Everything you should know about CBD in the UK.

This book is considered consumer information and is being used to reduce the potential harms associated with the uninformed consumption of CBD and THC products, their production, and safe sourcing in an emerging market.

About the Book
Bud & Tender®: This book is intended to educate people on cannabis as a whole. Hopefully after reading this book, consumers will be best placed to make informed decisions on which cannabis supplement is best suited for them.

1.0 Introduction
2.0 History of Cannabis
2.1 Historical Uses
2.2 Prohibition
3.0 The Cannabis Plant
3.1 Busting the Sativa vs Indica Myth
3.2 Structure and Growth
3.3 Seeds
3.4 Stalks and Stems
3.4 Flowers, Leaves and Trichomes
4.0 Constituents of Cannabis
4.1 Terpenes
4.1.1 The chemical composition of terpenes
4.2 Flavonoids
4.2.1 Cannflavin A, B and C
4.3 Phytocannabinoids.
5.0 Cannabinoids
5.1 Phytocannabinoids
5.2 Endocannabinoids
5.3 Synthetic cannabinoids
6.0 The Endocannabinoid System (ECS)
6.1 Basic Biology
6.2 Components of the ECS
6.2.1 Endocannabinoids
6.2.2 Enzymes
6.2.3 Receptors
6.3 Therapeutic potential
7.0 The Entourage Effect
8.0 Absorption and safety
8.1 Fast Pharmacology
8.2 Cannabinoid Pharmacology
9.0 Extracts and Oils
9.1 Cannabis products and terminology
10. Cannabinoid safety and tolerability
10.1 Safety
10.2 Drug interactions
11.0 International Perspectives and Storage
11.1 Preservation and longevity
11.2 Conclusions
12.0 References

1. Introduction

The public’s opinion of cannabis has varied tremendously over the last century. In recent decades, cannabis has been highly criminalized due to its potential to be abused as a psychotropic substance. Cannabis holds a wealth of opportunity and, unfortunately, the wider debate has been neglected and the numerous uses of cannabis overlooked. Cannabis and hemp are one and the same and hold exceptional potential for humanity. Up until now, Cannabis has been unexplored by science, leaving a wealth of explorative potential, offering an almost entirely new branch of science and medicine that can benefit all of society. Although they had passion, early cannabis advocates lacked critical academic research and science to support many of their arguments. This absence of evidence was primarily due to the ideological enforcement of a highly unproductive war on drugs, which has resulted in the global criminalization of the plant, which has left the vast potential of cannabis unexplored.

In this last decade, medical support for cannabis has been revitalized by a rapidly growing body of data that is uncovering the science behind these age-old medical claims. With abundant anecdotal reports of cancers being cured, and life-threatening illnesses being stopped in their tracks, it was only a matter of time before medical research was forced to explore these therapeutic claims. This modern research has identified an exciting biological link between humans and cannabis which has formed the basis for a new branch of medicine. The Endocannabinoid System (ECS) is a medical marvel discovered through the scientific study of cannabis. It is responsible for exerting the effects cannabis, and its discovery marks the beginning of an entirely unexplored branch of medicine. The use of cannabis by medical patients has become a passionately debated topic in the media and public forums, pressuring global political powers to re-evaluate their stance on the plant and its molecules. Across the UK, public cries for safe patient access to cannabis has provoked the British government to rethink their legal approach with a promising legislative step on the 1st of November 2018. Despite this new legislation, it remains exceedingly difficult for British patients to safely access cannabis products.

The governing body that provides national guidance and advice to the National Health Service (NHS) professionals is the National Institute for Health and Care Excellence (NICE). NICE provides a series of evidence-based guidelines that outline the best practices for UK medical professionals based on the extensive medical evidence and studies available to a committee of clinical experts. Medical professionals in the UK must adhere extremely closely to the NICE guidelines which are legally established operational frameworks that provide the basis for UK medicine. These guidelines are developed based on evidence built up over years of surgical procedures, clinical trials, and experimentation. Given this, cannabis presents a particularly sticky situation for all involved.

For decades medical research into cannabis was discontinued following a sustained campaign from the American Medical Association in 1945 that forbade the exploration of cannabis for medical use. This later resulted in the classification of cannabis as a substance of abuse, leaving cannabis research in its infancy for many years and leaving a wealth of untapped potential. Despite the recent renewal of medical cannabis research, compared to opiates and opioids, we are some thirty to forty years behind in our knowledge of cannabis medicines and their applications. This is the key issue currently facing NICE and the NHS.

Although at first glance it would appear the UK government have enabled medical access to cannabis, NICE and other regulatory agencies currently lack double-blind placebo-controlled drug testing studies that are required to develop medical guidelines for cannabis. Not only this, the tremendous unknown of the ECS means that not only are we unsure how to use these medicines, but we also do not understand how they even work.

This has heavily limited the accessibility of cannabis, which has ultimately stemmed from the historic ban on research. We are decades behind in our understanding of this exciting new branch of medicine. The current blame game surrounding medical cannabis has generated a cloud of misinformation and chaos for patients across the UK who still struggle for sustainable access. Although we lack the costly double-blind drug trials there still exists a wealth of published medical data demonstrating the vast potential of cannabis as a therapy in various diseases (British Medical Association, 1997; Kumar, Chambers, and Pertwee, 2008a; Ahmed and Katz, 2016). We are yet to even decode the mysteries of the ECS, the entire basis for cannabis medicine.
“In a 2018 study of Canadian cancer patients, 43% of patients surveyed reported that they were currently in use of cannabis (Martell et al., 2018)”

To highlight some of the limitations to this cannabis guidance, let us use the most recent research review conducted by NICE exploring the clinical and cost-effectiveness of cannabis-based medicinal products for people with chronic pain (NICE, 2019). When building this guidance, a very specific question was asked regarding the cost-effectiveness of products. The review identified 9,341 published scientific studies exploring the relationship between cannabis and chronic pain. However, specific to the questions being asked by NICE, are they cost-effective and safe, this review was left with just 20 double-blind randomized control trials (RCT) specifically exploring the cost- effectiveness and safety of basic cannabis products and without exploring the science itself. As essential as these guidelines are in medicine, it is apparent, and fair to argue that the NICE methodology overlooks a great deal of the fundamental scientific evidence and rationale, reducing much of their debate to cost-effectiveness rather than reflecting the reality of the scientific body of evidence. The use of cannabis in this form was deemed to be safe but the small selection of products investigated was not cost-effective. This creates a very disappointing environment for the scores of patients who desperately need our medical and legal system to catch up with the treatments they need now. A great deal of these patients are criminalized for their crude use of cannabis whilst they await a legal alternative. This book aims to broaden the cannabis debate and support patients left disillusioned by our cannabis laws by shining a light on many of the complexities and issues facing this new branch of science and industry.

The western world’s view of health is undergoing a gentle evolution. Western medicine is progressing away from doctor-centered medicine and now focusing on giving patients the power to choose their medical procedures and disease management strategies. Internationally, patients are becoming more informed of their illnesses and as such are demanding a greater say in their treatment strategies.
Unfortunately, conventional treatment options are limited for many diseases. For some conditions, tolerable treatment options are absent altogether. This desperation often encourages these patients to explore alternative sources of therapeutic relief and health maintenance, namely cannabis. Thanks mainly to the internet, the accessibility of medical literature has allowed patients to be increasingly informed on their medical conditions, and the alternative treatment options available elsewhere.

Medicine and pharmacy have evolved tremendously, a changed ethos that moves away from the one size fits all model for patient treatment to an individualized and personalized treatment strategy. This holistic view accounts for the unique circumstances of the individual by tailoring their treatment to their specific needs and desires. Not only this, but we are moving our focus from the treatment of disease to the prevention of disease through education and health awareness. In a world of growing misinformation, it is increasingly difficult to find the factual and referenced information, particularly with regards to cannabis and health. In recent years, the prevalence of anecdotal reports from patients crudely utilizing cannabis medicinally has surged drastically, provoking countless poorly informed news stories with oversimplified medical claims.

