Abstract
Background:
Cannabis has been used since ancient times to relieve neuropathic pain, to lower intraocular pressure, to increase appetite and finally to decrease nausea and vomiting. The combination of the psychoactive cannabis alkaloid Δ9-tetrahydrocannabinol (THC) with the non-psychotropic alkaloids cannabidiol (CBD) and cannabinol (CBN) demonstrated a higher activity than THC alone. The Italian National Institute of Health sought to establish conditions and indications on how to correctly use nationally produced cannabis to guarantee therapeutic continuity in individuals treated with medical cannabis.
Methods:
The evaluation of cannabinoids concentration and stability in standardized preparations of cannabis tea and cannabis oil was conducted using an easy and fast ultra-high performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) assay.
Results:
Extraction efficiency of oil was significantly higher than that of water with respect to the different cannabinoids. This was especially observed in the case of the pharmacologically active THC, CBD and their acidic precursors. Fifteen minutes boiling was sufficient to achieve the highest concentrations of cannabinoids in the cannabis tea solutions. At ambient temperature, a significant THC and CBD decrease to 50% or less of the initial concentration was observed over 3 and 7 days, respectively. When refrigerated at 4 °C, similar decreasing profiles were observed for the two compounds. The cannabinoids profile in cannabis oil obtained after pre-heating the flowering tops at 145 °C for 30 min in a static oven resulted in a complete decarboxylation of cannabinoid acids CBDA and THCA-A. Nevertheless, it was apparent that heat not only decarboxylated acidic compounds, but also significantly increased the final concentrations of cannabinoids in oil. The stability of cannabinoids in oil samples was higher than that in tea samples since the maximum decrease (72% of initial concentration) was observed in THC coming from unheated flowering tops at ambient temperature. In the case of the other cannabinoids, at ambient and refrigerated temperatures, 80%–85% of the initial concentrations were measured up to 14 days after oil preparation.
Conclusions:
As the first and most important aim of the different cannabis preparations is to guarantee therapeutic continuity in treated individuals, a strictly standardized preparation protocol is necessary to assure the availability of a homogeneous product of defined stability.
Acknowledgments
The authors thank Stefano Gentili, Chrystalla Kyriakou, Manuela Pellegrini, Maria Concetta Rotolo and Michele Sciotti for their technical assistance.
Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
Research funding: Funded by the project: “Implementazione dei Sistemi di Sorveglianza sul disturbo da gioco d’azzardo e sull’uso medico della cannabis sul territorio Nazionale” by the Italian Ministry of Health.
Employment or leadership: None declared.
Honorarium: None declared.
Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.
References
1. Website: World Drug Report 2016. Available at: https://www.unodc.org/doc/wdr2016/WORLD_DRUG_REPORT_2016_web.pdf. Accessed 21 Nov 2016.Search in Google Scholar
2. Pacula RL, Jacobson M, Maksabedian EJ. In the weeds: a baseline view of cannabis use among legalizing states and their neighbours. Addiction 2016;111:973–80.10.1111/add.13282Search in Google Scholar PubMed PubMed Central
3. Whiting PF, Wolff RF, Deshpande S, Di Nisio M, Duffy S, Hernandez AV, et al. Cannabinoids for Medical Use: A Systematic Review and Meta-analysis. J Am Med Assoc 2015;313:2456–73.10.1001/jama.2015.6358Search in Google Scholar PubMed
4. Kogan NM, Mechoulam R. Cannabinoids in health and disease. Dialogues Clin Neurosci 2007;9:413–30.10.31887/DCNS.2007.9.4/nkoganSearch in Google Scholar
5. Russo E, Guy GW. A tale of two cannabinoids: the therapeutic rationale for combining tetrahydrocannabinol and cannabidiol. Med Hypotheses 2006;66:234–46.10.1016/j.mehy.2005.08.026Search in Google Scholar PubMed
6. Muller-Vahl KR. Cannabinoids reduce symptoms of Tourette’s syndrome. Expert Opin Pharmacother 2003;4:1717–25.10.1517/14656566.4.10.1717Search in Google Scholar PubMed
7. Lastres-Becker I, Molina-Holgado F, Ramos JA, Mechoulam R, Fernandez-Ruiz J. Cannabinoids provide neuroprotection against 6-hydroxydopamine toxicity in vivo and in vitro: relevance to Parkinson’s disease. Neurobiol Dis 2005;19:96–107.10.1016/j.nbd.2004.11.009Search in Google Scholar PubMed
8. Novack GD. Cannabinoids for treatment of glaucoma. Curr Opin Ophthalmol 2016;27:146–50.10.1097/ICU.0000000000000242Search in Google Scholar PubMed
9. Abrams DI, Guzman M. Cannabis in cancer care. Clin Pharmacol Ther 2015;97:575–86.10.1002/cpt.108Search in Google Scholar PubMed
