Tetrahydrocannabivarin,6-Hydroxymelatonin,and Delta9-Tetrahydrocannabinol had the highest binding scores, indicating that they could inhibit Plasmodium tubulin and thus interfere with malaria cycle progression. This study could not find a significant correlation be- tween the physicochemical properties of the compounds and the binding affinities of the compounds to Plasmodium tubulin.However, 6-hydroxymelatonin and delta9-Tetrahydrocannabinol were found to have favourable drug description properties thereby suggesting a role of these compounds as drug leads. This claim is supported by the fact that tetrahydrocannabinol has a higher binding affinity than other cannabinoids, as demonstrated in the current study. However, to the best of our knowledge, there is no literature to support the potential anti-malarial activity of tetrahydrocannabivarin. Judging by the available computational data and evidence from literature, tetrahydrocannabinol and tetrahydrocannabivarin could berec- ommended as possible anti-malarial drug leads targeting αβtubulin. The amino acids interaction of the cannabinoids and vinblastine with the tubulin protein differed significantly with each compound. This reflects the diversity of physicochemical properties of the compounds. However, certain amino acids ASN99, ALA97, ALA247 and CYS353 were found to participate in the interaction for more than one ligand tested. Cannabis sativa L. is one of the earliest known cultivated plants since agricultural farming started around10,000 years ago . It is a multi-purpose crop plant with diverse agricultural and industrial applications ranging from the production of paper, wood, and fiber, to 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 already published in 1843 and described the use of plant extracts to treat patients suffering from tetanus, hydrophobia, and cholera .

However, the first chemical constituent identified was oxy-cannabis, isolated cannabinoid,and fully identified in 1940 was cannabidiol   followed by tetrahydro cannabinol  and cannabigerol  in 1964, and cannabichromene  in 1966. Identification of THC later led to an understanding of the endocannabinoid system followed by the discovery of the first cannabinoid receptor  in 1988 . CB1 receptor acts as a homeostatic regulator of neurotransmitters for pain relief mechanisms, but the same mode of action was responsible for intoxicating effects from cannabinoids’ excessive use.Thus, the understanding of mode of action of CB1 receptor raised concerns about the adverse effects of cannabis use. Consequently, the plant was removed from the medicinal category and recategorized exclusively to the category of drug-type plants.Cultivation and use of cannabis plants for recreational,medical, and industrial use were strictly banned and 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 to explore the chemo-diversity of cannabinoids for potential clinical value. In total, more than one thousand compounds—278 cannabinoids, 174 terpenes, 221 terpenoids, 19 flavonoids, 63 flavonoidglycosides, 46 polyphenols, 92 steroids—have been identified . Nearly 278 of these compounds are cannabinoids and classified as phytocannabinoids to distinguish them from endocannabinoids.Cannabimimetic drugs binding toCB1-receptors in the endocannabinoid system can also be found in algae, bryophytes, and monilophytes . The major cannabinoids in cannabis include THC, CBD, and CBC, their precursor CBG and cannabinol.To date, 10 CBN-type, 17CBG-type, 8 CBD-type, and 18 THC-type cannabinoids have been isolated . Cannabigerolic acid , a CBG-type cannabinoid, is the central precursor for the biosynthesisof psychoactive THC, mobile vertical rack non-psychoactive CBD, and CBC .Cannabinoid biosynthesis in plants occurs in specialized biosynthetic organs called glandular trichomes on female flowers and leaves. Several studies use metabolic profiling of trichomes to demonstrate variation in trichome size, density, and relative concentration of cannabinoids . However, the genetic mechanisms underlying the developmentalchanges in trichomes and consecutive cannabinoid content are still unknown. Apart from natural and chemical biosynthesis methods , heterologous biosynthesis of cannabinoids has also been reported .

