Journal:Cannabis sativa research trends, challenges, and new-age perspectives
| Full article title | Cannabis sativa research trends, challenges, and new-age perspectives |
|---|---|
| Journal | iScience |
| Author(s) | Hussain, Tajammul; Jeena, Ganga; Pitakbut, Thanet; Vasilev, Nikolay; Kayser, Oliver |
| Author affiliation(s) | TU Dortmund University |
| Primary contact | Email: Tajammul dot hussain at tu-dortmund dot de |
| Year published | 2021 |
| Volume and issue | 24(12) |
| Article # | 103391 |
| DOI | 10.1016/j.isci.2021.103391 |
| ISSN | 2589-0042 |
| Distribution license | Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International |
| Website | https://www.sciencedirect.com/science/article/pii/S2589004221013626 |
| Download | https://www.sciencedirect.com/science/article/pii/S2589004221013626/pdfft (PDF) |
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This article should be considered a work in progress and incomplete. Consider this article incomplete until this notice is removed. |
Abstract
Background: Cannabis sativa L. is one of the oldest known medicinal plants, cultivated for at least 10,000 years for several agricultural and industrial applications. However, the plant became controversial owing to some psychoactive components that have adverse effects on human health.
Methods: In this review, we analyze the trends in cannabis research for the past two centuries. We discuss the historical transitions of cannabis from the category of "herbal medicine" to an illicit drug and back to a medicinal product post-legalization. In addition, we address the new-age application of immuno-suppressive and anti-inflammatory cannabis extracts for the treatment of COVID-19 inflammation. We further address the influence of the legal aspects of cannabis cultivation for medicinal, pharmaceutical, and biotechnological research. Finally, we review the up-to-date cannabis-related genomic resources and advanced technologies for their potential application in genomic-based cannabis improvement.
Results: Overall, this review discusses the diverse aspects of cannabis research developments, ranging from traditional use as herbal medicine to the latest potential in COVID-19, legal practices with updated patent status, and current state of the art genetic and genomic tools reshaping cannabis biotechnology in the modern agriculture and pharmaceutical industries.
Conclusions: Remarkable growth in genomic data, combined with fast-paced development of artificial intelligence (AI)-based data analysis tools have made it possible to explore the Cannabis plant at the genetic and molecular levels. In the future, the combination of these genetic technologies will make it possible to obtain enhanced expression rates, which will lead to enhanced cannabinoid yields in an economically feasible manner. Pharmacological research, coupled with rapidly evolving genome-based biotechnology, will further facilitate exploring the Cannabis plant for its tremendous potential in drug discovery.
Keywords: cannabis, cannabis research, plant biology, plant genetics, genomics
Introduction
Cannabis sativa L. is one of the earliest known cultivated plants since agricultural farming started around 10,000 years ago. (Schultes et al., 1974) It is a multi-purpose crop plant with diverse agricultural and industrial applications, ranging from the production of paper, wood, and fiber, to its actual and potential use in the medicinal and pharmaceutical industries. The first-ever report to reveal the prospects of C. sativa L. as a medicinal plant was published in 1843 and described the use of plant extracts to treat patients suffering from tetanus, hydrophobia, and cholera. (O'Shaughnessy, 1843) However, the first chemical constituent identified was oxy-cannabis, in 1869 (Bolas and Francis, 1869). Cannabinoids were being isolated as early as 1896, followed by a variety of full identifications like:
- cannabidiol (CBD) in 1940 (Jacob and Todd, 1940),
- tetrahydrocannabinol (THC) in 1964 (Gaoni and Mechoulam, 1964; Santavý, 1964),
- cannabigerol (CBG) in 1964 (Gaoni and Mechoulam, 1966), and
- cannabichromene (CBC) in 1966. (Gaoni and Mechoulam, 1966)
Identification of THC later led to an understanding of the endocannabinoid system, followed by the discovery of the first cannabinoid receptor (CB1) in 1988. (Devane et al., 1988; Russo, 2016). The CB1 receptor acts as a homeostatic regulator of neurotransmitters for pain relief mechanisms, but the same mode of action was responsible for the intoxicating effects from excessive cannabinoids use. This greater understanding of the mode of action of the CB1 receptor raised concerns about the adverse effects of cannabis use. Consequently, the plant was removed from the "medicinal" category and re-categorized exclusively to the category of "illicit drug."
