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Hemp (Cannabis sativa L.) is an ancient, widespread, multipurpose crop cultivated all over the world, all parts of which can be potentially usable for the production of many different commodities with industrial interest. It is one of the oldest cultivated crops and until the first half of the 1900s, it was widely grown essentially as a fibre crop. Declining the demand for natural fibre consequential to the upper hand of synthetic fibre, and competition from other plant fibre sources led to reduce the demand for hemp. In addition, the use of some narcotic strains containing high and unhealthy level (>0.3%) of the only one psychoactive substance, namely the cannabinoid delta-9 tetrahydrocannabinol (THC), led to the crop’s prohibition during much of the 20th century. The clarification of the genetics and the biosynthetic pathway of the cannabinoids has been essential to identify three main different genotypes and the related chemical phenotypes of hemp plants, differing in the content of the two main hemp cannabinoids, THC and cannabidiol (CBD). Among these, the chemical phenotype commonly named “industrial hemp” includes hemp varieties which contain <0.3% or 0.2% of THC level that makes them unsuitable for narcotic purposes, but very useful for many other industrial applications. Therefore, from a legislative point of view, the main western countries such as United States, Canada, and European Union after a prohibition period, from the last decade of 1900s, have reintroduced and restored the industrial hemp cultivation.

C. sativa L. plants grown for an industrial purpose, are cultivated to obtain fibre, seeds, and their derivatives. These plants are popularly called “industrial hemp” or “fibre-type” hemp, and they contain low-THC level (i.e., <0.3 or 0.2%), whereas, C. sativa L. plants cultivated for narcotic/recreational purposes are characterized by high-THC level and those cultivated for medicinal purposes are characterized by high-THC and high-CBD levels.

1. Definition

Finally, in the US, the federal policy regarding hemp was significantly altered with the 2014 Farm Bill (Agricultural Act of 2014) that allowed the USDA and certain research institutions to grow hemp under an agricultural pilot program. Despite this act, industrial hemp continued to be a niche crop. The great novelty was four years later with the 2018 Farm Bill that has established a new federal hemp regulatory system under the USDA with the aim to facilitate the commercial cultivation, processing, and marketing of hemp and to essentially treat hemp like any other agricultural commodity. Indeed, it removed hemp (i.e., C. sativa L. varieties with a THC content <0.3% of the dry weight of leaves and flowering parts) and their products—among which is hempseed—from the statutory definition of the drug marijuana and the DEA schedule of controlled substances, opening the hemp industry for business [31] . 2018 was also the year in which the federal government of Canada legalized access to recreational cannabis (i.e., the drug-type C. sativa L.) through the entry into force of the Cannabis Act , Bill C-45 [40] . In Figure 3, the main highlights about the C. sativa L. legislation in Canada, the US, the EU and Italy among the EU states, are illustrated.

De Meijer and colleagues [23] for the first time gave a clear genetic meaning to the tripartite distribution of the chemotypes within the C. sativa L. population. Indeed, studying the inheritance of the chemotype traits of C. sativa L. plants, they identified the existence of a single locus named B locus, with two co-dominant alleles, named BT and BD , each of which codes for the THCA- and CBDA-synthases, respectively. Hence, according to this model, the THC-predominant phenotype (chemotype I) is related to the BT / BT genotype, the CBD-predominant phenotype (chemotype III) is determined by the BD / BD genotype, and the intermediate phenotype (chemotype II) is induced by the heterozygous state BT / BD . The same authors also showed that the value of the CBD/THC ratio in the heterozygous hybrids obtained from cross between parental homozygous pure-THC and pure-CBD, unexpectedly differed significantly and deviated from the expected 1.0 value. Therefore, they speculated that some heritable factor could affect the balance between THCA- and CBDA-synthase in their competition to convert the CBGA precursor. In particular, the authors hypothesized that the BT and BD alleles could be part of a wider allelic series coding for several isoenzymatic forms of THCA- and CBDA-synthase, respectively, with differential affinities for the CBGA substrate, resulting in significantly different CBD/THC ratios observed in the heterozygotes. Further studies pointed out the existence of several allelic variants of BD [7] [20] [24] and BT [7] [8] [24] [25] genes coding for less or totally non-functional CBDA- and THCA-synthase, respectively, and which therefore, influence the cannabinoid profile of the plant and, from a practical point of view, also represent an useful genetic marker to differentiate the drug-type from the fibre-type C. sativa L. plants. Interestingly, a higher number of allelic variants of wild-type BD locus was found in comparison to the BT locus. Hence, considering the high number of the cannabinoid synthase genes’ allelic variants and the higher mutation rate of the CBDA-synthase allele, Onofri and colleagues [7] proposed a phylogenetic hypothesis according to which it is possible to consider all cannabinoids’ allelic variants as a gene family and to speculate that the wild-type CBDA-synthase allele may be the ancestral form of this gene family, from which events of duplication would have led to a higher CBDA-synthase variation, resulting in the formation of the CBDA-synthase pseudogenes (i.e., the CBDA-synthase allelic variants) and to the rise of a new sequence coding for a new enzyme able to convert the CBDA substrate in a new product, the THCA. According to this evolutionary theory, it has also been hypothesized that the low-functionally THCA-synthase allele found in some fibre type (CBD-predominant) plants [25] , could be an evolutionarily intermediate between the CBDA-synthase ancestor and the fully functional THCA-synthase allele.