However, the considerable amount of side products is still one of the major bottlenecks  in cannabinoid production.This review highlights the latest research developments and challenges in cannabis plant sciences, the roleof trichomes as biosynthetic sites, with a special focus on plant biology. In addition, we discuss the existing legal practices with patent information for the 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. Scientific endeavors to experiment, observe, and understand the diverse medicinal applications of cannabis were still in the early stages. However, 1900s witnessed a series of legal regulation in the direction of the criminalization of cannabis. Cannabis was starting to be categorized into the list of narcotic drugs and Poisons Rules including the Pure Food and Drug Act  pushed for stricter measures for cannabis distribution. Later International opium Convention  called for measures to regulate Indian hemp. Exports unless exclusively for medical or scientific purposes or European hemp  were banned. Uniform State Narcotic Drug Act , Geneva Trafficking Conventions  resulted in criminalizing the cultivation, possession, manufacture, and distribution of cannabis derivatives. Marihuana Tax Act 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 purpose became increasingly difficult and severely limited the research of medicinal cannabis during this era . During the second period , 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 , isolation of the most psychoactive component of cannabis, the THC in 1964 . Isolation of the THC, discovery of CB1 , and CB2  receptors, followed by the Compassionate Investigational New Drug program  paved the way for decriminalization laws. The discovery of endocannabinoid and the role of cannabis in the medicinal field have been reviewed in  As a consequence a steep surge was observed in the number of cannabis-related articles from 445 articles and25 reviews during 1937–1964 to nearly 8,888 articles and 773 reviews during 1964–1996 , although with a short period of decline between 1973 and 1982. Finally, the third period began with the historical Compassionate Use Act of 1996 in California approving medical cannabis. Post legalization, cannabis has been extensively explored for its diverse potential in the pharmaceutical and medicinal industries. During the third period, cannabis research witnessed an unprecedented growth with nearly 67,777 articles, 13,202 reviews, and 493 preprints ,of which 97.01%articles were published in the last two decades since 2000  and the first draft of the cannabis genome in 2011  in this era were the two major accomplishments that exponentially accelerated the research development.

To further investigate the most researched field, the journals of cannabis articles were categorized into scientific and social areas.The journals related to social, law, and policy-based studies were merged into the subject category of social research. Although the majority of broad scientific subjects were grouped into the following seven major categories: medicinal,pharmaceutical-comprised of pharmacology, pharmaceuticals, drug, toxicology, and chemical studies,neurosciences-comprised of neurological, brain-related, psychiatry, psychology, and cognitive studies,  biochemistry-included biotechnology,microbiology,immunology,virology,andbiochemistry,genomics-grouped genetical and genomic studies,plant biology-included plant sciences, agricultural, botanical aspects, plant-pathogen and environment studies, and lastly,bio informatics. Journals that could not be classified into either of the aforementioned categories or social research categories were excluded from downstream evaluation. The Scientific subject areas  were further compared for the corresponding number of articles and journals. A distinct pattern was observed for the Clinical aspects of cannabis which remained a major focus since the very beginning with nearly 94.76% published articles including 64.51% articles in medicinal subject areas, 19.55% in pharmaceutical sciences, and 10.70% in neuro sciences. In contrast, plant biology and agricultural sciences comprised only 2.62% of articles, followed by 0.71% genomics, and 0.07% bio informatics-based cannabis research. Genomics and bio-informatics are relatively new subjects growing at a fast pace since the release of the first Cannabis draft genome in 2011 together. Recent advances in sequencing technologies have further propelled genomic and transcriptomic studies with the purpose of dissecting the regulatory networks. The growth of genomic data in public space has met with the fast-paced development of bio-informatics tools for data analysis. In addition, ongoing developments of machine-learning and artificial intelligence based genomic tools will facilitate genetic-level understanding of cannabis metabolism for the selective breeding of genetically modified cannabis with improved metabolic traits. Physiological, morphological, and developmental aspects of Cannabis are key in understanding the plant growth patterns and chemical profiles. However, plant growth and function are substantially influenced byabiotic factors and nutrient availability. Although botanical aspects , plant architecture,and florogenesis of female C. sativa plants  with detailed trichomemorphogenesis  provided crucial insight into plant biology. However, it also became increasingly important to determine the effect of abiotic factors on Cannabis growth and chemical yield, especially for large-scale commercial breeding programs. Hence, in-depth analysis of the effect of soil fertilization, salinity, temperature, and light conditions, as well as nutrient and water use efficiency is key in establishing industrial-scale systems for the cultivation of hemp and marijuana varieties.The first available records about the mineral nutrition of hemp plants were published by Tibeau et al.,in 1936 . Later in 1944, Clarence H Nelson published the effect of varying soil temperature on hemp growth .