Cultivation and use of the Cannabis plant for recreational, medical, and industrial use were strictly banned, which severely limited the scientific research in the field. Owing to strict legal regulations, the plant remained unexplored for its incredible potential in drug discovery for an extended period until it was legalized for medical use first in California and later in many countries around the globe. Extensive research followed legalization in order to explore the chemodiversity of cannabinoids for potential clinical value. In total, more than one thousand compounds have been identified, including 278 cannabinoids, 174 terpenes, 221 terpenoids, 19 flavonoids, 63 flavonoid glycosides, 46 polyphenols, and 92 steroids—have been identified. (ElSohly and Slade, 2005; Gould, 2015; Radwan et al., 2017) Nearly 278 of these compounds are cannabinoids and classified as phytocannabinoids (plant-based) to distinguish them from endocannabinoids (non-plant). Cannabimimetic drugs binding to CB1 receptors in the endocannabinoid system can also be found in algae, bryophytes, and monilophytes. (Carvalho, 2017; Kumar et al., 2019) The major cannabinoids in cannabis include THC, CBD, and CBC, as well as their precursors CBG and cannabinol (CBN). (Flores-Sanchez and Verpoorte, 2008) To date, 10 CBN-type, 17 CBG-type, 8 CBD-type, and 18 THC-type cannabinoids have been isolated. (Gaoni and Mechoulam, 1964) Cannabigerolic acid (CBGA), a CBG-type cannabinoid, is the central precursor for the biosynthesis of psychoactive THC, non-psychoactive CBD, and CBC. (ElSohly and Slade, 2005; Gould, 2015; Radwan et al., 2017)
Cannabinoid biosynthesis in plants occurs in specialized biosynthetic organs called glandular trichomes (Happyana et al., 2013) on female flowers and leaves. Several studies use metabolic profiling of trichomes to demonstrate variation in trichome size, density, and relative concentration of cannabinoids. (Happyana et al., 2013; Small and Naraine, 2016) However, the genetic mechanisms underlying the developmental changes in trichomes and consecutive cannabinoid content are still unknown. Apart from natural and chemical biosynthesis methods (Bovens et al., 2009), heterologous biosynthesis of cannabinoids has also been reported. (Luo et al., 2019) However, the considerable amount of side products is still one of the major bottlenecks in cannabinoid production. (Luo et al., 2019; Thomas et al., 2020)
This review highlights the latest research developments and challenges in Cannabis plant sciences, as well as the role of trichomes as biosynthetic sites, with a special focus on plant biology. Additionally, we discuss the existing legal practices with patent information for C. sativa L. We also discuss the new potential use of cannabinoids for COVID-19 treatment. Finally, we address the available genomic and transcriptomic resources and discuss their potential toward the genetic improvement of cannabis. Overall, we provide the first in-depth review of diverse aspects of C. sativa L. from traditional medicinal use to genomics insights and research perspective to broad industrial applications.
Methods
Cannabis-related publications were searched in four major scientific literature and citation databases of biomedical and life sciences journals: EMBL-EBI's Europe PMC (Data S1, Supplemental information), Elsevier's Scopus (Data S2, Supplemental information), National Library of Medicine's PubMed Central (Data S3, Supplemental information), and Clarivate's Web of Science. The search criteria—“cannabis OR marijuana OR hemp OR cannabinoids OR cannabidiol OR cannabinol”—were used to examine available research articles. Some 80,979 (EuropePMC), 64,637 (Scopus), 43,182 (Web of Science), and 28,759 (PubMed Central) cannabis-related research articles were found.
The sheer difference in the number of articles could be attributed to the years for which the cannabis records are present in the databases. Europe PMC currently holds cannabis records dating back 239 years, with the oldest publication dating to 1783, whereas Scopus has data for 194 years (dating back to 1828), Pubmed Central 182 years (dating back to 1840), and Web of Science 77 years (since 1945) (Figure 1A). Despite cannabis records only going back 77 years, the Web of Science record count exceeds Pubmed Central's, owing to a data acquisition policy similar to Scopus, wherein all the cited references for a publication are pulled and listed in the database.
Another major reason for the different records in the archives could be owing to the source repositories and partner journals. Although Pubmed Central has only 6.9 million articles from over 10,656 journals (as of April 2021), Scopus has more than 77.8 million records from nearly 23,500 journals, and Web of Science comprises over 171 million records, including journals, books, and proceedings. However, Europe PMC acquires data from multiple bibliographic repositories such as PubMed, MEDLINE, Pubmed Central, AGRICOLA, and Chinese Biological Abstracts (CBA) (Figure 1D). It includes more than 45.6 million documents, including articles, books, preprints, patents, conference papers, and microPublications.
Cannabis citation metadata was publicly available for bulk download from Europe PMC (6,586 journals), Scopus (8647 journals), and Pubmed Central (3864 journals) (Figure 1B). Among the various article identifiers used such as DOI, PMCID, and PMID, the DOI was found for 85.62% of records at Europe PMC, 85.44% of records at Scopus, and 91.9% of records at Pubmed Central. Since DOI was the only common identifier, it was used for the comparison of three datasets (Figure 1C). Cannabis records in Europe PMC comprised nearly 76.73% of Pubmed Central and 49.75% of Scopus data (Figure 1C). Hence, metadata from Europe PMC was selected for downstream bibliometric analysis. The majority of cannabis-related records in Europe PMC were from MEDLINE (94.94%), followed by 4.29% from Pubmed Central, with only 0.75% from Agricola and 0.02% from CBA (Figure 1D). The distribution of source databases indicates the most explored field in cannabis research for the last 239 years.
