Journal:Methods for quantification of cannabinoids: A narrative review

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Full article title Methods for quantification of cannabinoids: A narrative review
Journal Journal of Cannabis Research
Author(s) Lazarjani, Masoumeh P.; Torres, Stephanie; Hooker, Thom; Fowlie, Chris; Young, Owen; Seyfoddin, Ali
Author affiliation(s) Auckland University of Technology, Chapman University, ZeaCann Limited,
Primary contact Email: Online form
Year published 2020
Volume and issue 2
Article # 35
DOI 10.1186/s42238-020-00040-2
ISSN 2522-5782
Distribution license Creative Commons Attribution 4.0 International
Website https://jcannabisresearch.biomedcentral.com/articles/10.1186/s42238-020-00040-2
Download https://jcannabisresearch.biomedcentral.com/track/pdf/10.1186/s42238-020-00040-2.pdf (PDF)
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Abstract

Background: Around 144 cannabinoids have been identified in the Cannabis plant; among them tetrahydrocannabinol (THC) and cannabidiol (CBD) are the most prominent ones. Because of the legal restrictions on cannabis in many countries, it is difficult to obtain standards to use in research; nonetheless, it is important to develop a cannabinoid quantification technique, with practical pharmaceutical applications for quality control of future therapeutic cannabinoids.

Method: To find relevant articles for this narrative review paper, a combination of keywords such as "medicinal cannabis," "analytical," "quantification," and "cannabinoids" were searched for in PubMed, EMBASE, MEDLINE, Google Scholar, and Cochrane Library (Wiley) databases.

Results: The most common cannabinoid quantification techniques include gas chromatography (GC) and high-performance liquid chromatography (HPLC). Gas chromatography is often used in conjunction with mass spectrometry (MS) or flame ionization detection (FID). The major advantage of GC is with the quantification of terpenes. However, for evaluating acidic cannabinoids, it needs to be derivatized. The main advantage of HPLC is the ability to quantify both acidic and neutral forms of cannabinoids without derivatization, which is often accomplished with MS or ultraviolet (UV) detectors.

Conclusion: Based on the information presented in this review, the ideal cannabinoid quantification method is HPLC paired with tandem mass spectrometry (MS/MS).

Introduction

Cannabis sativa L. is an annual herbaceous flowering plant indigenous to eastern Asia.[1] The phenotypes of Cannabis are highly variable, and the plant is accepted to have two subspecies: C. sativa and C. indica.[2][3] A third variety, C. ruderalis, has been identified as a Cannabis species; however, it is not broadly recognized as a specific subspecies of C. sativa.[2][4] The Cannabis plant has been used for its therapeutic properties for thousands of years, and it was introduced to Western medicine in the nineteenth century, until it was later outlawed in the U.S. from the mid-1930s.[5]

The medicinal compounds from Cannabis plants are mostly concentrated in the female flowers of this dioecious species.[4] The so-called resin is the source of a wide variety of terpenoids and cannabinoids.[4] The therapeutic properties of cannabis are attributed to cannabinoids.[6] Cannabinoids are found in the resin produced by the trichomes, which are widely distributed on both the male and female plants, though they are most highly concentrated on the female flowers of the cannabis plant.[1][7] Cannabinoids are terpenophenolic compounds unique to Cannabis.[2] To date, 144 cannabinoids have been identified.[6] The two cannabinoids most well known for their therapeutic properties are tetrahydrocannabinol (THC) and cannabidiol (CBD).[2][8] THC and CBD are the neutral homologs of tetrahydrocannabinolic acid (THCA) and cannabidiolic acid (CBDA), respectively.[8] A conventional classification model of cannabinoids is due to their chemical contents dividing them into eleven subclasses, including THC, CBD, cannabigerol (CBG), cannabichromene (CBC), cannabinol (CBN), (−)-Δ8-trans-tetrahydrocannabinol (Δ8-THC), cannabicyclol (CBL), cannabinodiol (CBND), cannabielsoin (CBE), cannabitriol (CBT), and "miscellaneous types."[9] (Fig. 1).


