Journal of Ethnopharmacology 227 (2018) 300–315

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Journal of Ethnopharmacology

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Review Cannabis sativa: A comprehensive ethnopharmacological review of a medicinal plant with a long history T

Sara Anna Boninia, Marika Premolia, Simone Tambarob, Amit Kumarc, Giuseppina Maccarinellia, ⁎ Maurizio Memoa, Andrea Mastinua, a Department of Molecular and Translational Medicine, Division of Pharmacology, University of Brescia, Brescia, Italy b Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Division of Neurogeriatrics, Karolinska Institutet, Huddinge, Sweden c Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Division of Clinical Geriatrics, Karolinska Institutet, Huddinge, Sweden

ARTICLE INFO ABSTRACT

Keywords: Ethnopharmacological relevance: Cannabis sativa L. (C. sativa) is an annual dioecious plant, which shares its Cannabis sativa L. origins with the inception of the first agricultural human societies in Asia. Over the course of time different parts Ethnobotany of the plant have been utilized for therapeutic and recreational purposes, for instance, extraction of healing oils Phytocannabinoids from seed, or the use of inflorescences for their psychoactive effects. The key psychoactive constituent in C. sativa Terpenoids is called Δ-9-tetrahydrocannabinol (D9-THC). The endocannabinoid system seems to be phylogenetically an- Endocannabinoids cient, as it was present in the most primitive vertebrates with a neuronal network. N-arachidonoylethanolamine (AEA) and 2-arachidonoyl glycerol (2-AG) are the main endocannabinoids ligands present in the animal kingdom, and the main endocannabinoid receptors are cannabinoid type-1 (CB1) receptor and cannabinoid type- 2 (CB2) receptor. Aim of the study: The review aims to provide a critical and comprehensive evaluation, from the ancient times to our days, of the ethnological, botanical, chemical and pharmacological aspects of C. sativa, with a vision for promoting further pharmaceutical research to explore its complete potential as a therapeutic agent. Materials and methods: This study was performed by reviewing in extensive details the studies on historical significance and ethnopharmacological applications of C. sativa by using international scientific databases, books, Master’s and Ph.D. dissertations and government reports. In addition, we also try to gather relevant information from large regional as well as global unpublished resources. In addition, the plant taxonomy was validated using certified databases such as Medicinal Plant Names Services (MPNS) and The Plant List. Results and conclusions: A detailed comparative analysis of the available resources for C. sativa confirmed its origin and traditional spiritual, household and therapeutic uses and most importantly its popularity as a re- creational drug. The result of several studies suggested a deeper involvement of phytocannabinoids (the key compounds in C. sativa) in several others central and peripheral pathophysiological mechanisms such as food intake, inflammation, pain, colitis, sleep disorders, neurological and psychiatric illness. However, despite their numerous medicinal benefits, they are still considered as a menace to the society and banned throughout the world, except for few countries. We believe that this review will help lay the foundation for promoting ex- haustive pharmacological and pharmaceutical studies in order to better understand the clinical relevance and applications of non-psychoactive cannabinoids in the prevention and treatment of life-threatening diseases and help to improve the legal status of C. sativa.

1. Introduction recreational and religious purpose over the centuries (Piluzza et al., 2013). It contains a number of chemically active compounds, such as Cannabis sativa L. (C. sativa)(Fig. 1), also known as Indian hemp, is cannabinoids, terpenoids, flavonoids, and alkaloids (Andre et al., an herbaceous annual plant, cultivated mainly in Central Asia (India 2016). The most active compounds are the cannabinoids, a class of and China) since ancient times (Russo et al., 2008). C. sativa has been terpenophenolic compounds, accumulated mainly in the trichome used as a source of fibres, food, oil, and medicine as well as for cavity of the female flowers (Taura et al., 2007, Brenneisen, 2007). Out

⁎ Corresponding author. E-mail address: [email protected] (A. Mastinu). https://doi.org/10.1016/j.jep.2018.09.004 Received 4 May 2018; Received in revised form 2 September 2018; Accepted 3 September 2018 Available online 08 September 2018 0378-8741/ © 2018 Elsevier B.V. All rights reserved. S.A. Bonini et al. Journal of Ethnopharmacology 227 (2018) 300–315

2. Ethnobotanical aspects of Cannabis sativa L

2.1. Geographical and historical origins

Historically, Central Asia and South-East Asia have been proposed as potential regions for the natural origin and/or primary domestication of C. sativa, and are probably believed to play a vital role in its evo- lution (Stevens et al., 2016; Jiang et al., 2006). Moreover, C. sativa accompanied the progress of the first human societies in the changes that occurred after the glacial Pleistocene epoch. In particular, it seems that in Czech Palaeolithic sites, a variety of techniques was used that enabled the production of sophisticated plaited basketry based on C. sativa. It is perhaps the world oldest archaeological evidence of C. sativa use (Adovasio et al., 1996). Furthermore, several Neolithic pieces of evidence found in Taiwan suggest that C. sativa was used 12,000 years ago for several different purposes (Li, 1974) and played a significant role in early cordage and textile manufacturing. In fact, it has been referred to as the oldest known cultivated fibre plant (Cherney and Small, 2016), and even today it is used as a constituent of fishing nets (Savo et al., 2013). Clarke and Merlin argued that the discovery of C. sativa psychoactivity may be considered as an unintentional event (Merlin, 2003; Clarke and Merlin, 2013). The western-centred viewpoint of the American re- searchers maintains that, perhaps, the accidental burning of C. sativa plants, triggered by natural events, has revealed its psychotropic nature. An approach indigenous-centred can be added to the theory of Clarke and Merlin. In fact, observing primitive human societies, we can hypothesize how they interacted with the environment. Already in the 1980s, Luna L. E. reported how a group of shamans from Iquitos in Peru considered medicinal plants (Luna, 1984). They used a drink (aya- huasca) based on Banisteriopsis caapi and Psychotria viridis, during sha- manic rites, capable of generating psychedelic effects. These plants were considered "teachers" because the shamans could heal the disease of their village employing them, often fasting and accompanied by Fig. 1. Plantation of Cannabis sativa L. particular melodies. This "plant-teacher" approach has also been argued by other authors in the world (VanPool, 2009; Mafimisebi and of over 100 cannabinoids identified so far, the most potent one is trans- Oguntade, 2010; Jauregui et al., 2011; Gagliano, 2013; Armijos et al., Δ-9-tetrahydrocannabinol (D9-THC), mainly responsible for psychoac- 2014) and could explain the use of C. sativa in the religious rituals of tive effects (Whiting et al., 2015). early human societies. The first humans who adopted a more sedentary lifestyle mainly Since then the selection of different varieties of C. sativa has begun, started the cultivation of C. sativa (Russo, 2007). These people were some plants selected as cultivar, mainly used to produce textile fibres, also some of the earliest cultivators of versatile species of plants, grown others especially as drugs for religious rituals. and selected to obtain nutritious starch-containing food, tough water- C. sativa has also been recognized as a sacred plant by several re- resistant fibres, euphoric and medicinal drugs (Fort, 2012; Sauer, ligions over the centuries (Touwn, 1981). Indeed, the holy texts of 1952). Asiatic cultures refer to it as a plant with sacred virtues and considered In fact, the modern botanical varieties of C. sativa mainly used for it a part of religious rituals. In India and Tibet, Hinduism and tantric the manufacturing of fish nets (Savo et al., 2013), strings, ropes, tex- Buddhism traditions used flowers and resins of C. sativa to facilitate the tiles, and even paper have a low amount of psychoactive D9-THC (Tang meditation and communication with the spirits (Schultes et al., 1992). et al., 2016). On the contrary, D9-THC content in the plant used both as There is a Buddhist legend about the ability of the Bhang, a particular C. a medicine and/or as a voluptuary drug is much higher than in C. sativa sativa preparation, to have been the only source of nourishment for cultivated for fibres (Hanus, 2009). This is the reason why, today, Siddhartha Gautama during his six years of asceticism (Touwn, 1981). cultivation and use of C. sativa with high D9-THC content are illegal/ According to some authors, the word Cannabis was present in Semitic banned in most of the countries, and it is only allowed for research and languages like Hebrew, and it appears several times throughout the Old medical purposes. Hence, the adventure of C. sativa begins: from robust Testament. In fact, in some passages of Exodus, Isaiah, Jeremiah, and and durable textile fibre to voluptuous drug of the artists and writers in Ezekiel, the use of C. sativa as incense and sacred oil is cited (Bennett, the nineteenth century. This review will analyze from the ancient times 2011; Abel, 1980). since our days the anthropological and cultural aspects related to C. The medical use of C. sativa dates back about 5000 years ago, when sativa and how the different uses have selected the contemporary bo- the emperor Chen Nung (Fig. 2), defined king and “father” of Chinese tanical varieties. Moreover, some chemical aspects of the C. sativa will agriculture, drew up the first Chinese pharmacopeia (Abel, 1980). Ac- be described with a particular reference to phytocannabinoids and cording to this ancient text, C. sativa was prescribed for fatigue, rheu- terpenoids, including some of their therapeutic applications. matism, and malaria (Abel, 1980). Moreover, Chinese physicians used the seeds of C. sativa mainly for their vegetal oils and proteins. The seeds of C. sativa are rich in γ-linoleic acid (Anwara et al., 2006), that the physicians recommended for eczema and psoriasis, and its oral use for inflammatory diseases (Jeong et al., 2014). In addition, the use of C. sativa as a medicine is extensively reported (Fig. 3) on Assyrian clay

