**4. Looking forward**

Basic and clinical cannabinoid research has recently become a greater priority due to the increasing number of jurisdictions where legalization of *Cannabis* use for both medical and recreational purposes has occurred. There have been numerous health claims attributed to *Cannabis*, and the evidence supporting some of the claims remains inconclusive. According to the conclusion of a report by a Committee On The Health Effects Of Marijuana, the therapeutic benefit of *Cannabis* on chronic pain, chemotherapy-induced nausea and vomiting, and multiple sclerosis spasticity has been deemed effective, whereas insufficient evidence was available to support a similar conclusion in the treatment of cancer, anorexia and weight loss, irritable bowel syndrome, epilepsy, spinal cord injury-induced spasticity, Tourette's syndrome, amyotrophic lateral sclerosis, Huntington's disease, Parkinson's disease, dystonia, dementia, glaucoma, traumatic brain injury or intracranial hemorrhage, addiction, anxiety, depression, sleep disorders, posttraumatic stress disorder, schizophrenia, and other psychoses [8]. Thus, while tremendous advances have been made in understanding the biology of the ECS and of *Cannabis sativa*, it is clear that many aspects of the medical use of *Cannabis* require further clarification. Additionally, there has been a marked increase in the generation of novel synthetic cannabinoids over the last decade [18], the general availability of which has prompted concern among regulatory agencies due to their unknown safety profiles [19, 20]. This is highlighted by the rapidly increasing number of case reports detailing the effects of acute synthetic cannabinoid intoxication [21–23]. The potential dangers of synthetic cannabinoid use are attributable to the intrinsic properties of these substances and their metabolites. The potential for harm is further exacerbated by the poor pharmacological and toxicological characterization of synthetic cannabinoids. Thus, intensified research efforts into the health benefits and harms of *Cannabis* and cannabinoids will hasten the positive exploitation of *Cannabis* and reduce the drawbacks of *Cannabis* and synthetic cannabinoids.

[3] Pain S. A potted history. Nature. 2015;**525**:S10-S11

pubmed/26271952

9336020

from: http://pubs.acs.org/doi/abs/10.1021/ja01062a046

[4] Gaoni Y, Mechoulam R. Isolation, structure, and partial synthesis of an active constituent of Hashish. Journal of the American Chemical Society. 1964;**86**:1646-1647. Available

Introduction to Recent Advances in Cannabinoid Research

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7

[5] Gérard CM, Mollereau C, Vassart G, Parmentier M. Molecular cloning of a human cannabinoid receptor which is also expressed in testis. The Biochemical Journal. 1991;**279**(1):129-134. Available from: http://www.ncbi.nlm.nih.gov/pubmed/1718258 [6] Di Marzo V, Piscitelli F.The endocannabinoid system and its modulation by phytocannabinoids. Neurotherapeutics. 2015;**12**:692-698. Available from: http://www.ncbi.nlm.nih.gov/

[7] Pertwee RG. Pharmacology of cannabinoid CB1 and CB2 receptors. Pharmacology & Therapeutics. 1997;**74**:129-180. Available from: http://www.ncbi.nlm.nih.gov/pubmed/

[8] National Academies of Sciences and Medicine E. The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research. Washington, DC: The National Academies Press; 2017. Available from: https://www.nap. edu/catalog/24625/the-health-effects-of-cannabis-and-cannabinoids-the-current-state [9] Broyd SJ, van Hell HH, Beale C, Yücel M, Solowij N. Acute and chronic effects of cannabinoids on human cognition-a systematic review. Biological Psychiatry. 2016;**79**:557-567.

[10] van Bakel H, Stout JM, Cote AG, Tallon CM, Sharpe AG, Hughes TR, et al. The draft genome and transcriptome of *Cannabis sativa*. Genome Biology. 2011;**12**:R102. Available

[11] ElSohly MA, Radwan MM, Gul W, Chandra S, Galal A. Phytochemistry of *Cannabis sativa* L. Progress in the Chemistry of Organic Natural Products. 2017;**103**:1-36. Available

[12] Andre CM, Hausman J-F, Guerriero G. *Cannabis sativa*: The plant of the thousand and one molecules. Frontiers in Plant Science. 2016;**7**:19. Available from: http://www.ncbi.

[13] Shao Z, Yin J, Chapman K, Grzemska M, Clark L, Wang J, et al. High-resolution crystal structure of the human CB1 cannabinoid receptor. Nature. 2016;**540**(7634):602-606.

[14] Hua T, Vemuri K, Nikas SP, Laprairie RB, Wu Y, Qu L, et al. Crystal structures of agonist-bound human cannabinoid receptor CB1. Nature. 2017;**547**:468-471. Available from:

[15] Hua T, Vemuri K, Pu M, Qu L, Han GW, Wu Y, et al. Crystal structure of the human cannabinoid receptor CB1. Cell. 2016;**167**:750-762. e14. Available from: http://www.ncbi.