Fig1 Lazarjani BMCJournCannaRes2020 2.png

Fig. 1 The most common cannabinoids and their conversion pathway by decarboxylation because of heat or aging. CBGA can convert to CBDA and THCA by CBDA synthase and THCA synthase, respectively. CBGA: cannabigerolic acid, CBG: cannabigerol, CBDA: cannabidiolic acid, CBD: cannabidiol, THCA: tetrahydrocannabinolic acid, THC: tetrahyrocannabinol, CBN: cannabinol[10]

Because consumers have limited means to analyze the chemical composition of cannabis products, consumers may be inadvertently purchasing products with undesired properties given that different cannabinoids produce different effects.[11] As a result, it is important to implement methods of quality control so that consumers can be certain that what they are consuming will have the desired effects.[4][11][12] As cannabis use becomes progressively accepted, it becomes increasingly important to quantify the cannabinoid profile and content of cannabis preparations to ensure the uniformity and quality of the preparations.[13]

A variety of analytical techniques have been developed for the quantification and qualification of cannabinoids and other compounds in the Cannabis plant. Advances in analytical methods have also resulted in detection of various additional compounds from cannabis extracts in the last decade (e.g., terpenes). The purpose of this literature review is to explore cannabinoid quantification techniques and subsequently suggest an optimal method for pharmaceutical-grade quantification.

Methods

To find relevant papers for this narrative review, many databases were reviewed over a period of eight months. A combination of keywords such as "medicinal cannabis," "analytical," "quantification," and "cannabinoids" were searched. PubMed, EMBASE, MEDLINE, Google Scholar, and Cochrane Library (Wiley) databases were searched for English language papers published from 1967 to 2019. In the next step, the results were then scrutinized to discard irrelevant papers. Those papers which were deemed relevant were subjected to more detailed analysis. In total, the number of papers read was about 75, including around 15 irrelevant papers.

Quantitative analysis of cannabinoids

Gas chromatography

Gas chromatography (GC) is one of the most commonly used chromatographic methods in quantitative cannabinoid analysis.[14] Gas chromatography is typically completed in under 20 minutes at up to 300 °C and makes use of stationary phases with low polarities, such as 5% diphenyl- and 95% dimethylpolysiloxane.[15] It is important to note that the total quantity of cannabinoids in a sample is the sum of the acidic and neutral components.[7] Because gas chromatography requires high column temperatures, the acidic cannabinoids undergo decarboxylation during transit through the column.[1][7][14] As such, acidic cannabinoids cannot be determined unless they are derivatized prior to analysis.[14] Not only does derivatization preserve cannabinoid structure, but it also causes cannabinoids to become more volatile, thus improving peak shape.[15] Dussy et al.[12] suggested calculating the amount of neutral and acidic cannabinoids separately in order to accurately determine the total cannabinoid content. Gas chromatography resolves cannabinoids, but detection on elution presents its own challenges and solutions.

GC- FID/MS

GC is normally coupled with mass spectrometry (MS) or flame ionization detection (FID) to detect and quantify cannabinoids[7][14] (see Tables 1 and 2). MS employs standardized electron ionization to fragment analytes, permitting the use of compound libraries to identify the parent analyte. FID provides more accurate cannabinoid quantification because it makes use of relatively cheap authentic standards, whereas MS usually requires equivalent deuterated standards, which are expensive and not available for all cannabinoids.[7][14]

Table 1. An overview to the key properties of a common GC-MS method for analyzing cannabinoids with a capillary column, used in six different studies. LOD = limit of detection, LOQ = limit of quantitation. am stands for mass and z is charge number of ions; for GC-MS, z is almost always 1, so m/z is mass.
Key capillary column properties Cannabinoids analyzed Oven process Carrier gas Range LOD LOQ References
Silica capillary column coated with DB1 16 major cannabinoids Initial 10 °C, 108 °C /min, up to 280 °C. Hold for 30 min. Helium N/A N/A N/A [16]
VA5MS capillary column coated with DB1 Δ9-THC, CBD, CBN, CBG, THCA, CBGA, CBDA Initial 100 °C, 108 °C /min, up to 280 °C. Hold for 30 min. Helium N/A N/A N/A [14]
5% Cross-linked phenylmethylsiloxane capillary column CBG, CBD, CBDA, CBN, CBGA, THC, CBC, THCA Initial 50 °C, 6 °C /min, up to 300 °C. Hold for 4 min. (3 min solvent delay was applied.) Helium m/za 40–500 N/A N/A [17]
5% Diphenyl-/95% dimethylpolysiloxane capillary column THC-THCA Initial 70 °C, 40 °C /min up to 180 °C, then 10 °C/min up to 300 °C. Hold for 6.25 min. Helium 0.10–4.00% (w/w) 0.03% (w/w) 10% (w/w) [18]
Cross-linked poly-5% diphenyl-/95% dimethylpolysiloxane capillary column CBDA-CBD Initial 45 °C, 2 °C /min, up t0 100°C, then 5 °C /min up to 250 °C. Hold for 5 min. Helium m/z 40–500 N/A N/A [19]
5% Cross-linked phenylmethylsiloxane capillary column CBG, CBD, THC, CBC, CBN Initial 50 °C, 6 °C/min, up to 300 °C. Hold for 4 min. (3 min solvent delay was applied.) Helium m/z 40–400 N/A N/A [20]
Table 2. Key properties of a GC-FID method for analyzing cannabinoids with a capillary column, used in four different studies.
Capillary column properties Cannabinoids analyzed Oven process Carrier gas References
DB5 capillary column THCA, CBGA, CBCA, THC, CBG, CBC Initial 60 °C, 3 °C/min, up to 240 °C. Hold for 5 min. Nitrogen [21]
Silica capillary column coated with DB1 Δ9-THC, CBD, CBN, CBG, THCA, CBGA, CBDA Initial 100 °C, 108 °C/min, up to 280 °C. Hold for 30 min. Nitrogen [14]
DB5 5% diphenyl-/95% dimethylpolysiloxane capillary column THC-THCA Initial 200 °C, 10 °C/min, up to 300 °C. Hold for 2 min. Helium [18]
Cross-linked poly-5% diphenyl-/95% dimethylpolysiloxane capillary column CBDA-CBD Initial 45 °C, 2 °C/min, up to 100 °C then 5 °C/min, up to 250 °C. Hold for 5 min. Helium [19]