A great deal of research has been conducted on cannabis and its constituents. Every day, the therapeutic understanding and safety of the molecules in cannabis are being reinforced by new scientific evidence. The effects of cannabis are well studied; however, we are many decades away from converting this into the RCT’s being sought by NICE and the MHRA, a scenario that is rather impractical for the many thousands of patients suffering right now who could be benefitting from cannabis. The complexities of cannabis make it a class of its own, and for this reason, some of the shortcomings of our regulatory system are beginning to show, demonstrating that they require reformation and evolution. As the public demand for cannabis access increases, so too will the need for clinical research, the evidence to support their use and methods of using these drugs in a clinical setting (Ben Amar, 2006; Pisanti et al., 2017). Ultimately, what the regulators are seeking, is a selection of cannabis-based medicinal products which can be tested in their masses. This is a decades- long process, and as we have seen thus far, not the way to make impactful progress for the patients that are suffering here and now.

As the political system catches up, it is no secret that cannabis is being widely and crudely used by patients suffering from various chronic and terminal illnesses (Webb and Webb, 2014a; Martell et al., 2018). The therapeutic effects of cannabis vary significantly. Often used by those living with chronic pain but also utilized by sufferers of spinal cord injuries and movement disorders (British Medical Association., 1997; Kumar, Chambers and Pertwee, 2008). All of these people are criminals in the eyes of the law.

Prospective patients find themselves in a strange environment. As a population, we widely accept the medical use of cannabis, but our laws still criminalize the countless patients crudely utilizing cannabis at home who do not meet the strict medical criteria. In 2018, the law change had appeared to have made cannabis accessible medically, but to date, only a small handful of patients have gained legal access. In many cases, the parents of the epileptic children for whom this law was changed, are still forced to break the law to alleviate their child’s suffering. Being caught within this vortex has left many patients and families feeling trapped within a loop of frustration, a scenario perhaps depicted best by Penrose’s stairs.

In this book, we are going to guide you through the rich tapestry of cannabis, cannabinoids, their effects, and their relationship to human health and wellness through the lens of science. This book has been designed to give you the fullest and most complete understanding of cannabis, the current political situation, and the future of cannabis to ensure that the public is making informed decisions on their use of cannabis products. Consumers are bombarded with advertisements from companies selling Cannabidiol (CBD) products which often have little to no CBD in them. These products are abundant across the UK and unfortunately, at the time of writing, remain unregulated. This absence of oversight has left companies accountable only to themselves, and as a result, we have seen some of the largest high street brands blatantly retailing illicit products.

2.0 History of Cannabis

To put the cannabis debate in context it must be discussed within the hierarchy of drugs plants and substances. There has been a global tradition of herbal medicine across all cultures throughout human history. It has only been in recent decades that psychoactive substances such as cannabis have become criminalized and prohibited within society. There are abundant cultural and medical references to the consumption of drug plants and similarly fermented beverages from all corners of the globe (McGovern et al., 2004). Cannabis is a complex plant that contains an array of chemical compounds, each of which has been utilized creatively by humanity presenting a rich history for us to delve into which demonstrates the vast utility of this crop today (Kumar, Chambers and Pertwee, 2008b; Pertwee, 2014).

What does it mean for a substance to be psychoactive?
Psychoactive substances are a group of chemicals that act upon the central nervous system (CNS), altering brain function, producing alterations in perception, mood, consciousness, and behavior.
Ingestion and consumption of chemicals of this kind have been central to humanity for millennia.

Psychoactive substances are brokedown into 4 major categories, Stimulants, Depressants, Opioids, and Hn allucinogens. We already have access to a range of psychoactive substances in the UK, Nicotine, Caffeine, and Alcohol.

Nicotine and caffeine are classed as stimulants, these compounds enhance moods and increase energy within users. Stimulants are neurotransmitter blockers and slow the reabsorption of neurotransmitters into the CNS. Both drugs have the potential to generate numerous side effects and have addictive potential as well as the potential for psychological and physical dependence (Benowitz, 2010).

Similarly, alcohol, which is a depressant, can reduce feelings of tension and anxiety can become highly addictive causing dependence (Kuria et al., 2012).

Hallucinogens such as cannabis, psilocybin mushrooms, the peyote cactus, and mescaline alter consciousness and perception within humans, primarily, by mimicking human neurotransmitters, signalling molecules of the brain. Contrary to their legal classification as class-A drugs, hallucinogens have a very low potential for addiction, psychological dependence, and physical dependence and are extremely safe when administered under clinical conditions, with adverse reactions rare under the appropriate conditions (Johnson, Richards and Griffiths, 2008).

Hallucinogens have even been proposed as a therapeutic treatment for addiction whereby the patient’s unconscious relationship with their substance of addiction can be reperceived leading to new understandings of their addictive behaviours and revelations as to their impact. A meta-analysis exploring the use of LSD in the clinical treatment of alcoholism demonstrated that consistent and clinically significant beneficial effects could be derived from high-dose LSD (Bogenschutz and Johnson, 2016). This has extended to the use of magic mushrooms containing psilocybin in treating nicotine and alcohol dependence, with strikingly positive outcomes (Bogenschutz and Johnson, 2016).

Strangely psychoactive drugs have been particularly scrutinized and highly stigmatized within the UK, to the detriment of a great deal of scientific progress. As immoral as these drugs may be perceived in today’s society, our not too distant ancestors were well versed in psychoactive preparations. Early human encounters with psychoactive compounds found abundantly across the planet are thought to be one of the early triggers for the development of human consciousness. Mind- altering drugs have also been accepted by religious scholars as a source of mystical and religious experiences that have been documented throughout history (Kellenberger, 1978). One of the finest descriptions of modern society’s perspective on psychedelic drugs was written by Walter Clark in 1968, a period when psychedelics were first being scientifically explored.

"It is one of the tragedies of our time that dispassionate evaluation of the psychedelic drugs-their values and their dangers too-has been made so difficult, partly by the inability of even the educated mind to tolerate the intrusion of new methods and experiences on their accustomed comfortable thought patterns. So far, the voices most influential in swaying public attitudes toward the drugs and their users have been eminent medical men, mostly well-meaning psychiatrists acquainted only with the deleterious effects of drugs. What if the only information the public had about automobiles came from ambulance drivers! Quite contrary to public assumptions, the true experts are those who have had experience in carefully supervising a wide sampling of volunteer drug users. Since the important subjective dimension will always be missing for those who limit themselves simply to objective observation, the truly conscientious expert will be as willing to experiment on himself as he will be to subject others to the influence of the drugs"(Clark, 1968).

2.1 Historical Uses

Humans have a historic relationship with psychoactive herbal preparations, these have been utilized medicinally for millennia with ancient civilization across the globe documenting cultural and spiritual ties to mind-altering plants. Amongst these psychoactive shrubs is cannabis, one of the first crops to have been cultivated across East Asia. Although this has not been as apparent or pronounced in western culture, the cannabis plant has long since been a part of society and has been utilized by humanity throughout the development of various civilization for everything from textiles and medicines. Considering the failures of the war on drugs, perhaps our modern societies should look into the past and learn something from “the primitive” so that we might find out how to maximize the potential benefits and minimize the potential for harm of substances that humans have been using for millennia (Guerra-Doce, 2015).

Not just a Medicine
Some of the earliest evidence of cannabis use by humans has been traced back to ancient China where scientists have found cannabis residues which were burned during mortuary ceremonies as far back as 500BCE, some 2500 years ago (Ren et al., 2019). Archaeological findings from across the region have identified the remnants of cannabis in various forms and are believed to have played a ritualistic role in ancient ceremonies where psychoactive compounds were produced at high levels. In a cemetery in North-West China, thirteen nearly whole cannabis plants were found perfectly preserved in the form of a burial shroud which was placed upon a male corpse, this was dated to be approximately 2400-2800 years old (Jiang et al., 2016). Hemp, Cannabis sativa’s more fibrous cousin, was famously a key crop to King Henry VIII’s British Navy (Mark A. R. Kleiman, 2011).