Available from: http://www.ncbi.nlm.nih.gov/pubmed/26858214

Available from: http://www.ncbi.nlm.nih.gov/pubmed/27851727

from: http://www.ncbi.nlm.nih.gov/pubmed/22014239

from: http://www.ncbi.nlm.nih.gov/pubmed/28120229

http://www.ncbi.nlm.nih.gov/pubmed/28678776

nlm.nih.gov/pubmed/26870049

nlm.nih.gov/pubmed/27768894

#### **Author details**

Robert B Laprairie1,2 and Will Costain<sup>3</sup> \*

\*Address all correspondence to: will.costain@nrc-cnrc.gc.ca

1 College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, SK, Canada

2 Department of Pharmacology, College of Medicine, Dalhousie University, Halifax, NS, Canada

3 Human Health Therapeutics, National Research Council, Ottawa, ON, Canada

## **References**


[3] Pain S. A potted history. Nature. 2015;**525**:S10-S11

to the conclusion of a report by a Committee On The Health Effects Of Marijuana, the therapeutic benefit of *Cannabis* on chronic pain, chemotherapy-induced nausea and vomiting, and multiple sclerosis spasticity has been deemed effective, whereas insufficient evidence was available to support a similar conclusion in the treatment of cancer, anorexia and weight loss, irritable bowel syndrome, epilepsy, spinal cord injury-induced spasticity, Tourette's syndrome, amyotrophic lateral sclerosis, Huntington's disease, Parkinson's disease, dystonia, dementia, glaucoma, traumatic brain injury or intracranial hemorrhage, addiction, anxiety, depression, sleep disorders, posttraumatic stress disorder, schizophrenia, and other psychoses [8]. Thus, while tremendous advances have been made in understanding the biology of the ECS and of *Cannabis sativa*, it is clear that many aspects of the medical use of *Cannabis* require further clarification. Additionally, there has been a marked increase in the generation of novel synthetic cannabinoids over the last decade [18], the general availability of which has prompted concern among regulatory agencies due to their unknown safety profiles [19, 20]. This is highlighted by the rapidly increasing number of case reports detailing the effects of acute synthetic cannabinoid intoxication [21–23]. The potential dangers of synthetic cannabinoid use are attributable to the intrinsic properties of these substances and their metabolites. The potential for harm is further exacerbated by the poor pharmacological and toxicological characterization of synthetic cannabinoids. Thus, intensified research efforts into the health benefits and harms of *Cannabis* and cannabinoids will hasten the positive exploitation of

*Cannabis* and reduce the drawbacks of *Cannabis* and synthetic cannabinoids.

\*

3 Human Health Therapeutics, National Research Council, Ottawa, ON, Canada

1 College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, SK, Canada 2 Department of Pharmacology, College of Medicine, Dalhousie University, Halifax, NS,

[1] Pisanti S, Bifulco M. Modern history of medical cannabis: From widespread use to prohibitionism and back. Trends in Pharmacological Sciences. 2017;**38**:195-198. Available

[2] O'Shaughnessy WB. On the preparations of the Indian Hemp, or Gunjah (*Cannabis indica*), their effects on the animal system in health, and their utility in the treatment of tetanus and other convulsive diseases. The British and Foreign Medical Review. 1840;**10**:225-228. Available from: http://www.ncbi.nlm.nih.gov/pubmed/30161735

\*Address all correspondence to: will.costain@nrc-cnrc.gc.ca

from: http://www.ncbi.nlm.nih.gov/pubmed/28095988

**Author details**

Canada

**References**

Robert B Laprairie1,2 and Will Costain<sup>3</sup>

6 Recent Advances in Cannabinoid Research


[16] Krishnamurti C, Rao SC. The isolation of morphine by Serturner. Indian Journal of Anaesthesia. 2016;**60**:861-862. Available from: http://www.ncbi.nlm.nih.gov/pubmed/ 27942064

**Section 2**

**Pre-Clinical Research**


**Pre-Clinical Research**

[16] Krishnamurti C, Rao SC. The isolation of morphine by Serturner. Indian Journal of Anaesthesia. 2016;**60**:861-862. Available from: http://www.ncbi.nlm.nih.gov/pubmed/

[17] Manglik A, Kruse AC, Kobilka TS, Thian FS, Mathiesen JM, Sunahara RK, et al. Crystal structure of the μ-opioid receptor bound to a morphinan antagonist. Nature. 2012;**485**:321-326. Available from: http://www.ncbi.nlm.nih.gov/pubmed/22437502 [18] EMCDDA. Synthetic cannabinoids in Europe (Perspectives on drugs) | www.emcdda. europa.eu [Internet]. Lisbon; 2017. Available from: http://www.emcdda.europa.eu/

