Source:Committee on the Health Effects of Marijuana – The Health Effects of Cannabis & Cannabinoids-National Academies Press (2017)
Cannabis sativa is one of the world’s oldest cultivated plants (Russo, 2007). Although the earliest written records of the human use of cannabis date from the 6th century B.C. (ca. 2,600 cal BP), existing evidence suggests that its use in Europe and East Asia started in the early Holocene (ca. 8,000 cal BP) (Long et al., 2016). Many 19th-century practitioners ascribed medicinal properties to cannabis after the drug found its way to Europe during a period of colonial expansion into Africa and Asia. For example, William B. O’Shaughnessy, an Irish physician working at the Medical College and Hospital in Calcutta, first introduced cannabis (Indian hemp) to Western medicine as a treatment for tetanus and other convulsive diseases (O’Shaughnessy, 1840). At approximately the same time, French physician Jean-Jacques Moreau de Tours experimented with the use of cannabis preparations for the treatment of mental disorders (Moreau de Tours, 1845). Soon after, in 1851, cannabis was included in the 3rd edition of the Pharmacopoeia of the United States (USP). Subsequent revisions of the USP described in detail how to prepare extracts and tinctures of dried cannabis flowers to be used as analgesic, hypnotic, and anticonvulsant (Russo, 2007; U.S. Pharmacopoeial Convention, 1916). Growing concerns about cannabis resulted in the outlawing of cannabis in several states in the early 1900s and federal prohibition of the drug in 1937 with the passage of the Marihuana Tax Act. In response to these concerns, in 1942 the American Medical Association removed cannabis from the 12th edition of U.S. Pharmacopeia (IOM, 1999).
THE CANNABIS PLANT
Cannabis cultivars are considered as part of one genus, Cannabis, family Cannabaceae, order Urticales (Kuddus et al., 2013). Two accepted genera of Cannabaceae are Cannabis and Humulus (hops). There is, however, an ongoing debate concerning the taxonomic differentiation within the Cannabis genus (Laursen, 2015). On the basis of genetic variations, a multitypic genus with at least two putative species, Cannabis sativa and Cannabis indica, has been proposed by some researchers (Clarke and Merlin, 2015; Hillig, 2005). Other researchers have suggested a unique species Cannabis sativa with the genetic differences explained by variations at both the subspecies and the variety level or at a biotype level of putative taxa (Small, 2015).
Chemical Constituents of Cannabis
To date, more than 104 different cannabinoids1 have been identified in cannabis (ElSohly and Gul, 2014). Other compounds identified include terpenoids, flavonoids, nitrogenous compounds, and more common plant molecules (American Herbal Pharmacopoeia, 2013). Among these, D9-tetrahydrocannabinol (THC) has received the most attention for being responsible for the intoxicated state sought after by recreational cannabis users, owing to its ability to act as a partial agonist2 for type-1 cannabinoid (CB1) receptors. Cannabinoids exist mainly in the plant as their carboxylic precursors (D9-tetrahydrocannabinolic acid [THCA] and cannabidiolic acid [CBDA]) and are decarboxylated by light or heat while in storage or when combusted (Grotenhermen, 2003). D9-THC is synthesized within the glandular trichomes present in the flowers, leaves, and bracts of the female plant. It shares a common precursor, olivetoic acid, with another quantitatively important constituent of Cannabis sativa, cannabidiol (CBD), which is the most abundant cannabinoid in hemp (see Figure 2-1). For this reason, the genetic profile and relative level of expression of the enzymes responsible for their synthesis (genotype), namely THCA synthase and CBDA synthase, determine the chemical composition of a particular cultivar (chemotype). Cannabis plants typically exhibit one of the three main different chemotypes based on the absolute and relative concentrations of D9-THCA and CBDA (see Table 2-1), which makes it possible to distinguish among the D9-THC-type, or drug-type; the intermediate-type; and the CBD-type cannabis plants grown for fiber (industrial hemp) or seed oil in which the content of D9-THC does not exceed 0.3 percent on a dry-weight basis (Chandra et al., 2013). CBD is pharmacologically active, however, and, therefore, classifying cannabis in terms of drug- and fiber-producing seems inaccurate. Both THC- and CBD-types are considered drug-types, and both cultivars could theoretically be exploited to produce fiber.
