accessed 30 Dec 2017
Romano LL, Hazekamp A (2013) Cannabis oil: chemical evaluation of an upcoming cannabis-based medicine. Cannabinoids 1:1–11
Pacifici R, Marchei E, Salvatore F, Guandalini L, Busardò FP, Pichini S (2017) Evaluation of long-term stability of cannabinoids in standardized preparations of cannabis flowering tops and cannabis oil by ultra-high-performance liquid chromatography tandem mass spectrometry. Clin Chem Lab Med
Headache Classification Committee of the International Headache Society (IHS) (2013) The international classification of headache disorders, 3rd edition (beta version). Cephalalgia 33:629–808
Palazzoli F, Citti C, Licata M, Vilella A, Manca L, Zoli M, Vandelli MA, Forni F, Cannazza G (2017) Development of a simple and sensitive liquid chromatography triple quadrupole mass spectrometry (LC-MS/MS) method for the determination of cannabidiol (CBD), Δ9-tetrahydrocannabinol (THC) and its metabolites in rat whole blood after oral administration of a single high dose of CBD. J Pharm Biomed Anal 150:25–32
Zhang Y, Huo M, Zhou J, Xie S (2010) PKSolver: an add-in program for pharmacokinetic and pharmacodynamic data analysis in Microsoft Excel. Comput Methods Prog Biomed 99:306–314
Kandasamy R, Dawson CT, Craft RM, Morgan MM (2018) Anti-migraine effect of ∆9-tetrahydrocannabinol in the female rat. Eur J Pharmacol 818:271–277
Hazekamp A, Bastola K, Rashidi H, Bender J, Verpoorte R (2007) Cannabis tea revisited: a systematic evaluation of the cannabinoid composition of cannabis tea. J Ethnopharmacol 113:85–90
Hazekamp A, Verpoorte R (2006) Structure elucidation of the tetrahydrocannabinol complex with randomly methylated beta-cyclodextrin. Eur J Pharm Sci 29:340–347
Carcieri C, Tomasello C, Simiele M, De Nicolò A, Avataneo V, Canzoneri L, Cusato J, Di Perri G, D'Avolio A (2018) Cannabinoids concentration variability in cannabis olive oil galenic preparations. J Pharm Pharmacol 70(1):143–149
Pini LA, Guerzoni S, Cainazzo MM, Ferrari A, Sarchielli P, Tiraferri I, Ciccarese M, Zappaterra M (2012) Nabilone for the treatment of medication overuse headache: results of a preliminary double-blind, active-controlled, randomized trial. J Headache Pain 13(8):677–684
Vandrey R, Herrmann ES, Mitchell JM, Bigelow GE, Flegel R, LoDico C, Cone EJ (2017) Pharmacokinetic profile of oral cannabis in humans: blood and oral fluid disposition and relation to pharmacodynamic outcomes. J Anal Toxicol 41:83–99
Klein C, Karanges E, Spiro A, Wong A, Spencer J, Huynh T, Gunasekaran N, Karl T, Long LE, Huang XF, Liu K, Arnold JC, McGregor IS (2011) Cannabidiol potentiates Δ9-tetrahydrocannabinol (THC) behavioural effects and alters THC pharmacokinetics during acute and chronic treatment in adolescent rats. Psychopharmacology 218:443–457
Jiang R, Yamaori S, Takeda S, Yamamoto I, Watanabe K (2011) Identification of cytochrome P450 enzymes responsible for metabolism of cannabidiol by human liver microsomes. Life Sci 89:165–170
Eichler M, Spinedi L, Unfer-Grauwiler S, Bodmer M, Surber C, Luedi M, Drewe J (2012) Heat exposure of Cannabis sativa extracts affects the pharmacokinetic and metabolic profile in healthy male subjects. Planta Med 78:686–691
Ruhaak LR, Felth J, Karlsson PC, Rafter JJ, Verpoorte R, Bohlin L (2011) Evaluation of the cyclooxygenase inhibiting effects of six major cannabinoids isolated from Cannabis sativa. Biol Pharm Bull 34:774–778
De Petrocellis L, Ligresti A, Schiano Moriello A, Iappelli M, Verde R, Stott CG, Cristino L, Orlando P, Di Marzo V (2013) Non-THC cannabinoids inhibit prostate carcinoma growth in vitro and in vivo: pro-apoptotic effects and underlying mechanisms. Br J Pharmacol 168:79–102
Rock EM, Kopstick RL, Limebeer CL, Parker LA (2013) Tetrahydrocannabinolic acid reduces nausea-induced conditioned gaping in rats and vomiting in Suncus murinus. Br J Pharmacol 170:641–648
Bolognini D, Rock EM, Cluny NL, Cascio MG, Limebeer CL, Duncan M, Stott CG, Javid FA, Parker LA, Pertwee RG (2013) Cannabidiolic acid prevents vomiting in Suncus murinus and nausea-induced behaviour in rats by enhancing 5-HT1A receptor activation. Br J Pharmacol 168:1456–1470
Brierley DI, Samuels J, Duncan M, Whalley BJ, Williams CM (2016) Neuromotor tolerability and behavioural characterisation of cannabidiolic acid, a phytocannabinoid with therapeutic potential for anticipatory nausea. Psychopharmacology 233:243–254
Acknowledgments
We sincerely thank the staff and patients of Medical Toxicology and Headache Centre of Modena, who made possible the realization of the study.
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The study was approved by the Ethical Committee of Modena (protocol n. 41/2017) and completed in accordance with the ethical standards of the Helsinki Declaration. Written informed consent was obtained from all patients prior to study participation.
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The authors declare that they have no conflict of interest.
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Pellesi, L., Licata, M., Verri, P. et al. Pharmacokinetics and tolerability of oral cannabis preparations in patients with medication overuse headache (MOH)—a pilot study. Eur J Clin Pharmacol 74, 1427–1436 (2018). https://doi.org/10.1007/s00228-018-2516-3
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DOI: https://doi.org/10.1007/s00228-018-2516-3