Although this ancient use of cannabis may be somewhat disconnected from today’s modern society, in our not so distant past, cannabis was a common constituent found within many pharmaceutical preparations. We need only look as far back as the ‘60s and ‘70s where cannabinoid research was rejuvenated mainly in response to the widespread recreational use of the drug (Pertwee, 2006). In 1970, the tincture of cannabis was still a commercial product that was prepared from cannabis Sativa grown in Pakistan and imported in the United Kingdom under license (Gill, Paton and Pertwee, 1970).

2.1 Prohibition

Given the global use of cannabis both culturally and industrially, how has it come to be that psychoactive plants such as cannabis have become so heavily criminalized and prohibited in the western world? Several events have contributed to the current international drug climate and specific documents and publications proposed by the UN and Joint national committees. Much of modern medicine and drug policy stems from the early 19th-century pharmacy industry, a time plagued by both civil and international war. During this gruesome period, early pharmaceuticals such as painkillers and antiseptics were in tremendous demand. These early transactions and processes were the basis of what we now know as the modern pharmaceutical industry. However, this industrial production and unregulated access to refined opiates were not without its issues. This uncontrolled access nurtured an opiate and drug abuse epidemic which escalated to the point that on the 23rd of January 1912, following widespread pharmaceutical drug abuse, the International Opium Convention was signed in The Hague (UNODC, 2009), to interrupt the trade and crude consumption of opium for “non-medical” purposes.

The International Opium Convention laid the foundations for our existing drug laws. During this period heroin was emerging as a novel drug and was rather counterintuitively being marketed as a non-addictive alternative to morphine (UNODC, 2009).
In 1925, the international opium assembly, established by the United Nations, declared cannabis to be as potentially harmful as the opium poppy and cocoa bush, integrating it into the convention to restrict the supply of narcotic drugs (UNODC, 2008). In the following decades, this early convention set the stage for the incorporation of these classifications into national drug policies which gave way to the cornerstone of today’s international drug control regime; The 1961 UN Single Convention of Narcotic.

This 1961 Act further matured and by 1972 The Single Convention on Narcotic Drugs had been amended to highlight the need to provide adequate prevention, treatment, and rehabilitation services. Thankfully, this aged view of drugs is now in reform and reassuringly has received criticism from the highest regulatory offices. In part due to the failings of the war on drugs and the absurdity of its mission for a drug-free world, the prohibitionist stance is evolving into a more pragmatic and evidence-based approach. This global issue was summarised by Ruth Dreyfuss, The Chair of The Global Commission on Drug Policy: “The incoherence of the current classification system represents a big hurdle for the reforms that need to be undertaken. It is past high time to accept the fact that a society without drugs is an illusion and that we must now lay the foundations, based on scientific evidence, for their legal regulation. Let us now focus on what constitutes the real legitimacy of drug policy: life, health, and security for all” (UNODC, 2011).

3.0 The Cannabis Plant

The global presence and influence of cannabis has been no accident. Pollen fossil analysis has demonstrated extensive cannabis cultivation by the Romans throughout Italy. Primarily, its success stemmed from its robustness and ability to tolerate almost any soil condition (Mercuri, Accorsi, and Bandini Mazzanti, 2002; Merlin, 2003). The diverse utilities and adaptability of the plant made it an obvious option for support in humanity’s exploration of the free world. A plant deliberately cultivated by the British and Portuguese to support the self-sustaining colonies of the New World (Warf, 2014).

Early cannabis breeders were mainly interested in the fibrous stalks or the resinous flowers from the cannabis plant, cultivating two distinguished lineages referred to as hemp and cannabis, but both botanically classified as Cannabis sativa (Small, 2015). The overlap between the domesticated and wild forms of the plants has generated conflicting interpretations and classifications of the plant but ultimately the recommendation is that Cannabis sativa remain classed as a single species (Small, 2015). Marijuana is another term that you may have heard used to refer to Cannabis sativa, this a North American term for cannabis which was coined in the early 20th century to associate cannabis with ethnic minorities. Terms such as “Marijuana” and “Skunk” are not formally recognized in science and primarily utilized by media and law enforcement when referring to Cannabis sativa. In regions of the world where a recreational cannabis culture has developed, the narcotic subspecies have been classified in terms of its recreational effects. This recreational landscape has led to widespread hybridization and crossbreeding, producing street names such as “Blue Dream” and “Bubba Kush”. This cross-breeding has further muddied the genetic waters with terminology that has little to no taxonomic foundation (Pollio, 2016).

3.1 Busting the Sativa vs Indica Myth

The Sativa vs Indica terminology is something anyone entering the world of cannabis will undoubtedly encounter and so it is important to provide some clarity before such confusion takes place. In traditional taxonomic terms “Sativa” refers to plants of Indian heritage, and their descendants to Southeast Asia, South and East Africa, and even Americas. “Indica” refers to Afghani landraces, together with their descendants in parts of Pakistan (McPartland, 2017). Although the phytochemical and genetic research supports the separation of “Sativa” and “Indica”, this terminology no longer aligns with formal botanical Cannabis sativa and Cannabis indica. The rate of diversification and the extensive crossbreeding between cannabis strains has meant that distinguishing the plant in terms of “Sativa” and “Indica” has become nearly impossible (McPartland, 2017). Cannabis varieties named with vernacular names by medical patients and recreational users lack adequate descriptions as characterized by the International Code of Nomenclature for Cultivated Plants (ICNCP). These terms have no taxonomical validity making the “Sativa” and “Indica” distinctions almost meaningless (Pollio, 2016). Cannabis sativa is also sometimes referred to as cannabis sativa L. to demark Carl Linnaeus, the father of modern taxonomy, as the authority for the first use of the cannabis sativa species name. To complicate the debate further, there exists a third classification, Cannabis ruderalis. First described by Russian botanist D. E. Janischewsky in 1924, it is generally accepted as a subspecies of Cannabis sativa, but a feral breed of the plant that is much smaller than common cannabis with a visible difference in flowers and leaves (Hillig and Mahlberg, 2004).

3.2 Structure and Growth

Cannabis is a predominantly dioecious plant, meaning it has distinguished male and female flowers that form on different plants. The two sexes are morphologically indistinguishable before the development of inflorescences (flowers), but in the generative phase, sexual dimorphism is extremely pronounced (Tang, 2018). The cannabis plant is highly absorbent and accumulates a great number of chemicals and elements from the soil it is grown in. The phytoremediation potential of hemp (Cannabis sativa) has been explored and successfully used to decontaminate heavy metal polluted soils (Linger et al., 2002; Kumar et al., 2017; Husain et al., 2019). The growth of Cannabis sativa has 9 distinct stages each with their substages of development, they include; germination and sprouting (0), leaf development (1), the formation of lateral shoots (2), stem elongation (3), inflorescence emergence (5), flowering (6), development of fruit (7), ripening of fruit (8) and senescence (9) (Mishchenko et al., 2017).

3.3 Seeds

Cannabis is a robust and high yielding crop that lends a great deal of its success to the physiology of its seeds. Cannabis seeds have their unique properties and themselves have a great deal of potential for scientific exploration. The seed is ellipsoid, slightly compressed, smooth, 2–6 mm in length, and 2–4 mm in diameter, it is light brown to dark grey, in some cases mottled (Vonapartis et al., 2015). Technically a nut, hemp seeds typically contain over 30% oil and about 25% protein, with considerable amounts of dietary fiber, vitamins, and minerals (Callaway, 2004). Hempseed oil is over 80% in polyunsaturated fatty acids (PUFAs) and is an exceptionally rich source of the two essential fatty acids (EFAs) linoleic acid (omega-
6) and alpha-linolenic acid (omega-3) (Callaway, 2004). Unfortunately, there has been a growing trend in companies falsely selling hemp seed oil as CBD oil, these are entirely different products. In addition to being highly nutritious, Cannabis sativa seeds and sprouts have demonstrated promising antioxidant activity in blood samples and in vitro led studies with research proposing further exploration of their use as a functional food otherwise known as a
superfood (Frassinetti et al., 2018). These constituents have led to research exploring the use of hempseed to beneficially influence heart disease (Rodriguez-Leyva and Pierce, 2010).