In a series of studies conducted in the late 1930s and early 1940s, Roger Adams and coworkers isolated cannabinol and CBD from hemp oil and then isomerized CBD into a mixture of two tetrahydrocannabinols with “marihuana-like” physiological activity in dogs, proving their structure except for the final placement of one double bond (Adams et al., 1940a,b). Two years later, tetrahydrocannabinol was first isolated from cannabis resin (Wollner et al., 1942). In 1964, thanks to the development of such potent analytical techniques as nuclear magnetic resonance imaging, Gaoni and Mechoulam were able to identify the position of this elusive double bond, thus resolving the final structure of D9-THC (Gaoni and Mechoulam, 1964). In the late 1980s William Devane and Allyn Howlett first postulated the existence of cannabinoid receptors by showing how synthetic molecules designed to mimic the actions of D9-THC were able to bind a selective site in brain membranes, thus inhibiting the intracellular synthesis of cyclic adenosine monophosphate (cAMP) through a G protein–mediated mechanism (Devane et al., 1988). The mapping of cannabinoid-binding sites in the rat brain (Herkenham et al., 1990) and the molecular cloning of the first cannabinoid receptor gene (Matsuda et al., 1990) subsequently corroborated this hypothesis. Three years later, a second G protein–coupled cannabinoid receptor was cloned from a promyelocytic cell line and termed CB2 (Munro et al., 1993). Both CB1 and CB2 signal through the transducing G proteins, Gi and Go, and their activation by D9-THC or other agonists causes the inhibition of adenylyl cyclase activity, the closing of voltage-gated calcium channels, the opening of inwardly rectifying potassium channels, and the stimulation of mitogen-activated protein kinases such as extracellular signal–regulated kinases (ERKs) and focal adhesion kinases (FAKs) (Mackie, 2006). The expression pattern of CB1 receptors in brain structures correlates with the psychoactive effects of cannabis. In mammals, high concen trations of CB1 are found in areas that regulate appetite, memory, fear extinction, motor responses, and posture such as the hippocampus, basal ganglia, basolateral amygdala, hypothalamus, and cerebellum (Mackie, 2006). CB1 is also found in a number of nonneural tissues, including the gastrointestinal tract, adipocytes, liver, and skeletal muscle. In addition to CB1, the brain also contains a small number of CB2 receptors, although this subtype is mainly expressed in macrophages and macrophage-derived cells such as microglia, osteoclasts, and osteoblasts (Mackie, 2006).
Pharmacological Properties of Cannabidiol Cannabidiol was first isolated from hemp oil in 1940 (Adams et al., 1940a) and its structure predicted by chemical methods (Adams et al., 1940b); its fine structure was determined in later studies (Mechoulam and Shvo, 1963). CBD lacks the cannabis-like intoxicating properties of D9-THC and, for this reason, has been traditionally considered non-psychoactive. CBD displays very low affinity for CB1 and CB2 cannabinoid receptors (Thomas et al., 2007), but it might be able to negatively modulate CB1 via an allosteric mechanism (Laprairie et al., 2015)3; however, CBD can interfere with the deactivation of the endocannabinoid molecule anandamide, by targeting either its uptake or its enzymatic degradation, catalyzed by fattyacid amide hydrolase (FAAH), which could indirectly activate CB1 (De Petrocellis et al., 2011; Elmes et al., 2015) (see Box 2-1). CBD is also a known agonist of serotonin 5-HT1A receptors (Russo et al., 2005) and transient receptor potential vanilloid type 1 (TRPV1) receptors (Bisogno et al., 2001). It can also enhance adenosine receptor signaling by inhibiting adenosine inactivation, suggesting a potential therapeutic role in pain and inflammation (Carrier et al., 2006). The antioxidant and anti-inflammatory properties of this compound may explain its potential neuroprotective actions (Scuderi et al., 2009). Irrespective of the mechanism of action, there is evidence that CBD could potentially be exploited in the treatment and symptom relief of various neurological disorders such as epilepsy and seizures (Hofmann and Frazier, 2013; Jones et al., 2010), psychosis (Leweke et al., 2016), anxiety (Bergamaschi et al., 2011), movement disorders (e.g., Huntington’s disease and amyotrophic lateral sclerosis) (de Lago and Fernandez-Ruiz, 2007; Iuvone et al., 2009), and multiple sclerosis (Lakhan and Rowland, 2009).