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## Meet the editor

Dr. Steven P. James is the founder of Steven P. James, MD INC, a medical education consulting group focused on providing medical education on topics of neuroscience and cannabinoids. He is also co-founder and chief medical officer (CMO) of Clarity Telehealth, a company dedicated to improving access to patient care and educating healthcare providers and their patients on mental health. He is a medical author and writer and recently

published *The Clinicians Guide to Cannabinoid Science*. He has almost three decades of experience as a physician-executive in the pharmaceutical industry. In addition, he is a frequent presenter to both healthcare professionals and the public on topics related to the science of cannabinoids, psychopharmacology, and medical history. He has appeared on ABC's *Good Morning America* and local television and radio programs. Dr. James was born and raised in Owensboro, KY, USA, and attended the University of Kentucky (UK), where he obtained a BS and MD in 1979. He received an MBA from the University of California, Irvine in 1994. He completed his psychiatry residency at New York Presbyterian Hospital (Cornell), a fellowship in psychopharmacology at Stanford University, and a clinical fellowship in psychobiology at the National Institute of Mental Health (NIMH). He subsequently served as Assistant Professor of Psychiatry and cofounder of the Penn Center for Sleep Disorders at the University of Pennsylvania, USA. Currently, he is on the voluntary faculty of psychiatry in the UK. In the pharmaceutical industry, Dr. James has worked in drug development, medical affairs, and global business units for more than 30 years at several companies including Eli Lilly, Elan, Allergan (now AbbVie), Shire, and Merck-Serono. After retiring from the pharmaceutical industry, Dr. James has continued to pursue his career-long interests in improving patient access to mental health, advancing scientific innovation into clinical treatment, and integrating psychiatry into mainstream medical practice. Dr. James is a distinguished fellow and board-certified in the American Board of Psychiatry and Neurology (Psychiatry) and a lifetime fellow of the American Board of Sleep Medicine (ABSM).

### Contents


### **Chapter 6 101** Evidence of Health Effects Associated with Marijuana Use: A Comprehensive Public Health Review *by Richard Holdman*

## Preface

My interest in cannabinoids and their potential benefit in health care did not arise in medical school, residency, fellowships, or my subsequent clinical work. Only after working for two decades as a physician-scientist in the pharmaceutical industry did I become aware of the importance of cannabinoids in maintaining health and homeostasis. I was intrigued by the scientific evidence suggesting cannabinoids are beneficial for a variety of poorly treated medical conditions. And I was disappointed with how limited this knowledge about cannabinoids was in the general medical community. For healthcare professionals, learning should be a lifetime pursuit built on the foundation of their scientific training. Unfortunately, many clinicians were never exposed to the established scientific data or therapeutic potential of cannabinoids. In general, they have concerns about mental health and addiction from the use of cannabis. At the same time, the public acceptance of cannabis as a potential treatment option is growing rapidly along with the perception (not always warranted) of safety.

It is evident an urgent need exists for additional education about the evolving areas of scientific discovery and the current uses of cannabinoids. I am delighted to serve as editor of *Cannabinoids - Recent Perspectives and Applications in Human Health* and expect this book to address these twin needs and provide both an interesting introduction to developing areas of research and a timely update on clinical applications.

It seems as if everyone (layperson and healthcare professional) is now aware that cannabinoids are naturally occurring compounds found in plants like hemp and cannabis. Most of the earlier interest in cannabinoids from medical scientists, however, was related to their dramatic disruptions of mental health and concerns about tolerance and addiction. Absent was the knowledge about the molecular basis that produced the positive and negative effects of cannabinoids. Finally, in the late twentieth century, the beginning of a revolution in cannabinoid research arrived. Research began to uncover the structure of cannabinoids, leading to unexpected findings about their effects on the human body and their role in human health and disease.

It is established that cannabinoids from plants influence the human body through the Endocannabinoid System (ECS). This breakthrough discovery was a groundbreaking moment in cannabinoid science and revealed the presence of an entire system within the human body previously unsuspected. The ECS is a major regulator of homeostasis in the human body and consists of endocannabinoids, receptors, and enzymes that modulate various physiological processes in the body. The cannabinoids interact with the cannabinoid receptors that are found throughout the central and peripheral nervous systems and modulate neural activity and neurotransmission. Cannabinoids also act on other systems such as the digestive system, immune system, and cardiovascular system. Studies have found that cannabinoids can reduce inflammation, improve pain modulation and neuroprotection, modulate gene expression and metabolism, increase appetite, regulate moods and emotions, help treat certain types of cancer, and may even protect against neurodegenerative diseases. Research continues to discover new ways cannabinoids can be used for therapeutic purposes. At the center of this research is the ECS, which promises to revolutionize how cannabinoids are used for medical purposes.

The legalization of cannabis and the greater social acceptance of marijuana has unexpectedly led to more clinical research into the potential benefits of this plant. Much of this new research has been driven by serendipitous clinical observations about how cannabis helped people in ways that were not necessarily expected. These anecdotal reports of people benefiting from the use of cannabis and these stories have been around for a long time and clinical research is needed to determine if these effects can be reliably reproduced and whether they translate into clinical benefits.