3.4 Stalks and Stems

Cannabis is a highly fibrous plant known for the low density and high tensile strength of its fibers. These fibers are contained within the woody stems and stalks of the cannabis plant and have been the source for rope, clothing, and building materials. The stems of the hemp plant are hollow and consist of a high-cellulose low-lignin bark containing long fibers, and a low- cellulose high-lignin core containing short fibers (van der Werf et al., 1994). At high planting densities, hemp plants develop thinner stems with fewer branches whereas at low density the plants are highly branched with much thicker stems, these can be separated into two components: the tissues outside the vascular cambium (bark) and the tissues inside the vascular cambium (core) (Tang, 2018). These fibers are comparable to flax and once refined can be used for high-performance composites such as vehicle panels and structures (Musio, Müssig, and Amaducci, 2018).

3.5 Flowers, Leaves and Trichomes

In drug varieties of Cannabis sativa, the flowers of the plant are highly resinous containing a cocktail of therapeutic compounds. The flowers of cannabis are the primary constituent of what has been labeled “medical cannabis” also referred to popularly in the UK media as “skunk”. These resinous flowers have been the primary concern of authorities. It is the molecules within this cannabis resin that provide the psychoactive and therapeutic effects that are pursued by patients and recreational users. The conditions the plant is grown in heavily affect the ratios of the compounds within the resin, this makes mass production of cannabis inflorescences extremely difficult to standardize in large quantities (Tipple et al., 2016). Hundreds of specialized metabolites with potential medical applications are produced and accumulated in the glandular trichomes that are highly abundant mainly on female inflorescences (Spitzer-Rimon et al., 2019).

Trichomes are small hair-like resinous glands with bulbous heads, found on cannabis flowers and leaves. The specifics of the plant’s trichome genes determine the medicinal, psychoactive, and sensory properties of cannabis products (Livingston et al., 2020). The word trichome comes from the Greek word trikhōma, which means “growth of hair”. Trichomes emerge as the cannabis plant blooms into a flower. They simply look like crystals covering the flower and are present on approximately 30% of all vascular plants (Fahn, 2000). Trichomes can protect the plant from wind damage and even prevent fungal growth and offer a varying array of smells, tastes, and potency (Wagner, 1991). Within this covering of trichomes, chemical compounds are synthesized and secreted which support the health of the plant itself as well as humans, animals, and insects. These chemical compounds are stored in vacuoles and move up the stalk to the trichome head for secretion as the flower reaches maturity. These secretions are produced most abundantly by the capitate stalked family of trichome (Figure 6. Image D), which produces the three key chemical constituents of cannabis; cannabinoids, terpenes, and flavonoids (Dayanandan and Kaufman, 1976; Mahlberg and Eun, 2004). These secretions occur at specific points in the plant’s growth, soil, water, and light conditions significantly alter ratios of these secretions resulting in tremendous variety (Magagnini, Grassi and Kotiranta, 2018). This complexity is another key factor that makes the large-scale cultivation and standardization of cannabis particularly difficult.

4.0 Constituents of Cannabis

Similarly, to other plants, cannabis contains a spectrum of elements that contribute to the appearance and application. These elements are produced in varying portions in response to the plant’s environment and genetic composition. The diversity of compounds within cannabis has made it particularly difficult to legislate for. Fortunately, this has not stifled research. Recent advances in technology have made cannabis analysis easier than ever enabling this recent surge in cannabis research and development. Overall, at least 545 unique compounds have been isolated from the Cannabis sativa plant (Pertwee, 2014). Each of these can be classified into distinct chemical groups. In this chapter, we will be discussing the three main classes of therapeutic compounds found within all cannabis strains, terpenes, flavonoids, and cannabinoids. For this chapter, we will be focusing on these three groups, there are however a plethora of other compounds classes including 50 identified hydrocarbons, 34 sugars, and related compounds, 27 nitrogenous compounds, 25 non- cannabinoid phenols, 23 fatty acids, 23 flavonoids, 20 simple acids, 13 simple ketones, 13 simple esters and lactones, 12 simple aldehydes, 11 proteins, 11 steroids, 9 elements, 3 vitamins, and 2 pigments (Gupta, 2016). The ratios of these molecules are as unique to the plant as fingerprints to humans. This resilient plant has seen this resurgence of interest because of these multi-purpose applications and its treasure trove of phytochemicals.

4.1 Terpenes

Terpenes are one of the three key classes of the therapeutic compounds found within Cannabis sativa. They are a diverse class of aromatic compounds found universally across the plant kingdom and interestingly also known to be utilized by insects (Breitmaier, 2006). Terpenes are some of the key ingredients found in essential oils as well as other products utilized in perfumery and aromatherapy (Omar et al., 2016). Generally regarded as safe (GRAS) by the Food and Drug Administration, terpenes are a key component used in cosmetology to increase skin penetration of transdermal products such as creams (Aqil et al., 2007).

Terpenes are quite potent molecules and affect animal and even human behaviour. Inhalation from ambient air can result in measurable levels in the blood (Ethan B Russo, 2011).

Lavender, and its key terpene constituent linalool, have well-documented sedative effects (Buchbauer et al., 1991). The scent and aroma of terpenes are partly the reason why different strains of Cannabis sativa and been given different recreational names. These aromatic molecules exert their effects within the body and have been suggested to work synergistically with phytocannabinoids to amplify the therapeutic effectiveness of phytocannabinoids.

Terpenes and terpenoids (terpene like molecules) share a precursor with phytocannabinoids and are all flavour and fragrance components common to human diets. Among such, the most popular ones are limonene and pinene (Ethan B Russo, 2011).

Over 150 terpenes have been documented in cannabis strains, each of which is uniquely produced or exaggerated by certain strains contributing to the user's preferences in fragrance (Booth and Bohlmann, 2019). These unique terpene ratios may be used as chemical markers for the chemical categorization of cannabis strains (Elzinga S et al., 2015; Aizpurua-Olaizola et al., 2016). Further research is anticipated to optimize the breeding of strain‐specific synergistic ratios of cannabinoids, terpenes, and other phytochemicals for more predictable user effects, characteristics, and improved symptom and disease‐targeted therapies (Baron, 2018). There is a corner of the industry exploring the matching of cannabis terpene profiles to diseases and symptoms, without more robust knowledge of the endocannabinoid system there will remain many limitations to these procedures.

4.1.1 The Chemical Composition of Terpenes

Terpene groups can be classed by the number of isoprene units in the compound, forming chains to create larger and more complex compounds. Isoprene is a molecule produced by plants, it is an organic compound with the formula C5H8, which means it is made up of 5 carbon atoms and 8 hydrogen atoms. For reference, a water molecule is composed of 2 hydrogen atoms and an oxygen atom, otherwise known as H2O. Chains of isoprene units can combine to create larger compounds, a chain of eight isoprene units would have the molecular formula C40H64.

As we exceed beyond 8 isoprene units, we have polyterpenes, this family can have many multiples of isoprene units. Compared to cannabinoids, terpenes are very volatile.

Monoterpenes are made up of the fewest atoms and as a result are the most volatile due to their lower molecular weight.
Terpenes are yet another promising class of compound within cannabis which offers yet more exciting potential for humans and society. As you can see, Cannabis sativa is a complex plant containing extremely diverse chemicals each with its own story to tell. CBD is just the tip of the cannabis iceberg.