Historically, industrial hemp or simply, hemp, that is, C. sativa L. plants grown for fibre and/or seeds, was frequently cultivated over the world, mainly for the production of technical textiles, until the first half of the 21st century. In the US, hemp was widely grown from the colonial period into the mid-1800s. In the early 1900s and prior to the late 1950s, hemp continued to be grown, being considered as an agricultural commodity: the US Department of Agriculture (USDA) supported its production, and USDA researchers continued to publish information related to hemp production and also reported on hemp’s potential for use in textiles and in paper manufacturing [31] . In Europe, at the end of the 1950s, Italy was the second country in the world after Russia for the areas under hemp cultivation (over 100,000 hectares) and was the world’s best for the quality of the obtained products [32] . However, following the discovery of the psychotropic activity of THC, and the increasing awareness of its deleterious effects on human health, many countries began to take measures in an effort to stem the use of C. sativa L. plants’ flowers and leaves for their psychotropic effects. The first provision was taken in the US and Canada. In the US, between 1914 and 1933, 33 states passed laws restricting legal production to medicinal and industrial purposes only. In 1937, the Marihuana Tax Act defined hemp as a narcotic drug, without any distinguishing between low THC plants (hemp) and high THC (drug hemp or simply, marijuana) ones: both were considered schedule I controlled substances, and it was required that farmers growing hemp hold a federal registration and special tax stamp. This effectively limited further production expansion; in fact, after 1943, production of hemp started to decline until the late 1950s when no production was recorded. Finally, in 1970, The Controlled Substances Act (CSA) was issued, and it placed the control of selected plants, drugs, and chemical substances under federal jurisdiction. Among the selected plants, there were also C. sativa L. ones to which were given the statutory definition of marijuana and were put in the Drug Enforcement Administration (DEA) schedule of controlled substances [31] . In Canada, the cultivation of hemp has been prohibited due to the presence of THC, in 1938 with the Canadian Opium and Narcotics Act [33] [34] . In 1961, the United Nation (UN) endorsed and adopted the single convention on narcotic drugs, which established a universal system for limiting the cultivation, production, distribution, trade, possession, and use of narcotic substances to medical and scientific purposes, with a special focus on plant-derived substances, among which is cannabis. In the article 28, paragraph 2 of this convention, cannabis was defined as “the flowering or fruiting tops of the C. sativa L. plant (excluding the seeds and leaves when not accompanied by the tops) from which the resin has not been extracted, by whatever name they may be designated”. The same article described a system of control required if a country decides to permit the cultivation of C. sativa L. that is not for industrial or horticultural purposes [4] [35] . Ten years later, in 1971, the UN endorsed the convention on psychotropic substances which established an international control system for psychotropic substances, among which is THC [36] . In line with these directives, in 1975 the Italian Republic issued the law n. 685/1975, introducing cannabis (intended as a drug product obtained from C. sativa L. plants) in the schedule of controlled substances.

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