**3. Clinical research**

was first isolated and described by Dr. Raphael Mechoulam in 1964 [4]. Following this discovery, it was not until 1991 that a human cannabinoid receptor—later named the type 1 cannabinoid receptor (CB1R)—was identified, isolated, and cloned [5]. Other components of the endogenous cannabinoid system (ECS) were subsequently identified in rapid succession, including the endogenous cannabinoid anandamide (AEA) and 2-arachidonoylglycerol (2-AG), the type 2 cannabinoid receptor (CB2R), and the anabolic and catabolic enzymes that synthesize and degrade the endogenous cannabinoids, respectively [6]. During this period there was also a rapid growth in tool compounds (synthetic cannabinoids) to study the ECS and a race to understand the physiological and behavioral effects cannabinoids evoke *in vivo* [7]. With this rapid growth came some of the first modern preclinical and clinical data to suggest clinical efficacy of cannabinoid-based medicines in the treatment of pain, anxiety, addiction, and metabolic disorders [8], as well as preclinical and clinical data that indicated the potential harms associated with *Cannabis* use, in particular the long-term use of THC in the context of the developing brain [9]. Our understanding of *Cannabis sativa* itself was also growing during the 1990s and 2000s, with the draft sequence of the genome published in 2011 [10] and more than 220 identified constituents (>100 cannabinoids and >120 terpenes) now identified in the plant [11, 12]. Most recently, several crystal structures of CB1R were solved in 2016 and 2017 by large interdisciplinary research groups [13–15]. These crystal structures will allow for rational drug design and comprehension of drug-receptor relationships for the

Although the field of cannabinoid research has seen incredible growth during the past three decades, many questions remain unanswered. As a demonstration of the cannabinoid field's infancy, the clinically relevant pharmacological effects of morphine have been documented since 1817 [16], and the crystal structure of the μ-opioid receptor was solved in 2012 [17]. The illegal status of *Cannabis* in most constituencies has represented a significant barrier to basic, epidemiological, and clinical research. However, interest in the potential applications of cannabinoids and their biology has grown tremendously since the discovery of the ECS. What was once a field with a single manuscript in 1964 has now grown to an area averaging 1500 studies per year in a veritable gold rush into a relatively poorly characterized system. With this book, our goal is to highlight the impressive work of some researchers in this field as they address what will become the critical scientific questions of our time concerning *Cannabis*.

This book presents a collection of chapters addressing important preclinical topics, including the utility of the zebrafish model in cannabinoid research (Chapter 1), insights derived from the structural analysis of CB1R crystal structures (Chapter 2), and the analysis of medical *Cannabis* quality traits (Chapter 3). Dr. Ellis describes the historical usage of the zebrafish model and its applicability to studies of various aspects of vertebrate and mammalian biology, including neurobiology and neurological disorders, while focusing on the role of the endocannabinoid system. Dr. Al-Zoubi et al. provide an in-depth analysis of the unique aspects of cannabinoid receptors gleaned from studies of hCB1R crystal structures. These authors

first time in the cannabinoid field.

4 Recent Advances in Cannabinoid Research

**2. Preclinical research**

The clinical research described in this book focuses on the clinical effects of *Cannabis* and cannabinoids on cognition (Chapter 4), the treatment of pain (Chapter 5), Tourette's syndrome (Chapter 6), *Cannabis* use disorder and *Cannabis* withdrawal (Chapters 7 and 8), cannabinoid dosing considerations in pediatric populations (Chapter 9), and *Cannabis* use for treating pediatric and adult epilepsy (Chapter 10). Dr. Weston-Green provides a comprehensive overview of cannabinoid-dependent effects on cognition, including discussions about (1) the many "lesser-known" plant cannabinoids beyond THC and cannabidiol that have been under-assessed to date and (2) the potential "entourage effects" of cannabinoid combinations occurring in *Cannabis* products. Dr. Uhelski et al. review the anti-nociceptive properties of cannabinoids and the preclinical as well as clinical evidence for the use of cannabinoids as analgesics for peripheral pain. *Cannabis*-based medicines (CBM) are presently being examined for a wide array of psychiatric conditions for which the evidence base is small yet growing. Dr. Szejko provides a review of the clinical evidence for CBM in Tourette's syndrome and the potential mechanisms of action at work for cannabinoids in this disorder. *Cannabis* and the ECS are now recognized for their potential to treat substance abuse disorders, including opioid addiction and *Cannabis* use disorder itself. Dr. Balodis et al. provide a comprehensive review of *Cannabis* use disorder, its epidemiology, potential harms, and other important considerations. Dr. Ferreira et al. review the potential of cannabinoids—including novel bioligands—to treat substance use disorders. At long last, cannabidiol is now recognized and accepted as an anticonvulsant medication for the treatment of refractory pediatric epilepsies, such as Dravet and Lennox-Gastaut syndromes, with the recent FDA approval of Epidiolex® for these conditions. In the final chapters of this book, Dr. Huntsman et al. review the clinical evidence for high-cannabidiol *Cannabis* herbal extracts for the treatment of pediatric and adult epilepsies, while Dr. Alcorn et al. review critical dosing considerations and pharmacokinetic parameters for *Cannabis* in the pediatric population.