4.2 Flavonoids

Another class of therapeutic compounds is flavonoids. The flavonoid pigments are responsible for most flower colours present in nature and responsible for giving the Cannabis sativa plant its trademark deep green colouring. They are found within the flowers, leaves, twigs, and pollen of cannabis plants but yet to be found in trichomes (Ross et al., 2005; Flores-Sanchez and Verpoorte, 2008).

Flavonoids are hence one of the key elements in the attraction of pollinating insects to plant species (Harborne, Grayer, and Grayer, 2017). In the animal kingdom, pollinators such as bees and butterflies exhibit particular colour preferences, so that bee-pollinated flowers tend to be blue in colour and butterfly-pollinated flowers pink or mauve (Harborne, Grayer and Grayer, 2017). Beyond their appeal to bees and butterflies, the unique flavonoids in cannabis offer great medical benefits to humans. This branch of cannabis molecules is amongst some of the least researched molecules with little known as to the full potential they possess.

4.2.1 Cannflavin A, B, and C

Flavonoids have a similar range in variety as cannabinoids. In total, nearly 20 different flavonoids have been identified in cannabis (Fraguas-Sánchez, Martín-Sabroso and Torres-Suárez, 2018). There are also many groups of flavonoids that are dispersed across the plant kingdom. In this chapter, will just briefly touch on the key cannabis flavonoids, cannflavins (Panche, Diwan and Chandra, 2016).

The primary flavonoids found uniquely in Cannabis sativa are Cannflavin A and B, they are unique to Cannabis sativa and as yet have not been found anywhere else in nature (Fornaro et al., 2016). Cannflavin C has only been a recent discovery with its first identification in cannabis only as far back as 2008 (Radwan et al., 2008). Very little is known about these molecules and many of them have only just been discovered. cannflavins A and B as thirty times more prevalent than aspirin. Hemp seeds are highly nutritious with cannflavins A and B being produced in the sprouts of hemp seeds. Similar to terpenes, many of these compounds have also been shown to have anti-inflammatory, neuroprotective, and anti-cancer effects (Werz et al., 2014). As a food nutrient, there have been correlations between dietary phenolic compound intake, such as flavonoids, and reduced incidence of chronic diseases such as neurodegenerative diseases, cancers, and cardiovascular disorder (Larondelle, Evers, and André, 2010).

In addition to the well-known CBD and THC molecules, the vast chemistry of cannabis only warrants further adoption and exploration.
These molecules are just one small aspect of the plant. Most of our current cannabis debate is around the most abundant and final key group of therapeutic molecules in cannabis, Phytocannabinoids. These molecules require a chapter of their own and as such will be discussed in further detail in chapter 5.

4.3 Phytocannabinoids.

The most abundant class of phytochemicals in Cannabis sativa are phytocannabinoids. Like many drug classes, Phytocannabinoids are derived from the cannabis plant similarly to how opioids are derived from the opium poppy and nicotine from tobacco. Until 1964 and the isolation of THC by Yehiel Gaoni and Raphael Mechoulam, it was unknown what caused the effects of cannabis. Whilst exploring what is was within cannabis that led to its psychoactive effects, an entirely new class of drugs was discovered; Phytocannabinoids. The initial discovery of these cannabis-derived cannabinoids and the reason for the “Phyto” prefix is that their discovery has led to the identification of several families of cannabinoid. All of these are referred to as cannabinoids but distinguished by the prefixes, Phyto, Endogenous, and Synthetic. These cannabinoids require a chapter of their own, we continue this discussion in chapter 5.

5.0 Cannabinoids

“Cannabinoid” is a very broad term, referring not only to a class of molecules derived from Cannabis Sativa but also their derivatives and converted products (Pertwee, 2014). Cannabinoids are a relatively new class of molecule which were formerly unknown to science until 1964, when we first isolated and synthesized the primary psychoactive component cannabis, the infamous tetrahydrocannabinol (THC) (Gaoni and Mechoulam, 1964). Until the synthesis of THC, little was known about what it was within cannabis that produced these psychoactive effects. This discovery was the basis for an entirely new class of drugs, cannabinoids. The initial identification of THC laid the foundation for the studies today which has demonstrated the production of naturally occurring cannabinoids by vertebrates and invertebrates from across the animal kingdom (Salzet and Stefano, 2002).

Early cannabinoid research identified a unique relationship between these cannabis-derived cannabinoids or “phytocannabinoids” and human health. This extensive relationship has now expanded to include a class of endogenous (internal) molecules known as “endocannabinoids” which we humans all naturally produce within our bodies. Humans and almost all life utilize these endogenous, internal, cannabinoids as chemical messages through which our body’s trillions of cells communicate. These messaging molecules are part of a larger internal communication system that regulates all cell health and function in most living creatures. So much so that it is possible to use invertebrates as models to explore these internal cannabinoid communications (Salzet and Stefano, 2002). The existence of these molecules and this incredible communication system were only discovered due to this exploration of cannabis and THC. The story doesn’t stop there. To further explore these endocannabinoids and the ECS, we artificially produced chemically targeted molecules called “synthetic cannabinoids” which enabled further investigation of this relationship between cannabinoids and human health.

Quick Chemistry
All cannabinoids, and drugs for that matter, are built from a chemical cocktail of molecules and atoms, and either is produced in nature or synthesized artificially. Atoms are the building blocks of life; they make up everything you see around you. These atoms form molecules and molecules form compounds. Nature builds its compounds which we have been utilizing for various effects throughout our existence. Scientists observing these phenomena can synthesize and artificially produce compounds, a science known as biomimetics, the process of mimicking biology. Following the chemical recipes provided by nature, we have been able to build a pretty clear picture of cannabinoids and their influences on humans and health. Let us look a little further into these three groups of cannabinoids and the unique roles they play in medicine and nature.

5.1 Phytocannabinoids

Phytocannabinoids are commonly discussed in the media with a great deal of focus being placed on just two of these molecules, cannabidiol (CBD), and the infamous THC. THC and CBD are the two most abundant compounds produced by Cannabis Sativa.

Phytocannabinoids are to cannabis what caffeine is to coffee beans, what opioids are to opium and what nicotine is to tobacco, a derivative, or extract. In our frenzied focus on THC and CBD, some of the most newsworthy features of cannabis have been overlooked. Primarily, almost one hundred other phytocannabinoids that each have their range of unexplored potential (Pertwee, 2014). The early research has been promising, some studies are demonstrating that these other phytocannabinoids such as cannabigerol (CBG) and cannabichromene (CBC) have potential as anti-inflammatory medications (Izzo et al., 2012; Borrelli et al., 2013).

A great deal of research has already been conducted into the wider medical potential of the other phytocannabinoids. A wealth of exciting findings are showing that these molecules may even surpass the therapeutic promise of CBD and THC. The key issue right across the cannabis debate is that science has little understanding as to how these compounds exert their effects and the pathways that they work through. These effects are known to be transmitted and passed on through a variety of cellular messaging pathways, but our knowledge of these mechanisms is still in its infancy. Through exploring these complex interactions, we unearthed evidence of a unique physiological relationship between cannabis and its actions on a newly discovered cellular system. The endocannabinoid system, the prefix “endo” meaning within the body, regulates, and acts as a feedback system to the millions of cellular communications that take place throughout the body every second. This special system and relationship to cannabis are explored in chapter 5.