References

  1. ↑ 1.0 1.1 1.2 De Backer, B.; Debrus, B.; Lebrun, P. et al. (2009). "Innovative development and validation of an HPLC/DAD method for the qualitative and quantitative determination of major cannabinoids in cannabis plant material". Journal of Chromatography B 877 (32): 4115–24. doi:10.1016/j.jchromb.2009.11.004. PMID 19932642. 
  2. ↑ 2.0 2.1 2.2 2.3 Hillig, K.W.; Mahlberg, P.G. (2004). "A chemotaxonomic analysis of cannabinoid variation in Cannabis (Cannabaceae)". American Journal of Botany 91 (6): 966-75. doi:10.3732/ajb.91.6.966. PMID 21653452. 
  3. ↑ Knight, G.; Hansen, S.; Connor, M. et al. (2010). "The results of an experimental indoor hydroponic Cannabis growing study, using the 'Screen of Green' (ScrOG) method-Yield, tetrahydrocannabinol (THC) and DNA analysis". Forensic Science International 202 (1–3): 36–44. doi:10.1016/j.forsciint.2010.04.022. PMID 20462712. 
  4. ↑ 4.0 4.1 4.2 4.3 Fischedick, J.T.; Van Der Kooy, F.; Verpoorte, R. (2010). "Cannabinoid receptor 1 binding activity and quantitative analysis of Cannabis sativa L. smoke and vapor". Chemical & Pharmaceutical Bulletin 58 (2): 201–7. doi:10.1248/cpb.58.201. PMID 20118579. 
  5. ↑ Aizpurua-Olaizola, O.; Omar, J.; Navarro, P. et al. (2014). "Identification and quantification of cannabinoids in Cannabis sativa L. plants by high performance liquid chromatography-mass spectrometry". Analytical and Bioanalytical Chemistry 406 (29): 7549-60. doi:10.1007/s00216-014-8177-x. PMID 25338935. 
  6. ↑ 6.0 6.1 Hazekamp, A.; Choi Y.H.; Verpoorte, R. (2004). "Quantitative analysis of cannabinoids from Cannabis sativa using 1H-NMR". Chemical and Pharmaceutical Bulletin 52 (6): 718–21. doi:10.1248/cpb.52.718. PMID 15187394. 
  7. ↑ 7.0 7.1 7.2 7.3 7.4 Citti, C.; Braghiroli, D.; Vandelli, M.A. et al. (2018). "Pharmaceutical and biomedical analysis of cannabinoids: A critical review". Journal of Pharmaceutical and Biomedical Analysis 147: 565–79. doi:10.1016/j.jpba.2017.06.003. PMID 28641906. 
  8. ↑ 8.0 8.1 Aizpurua-Olaizola, O.; Soydaner, U.; Öztürk, E. et al. (2016). "Evolution of the Cannabinoid and Terpene Content during the Growth of Cannabis sativa Plants from Different Chemotypes". Journal of Natural Products 79 (2): 324-31. doi:10.1021/acs.jnatprod.5b00949. PMID 26836472. 
  9. ↑ Berman, P.; Futoran, K.; Lewitus, G.M. et al. (2018). "A new ESI-LC/MS approach for comprehensive metabolic profiling of phytocannabinoids in Cannabis". Scientific Reports 8 (1): 14280. doi:10.1038/s41598-018-32651-4. PMC PMC6155167. PMID 30250104. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=PMC6155167. 
  10. ↑ Fathordoobady, F.; Singh, A.; Kitts, D.D. et al. (2019). "Hemp (Cannabis sativa L.) Extract: Anti-Microbial Properties, Methods of Extraction, and Potential Oral Delivery". Food Reviews International 35 (7): 664–84. doi:10.1080/87559129.2019.1600539. 
  11. ↑ 11.0 11.1 Fischedick, J.T.; Hazekamp, A.; Erkelens, T. et al. (2010). "Metabolic fingerprinting of Cannabis sativa L., cannabinoids and terpenoids for chemotaxonomic and drug standardization purposes". Phytochemistry 71 (17–18): 2058–73. doi:10.1016/j.phytochem.2010.10.001. PMID 21040939. 