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Fig. 2. Depiction of Emperor Chen Nung and in the upper left corner, the evolution of the Chinese characters of the word "Cannabis sativa". tablets (Anderson and Scurlock, 2005) and on the Egyptian Ebers Pa- pyrus dated to about 3000 years ago (Epstein, 2010). C. sativa was also well known among the ancient Greeks and Romans (Mercuri et al., 2002). The historian Herodotus (about 400 B.C.) mentioned its use among the Indians, and Diodorus Siculus (about 60 B.C.) reported that the ancient Egyptian women used C. sativa to reduce pain and improve their mood (Carod-Artal, 2013). In addition, the Roman historian Pliny the Elder recounted the use of C. sativa roots for easing the pain (Ryz et al., 2017). In the same period, Pedacius Dioscorides, a Greek physi- cian, classified different plants, including C. sativa, and described their useful benefits (Riddle, 2011). A Roman physician, Galen, considered highly influential in the Ancient and Middle Ages, also wrote some Fig. 4. England or Northern France miniatures from late 12th-century, once notes about C. sativa. In particular, he described a practice, diffused owned by the monastery at Ourscamps and now in the collection at the British among Roman aristocrats, to conclude their lunch with a cannabis- Library. based dessert (Butrica, 2002). In the medieval Arabic culture, the use of cannabis was associated particular, Italians began the first large-scale cultivation and commer- with disadvantaged social conditions. An example is a myth of “Old cialization of the plant in the Mediterranean area. Conversely, C. sativa Man of the Mountains” and the followers of Hasan, the “ashishin”,as was not known in the Americas until the arrival and settlement of the written in the chronicles by Marco Polo (Fleischhauer, 1956). The first European colonists. During this period C. sativa was used primarily various forms of C. sativa were known to medieval Europe. In for the strength and the resistance of its fibres. Indeed, the Spanish and

Fig. 3. Egyptian Ebers Papyrus (A), ancient Egyptian goddess Seshat (Goddess of wisdom, knowledge, writing, and architecture) is depicted with perhaps a hemp leaf in her headdress (B), and a detail of Assyrian clay tablets (C).

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English colonies in the Americas mainly imported the botanical vari- eties ideal for textile manufacturing. In addition, although large quantities of C. sativa were marketed throughout the Modern Age in Europe, these were exclusively destined for manufacturing commerce (Anon, 1972). Nevertheless, some inebriating effects of C. sativa in magic and traditional medicine were also known (Benet, 1975). Pope Innocent VIII issued a papal bull condemning the witchcraft and the use of C. sativa in 1484 (Kors and Peters, 2000). Moreover, many herbalist treatises of these years argued on the therapeutic value of the C. sativa seeds and flowers (Fig. 4). In the following centuries, the European citizens learned numerous uses of C. sativa thanks to travelogues, written by adventurers, sea captains, wealthy travellers, priests, and traders headed to Africa and the East Indies (Abel, 1980). In particular, with the conquest of India, the voluptuous uses of C. sativa were better known across the European continent. Garcia da Orta and Cristobal Acosta, two Portuguese doctors, wrote about the effects of C. sativa, which included euphoria, sedation, stimulation of appetite, hallucinations, and aphrodisiac effects (Lee, 2013). Moreover, during the British colonialism of the East India Company, C. sativa was mar- “ ’ ” keted in Asia through a variety of formulations such as Bhang, Ganja or Fig. 6. Les Femmes d Alger dans leur appartement , Eugène Delacroix, 1834, Louvre Museum. Painting both Orientalist and romantic. Orientalism was Charas. Ganja and Charas are preparations of flower and resin with high characteristic of artists and writers in the nineteenth century. psychoactive contents (O’Shaughnessy, 1843). On the contrary, Bhang has a low psychotropic effect comparable to that of some Western al- coholic drinks. Also, in the middle of the eighteenth century, the mental illness (Moreau, 1973). He thought that the voluptuary use of C. Swedish botanist Carl Linnaeus worked on writing the Species Plan- sativa could generate sensations common to the hallucinations and tarum (Fig. 5), coins for the first time the name Cannabis sativa. How- delusions in psychotic individuals (Moreau, 1973). In addition, in the ever, thanks to the chronicles of Indies travellers, other botanists began English medicine of the nineteenth century, C. sativa was introduced as fl to discuss the existence of distinct types of Cannabis based on size, an analgesic, anti-in ammatory, anti-emetic and anti-convulsant shape and resin contents. In particular, Jean Lamarck reserved the (Aldrich, 1997). fi name Cannabis sativa for the European plant and Cannabis indica for the Despite the bene ts described above, it was strongly prohibited in ff Indian origin varieties (Small and Cronquist, 1976). the twentieth century due to its remarkable psychoactive e ects and The myth of the Orient that pervaded the nineteenth century (Fig. 6) was removed from the British Pharmacopoeia in 1932 and included as a also brought with it the development of private hashish consumer banned substance for therapeutic use, in the Act of the Parliament of clubs. Many Romantic artists and writers frequented these clubs such as the United Kingdom, Misuse of Drugs Regulation Act in 1971 (Hall, Théophile Gautier, Charles Baudelaire, Honoré de Balzac, Alexandre 2008). In 1937 production, possession or transfer of C. sativa was for- Dumas, and Gustave Flaubert (Levinthal, 2012). In 1830, the French bidden in the USA due to federal law "The Marihuana Tax Act" (Bonnie physician Jacques Joseph Moreau studied the effects of C. sativa in and Whitebread, 1974). Despite these restrictions, the use of C. sativa as a local and tradi- tional medicine by shamans and healers, an intense pharmacological research on its chemical components, and several socio-cultural debates on it continued. Today many indigenous communities in the world use C. sativa derivatives for several diseases. In the Miandam area of Swat, North Pakistan, leaves of C. sativa are used for wound healing; powdered leaves as anodyne, sedative, tonic and narcotic (Akhtar et al., 2013). Small ethnic groups of rural villages from Nepal, Arunachal Pradesh, and Haryana use C. sativa for human and livestock gastrointestinal diseases, pain and snake bite (Panghal et al., 2010; Kunwar et al., 2010; Namsa et al., 2011; Abbasi et al., 2013). Moreover, some livestock farmers in Uganda and Kenia use C. sativa as an ethnoveterinary remedy (Gakuubi and Wanzala, 2012; Nabukenya et al., 2014). Lastly, even in some isolated ethnic groups of the Caucasus, the traditional use of cannabis as a traditional remedy is preserved (Bussmann et al., 2016). From a pharmacological point of view, in 1964, Gaoni and Mechoulam opened the way for studying cannabinoids by isolating and synthesizing the main phytocannabinoid, D9-THC (Mechoulam and Gaoni, 1965). In the 1980s, Pfizer worked on the development of syn- thetic ligands of cannabinoid receptors (Pertwee, 2006). Subsequently, the cannabinoid type-1 (CB1) receptor was first discovered in 1990, then the cannabinoid type-2 (CB2) receptor in 1993 (Pertwee, 2006). Moreover, in the 1990s the two endogenous CB receptor ligands, ara- chidonoylethanolamine, and 2-arachidonylglycerol, were also dis- covered (Pertwee, 2006). Finally, around the same time, Di Marzo and colleagues coined the term “endocannabinoid system”, which com- Fig. 5. Cannabis sativa Linnaeus from Franz Eugen Köhler's Medizinal-Pflantzen, prises endogenous ligands, receptors, and synthesis and degradation 1887, Germany. enzymes (Di Marzo et al., 1994). All these discoveries/research on C.