How are they created?
The production of phytocannabinoids is governed by the chemical soup produced within cannabis which constantly evolves throughout the plant’s lifecycle. These phytocannabinoids are produced in varying quantities in the trichomes of the cannabis plant (Mahlberg and Eun, 2004). The unique chemical ingredients in cannabis provide the necessary elements for a chemical cocktail of ingredients that when combined, create molecules. These precursor molecules combine like ingredients within the plant. This binding and conversion of molecules are facilitated by small chemical factories known as enzymes. Enzymes are the universal synthesizers of chemical reactions made up of large numbers of amino acids and proteins. The enzymes that produce these molecules in cannabis are known as synthase enzymes. These enzymes synthesize enzymes and convert the chemical building blocks present within the plant into phytocannabinoids (Zirpel, Kayser, and Stehle, 2018). The complexity of phytocannabinoids is in part due to their ability to also undergo non- enzymatic transformations and other chemical changes without the need for enzymes. This means that in the presence of heat, light, and atmospheric oxygen, phytocannabinoids can break down and convert into other cannabinoids and metabolites (Flores-Sanchez and Verpoorte, 2008). This a large problem for on the shelf cannabis products.

To outline this synthesis, we shall use two of the best-known phytocannabinoids, THC, and CBD. Currently in the UK, one of these molecules is a controlled class B drug and the other is considered a novel food, available for widespread consumption in foods and available in high street shops. They are almost the same compound, even sharing the same molecular formula, C21H30O2. Contrary to popular belief, both THC and CBD have psychoactive properties. CBD has well-studied effects on mood, even exhibiting antipsychotic effects in studies exploring psychosis (Zuardi, 2008). What we are addressing here is the term psychoactive, which refers to a substance affecting the mind. This is not to be feared. Chocolate is another commonly psychoactive, as well as nicotine and caffeine. THC and CBD have a similar molecular life cycle and both drugs sharing the same precursor cannabigerol- acid (CBGA). At the right stage in the plant’s maturation and under the correct environmental conditions, these CBDA and THCA synthase enzymes begin to convert CBGA into the raw acidic forms of CBD and THC, Tetrahydrocannabinol-acid (THCA) and Cannabidiolic-acid (CBDA) (Zirpel, Kayser and Stehle, 2018).

Phytocannabinoids are stored within the cannabis plant in their “raw” acidic form. THCA and CBDA are secondary molecules that require activation to become biologically active. For this to happen CBDA and THCA require decarboxylation, which is a process where molecules lose a carbon dioxide (CO2) molecule form their structure. In cannabis, this process converts THCA and CBDA into their active forms: THC and CBD. Decarboxylation can occur spontaneously in the plant material and is accelerated by heating at high temperature (>100 °C)(Hanuš et al., 2016). This is one key reason that cannabis has historically been smoked, to activate the contents. These cannabinoid acids have their exciting anti-inflammatory and neuroprotective and share many of the same therapeutic properties like THC and CBD (Takeda et al., 2012; Nadal et al., 2017). As you can see, very little separates THC and CBD so it is a great shame that one carries a heavy legal penalty and the other can be consumed en-masse as a novel food.

One thing to be careful of is that THC and CBD can degrade further into the illegal drug, Cannabinol or CBN if stored incorrectly and exposed to heat and light. Interestingly, this degradation can be measured to indicate the age of a cannabis sample (Ross and El Sohly, 1999). This degradation potential further complicates the regulatory process as it is difficult to guarantee the content of these products following the initial testing and packaging. Given this, the contents of any CBD product may be very different from the actual content as the time of purchase and use. This is another challenge facing the cannabis industry.

5.2 Endocannabinoids

Similar to cannabis, we humans produce our cannabinoids, endocannabinoids. These are utilized by the body as communication compounds which are exchanged between cells in a constant chemical dance. These molecules are produced naturally by our cells, this phenomenon was first identified whilst exploring the effects of cannabis. The godfathers of cannabis research speculated that for THC to exert its effect it must have to bind in some way to our cells and physiology. Thus, began the search for this active site where THC exerted its effects within the body. Through this avenue of investigation, we discovered the CB1 Receptor (cannabinoid receptor 1), the binding site of THC, and the receptor responsible for propagating the psychoactive effects (Matsuda et al., 1990). The identification of this receptor gave way yet more questions, why was this receptor inside our bodies, and what is its function in humans and health? Little did they know this was the foundation of a much larger system, the endocannabinoid system.

Following a series of studies that analysed porcine (pig) brains through mass spectroscopy in 2008, endogenous cannabinoids were born. Within these samples, a molecule was isolated and found to be competing with a radiolabelled synthetic probe targeted specifically towards the CB1 receptor. This molecule competing with THC is anandamide (AEA), ‘ananda’ meaning ‘bliss’ or ‘happiness’ in Sanskrit (Devane et al., 1992). AEA and its sister endocannabinoids are integral to the maintenance of most bodily functions and are an integral system in human life. These endocannabinoids are key modulators of pain. A case that best demonstrates this is one of a woman who had natural very high levels of AEA in her body due to a genetic mutation. She famously presented with a long history of undergoing surgical procedures without the need for anaesthetics (Habib et al., 2019).

The true extent of these compounds is only just being uncovered with more likely to be discovered in the coming years. Over the next few decades, it will be exciting to watch science shine a light on the incredible opportunity that these compounds and this endocannabinoid system present to medicine and science. AEA is just one of the few endocannabinoids we have identified to date, each of which has its own unique and exciting roles in maintaining human health. So far, the most-researched endocannabinoids are anandamide (arachidonoylethanolamide; AEA) and 2-arachidonoylglycerol (2- AG), yet the eCBs family includes also virodhamine, noladin ether, and N-arachidonoyldopamine (NADA), besides homo-linolenylethanolamide (HEA), docosatetraenylethanolamide (DEA), and other compounds such as palmitoylethanolamide (PEA) and oleoylethanolamide (OEA) (Battista et al., 2012). Given the length of the names of some of these compounds, you can see why acronyms are so popular in cannabinoid medicine. The implication of these compounds in wider human health and disease will be discussed in chapter 6.

5.3 Synthetic Cannabinoids

Synthetic cannabinoids are not something to be feared. They were primarily created to support the exploration of the various aspects of the endocannabinoid system. Without these synthetics, it would have been extremely difficult to study how phytocannabinoids and the endocannabinoid system work. These molecules also have a wealth of potential as medicines. Molecules and medicines often have chemical cousins which are mirror images of one another and as such share a molecular formula but differ in their arrangement. Cannabinoids offer a wealth of opportunity for synthetic chemists and so it is key to a not stifle exploration of these areas.

A big problem with cannabis-based medicines is that they can produce unwanted and sometimes avoidable side effects. With our ability to synthetically create and manipulate cannabinoids, we can create and match cannabinoids and target them to act on specific bodily tissues and areas that require treatment, thereby reducing the prevalence of unwanted side effects. Crude cannabis use and consumption of cannabis oils do have their therapeutic merit but are the military equivalent of carpet bombing which can result in accidental loss through a loss of accuracy. Synthetic cannabinoids offer a way of precisely striking disease without the off-site casualties or side effects. Within this exciting synthetic creativity, the black market has predictably identified its own avenues of exploration.

Medicine vs legal highs
There is a black market that is thriving from the distribution of synthetic cannabinoids into Britain’s communities. These synthetic cannabinoids are often engineered to directly mimic the effects of cannabis using synthetically engineered molecules. These can often be hundreds of times more potent than phytocannabinoids and endocannabinoids and as a result, can cause damage to the endocannabinoid system. If abused these molecules lead to lasting physiological damage as they can overstimulate and damage the signalling systems of the body. The reason these black-market products are termed “legal highs”, is that new molecules can be created at a much faster pace than the legal system can outlaw them. In that interim period, these synthetic versions of THC are sprayed onto plant matter and marketed as synthetic cannabis or “spice”. Spice has been responsible for the news reports we have seen of users presenting “zombie-like” like effects that are seen across Britain and the US. These synthetic drugs are far more potent than the natural THC, they are odourless, and as one molecule is banned another newer slightly altered chemical cousins can be created and distributed. This means that they have become a stealthy and potent alternative to cannabis. The novelty of these molecules means they do not show up on drug tests as the development of a viable testing procedure is further behind the legislation.