10. 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 6 Dec 2016.Search in Google Scholar
11. Verhoeckx KC, Korthout HA, van Meeteren-Kreikamp AP, Ehlert KA, Wang M, van der Greef J, et al. Unheated cannabis sativa extracts and its major compound THC-acid have potential immuno-modulating properties not mediated by CB1 and CB2 receptor coupled pathways. Int Immunopharmacol 2006;6:656–65.10.1016/j.intimp.2005.10.002Search in Google Scholar PubMed
12. Ruhaak LR, Felth J, Karlsson PC, Rafter JJ, Verpoorte R, Bohlin L. Evaluation of the cyclooxygenase inhibiting effects of six major cannabinoids isolated from Cannabis sativa. Biol Pharm Bull 2011;34:774–8.10.1248/bpb.34.774Search in Google Scholar PubMed
13. Moldzio R, Pacher T, Krewenka C, Kranner B, Novak J, Duvigneau JC, et al. Effects of cannabinoids Δ(9)-tetrahydrocannabinol, Δ(9)-tetrahydrocannabinolic acid and cannabidiol in MPP(+) affected murine mesencephalic cultures. Phytomedicine 2012;19:819–24.10.1016/j.phymed.2012.04.002Search in Google Scholar
14. Rock EM, Kopstick RL, Limebeer CL, Parker LA. Tetrahydrocannabinolic acid reduces nausea-induced conditioned gaping in rats and vomiting in Suncus murinus. Br J Pharmacol 2013;170:641–8.10.1111/bph.12316Search in Google Scholar
15. Bolognini D, Rock EM, Cluny NL, Cascio MG, Limebeer CL, Duncan M, et al. Cannabidiolic acid prevents vomiting in Suncus murinus and nausea-induced behaviour in rats by enhancing 5-HT1A receptor activation. Br J Pharmacol 2013;168:1456–70.10.1111/bph.12043Search in Google Scholar
16. Takeda S, Okazaki H, Ikeda E, Abe S, Yoshioka Y, Watanabe K, et al. Down-regulation of cyclooxygenase-2 (COX-2) by cannabidiolic acid in human breast cancer cells. J Toxicol Sci 2014;39:711–6.10.2131/jts.39.711Search in Google Scholar
17. Rock EM, Limebeer CL, Parker LA. Effect of combined doses of Δ(9)-tetrahydrocannabinol (THC) and cannabidiolic acid (CBDA) on acute and anticipatory nausea using rat (Sprague- Dawley) models of conditioned gaping. Psychopharmacology 2015;232:4445–4.10.1007/s00213-015-4080-1Search in Google Scholar
18. Brierley DI, Samuels J, Duncan M, Whalley BJ, Williams CM. Neuromotor tolerability and behavioural characterisation of cannabidiolic acid, a phytocannabinoid with therapeutic potential for anticipatory nausea. Psychopharmacology 2016;233:243–54.10.1007/s00213-015-4100-1Search in Google Scholar
19. Christophersen AS. Tetrahydrocannabinol stability in whole blood: plastic versus glass containers. J Anal Toxicol 1986;10:129–31.10.1093/jat/10.4.129Search in Google Scholar
20. Ventura M, Pichini S, Ventura R, Leal S, Zuccaro P, Pacifici R, et al. Stability of drugs of abuse in oral fluid collection devices with purpose of external quality assessment schemes. Ther Drug Monit 2009;31:277–80.10.1097/FTD.0b013e318198670bSearch in Google Scholar
21. Website: Recommended methods for the identification and analysis of cannabis and cannabis products 2009. Available at http://www.unodc.org/documents/scientific/ST-NAR-40-Ebook.pdf Accessed 6 december, 2016).Search in Google Scholar
22. Romano LL, Hazekamp A. Cannabis oil: chemical evaluation of an upcoming cannabis-based medicine. Cannabinoids 2013;1:1–11.Search in Google Scholar
23. Website: FDA Pharmaceutical Quality/CMC; Guidance for Industry, Analytical Procedures and Methods Validation for Drugs and Biologics, US Department of Health and Human Services, Food and Drug Administration. http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm386366.pdf. Accessed 18 Nov 2016.Search in Google Scholar
24. Website: ICH Topic Q 2 (R1) Validation of Analytical Procedures: Text and Methodology, 2005. http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q2_R1/Step4/Q2_R1__Guideline.pdf. Accessed 18 Nov 2016.Search in Google Scholar
25. Hazekamp A, Bastola K, Rashidi H, Bender J, Verpoorte R. Cannabis tea revisited: a systematic evaluation of the cannabinoid composition of cannabis tea. J Ethnopharmacol 2007;233:85–90.10.1016/j.jep.2007.05.019Search in Google Scholar
26. Veress T, Szanto JI, Leisztner L. Determination of cannabinoid acids by high-performance liquid chromatography of their neutral derivatives formed thermal decarboxylation. J Chrom A 1990;520:339–47.10.1016/0021-9673(90)85118-FSearch in Google Scholar
27. Citti C, Ciccarella G, Braghiroli D, Parenti C, Vandelli MA, Cannazza G. Medicinal cannabis: Principal cannabinoids concentration and their stability evaluated by a high performance liquid chromatography coupled to diode array and quadrupole time of flight mass spectrometry method. J Pharm Biomed Anal 2016;128:201–9.10.1016/j.jpba.2016.05.033Search in Google Scholar PubMed
28. Russo EB, McPartland JM. Cannabis is more than simply delta(9)-tetrahydrocannabinol. Psychopharmacology (Berl) 2003;165:431–2.10.1007/s00213-002-1348-zSearch in Google Scholar PubMed
©2017 Walter de Gruyter GmbH, Berlin/Boston