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Fig. 7. Male (A) and female (B) flowers of Cannabis sativa L. sativa have contributed to the identification of new synthetic molecules 3. Botanical aspects of Cannabis sativa that are able to modulate the endocannabinoid system in inflammation, pain and metabolic processes (Lazzari et al., 2011, 2012, 2017; Mastinu 3.1. Biology of the plant et al., 2012, 2013, 2018; Manca et al., 2013; Tambaro et al., 2014; Bonini et al., 2016). As previously mentioned, C. sativa was among the first plants to be Even today, there is a continuous debate over the legal status of C. grown in the early human sedentary communities, and it was utilized sativa in many western governments (McGinty et al., 2017). In parti- for 10,000 years or more (Russo et al., 2008). Regarding the tax- cular, the freedom to use C. sativa for the medical or recreational pur- onomical classification, Schulte and Anderson described three hy- pose is viewed by many people as a conquest for civil rights and by pothetical species, Cannabis sativa Linnaeus, Cannabis indica Lamarck, others as a major sociocultural problem. Who has had experience of C. and Cannabis ruderalis Janisch (Schultes et al., 1974; Anderson, 1980). sativa argues that it has: heightened the senses; improved acoustic These three species differ fundamentally in terms of height and content perception, soothed emotions; facilitated communication; promoted of psychoactive molecules. Genetic-taxonomic analyses of allozyme creative thought by facilitating “thinking outside the box” and thereby frequency in different genes have established that there was a previous enhanced creativity (Fachner, 2008; Kowal et al., 2015). An American geographical separation that existed between C. sativa (“European”), C. ethnobotanist, Terrance McKenna, hypothesized that the use of C. sativa indica (“South Asiatic-African”) and C. ruderalis (“Central Asiatic”) by humans may have stimulated the emergence of language and com- (Gilmore et al., 2003). These genetic differences have been observed munication favouring the leap forward to civilization (McKenna, 1992). especially in the species for D9-THC extraction and have remarkably In addition, some schools of thought argued that the ingestion of psy- increased in the last 50 years due to the breeding human pressure chedelic substances in a carefully monitored context could induce an (Russo, 2007). Anyways, the debate on the taxonomy of C. sativa still experience that is medically safe and that provokes profound, durable remains open as reported by some authors (Hillig, 2005; Watts, 2006; psychological and behavioural changes (Nichols, 2016). Indeed, an Small, 2015; Clarke and Merlin, 2016). In this review, we will discuss, answer to the crisis of novel psychiatric medication development is the in particular, the C. sativa specie. psychedelic-assisted psychotherapy (PAP). To date, there are promising C. sativa is a dioecious, rarely monoecious, annual plant of the fa- clinical trials of PAP with LSD, MDMA, ketamine, psilocybin, and ibo- mily Cannabinaceae, having erected stems, which, depending on the gaine as a treatment for alcohol dependence, nicotine dependence, environmental conditions and the genetic variety, can reach up to 5 m anxiety related to a terminal illness, and chronic post-traumatic stress (Farag and Kayser, 2017). The palmate leaves, usually composed of five disorders (Schenberg, 2018). Regarding C. sativa, several studies re- to seven leaflets, are linear-lanceolate, tapering at both ends and the ported that it can eliminate nightmares of traumatic events and can margins sharply serrate. The male flowers (Fig. 7A) do not present improve sleep (Pedersen and Sandberg, 2013; Babson et al., 2017). In petals, axillary or terminal panicles, have five yellowish tepals and five particular, war veterans described the use of C. sativa as more effective anthers. The female flowers (Fig. 7B) germinate in the axils and term- and less complicated by side effects compared to alcohol or other inally with one single-ovulate closely adherent perianth. A single, psychopharmaceuticals (Betthauser et al., 2015). Indeed, C. sativa can small, smooth, light brownish-grey fruit is produced per flower and be part of a psychotherapeutic strategy that aids with introspection and propagated, thanks to bird predation. Moreover, C. sativa is rich in direct confrontation of the sources of personal trauma. trichomes (Fig. 8), epidermal glandular protuberances covering the These promising finding in the pharmacological and psychother- leaves, bracts, and stems of the plant (Happyana et al., 2013; apeutic effects of cannabis can be the basis on which the legislator can Huchelmann et al., 2017). These glandular trichomes enclose secondary evaluate the legalization of C. sativa. Still, in many countries, the cul- metabolites as phytocannabinoids, responsible for the defence and in- tivation and marketing of C. sativa are illegal. This promotes smuggling teraction with herbivores and pests, and terpenoids, which generate the and makes it difficult to find standardized extracts (Dragone et al., typical smell of the C. sativa (Andre et al., 2016). The form of the plant 2018). Therefore, a medically controlled and chemically standardized varies according to the climate and variety. In fact, it grows more use may be, today, the legal answer to the use of C. sativa. commonly as a persistent weed at the edge of the cultivated fields on