The criminal system has also seen these drugs become a nuisance drug regularly found being smuggled into prisons and covertly consumed amongst inmates. These synthetic cannabinoid products avoid the law through the vague veil of being classified as incense and potpourri, but which ironically poses a greater risk to the public than the naturally occurring cannabis. Evidence has found using synthetic cannabinoids to increase the relative risk of needing Emergency medical treatment by 30 times that of regular cannabis users These are not to be considered safer alternatives to herbal cannabis and pose an inherent danger to users (Spaderna, Addy and D’Souza, 2013; Winstock et al., 2015; Tai and Fantegrossi, 2016).

“These synthetic drugs replicate the effects of natural cannabis but induce severe adverse effects including respiratory difficulties, hypertension, tachycardia, chest pain, muscle twitches, acute renal failure, anxiety, agitation, psychosis, suicidal ideation, and cognitive impairment. Chronic use of synthetic cannabinoids has been associated with serious psychiatric and medical conditions and even death” (Cohen and Weinstein, 2018).

6. The Endocannabinoid System (ECS)

In truth, this chapter warrants a book of its own. In our opinion, the endocannabinoid system (ECS) is one of the greatest medical discoveries of the early 21st century. The ECS is the entire basis for cannabis and its use as a medicine. This is the communication system through which the phytocannabinoids in cannabis produce their renowned therapeutic effects. The endogenous cannabinoid signalling system is a communication system that appeared early on in life’s evolution and as such is integral to most life species (Salzet and Stefano, 2002). It is instrumental in the regulation of numerous bodily functions throughout the body, a system found in all vertebrates (Salzet and Stefano, 2002).

6.1 Basic Biology

The human body is comprised of many trillions of cells that form a vast constantly adapting network. Each of us is delicate biological machines made up of these cells, each of which plays a unique role in the overall human-machine. Cells work together to create tissues, tissues work together to form organs, and organs work together to form you. Each of these trillions of cells is in constant communication with their neighbours and colleagues from throughout our body. Scientists refer to this signalling as ‘cellular communication’. The ECS is responsible for providing chemical feedback for these millions of communications. Cells communicate using signalling molecules known as “ligands”. These ligands have special binding locations known as receptors that receive the signal. Depending on the signal and receptor, a response is achieved within the receiving cell and this makes up the foundations of cellular communication. The message received can kickstart a chain reaction of events within the target cell all of which are highly variable depending on the requirements.

Homeostasis is the constant balancing act that these communications aim to achieve. This balancing act prevents these communications from leaning to either extreme and becoming harmful to the body's tissues and organs. Maintaining and nourishing this homeostasis is crucial to the overall wellbeing of our bodies and organs. Given that we are almost entirely made up of cells, the discovery of the ECS and its impact on human health is incredibly significant to medicine and science. Each of our cells is exchanging thousands of communications every second, constantly sending and receiving signals to maintain the health of themselves and the overall human-machine.

Cells communicate the status of their health to others, just like we do. These communications indicate whether the cell is in a state of good health or distress, the body then reacts accordingly to provide what is needed. The ECS provides the feedback response to the communication network. Clear cellular communications are key to ensuring the human-machine operates efficiently, they are responsible for coordinating immune responses, cell movement, and transformations. The feedback that is relayed by the cells and their ECS is then interpreted by the brain and a proportional response produced. This constant exchange of information occurs on a microscopic level but is responsible for maintaining everything from blood pressure to hunger. This rapid communication occurs throughout your lifetime with many millions of cells reproducing and renewing every day. These cells are constantly exchanging information to coordinate every thought feeling and action that you experience.

In principle, this can be compared to emailing and telecommunications. Each day, millions of emails (signals) are sent out to specific email addresses, and each day millions of responses returned. Much the same as how emails require a recipient, the brain similarly coordinates cellular health through this message and response system with specific reception sites for messages. When communication is interrupted between Email correspondents, follow-ups and reminders would typically be sent to further encourage a response. The same is true for cells if the feedback is not received a build-up stimulatory signals begin to oversaturate the target with information. Endocannabinoid system alteration or imbalances of this kind have been observed in most diseases.

In real life, businesses do not just communicate by email, and similarly, cells are not limited to chemical signalling and even including bioelectricity (McCaig, Song and Rajnicek, 2009). Through this system of communication, the body can gauge the health of cells, tissues, and organs. The theory stands that if the body can manage its health through these systems, we too may be able to utilize these systems medically to treat disease. Once our understanding of the ECS develops we will be able to artificially alter the ECS with technologies that manipulate the levels of endocannabinoids, enzymes, and receptors throughout the body. By conveying the complexity of cellular communication and our limited understanding of the endocannabinoid system, we hope to show you the depths to which this cannabis debate delves. As our understanding of the ECS grows, so will our ability to manipulate this system to develop more accurate therapies that will enable us to cure diseases through the therapeutic manipulation of the endocannabinoid system.

6.2 Components of the ECS

The ECS is a relatively simple system that consists of three elements that are in a constant state of fluidity. Much like the cannabinoid ratios in cannabis, the endocannabinoid system is as highly variable and as unique as a fingerprint. The variability and individual differences between every human’s ECS are the underlying reason as to why the user experience of cannabis and its effects are so variable. The variability in the elements of the endocannabinoid system is referred to as ECS tone. Similar to how we refer to the tone of muscles, the tone of the endocannabinoid system can vary highly between humans (Acharya et al., 2017). What we are realizing is that alterations in this ECS “tone” correspond to health and disease (Battista et al., 2012). Our knowledge of the ECS is still in its infancy and as such, we are still discovering the full extent of this system.

6.2.1 Endocannabinoids

The key elements that make up the endocannabinoid system are endocannabinoids. These are the chemical messages that are exchanged by cells like emails. The exchange of endocannabinoids is essential at multiple levels of communication. These exchanges occur between neighbouring cells but are also found in blood and saliva, as well as breast milk in humans (Di Marzo et al., 1998). Two of the key endocannabinoids initially elucidated are anandamide (AEA) and 2-arachidonoylglycerol (2- AG), these endogenous molecules mediate the actions of cannabinoid receptors which are found on all cells throughout the body (Howlett and Mukhopadhyay, 2000). We often focus on cannabis and its therapeutic properties but rarely on the potential of endocannabinoids, each of which exerts their therapeutic effects and has potential as a supplementary treatment where we can recode and readjust the endocannabinoid system to alleviate illness. These endogenous cannabinoids act on communication pathways already known to medicine which has given us a strong picture as to the effects they exert (Akbar et al., 2008). Molecules such as anandamide have already demonstrated promising anti-inflammatory and anti-cancer properties (De Petrocellis et al., 1998; Ma et al., 2016).

6.2.2 Enzymes

Enzymes are microscopic proteins, made up of uniquely coiled chains of amino acid work to accelerate the rate of chemical reactions within cells. Enzymes are the key mediators that balance the levels of endocannabinoids through a careful balance of production and degradation. These chemical reactions occur almost instantaneously to rapidly supply or deny cellular information building endocannabinoids, such as anandamide, from precursors to later digest them back down into other useful elements.

The synthesis and degradation of endocannabinoids is not a simple process and it sometimes involves several stages of conversion. Endocannabinoids are synthesized on demand by a collection of enzymes, AEA is catalysed from N-acyl-phosphatidylethanolamine (NAPE) by NAPE-specific phospholipase D(NAPE-PLD) (Pacher et al., 2006). 2 –AG is produced from diacylglycerol (DAG) by either DAG lipase (DAGL) α or β, though most are generated by the DAGLα (Di Marzo and De Petrocellis, 2012; Murataeva, Straiker, and Mackie, 2014). Once their function has been achieved, AEA and 2-AG are degraded by fatty acid amide hydrolase(FAAH) and monoacylglycerol lipase (MAGL) respectively (McKinney and Cravatt, 2005; Mouslech and Valla, 2009; Fu et al., 2012; Zou and Kumar, 2018). Enzymes can be blocked or inhibited to boost or reduce their activity, resulting in alterations in endocannabinoid and receptor activity (Wei et al., 2016).