In the past two decades, more than 25,000 articles about cannabinoids have been published in the peer-reviewed medical literature. It would be fair to say that during this recent period, cannabinoids have finally been studied more rigorously than at any other time in history. This scientific curiosity about cannabinoids has been fed by multiple and often unrelated research studies. In this publication, we hope to significantly add to this body of knowledge and encourage the clinician and researcher to do additional activities. One important consequence of this effort is the recent approval by regulatory agencies after a review of well-conducted randomized clinical trials of plant-based Epidiolex and Sativex, which further normalizes the use of cannabinoids in the medical field.

The recent approval of Epidiolex, a cannabidiol (CBD)-based prescription drug, has been an exciting development in the world of cannabinoids. CBD is a non-psychoactive cannabinoid that has shown great potential as a therapeutic agent for two rare forms of epilepsy. The FDA and EMA approval of Epidiolex marks the first time a plant-based cannabinoid has been approved for medical use in the United States and Europe and is available to the patient by prescription filled at the pharmacy.

The approval of Epidiolex has been an exciting development and will pave the way for further research into CBD's potential and the medical applications of other plant-based cannabinoids. With the approval of Epidiolex, further, CBD research is expected to gain momentum in both the United States and Europe.

The FDA and EMA approval of Epidiolex marks the first time a plant-based cannabinoid has been approved for medical use in the United States. As a result of the decriminalization of Cannabinoids, other CBD products can now be studied although these molecules may have significant differences in quality and safety when compared to the approved CBD Epidiolex.

As a result, CBD products can vary greatly in quality and do not have the same safety and efficacy data that Epidiolex has.

Sativex is a second plant-based cannabinoid combination product first approved in the United Kingdom in 2010. It is now currently approved in twenty-nine countries for the treatment of adult patients with moderate-to-severe spasticity due to multiple sclerosis who have not responded adequately to other anti-spasticity medications.

**V**

(THC).

However, the FDA has not approved Sativex for use in the United States due to concerns about its safety and efficacy. The FDA also expressed concern that Sativex could be abused or misused, as it contains psychoactive tetrahydrocannabinol

These approvals have led to increased acceptance of cannabinoid-based treatments as well as greater public awareness about their potential uses. This has opened a new world of treatment possibilities for patients who are often untreatable by traditional medications. Ultimately, randomized controlled trials will provide a more comprehensive picture of the use of cannabinoids in medicine, making them much more accessible and applicable for healthcare professionals and patients. This process will be especially important for cannabinoids to assume a greater role in clinical practice, as it will provide additional strong and credible science about the safety and benefits of therapies. By establishing the road forward for new plant-based cannabinoids, we

As new research comes out, this book will serve as an invaluable resource for a variety of healthcare professionals – from medical doctors and pharmacists to nurses and allied healthcare providers – to further the knowledge necessary for quality care. It is our hope that this book will equip these professionals with the necessary information to navigate the field of cannabinoids and their potential clinical applications to best serve their patients. We believe this book will be instrumental in furthering the understanding of healthcare professionals regarding cannabinoids while also providing an

I would like to acknowledge the diligent and always pleasant support of Author Service Manager Tea Jurcic at IntechOpen. Without her constant encouragement, this

> **Steven P. James, MD** Independent Researcher, Rancho Santa Fe, CA, USA

will then enter an even more exciting phase in the world of cannabinoids.

updated resource that they can turn to as new research emerges.

book would never have been completed.

However, the FDA has not approved Sativex for use in the United States due to concerns about its safety and efficacy. The FDA also expressed concern that Sativex could be abused or misused, as it contains psychoactive tetrahydrocannabinol (THC).

These approvals have led to increased acceptance of cannabinoid-based treatments as well as greater public awareness about their potential uses. This has opened a new world of treatment possibilities for patients who are often untreatable by traditional medications. Ultimately, randomized controlled trials will provide a more comprehensive picture of the use of cannabinoids in medicine, making them much more accessible and applicable for healthcare professionals and patients. This process will be especially important for cannabinoids to assume a greater role in clinical practice, as it will provide additional strong and credible science about the safety and benefits of therapies. By establishing the road forward for new plant-based cannabinoids, we will then enter an even more exciting phase in the world of cannabinoids.

As new research comes out, this book will serve as an invaluable resource for a variety of healthcare professionals – from medical doctors and pharmacists to nurses and allied healthcare providers – to further the knowledge necessary for quality care. It is our hope that this book will equip these professionals with the necessary information to navigate the field of cannabinoids and their potential clinical applications to best serve their patients. We believe this book will be instrumental in furthering the understanding of healthcare professionals regarding cannabinoids while also providing an updated resource that they can turn to as new research emerges.

I would like to acknowledge the diligent and always pleasant support of Author Service Manager Tea Jurcic at IntechOpen. Without her constant encouragement, this book would never have been completed.

> **Steven P. James, MD** Independent Researcher, Rancho Santa Fe, CA, USA

**1**

Section 1

The Science of Cannabinoids

Section 1