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Fig. 8. Trichomes of Cannabis sativa L. land with high nitrogen content (Raman, 1998). After 8–12 days, C. 4. Chemical aspects of Cannabis sativa sativa seeds germinate and their coat splits, opens and exposes the root and two circular embryonic cotyledons leave. During its growth, the 4.1. Phytocannabinoids plant requires a moderate level of environmental and soil humidity and a good light intensity. C. sativa grows vertically and produces con- Currently, 538 natural compounds were identified from C. sativa.Of tinuously new leaves mostly in pre-flowering phase, with the produc- these, more than 100 are identi fied as phytocannabinoids, because of tion of new branches and nodes. These phases last about 6–22 weeks the shared chemical structure (Hanus et al., 2016). From a chemical and need low light (Raman, 1998). point of view, phytocannabinoids have a lipid structure featuring al- The phytocannabinoids contents of C. sativa are influenced by par- kylresorcinol and monoterpene moieties in their molecules (Hanus ticular extreme environmental conditions of humidity, temperature, et al., 2016; Hill et al., 2012). Moreover, they are mostly present in the radiation, soil nutrients, and parasites (Russo, 2011). Phytocannabi- resin secreted from the trichomes of female plants, while male leaves of noids and several terpenes, present in C. sativa leaves and flowers, serve C. sativa have few glandular trichomes that can produce small amounts as a barrier to water loss, as observed in analogy to the waxy coatings of of psychoactive molecules. Phytocannabinoids are classified as neutral the cacti and other succulent plants (Pate, 1994). Moreover, sparse cannabinoids (without carboxyl group) and cannabinoid acids (with rainfall, low humidity, and sunny climate generate a plant rich in carboxyl group) (Hanus et al., 2016). In C. sativa, cannabinoids are psychoactive components. In addition, the same C. sativa pollen shows biosynthesized and accumulated as cannabinoid acids, and subse- an increase in the phytocannabinoids content with decreased humidity. quently decarboxylated into their neutral forms. In particular, alkyla- Indeed, D9-THC, the main component of the trichomes resin, plays a tion of olivetolic acid with geranyl-pyrophosphate by a pre- protective function thanks to its viscous and hydrophobic nature and nyltransferase produces cannabigerolic acid (CBGA). Thanks to the low volatility (Pate, 1994). Also, the temperature has a role in de- action of cannabinoid synthase enzymes, CBGA generates cannabidiolic termining the cannabinoid amount, but only through its association acid (CBDA), cannabichromenic acid (CBCA) and Δ-9-tetra- with environmental humidity. Furthermore, C. sativa exposure to high hydrocannabinolic acid (D9-THCA) (Sirikantaramas and Taura, 2017). ultraviolet radiation (UV-B 280–315 nm) produces significantly greater The biosynthesis of the main phytocannabinoids is summarized in quantities of D9-THC. Indeed, D9-THC is more stable to UV-B radiations Fig. 9. as compared to other cannabinoids, which may be more rapidly de- The phytocannabinoids can be divided into 10 subclasses (Fig. 10), graded on exposure to UV-B radiations (Pate, 1994). Soil nutrients also as reported by many authors (Hanus et al., 2016; Hill et al., 2012; influence the cannabinoid production. In particular, on one hand, there Sirikantaramas and Taura, 2017; Izzo et al., 2009). Some of these are is a negative correlation between soil K content and D9-THC con- discussed below. centration in C. sativa, and on the other hand, K-P interaction, N and Ca Cannabigerol (CBG) type: These phytocannabinoids have a het- are positively correlated with it. Also, Mg and Fe are important for the erogeneous chemical structure and do not produce psychoactive action phytocannabinoids production, because they may serve as co-factors for mediated by the CB1 receptor (Izzo et al., 2009). On the other hand, it the enzymatic reactions (Pate, 1994; Latta and Eaton, 1975). Finally, seems that an extract of C. sativa with a high concentration of CBG, terpenes and phytocannabinoids can block other sources of environ- without D9-THC, increases food consumption in rats (Brierley et al., mental stress such as attacks by bacteria, fungi, and insect, or compe- 2017). CBG type compounds show a poor inhibition of the serotonin tition with surrounding vegetation. Especially the C. sativa female receptors 5HT1A and bind to menthol receptor TRPM8 by blocking its plants often noted for its aromatic quality and many of the terpenes action in the sensory neurons (Borrelli et al., 2014; Cascio et al., 2010). produced (pinene, limonene, terpineol, and borneol), are known to Moreover, CBG is an α-2 adrenergic receptor agonist able to inhibit the possess insect-repellent properties and may help to suppress the growth release of catecholamine with sedation, muscle relaxation and analgesia of the surrounding vegetation (McPartland, 1997). Moreover, the same effects (Cascio et al., 2010). In addition, CBG decreases acetylcholine- resin of the glandular trichomes is a sophisticated defensive system to induced contractions in the human bladder, and this action is not af- ensnare insects and may show antibiotic and antifungal properties fected by CB1 or CB2 receptor antagonists (Pagano et al., 2015). Re- (Appendino et al., 2008). cently, Smeriglio and colleagues reported that extracts of C. sativa, with CBD/CBDA or CBG/ CBGA, inhibit the aldose reductase activity and could be useful for the prevention and therapy of diabetic complications

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Fig. 9. Biosynthesis of main phytocannabi- noids. Geranyl diphosphate and olivetolic acid are converted by a synthase in CBGA, the central precursors of D9-THCA, CBDA, and CBCA, which contain an n-pentyl side chain (C5-phytocannabinoids). From the decarbox- ylation of these precursors are formed Δ-9- tetrahydrocannabinol (D9-THC) and its meta- bolite cannabinol (CBN), cannabidiol (CBD), cannabichromene (CBC) and its chemical ar- tefact cannabicyclol (CBL). On the other hand, from geranyl diphosphate and divarinc acid is formed cannabigerovarinic acid (CBGVA) an n- propyl side chain, C3-phytocannabinoids. From CBGVA are synthesized Δ-9-tetra- hydrocannabivarin acid (D9-THCVA), canna- bidivarin acid (CBDVA) and cannabichrome- varin acid (CBCVA). Their decarbosylation forms the respective cannabinoids, D9-THCV, CBNV, CBDV, CBCV, and CBLV.

(Smeriglio et al., 2018). curative effect on the inflammatory bowel disease. Finally, Shinjyo and Cannabichromene (CBC) type: From a structural point of view, CBC colleagues suggest a potential effect of CBC on neural stem cells in the is one of the most stable phytocannabinoids; in fact, it has been de- adult brain. In particular, CBC can positively influence the viability of tected in century-old samples of C. sativa (Russo et al., 2008). The CBC the Nestin-positive stem cell population in differentiating NSPCs amount is strictly associated with D9-THC, suggesting a chemical re- through the up-regulation of ERK phosphorylation mediated by the lationship between the oxidase involved in the generation of CBC and adenosine A1 receptor (Shinjyo and Di Marzo, 2013). D9-THC from CBG (Izzo et al., 2009). Higher contents of CBC have been Cannabidiol (CBD) type: Cannabidiolic acid (CBDA) and CBD are found in the vegetative stage of C. sativa as compared to its re- the most abundant phytocannabinoids in the species of Cannabis for productive stage. Moreover, CBC-type compounds do not show any textile uses (Hanus et al., 2016; Izzo et al., 2009). Despite the structural CB1-mediated psychoactivity, although CBC is a potent activator of a similarity between CBD and D9-THC, CBD has a low agonism for can- transient receptor potential channel, the TRPA1 in inflammatory pro- nabinoid receptors; in particular, it is considered as an allosteric ne- cesses (De Petrocellis et al., 2008). In particular, CBC seems to reduce gative modulator of CB1 and CB2 receptors (Pertwee, 2008; Casajuana nitric oxide, IL‐10, and interferon‐γ levels in peritoneal macrophages Köguel et al., 2018). Nevertheless, CBD can be electrophilically cyclised activated by LPS as reported by Dr. Romano and colleagues (Romano to D9-THC in an acid environment. This could also explain the D9-THC et al., 2013). Then, CBC action might limit the NO effects and have a production in tobacco cigarettes (water suspensions acidic) when they

Fig. 10. Examples of phytocannabinoids of Cannabis sativa. Δ-9-tetrahydrocannabinol (D9-THC), cannabidiol (CBD), cannabigerol (CBG), Δ-9-tetra- hydrocannabivarin (D9-THCV), cannabichromene (CBC), cannabicyclol (CBL), cannabinol (CBN).