The first publication with a detailed response of greenhouse cultivated cannabis to nitrogen, phosphorus , and potassium  was published in 1977 . Furthermore, two parallel reports by HMGet al., in 1995 discussed the impact of nitrogen fertilization on sex expression in hemp ,vertical grow rack and the effect of temperature on leaf and canopy formation . Importantly, most physiological studies in the second and third period  were published for hemp with a focus on photosynthetic response and biomass yield with varying conditions such as temperature, water availability, nitrogen, and mineral nutrition . However, the first study to assess the chemical response of hemp plants was published in 1997.Since the physiological response of drug-type medical cannabis plants may differ from hemp plants owing to the distinct genetic and chemical differences. Hence, a clear understanding of optimum factors for medical cannabis is inevitable for the efficient cultivation of plants with desired chemical composition. Among the first few studies that addressed medical cannabis, photosynthetic response to photon flux densities,temperature, and CO2 conditions were published by Chandra et al., in 2008 and 2011 . Bernstein and the group further addressed the growth and chemical response of medical cannabis to mineral nutrition especially N, P, and K . Saloner and Bernstein  reported optimum N concentration at 160 mg L_1, N with lower levels showed several symptoms inducing necrosis and growth retardation while the higher levels impacted in reducing concentrations of THCA and CBDA. Shiponi and Bernstein  showed a negative association of cannabinoid concentrations and yield with increasing P supply. Saloner et al. further  determined genotype-dependent effect of K nutrition on medical cannabis reporting 240 ppm K detrimental for the genotype Royal Medic and stimulant for Desert Queen genotype while 15 ppm K was insufficient for both genotypes. Further in 2019 Bernstein et al.  discussed the combined effect of NPK nutrition upon cannabinoid concentration. In addition to soil nutrients, heavy metal uptake potential of hemp varieties has also been thoroughly investigated by multiple reports in past years . Industrial hemp varieties of C. sativa have also been shown to grow in soils contaminated with heavy metals and reported for heavy metal accumulation. Several field projects have assessed the phytoremediation potential of hemp plants for the reclamation of contaminated and radioactive soils. Cannabis cultivars are classified into drug-type  fiber-type  and neutral plants with distinct cannabinoid constitutions. Drug-type cultivars with THC/CBD ratioR10 are classified as chemotype I, while those with THC/CBD ratio ranging from 0.2 to 10 are grouped as chemotype II.In contrast, fiber-type cultivars with THC/CBD ratio <0.2 are categorized as chemotype III. Chemotype IValso has low THC contents but with the potent percentage of CBG. Furthermore, the chemotypes producing very little to almost zero cannabinoid compounds  are grouped as chemotype V -was first described byMandolino et al. . Apart from cannabinoid  content, drug and fiber-type plants have significant genetic variation. Sawleret al., 2015 described that marijuana is genetically inclined toward ‘‘sativa’’ and hemp have a similarity with the ‘‘indica’’ type . Moreover, each plant type has unique applications differentiating them from each other. For example, the fiber-type “hemp’’ plant has mostly food and industrial applications,including production dietary products, hemp oil, seeds, and fiber, while the ‘‘marijuana’’ drugtype plant is used exclusively for medicinal and recreational purposes.Despite such a huge genetic and application diversity, both types of cannabis plants were categorized as‘‘Scheduled 1 drug’’ according to the ‘‘Controlled Substances Act’’ in 1970 . These restrictions had a serious impact on the research preventing the scientific community to study the potential of diverse yielding traits for hemp. However, after 44 years in 2014 the ‘‘agricultural act section 7606’’ was implemented which distinguish hemp from marijuana .