[19] Costain WJ, Rasquinha I, Comas T, Hewitt M, Aylsworth A, Rouleau Y, et al. Analysis of the pharmacological properties of JWH-122 isomers and THJ-2201, RCS-4 and AB-CHMINACA in HEK293T cells and hippocampal neurons. European Journal of Pharmacology. 2018;**823**:96-104. Available from: http://www.ncbi.nlm.nih.gov/pubmed/

[20] Costain WJ, Tauskela JS, Rasquinha I, Comas T, Hewitt M, Marleau V, etal. Pharmacological characterization of emerging synthetic cannabinoids in HEK293T cells and hippocampal neurons. European Journal of Pharmacology. 2016;**786**:234-245. Available from: http://

[21] Brown GR, McLaughlin K, Vaughn K. Identifying and treating patients with synthetic psychoactive drug intoxication. Journal of the American Academy of Physician Assistants. 2018;**31**:1-5. Available from: http://www.ncbi.nlm.nih.gov/pubmed/30048361

[22] Hobbs M, Kalk NJ, Morrison PD, Stone JM. Spicing it up - synthetic cannabinoid receptor agonists and psychosis—a systematic review. European Neuropsychopharmacology. 2018;**28**:1289-1304. Available from: http://www.ncbi.nlm.nih.gov/pubmed/30454908 [23] Akram H, Mokrysz C, Curran HV. What are the psychological effects of using synthetic cannabinoids? A systematic review. Journal of Psychopharmacology. 2019;**33**:271-283.

Available from: http://www.ncbi.nlm.nih.gov/pubmed/30789300

27942064

8 Recent Advances in Cannabinoid Research

29408093

publications/pods/synthetic-cannabinoids

www.ncbi.nlm.nih.gov/pubmed/27260125

**Chapter 2**

**Provisional chapter**

**Zebrafish as a High-Throughput In Vivo Model for**

**Zebrafish as a High-Throughput In Vivo Model for** 

DOI: 10.5772/intechopen.79321

Zebrafish represent an established vertebrate model system that helps to bridge the research gap between cell line/invertebrate studies and mammalian systems. While the initial testing of tetrahydrocannabinol (THC) using Zebrafish occurred in 1975, zebrafish are currently a burgeoning model for testing the bioactivity of cannabinoids. Zebrafish express both CB1 and CB2 receptors along with all of the other major endocannabinoidrelated genes. Zebrafish endocannabinoid gene function has been associated with addiction, anxiety, development, energy homeostasis and food intake, immune system function, learning and memory. Both adult and larval zebrafish have been used to test the therapeutic potential of THC and cannabidiol (CBD) against various disease models such as models of nociception, epilepsy, stress/anxiety and addiction. This chapter will review recent studies that have used zebrafish as a model for testing the bioactivity of

The use of zebrafish as a vertebrate model for biological research began in the late 1960s in the lab of George Streisinger at the University of Oregon. However, it was not until the middle of the 1980s that a community of researchers working on zebrafish began to emerge. Since that time the use of zebrafish as a model organism has continued to increase. Over the past 3 decades the use of zebrafish as a model species has contributed to our understanding of

cannabinoids and provide insight on potential future work in this area.

**Keywords:** zebrafish, cannabinoid, pain, stress, addiction, epilepsy

developmental biology, toxicology, drug efficacy and disease.

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,

distribution, and reproduction in any medium, provided the original work is properly cited.

**Testing the Bioactivity of Cannabinoids**

**Testing the Bioactivity of Cannabinoids**

Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.79321

Lee Ellis

Lee Ellis

**Abstract**

**1. Introduction**

#### **Zebrafish as a High-Throughput In Vivo Model for Testing the Bioactivity of Cannabinoids Zebrafish as a High-Throughput In Vivo Model for Testing the Bioactivity of Cannabinoids**

DOI: 10.5772/intechopen.79321

Lee Ellis Lee Ellis

Additional information is available at the end of the chapter Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.79321

#### **Abstract**

Zebrafish represent an established vertebrate model system that helps to bridge the research gap between cell line/invertebrate studies and mammalian systems. While the initial testing of tetrahydrocannabinol (THC) using Zebrafish occurred in 1975, zebrafish are currently a burgeoning model for testing the bioactivity of cannabinoids. Zebrafish express both CB1 and CB2 receptors along with all of the other major endocannabinoidrelated genes. Zebrafish endocannabinoid gene function has been associated with addiction, anxiety, development, energy homeostasis and food intake, immune system function, learning and memory. Both adult and larval zebrafish have been used to test the therapeutic potential of THC and cannabidiol (CBD) against various disease models such as models of nociception, epilepsy, stress/anxiety and addiction. This chapter will review recent studies that have used zebrafish as a model for testing the bioactivity of cannabinoids and provide insight on potential future work in this area.

**Keywords:** zebrafish, cannabinoid, pain, stress, addiction, epilepsy