  12. ↑ 12.0 12.1 Dussy, F.E.; Hamberg, C.; Luginbühl, M. et al. (2005). "Isolation of Delta9-THCA-A from hemp and analytical aspects concerning the determination of Delta9-THC in cannabis products". Forensic Science International 149 (1): 3–10. doi:10.1016/j.forsciint.2004.05.015. PMID 15734104. 
  13. ↑ Omar, J.; Olivares, M.; Amigo, J.M. et al. (2014). "Resolution of co-eluting compounds of Cannabis sativa in comprehensive two-dimensional gas chromatography/mass spectrometry detection with Multivariate Curve Resolution-Alternating Least Squares". Talanta 121: 273–80. doi:10.1016/j.talanta.2013.12.044. PMID 24607138. 
  14. ↑ 14.0 14.1 14.2 14.3 14.4 14.5 14.6 Hazekamp, A.; Simons, R.; Peltenburg-Looman, A. et al. (2004). "Preparative Isolation of Cannabinoids from Cannabis sativa by Centrifugal Partition Chromatography". Journal of Liquid Chromatography & Related Technologies 27 (15): 2421–39. doi:10.1081/JLC-200028170. 
  15. ↑ 15.0 15.1 Leghissa, A.; Hildenbrand, Z.L.; Schug, K.A. (2018). "A review of methods for the chemical characterization of cannabis natural products". Journal of Separation Science 41 (1): 398-415. doi:10.1002/jssc.201701003. PMID 28986974. 
  16. ↑ Hazekamp, A.; Peltenburg, A.; Verpoorte, R. et al. (2005). "Chromatographic and Spectroscopic Data of Cannabinoids from Cannabis sativa L.". Journal of Liquid Chromatography & Related Technologies 28 (15): 2361–82. doi:10.1080/10826070500187558. 
  17. ↑ Namdar, D.; Mazuz, M; Ion, A. et al. (2018). "Variation in the compositions of cannabinoid and terpenoids in Cannabis sativa derived from inflorescence position along the stem and extraction methods". Industrial Crops and Products 113: 376–82. doi:10.1016/j.indcrop.2018.01.060. 
  18. ↑ 18.0 18.1 Casiraghi, A.; Roda, G.; Casagni, E. et al. (2018). "Extraction Method and Analysis of Cannabinoids in Cannabis Olive Oil Preparations". Planta Medica 84 (4): 242-249. doi:10.1055/s-0043-123074. PMID 29202510. 
  19. ↑ 19.0 19.1 Pellati, F.; Brighenti, V.; Sperlea, J. et al. (2018). "New Methods for the Comprehensive Analysis of Bioactive Compounds in Cannabis sativa L. (hemp)". Molecules 23 (10): 2639. doi:10.3390/molecules23102639. PMC PMC6222702. PMID 30322208. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=PMC6222702. 
  20. ↑ Namdar, D.; Charuvi, D.; Ajjampura, V. et al. (2019). "LED lighting affects the composition and biological activity of Cannabis sativa secondary metabolites". Industrial Crops and Products 132: 177–85. doi:10.1016/j.indcrop.2019.02.016. 
  21. ↑ Romano, L.L.; Hazekamp, A. (2013). "Cannabis oil: Chemical evaluation of an upcoming cannabis-based medicine". Cannabinoids 1 (1): 1–11. https://www.cannabis-med.org/index.php?tpl=cannabinoids&id=276&lng=en&red=cannabinoidslist. 

Notes

This presentation is faithful to the original, with only a few minor changes to presentation. Some grammar and punctuation was cleaned up to improve readability. In some cases important information was missing from the references, and that information was added. The original article lists references in alphabetical order; this wiki organizes them by order of appearance, by design. Several of the original citations had incorrect publication years; they were corrected for this version.

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