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Fig. 11. Examples of terpenoids of C. sativa. are added with CBD. Current evidence showed that CBD exerts phar- Lastly, after D9-THC administration, hypo locomotion, hypothermia, macological effects via specific molecular targets such as adenosine catalepsy, analgesia, and increased food intake have been reported receptors, glycine receptors, opioid receptors, serotonin receptors, non- (Pertwee, 2008). endocannabinoid G protein-coupled receptors, nicotinic acetylcholine Δ-9-tetrahydrocannabivarin (D9-THCV) is another THC-type com- receptors, proliferator-activated receptors (Ibeas Bih et al., 2015). pound, mainly identified in hashish of Pakistani C. sativa (Tayyab and Moreover, CBD shows anticonvulsant, anti-spasmodic, anxiolytic, anti- Shahwar, 2015). This molecule is considered as an antagonist of the nausea, anti-rheumatoid arthritis, and neuroprotective properties CB1 receptor (Dennis et al., 2008) since at low doses (< 3 mg/kg), it (Pertwee, 2008). Recently, it has been demonstrated that CBD is an antagonizes the D9-THC effects by acting on food intake in mice. On the inverse agonist for G protein-coupled orphan receptors such as GPR3, contrary, at higher doses (10 mg/kg) D9-THCV shows an agonist profile GPR6, and GPR12, suggesting new therapeutic uses of CBD for Alz- (Pertwee, 2008). In addition, D9-THCV can activate CB2 receptors heimer's disease, Parkinson's disease, cancer, and infertility (Laun et al., (Bolognini et al., 2010) and inhibit LPS-stimulated nitric oxide pro- 2018). duction in macrophages (Romano et al., 2016). Tetrahydrocannabinol type: Trans-Δ-9-tetrahydrocannabinol (D9- Cannabicyclol (CBL) type: A racemic mixture of phytocannabinoids THC) is the key compound of the C. sativa with major psychoactive that occurs during storage of the C. sativa parts in the presence of light, effects (Pertwee, 2008). The D9-THC main precursors, without psy- but with still unknown biological properties (Hanus et al., 2016). chotropic actions, are the D9-THC acid A and B. Several D9-THC ste- Cannabinol (CBN) types: CBN concentration in C. sativa products reoisomers, degradation products or enzymatically generated by pro- depends on the age and storage conditions. CBN is highly stable toward ducts, occur as minor constituents of this class. Indeed, D9-THC in the oxidative degradation. Moreover, many CBN degradation derivatives C. sativa or extracted and chemically purified is unstable, it is presented are the same as obtained by the spontaneous oxidative aromatization of as an amorphous gum that changes quickly to brown (Hanus et al., D9-THC in C. sativa. Finally, a low CBN affinity for CB1 and CB2 re- 2016). D9-THC degradation is mostly oxidative since it has been esti- ceptors has been observed (Hanus et al., 2016). mated in about 10% of the pure product, but the CBN, main final me- tabolite, was significantly lower. Therefore, C. sativa has other meta- bolic pathways for D9-THC degradation as hypothesized (Hanus et al., 4.2. Terpenoids 2016; Andre et al., 2016). Among the more stable metabolites, it is worth mentioning Δ-8-tetrahydrocannabinol, derived by an acidic iso- Over 200 Terpenoids, responsible for the fragrance of C. sativa, have merization of D9-THC with a shift of the endocyclic double bond been identified in the flower, leaves of the plant, and may represent (Hanus et al., 2016). In addition, from dihydrocannabinol, D9-THC 10% of the trichome contents (Booth et al., 2017). Limonene, myrcene, intermediate, could derive tri-hydrocannabinol, identified in the pollen and pinene are most common and highly volatile. They are repellent to of cannabis. Other D9-THC isomers have been also identified, such as insects and act as antifeedants for grazing animals. The mixture of cis-Δ-9-tetrahydrocannabinol, perhaps a chemical artefact, Δ-6a- and Δ- different C. sativa terpenoids and phytocannabinoid acids shows a sy- 10a-tetrahydrocannabinol, unknown as natural products but synthesized nergistic mechano-chemical defensive strategy against many predators by oxidative aromatization of D9-THC (Hanus et al., 2016). From a (Farag and Kayser, 2017). pharmacological point of view, D9-THC is a partial agonist at both The terpenoid production changes with environmental specific cannabinoid receptors: CB1, a modulator of psychoactive effects, and conditions. Indeed, as observed for the phytocannabinoids, terpenoids CB2, a modulator of immunological and anti-inflammatory effects are produced as a defence mechanism: the amount of terpenoids in- (Pertwee, 2008). The psychoactive effects of D9-THC include anxiety, creases with the light exposure (stressful condition for the plant) but paranoia, perceptual alterations, and cognitive deficits. All these CB1- decreases with soil fertility (Farag and Kayser, 2017). Terpenoids are mediated effects are caused by the perturbation of GABA/glutamatergic lipophilic molecules that interact with cell membranes of animals, at neurotransmission and dopamine release, and above all, they are gen- the cerebral and peripheral level (Russo, 2011). In particular, a test of erally acute, transient, and self-limited (Pertwee, 2008). Moreover, a smell in mice exposed to terpenoid for 1 h, demonstrated profound ef- low D9-THC acute toxicity in murine models has also been observed. fects on mice behaviour, suggesting a potential effect on the brain (Russo, 2011). The pharmacological profiles of some terpenoids are