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Trends of cannabis research from 1783 to 2021
C. sativa L. originated in central Asia and later spread to Europe during its cultivation, with diverse applications. Archaeological evidence of early medical use was found in fossil records dating back to 315–392 A.D. (Zias et al., 1993) Researchers largely have a consensus that the plant has at various times been used as traditional medicine. (Bridgeman and Abazia, 2017)
Based on our search results, spanning more than two centuries, we divide the scientific era into four periods (Figure 1E). Period Zero (1783–1840) marked the first-ever mention of Cannabis as a category of medicinal plant, in the years 1783 (Laurentius Crellius and Huntero, 1783) and 1787. (Wright et al., 1787) According to Europe PMC results, there were only 52 articles and 38 reviews in the next five decades. Most reports mentioned the botanical aspects of hemp and the quality of its fiber, with few observations about its use in traditional medicines.
Period I (1840–1937) began with the detailed evidence-based report of the chemical properties and medicinal potential of Cannabis indica (hemp) by William O'Shaughnessy (O'Shaughnessy, 1843), followed by an array of medicinal reports in articles from 1923. We identified 183 reviews in the subsequent 96 years. Scientific endeavors to experiment, observe, and understand the diverse medicinal applications of cannabis were still in the early stages. However, the 1900s witnessed a series of legal regulations in the direction of the criminalization of cannabis. Cannabis was starting to be categorized into lists of narcotic drugs, and "poisons rules," including the Pure Food and Drug Act of 1906, pushed for stricter measures for cannabis distribution. Later, the Second International Opium Convention of 1925 called for measures to regulate Indian hemp. Exports, unless exclusively for medical or scientific purposes or European hemp (for fiber), were banned. The Uniform State Narcotic Drug Act of 1925 and the Geneva Trafficking Conventions of 1936 resulted in criminalizing the cultivation, possession, manufacture, and distribution of cannabis derivatives. The Marihuana Tax Act of 1937 levied heavy taxes on the possession and selling of cannabis, excluding medical, and industrial use. As a consequence, the cultivation and procurement of cannabis for research purposes became increasingly difficult, severely limiting the research of medicinal cannabis during this era (see Figure 1E: Period I).
During Period II (1937–1996), cannabis research suffered major restrictions, owing to legal regulations in the first two decades, until the identification of the first cannabinoid—cannabidiolic acid—in 1954 (Hanuš et al., 1975; Krejčí and Šantavý, 1955; Krejčí et al., 1958; Santavý, 1964) and the isolation of the most psychoactive component of cannabis—THC—in 1964. (Mechoulam et al., 1964) Other discoveries paved the way for decriminalization laws, including isolation of THC, discovery of the CB1 (Devane et al., 1988) and CB2 (Munro et al., 1993) receptors, and the emergence of the Compassionate Investigational New Drug program in 1978. The discovery of endocannabinoids and a growing understanding of the potential role of cannabis in the medicinal field also played a role during this period. (Hanus, 2009; Kabelik and Santavy, 1955) A significant uptick in published cannabis research was observed during this period, with 445 cannabis-related articles and 25 reviews being found between 1937 and 1964, ramping up to 8,888 articles and 773 reviews between 1964 and 1996 (see Figure 1E: Period II), although with a notably short period of decline in publications between 1973 and 1982.
Finally, Period III (1996-2021) began with the historical Compassionate Use Act of 1996 in California approving medical cannabis. Post-legalization (1996 onwards), cannabis has been extensively explored for its diverse potential in the pharmaceutical and medicinal industries. During Period III, cannabis research witnessed unprecedented growth, with nearly 67,777 articles, 13,202 reviews, and 493 preprints showing up in Europe PMC, of which 97.01% articles were published since 2000 (see Figure 1E: Period III). Approval of the first cannabis-based inhaler spray in 2005 (Perras, 2005; Pain, 2015) and publication of the first draft of the cannabis genome in 2011 (van Bakel et al., 2011) in this era were the two major accomplishments that exponentially accelerated research development.
References
Notes
This presentation is faithful to the original, with only a few minor changes to presentation. References aren't listed in the order they appear in the original, but they do for this version, by design. In some cases important information was missing from the references, and that information was added. A few words were added, updated, or shifted for improved grammar and readability, but this version is otherwise unchanged in compliance with the "NoDerivatives" portion of the original's license.