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Fig. 12. Examples of other cannabimimetic phytochemicals. briefly illustrated below (Fig. 11). ulcers in the United Kingdom with a cannabis extract. Full agonist se- D-limonene, common in lemons and other citrus essences, is a ter- lectivity at the CB2 receptor is the greatest revelation regarding car- penoid quite distributed in nature, but little investigated in C. sativa. yophyllene (Fidyt et al., 2016). Indeed, some authors demonstrated that The molecular structure of this terpenoid shows strong free radical this terpenoid produces anti-inflammatory and analgesic activities at scavenging properties (Bai et al., 2016). Moreover, the anxiolytic ac- the dose of 5 mg/kg in wild-type, but not in CB2 knockout mice (Russo, tivity of D-limonene mediated by serotonin and dopamine in the pre- 2011; Fidyt et al., 2016; Klauke et al., 2014). Caryophyllene offers great frontal cortex and hippocampal region of mice has been reported (Yun, promise as a therapeutic compound. 2014). In addition, perillic acid, a limonene immediate hepatic meta- Caryophyllene oxide is a sesquiterpenoid oxide with antifungal and bolite, shows anti-stress effects in the rat brain (D’Alessio et al., 2014). insecticidal/antifeedant in plant defence (Yang et al., 1999). Moreover, Subsequent investigations highlighted several effects in the apoptosis of this molecule also demonstrates anti-platelet aggregation properties in breast cancer cells (Jia et al., 2013). Further, limonene effectiveness vitro. Lastly, caryophyllene oxide is the component responsible for against gastro-oesophageal reflux resulted in a patent submission cannabis identification by drug-sniffing dogs (Opdyke, 1983). (Wilkins, 1999). Phytol is a diterpene, present in extracts of C. sativa as a degradation Beta-myrcene is a terpenoid widespread in C. sativa, with prominent product of chlorophyll and tocopherol. Phytol-inhibited degradative brain activities. In particular, myrcene shows an analgesic profile in enzymes of GABA increase its expression, contributing to the relaxing mouse models (de Cássia da Silveira et al., 2017). It is added to the effects of C. sativa (Bang et al., 2002). Humulus lupulus based preparations with recognized sedative effects (Russo, 2011; de Cássia da Silveira et al., 2017). Furthermore, myrcene 4.3. Other cannabimimetic phytochemicals acts as a muscle relaxant in mice and has demonstrated anti-in- flammatory activity via prostaglandin E-2 (Russo, 2011). To date, other plants have been also identified that synthesize sec- These data suggest that myrcene, along with some fitocannabinoids, ondary metabolites with cannabimimetic action (Fig. 12). These in- contributes to the sedative and anti-inflammatory effects of C. sativa. clude Radula perrottetii, Radula laxiramea, and Radula marginata. From Alpha-pinene is a bicyclic monoterpene, it appears in conifers and these three species (endemic to New Zealand), a cannabinoid similar to other innumerable plants in nature, with an insect-repellent role. D9-THC was isolated, namely perrottetinene (Hanus, 2009). In addi- Pinene has been demonstrated to have anti-inflammatory, bronchodi- tion, several other plant species can produce secondary metabolites that lator antibacterial effects in several experimental models (Kim et al., potentially modulate the endocannabinoid system. N-alkylamides from 2015). Moreover, this monoterpenoid seems to be an acet- Lepidium meyenii (maca or Peruvian ginseng) and N-isobutylamide ylcholinesterase inhibitor. This characteristic could counteract short- guineensine from Piper nigrum (black pepper) show cannabinoidergic term memory deficits induced by D9-THC (Owokotomo et al., 2015). action in vitro and in BALB/c mice, respectively (Hajdu et al., 2014; D-linalool is a monoterpenoid alcohol with anxiolytic and sedative Nicolussi et al., 2014). In addition, Leonti and colleagues have de- activity (Souto-Maior et al., 2011). Linalool also shows local anaesthetic monstrated that a polyacetylene falcarinol (panaxynol, carotatoxin), effects comparable to those of procaine and menthol. Indeed, it has found in carrots, parsley, celery, and in Panax ginseng, was capable to been able to produce hot-plate analgesia in mice after an adenosine inhibit CB1 receptor activation by AEA in vitro (Leonti et al., 2010). antagonist administration (Tsuchiya, 2017). Linalool has antic- onvulsant, anti-glutamatergic and anti-nociceptive activities at high 5. Pharmacological aspects of Cannabis sativa doses in mice (Souto-Maior et al., 2017). Furthermore, linalool may affect several components of the glutamatergic transmission as pre- 5.1. Cannabinoids in Animal kingdom viously reported (Elisabetsky et al., 1995). Beta-caryophyllene is the predominant sesquiterpenoid en- N-arachidonoylethanolamine (AEA) and 2-arachidonoyl glycerol (2- countered in C. sativa and in other plants such as Carum nigrum, AG) are the main endocannabinoids ligands present in the Animal Syzygium aromaticum, Humulus lupulus, Ocimum gratissimum, Ocimum kingdom (McPartland, 2004). AEA and 2-AG are produced from cell micranthum, Origanum vulgare, Piper nigrum (Russo, 2011). The evolu- membrane phospholipids, which contain arachidonate, and are im- tionary capability of caryophyllene is due to its ability to attract pre- mediately released. Fatty acid amide hydrolase (FAAH) and mono- datory insects, like green lacewings, while simultaneously inhibiting acylglycerol lipase (MAGL) are degradation enzymes of AEA and 2-AG, herbivory insects (Russo, 2011). It shows anti-inflammatory and anti- respectively, which through their hydrolysis regulate cannabinoidergic malarial activities and has been claimed in the past to treat duodenal tone. The two main endocannabinoid receptors are cannabinoid type-1

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compared to CB1 receptors; however, during inflammation CB2 re- ceptors levels drastically increase in microglia and other glial cells (Savonenko et al., 2015). Given the expression of cannabinoids re- ceptors in the nervous system, and the interactions between cannabi- noids with neurotransmitters, such as dopamine, glutamate, serotonin, and gamma-aminobutyric acid, it can be possible that cannabis has great medical potential (Thompson et al., 2003). In the last decades, a large number of cannabinoid compounds able to modulate the CB1, CB2 receptors and the metabolism of the endocannabinoids, AEA and 2- AG, have been developed and characterized (Rampa et al., 2012; Giacoppo et al., 2014). These findings illustrate the physiological im- portance of the endocannabinoid system.

5.2. Cannabinoids and diseases

The use of different preparations of C. sativa (both natural and synthetic) is associated with therapeutic strategies for many diseases. Certainly, due to the diffuse presence of the ECS in the brain and per- iphery, its activation or inhibition regulates several pathophysiological phenomena (Mastinu et al., 2018)(Table 1). Fig. 13. Endocannabinoid system. ECS is involved in various disorders, including metabolic and neu- roinflammatory pathologies. Especially, in the brain, cannabinoids (CB1) receptor and cannabinoid type-2 (CB2) receptor (Mechoulam modulate hunger/satiety and neuroinflammation, and in the periphery, et al., 1998). they are involved in the peripheral metabolic reactions of liver, fat, The endocannabinoid system (ECS) appears in the most primitive muscles and anti-inflammatory response in the blood cells (Mastinu animal with a nerve network such as Hydra and in mammals, birds, et al., 2018). amphibians, fish and several echinoderms and mussels (Salzet et al., Nonetheless, cannabinoids are also associated with an increased risk 2000). However, the presence of ECS has not been identified in all of short-term adverse events such as asthenia, balance problems, con- terrestrial invertebrates. Few studies have reported cannabinoid re- fusion, dizziness, disorientation, diarrhoea, euphoria, drowsiness, dry ceptors and/or enzymes in insects. They found that C. sativa is able to mouth, fatigue, hallucination, nausea, somnolence, vomiting (Lim evoke neurological and behavioural changes in insects, as a result, et al., 2017) and anxiety (Whiting et al., 2015). agronomists have long utilized its extracts as insect repellents (McPartland et al., 2001). • Pain In mammals, the ECS exerts a significant neuromodulatory effect Whiting and colleagues (Whiting et al., 2015) performed a meta- (Mechoulam et al., 1998)(Fig. 13). Mice with a targeted deletion of analysis study to evaluate the pharmacological potential of C. sativa; CB1 receptors exhibit altered nociceptive responses, extreme hypomo- they reported the evidence to support the use of cannabinoids for bility, and significantly increased mortality (Zimmer et al., 1999). the treatment of chronic neuropathic or cancer pain (smoked D9- Human brains contain very high levels of cannabinoid receptors, THC and nabiximols) (Solowij and Battisti, 2008). A study per- about 10 times greater than opioid receptors (Sim et al., 1996). In formed on a rat model of cisplatin-induced peripheral neuropathy particular, CB1 receptors are broadly expressed in the hippocampus, demonstrated a dose-dependent effectiveness of PrNMI, a synthetic basal ganglia, amygdala, cortical areas and cerebellum, all regions that peripherally restricted cannabinoid compound, in suppressing che- are involved in the mood, cognitive functions and motor control (Tsou motherapy-induced peripheral neuropathy; this effect was mediated et al., 1998). Lower expressions have been found in other brain areas, by CB1 receptors activation (Mulpuri et al., 2018). Mellar Davies for example in the brainstem, where the regulatory centres for re- recently wrote a review on cannabinoids and pain management, spiration and cardiac function are located (Akerman et al., 2013). CB1 underling the analgesic potential with reduced cannabimimetic side receptors have also been localized in peripheral areas such as intestine, effects and good therapeutic index of peripherally restricted can- liver, adipose tissue and immune cells (Jourdan et al., 2010). The brain nabinoids, regionally administered cannabinoids, bifunctional can- expression of CB2 receptors in physiological condition is much lower nabinoid ligands, cannabinoid enzyme inhibitors, endocannabinoids

Table 1 Summary of phytocannabinoids involvement in several disorders.

Disorders Phytocannabinoids Pathways Ref.

Pain D9-THC, CBD Peripheral CB1 receptor, CB2 receptor, TRPV1, (Whiting et al., 2015; Starowicz and Finn, 2017) GPR55 AND PPARs Multiple sclerosis D9-THC, CBD CB1 and CB2 receptors (Rice and Cameron, 2018; Allan et al., 2018) Anorexia D9-THC, CBG CB1 and CB2 receptors (Scherma et al., 2017; Brierley et al., 2017) Nausea and vomiting D9-THC CB1 and CB2 receptors (Whiting et al., 2015) Colitis CBD, CBC, CBG, D9-THCA CB2 receptor (Naftali et al., 2014; Pagano et al., 2016; Hasenoehrl et al., 2017) Sleep disorders D9-THC, CBD CB1 and CB2 receptors (Babson et al., 2017) Tourette’s syndrome D9-THC, CBD CB1 and CB2 receptors (Jakubovski and Müller-Vahl, 2017; Abi-Jaoude et al., 2017) Anxiety CBD CB2 receptor (Lim et al., 2017) Epilepsy D9-THC, CBD, D9-THCV? CB1 and CB2 receptors (Hill et al., 2012; Szaflarski et al., 2018) Schizophrenia CBD CB2 receptor, dopamine, and serotonin receptors? (Deiana, 2013; Hudson et al., 2018) Alzheimer’s disease D9-THC, CBD CB1 and CB2 receptors, GPR3, GPR6, and GPR12 (Currais et al., 2016: Bilkei-Gorzo et al., 2017; Laun et al., 2018; Fernandez-Ruiz, 2018) Parkinson’s disease D9-THC?, CBD, D9-THCV, CB1 and CB2 receptors (Hill et al., 2012; Fernandez-Ruiz, 2018)

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that do not interact with classic cannabinoid receptors, cannabinoid 2015). Indeed, nabilone treatment decreases nausea and vomiting receptor antagonists and selective CB1 receptor agonists (Davis, episodes when compared to metoclopramide (D2 antagonist) in 2014). Indeed, alternative strategies exist to take advantage of the chemotherapy patients (Sharkey et al., 2014, Badowsky, 2017). cannabinoids analgesic effect avoiding their psychoactive effects, Moreover, cancer patients treated with another synthetic analogue such as using peripherally restricted CB1 receptor agonists, selective of D9-THC, dronabinol, showed a less severe nausea and the dura- CB2 receptor agonists, inhibitors of endocannabinoid catabolism or tion was significantly shorter than patients treated with pro- uptake, and modulating other non-CB1/CB2 receptor targets of chlorperazine (D2 antagonist) (Badowski, 2017). cannabinoids including TRPV1, GPR55, and PPARs (Starowicz and However, even for these C. sativa derivatives, some side effects have Finn, 2017). been observed (Tafelski et al., 2016, Schussel et al., 2018). There- • Colitis fore, more studies are needed to clarify the safety of cannabinoids Different preparations of C. sativa have been used for the treatment for nausea and vomiting treatment. of gut diseases, such as gastrointestinal pain, gastroenteritis, and • Anorexia diarrhoea (Couch et al., 2018). Phytocannabinoids can exert anti- Cannabinoids are involved in overall body weight control by inter- inflammatory functions on the gut by mainly activating the CB2 fering with several central and peripheral regulatory circuits that receptor, and promoting wound healing via activation of the CB1 orchestrate energy homeostasis (Horn et al., 2018; Mastinu et al., receptor. Isolated C. sativa constituents, including CBC, CBD, and 2018). In people suffering from anorexia and bulimia nervosa, an CBG, have shown to exert favourable effects in experimental models increased expression of the CB1 receptor has been found in insular of inflammatory bowel disease after an inflammatory insult, as re- cortex and inferior temporal and frontal lobe; this suggests an im- ported by several authors (Naftali et al., 2014; Pagano et al., 2016, pairment in the processing of interceptive, gustatory and reward- Hasenoehrl et al., 2017). Moreover, Nallathambi and colleagues related behaviour (Gérard et al., 2011). In an activity-based anor- have also observed an anti-inflammatory activity of D9-THCA on exia rat model, subchronic treatment with both the natural D9-THC colon epithelial cells (Nallathambi et al., 2017). and the synthetic CB1/CB2 receptor agonist CP-55,940 was able to • Spasticity significantly decrease body weight loss and running wheel activity, Over 85% of people with multiple sclerosis (MS) show some spas- in addition to increasing leptin signalling and reducing corticos- ticity. The drugs currently used to treat MS-associated spasticity are terone plasma levels (Scherma et al., 2017). Several studies support baclofen, tizanidine, diazepam, and botulinum toxin (Flachenecker the pharmacological stimulation of CB1 signalling in order to re- et al., 2014). These medications are not always completely effective cover body weight in patients with psychiatric disorders suffering and their use or dose may be limited by side effects (Soelberg from anorexia nervosa or bulimia, or patients affected by the cancer Sorensen, 2017). That is why the use of C. sativa is increasing in the anorexia-cachexia (Koch, 2017; Andries et al., 2014). Some clinical world among the MS patients. Indeed, several studies report the trials demonstrated the effectiveness of dronabinol, a CB1/CB2 benefit of the pharmacological use of cannabinoids in MS-associated agonist, in regain body weight in patients with anorexia nervosa and spasticity (Koppel et al., 2014; Nielsen et al., 2018; Allan et al., cancer anorexia-cachexia syndrome (Andries et al., 2014; Inui, 2018). Nabiximols (Sativex oral spray approved by regulatory 2002). agencies of Canada, New Zealand, and several European countries), • Sleep disorders oral cannabis extract, and synthetic tetrahydrocannabinol resulted In the last decades, medical interest has come on the potential use of to be effective at reducing patient-reported symptoms of spasticity cannabis and cannabinoids in sleep disorders. Indeed, some can- and pain in MS people with an inadequate response to other drugs. nabis components may act on specific sleep alterations improving In particular, nabiximols is generally well tolerated by MS patients sleep quality. In particular, CBD may have therapeutic potential for and it shows a low abuse potential, low risk of psychoactive effects the treatment of insomnia in REM sleep behaviour disorder and also and no evidence of dose tolerance (Keating, 2017). Moreover, the in excessive daytime sleepiness. D9-THC may decrease sleep latency improvements in spasticity, health-related quality of life and activ- but the long-term administration could impair sleep quality (Chait, ities of daily living, observed in MS patients, were lasting over time 1990; Barratt et al., 1974; Freemon, 1982). Short-term treatment (Keating, 2017). However, some authors have highlighted several with nabilone and dronabinol may be beneficial in obstructive sleep criticisms in the use of C. sativa derivatives in patients with MS apnoea, modulating serotonin tone (Ramar et al., 2018; Calik and (Pavisian et al., 2014; Rudroff and Honce, 2017; Rice and Cameron, Carley, 2017); the effect of nabilone may be useful also to reduce 2018; Herzog et al., 2018). Firstly, side effects are observed such as nightmares associated with post-traumatic stress disorders and im- an increased risk of developing psychosis, alterations of the working prove sleep in patients with chronic pain (Babson et al., 2017). memory, executive function and other cognitive functions. Sec- • Tourette syndrome ondly, due to the different legal status between Europe and USA, The use of cannabinoids might play a role in the treatment of cannabis derivatives used in studies do not always belong to the Tourette’s syndrome. Indeed, some clinical studies reported an im- same varieties/cultivars, opening the question on which is the best provement of vocal blocking tics and comorbid Tourette syndrome- strain. Therefore, the use of C. sativa derivatives in MS-associated associated conditions in patients with treatment-resistant Tourette spasticity will require further large, multicentre, randomized, pla- syndrome after a chronic cannabis or dronabinol treatment cebo-controlled studies. (Jakubovski and Müller-Vahl, 2017; Abi-Jaoude et al., 2017). • Nausea and vomiting • Anxiety The ability of C. sativa to limit or prevent nausea and vomiting from Recent studies have demonstrated that cannabis can have both an- a variety of causes has long been known. This has led to extensive xiogenic and anxiolytic effects. As C. sativa contains D9-THC and researches that have revealed an important role for cannabis deri- CBD, with different psychoactive properties: low doses of D9-THC vatives in nausea and vomiting therapies (Sharkey et al., 2014). have anxiolytic effects, high doses are anxiogenic whereas CBD has Thanks to the distribution of the endocannabinoid system in the anxiolytic effects in both animals and humans due to its action on intestine, several C. sativa derivatives are available for the treatment limbic and paralimbic areas (Whiting et al., 2015). This anxiolytic of nausea and vomiting. Nabilone, a synthetic analogue of D9-THC, effect of CBD can explain why many patients with anxiety disorders has been approved in 1985 by FDA (Food and Drug Administration) use cannabis as a “self-medication” to obtain relief from anxiety for the treatment of chemotherapy-induced nausea and vomiting symptoms (Lim et al., 2017). These data suggest a potential benefit that has not responded to conventional antiemetic agents (dopamine of using CBD for anxiety disorders, although further studies are receptor 2 (D2) antagonists) (Sharkey et al., 2014; Whiting et al., necessary to confirm these observations (Crippa et al., 2009).

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• Epilepsy C. sativa used as oil, fibre, and medicine immediately became pop- Preclinical evidence supports the use of cannabinoids in the treat- ular as recreational drug and spread rapidly from Asia to whole world. ment of epilepsy. CBD and cannabidivarin, the propyl variant of C. sativa is found in the most varied forms and environments on every CBD, have been evaluated in preclinical and clinical studies for their continent. Its pharmacological effects change according to the amount anticonvulsant effects, however, the exact mechanisms by which of phytocannabinoids. Moreover, pharmacological research has these drugs exert their anti-seizure effects are not well understood exploited the involvement of the ECS in various physio-pathological (Fusar-Poli et al., 2009). Recently, in a large, prospective, single- mechanisms at central and peripheral levels. Energy metabolism, neu- centre, open-label study 72 children and 60 adults with treatment- ropathic pain, and inflammation are some of the processes where resistant epilepsy showed significant improvements in illness phe- phytocannabinoids exert their modulatory function. Today, new fron- notype after CBD treatment (Szaflarski et al., 2018). Moreover, this tiers are opening for the use of CB1 agonists, such as in the processes of year for the first time the Food and Drug Administration (FDA) memory consolidation in post-traumatic stress disorders. For example, approved a drug, EPIDIOLEX®, which contains CBD derived from C. the use of C. sativa seems to have positive effects on war veterans. sativa, for the treatment of two rare and severe forms of epilepsy, Furthermore, intensive research on new CB2 receptor-selective agonists Lennox-Gastaut syndrome, and Dravet syndrome. Finally, a retro- is helping in defining the role of CB2 receptors in central and peripheral spective study assessed the safety, tolerability, and efficacy of CBD inflammatory processes. Finally, an active debate on the positive/ne- as a promising treatment option for refractory behavioural problems gative effects of C. sativa products is increasing in the western world in children with ASD (Aran et al., 2018). All these data support the and conditioning the legislator in favour of legal use. In 2018, for the potential use of CBD in the treatment of seizures, epilepsy and other first time in the USA at the federal level, FDA authorized the use of a neurodevelopmental disorders. derivative of C. sativa for the treatment of epilepsy. • Alzheimer’s disease Many questions remain open with numerous contradictory ther- Recently, endocannabinoids were considered an important target apeutic effects reported. Is there a real correlation on the voluptuary for the treatment of age-related neurodegenerative conditions such use of C. sativa and psychiatric diseases such as schizophrenia? Why is as Alzheimer´s diseases (AD) (Aso and Ferrer, 2016; Fernández- the action of individual phytocannabinoids not always comparable with Ruiz, 2018). In particular, the effect of cannabis on memory and the consumption of C. sativa? Can the activation of CB1 receptors im- dementia has been very controversial over the past years, with prove cognitive functions linked to memory? Furthermore, how can several findings reporting opposite effects in young and adult user, some CB1 agonist compounds act on memory consolidation mechan- both with low and high doses of cannabis (Patton et al., 2002). isms? Is the use of CB1 antagonists as regulators of energy metabolism However, to date, it seems largely accepted that low doses of can- now over? Finally, what is the exact function of CB2 receptors in the nabis in adults can have a beneficial impact in preventing or even central nervous system? treating AD. Several in vitro and in vivo preclinical findings de- Extensive pharmacological studies are still needed to better under- monstrate that some cannabinoid compounds induce neuroprotec- stand the clinical relevance and applications of non-psychoactive can- tion against amyloid beta (Aβ) toxicity and neuronal death. A study nabinoids in the prevention and treatment of life-threatening diseases. described that a low dose of D9-THC can significantly increase the Moreover, psychoactive cannabinoids chemically standardized and neurogenesis in the hippocampus of aged rats (Suliman et al., 2018). administered clinically under medical supervision may be the legal A similar finding has also been reported recently in old mice, where answer to the use of C. sativa. a chronic low dose of D9-THC increased hippocampal spine density accompanied by restored cognitive function (Bilkei-Gorzo et al., References 2017). D9-THC can also promote the removal of the intraneuronal accumulation of Aβ and block the inflammatory response (Currais Abbasi, A.M., Khan, S.M., Ahmad, M., Khan, M.A., Quave, C.L., Pieroni, A., 2013. et al., 2016). Other promising results have been also reported with Botanical ethnoveterinary therapies in three districts of the Lesser Himalayas of Pakistan. J. Ethnobiol. 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