6.2.3 Receptors

Cannabinoids were initially thought to work none specifically in the body, working like alcohol by disrupting communications by attaching to the outside of cell membranes without any specific target site. What we now know is that cannabinoids bind to certain receptors. Cannabinoid receptors are found on the outsides of cells as well as within the cell itself where they act to coordinate internal communications (Brailoiu et al., 2011). The most known and well-discussed endocannabinoid system receptors are the Cannabinoid Receptor 1(CB1) and Cannabinoid receptor 2(CB2), named simply by their order of discovery.

Receptors are expressed in varying densities on the outside surface of cells to manage the degree of stimulation being received. These receptors are entrenched in the outer layer of the cells surface similar to the dimples on a golf ball. This cell surface is comprised of numerous other receptor types and so this blueprint of receptors outlines corresponds to the needs of the cell. We often observe disease dependent alterations in the distribution and density of cannabinoid receptors which highlights a unique trend. Beyond the classical CB1 and CB2, the endocannabinoid system has multiple other receptors that contribute to its overall function; transient receptor potential vanilloid channels (TRPV’s), G protein-coupled receptor’s (GPR’s), 5-hydroxytryptamine receptors(5-HT) and peroxisome proliferator-activated receptors (PPAR’s), it is accepted that there are yet more to be discovered (Ligresti et al., 2006; Pistis and Melis, 2010; Battista et al., 2012; Di Marzo and Piscitelli, 2015; Sharkey and Wiley, 2016).

The activation of these receptors has many cascading effects that produce measurable alterations in our health. For example, the PPAR family of receptors plays a major regulatory role in energy homeostasis and metabolic function. Molecules that bind to PPAR’s have demonstrated promise in diabetes, adipocyte differentiation, inflammation, cancer, lung diseases, neurodegenerative disorders, fertility or reproduction, pain, and obesity (Tyagi et al., 2011). Groups such as the 5-HT receptors, also known as serotonin receptors, are inherently linked to anxiety and depression-like behaviours and mood disorders (Garcia-Garcia, Newman-Tancredi, and Leonardo, 2014). The TRPV family of receptors is heavily involved in the transmission of inflammation and pain of various sorts, and as such is a target in for novel therapeutics even before its recognition as an ECS receptor (Hazan et al., 2015; Du et al., 2019). The connections and overlaps in communication are abundant. By developing our knowledge of these receptors, it will become increasingly clear to us how phytocannabinoids interact with this system and produce their well-documented therapeutic effects.

Since their identification, ECS receptors have been implicated in a multitude of significant regulatory physiological processes including appetite, metabolism, pain sensation, mood, and immune function (Tibiriça, 2010; Cani, 2012). As we unpick this complex network of communication, we will undoubtedly uncover a bounty of therapeutic secrets, each of which will provide exciting new avenues for discovering novel treatments and disease management strategies.

6.3 Therapeutic potential

What we are discovering in cannabinoid medicine is that the ECS feedback system responds differently when we are ill. As previously mentioned, the ECS can be highly variable between individuals and the elements of the ECS can be expressed in varying ratios. This can take the form of increased or decreased levels of endocannabinoids, altered levels of the synthesizing and degrading enzymes, or changes in the prevalence and distribution of receptors.

We are realizing that in disease states, this regulatory system suffers a loss of function and certain elements of the become exaggerated or degenerate. In diseases such as cancer, healthy cells and cancerous cells show very different endocannabinoid system patterns (Chen et al., 2015). This may present several ways and be caused by several factors that we are slowly beginning to understand. A strong example of this dysregulation is epilepsy. Explorative studies investigating how the ECS may be altered in the epileptic brain have shown that elements of the ECS may be damaged or under-expressed. The CB1 receptor has been repeatedly observed to be deficient in the epileptic person’s hippocampus (Ludányi et al., 2008).

The significance of this is that THC, the most abundant compound in cannabis, targets and activates the CB1 receptor. The basic principle is that the binding of THC to CB1 initiates this anti-epileptic effect. Though this is a generalization, the effect is highly dependent on the fingerprint of the individual’s ECS. This also points us in the direction of personalized cannabinoid medicine that can factor in this unique cellular fingerprint as one size does not fit all. The CB1 distribution across the neuronal tissues is highly variable, and as a result, this underlying alteration in the endocannabinoid system may vary, case by case. There are many forms of epilepsy each affecting different regions of the brain, depending specifically on which types of neurons in the brain, the treatment strategy will need to be adjusted.

It is becoming clear that this same relationship is true for many diseases, ranging from cancer to arthritis. For this reason, we must discuss the ECS in greater detail when debating medical cannabis. Truly, it is the ECS that offers the greatest therapeutic potential but our knowledge of it is still in its infancy, as this matures so will its treatment potential (Pertwee, 2005).

Though crude cannabis consumption works very well for some, it is by no means the future of medicine and is still very much the equivalent consuming raw opium. Cannabis lacks the specificity of conventional medicines but is arguably far safer than some treatments we administer. Cannabis has tremendous potential across the board for general symptom management and relief. In terms of what can be achieved medically, the endocannabinoid system and its targeted manipulation hold true potential. Synthetic cannabinoids modulate the endocannabinoid with more precision, creating 21st-century therapies to renew our cells and biology. Our rapid rate of technological advancement will help us process the overwhelming volumes of data, giving us the capabilities to then reprogram and re-coordinate this dysregulated cellular communication which is the basis for many diseases.

The endocannabinoid system is only a recent discovery, and the scale of its potential is only just being recognized by science.

7. The Entourage Effect

The diverse range of therapeutic constituents make cannabis a therapeutic dream for researchers but a nightmare for regulators. It is a plant of over a thousand molecules. Each of these possessing diverse therapeutic properties, and as such its crude use has typically generated tremendous symptom and disease relief. As discussed in chapter 4, the three major chemical groups of cannabis (phytocannabinoids, terpenes, and flavonoids) all possess therapeutic properties. The combined consumption of these through the crude use of cannabis has allowed early users to gain the highest degree of symptom relief possible. When studying cannabis, researchers have been keen to identify the effects of its isolated constituents. Choosing to identify the strongest therapeutic combination, research set out to explore whether this therapeutic effect could be achieved by the molecules in isolation. The aim of isolating these molecules was to negate the unwanted side effects of the psychoactive THC.

By isolating these elements, scientists hoped to find the optimal therapeutic cannabis extract, increasing the efficiency of cannabis medicines, and reducing unwanted side effects. What we discovered was that isolated phytocannabinoids such as CBD do have therapeutic value, they are effective and useful research tools. Ultimately, for a vast number of patients seeking relief, crude cannabis with all its constituents including THC seems to be the product of choice. Although, not necessarily the cleanest or most refined form of consumption, smoking or vaporization does seem to be the most effective. For patients who need it most, this is all that matters. For many, this was why they break the law despite the availability of CBD products.

Due to the identified potent medicinal properties of cannabinoids, terpenes, flavonoids, and other phenolics found within the cannabis plant, the whole cannabis plant represents a more effective medicine than isolated or synthesized compounds. Through researching cannabis and its applications as a crude medicine, we have had to map the therapeutic spectrum of the individual molecules and to understand how exactly cannabis functions so effectively.

By isolating terpenes, cannabinoids, and flavonoids we have been able to demonstrate the therapeutic use of these drugs individually. By creating highly purified isolated phytocannabinoids it has been easy for companies to develop cannabis-based medical products. The major phytocannabinoid compounds, THC and CBD, have been explored in numerous ratios and combinations but regardless of this, the combination treatments demonstrate greater efficacy (Ethan B. Russo, 2011; Ribeiro, 2018). The issue is when applied in complex combinations it is almost impossible to determine which molecules are producing which effects and as a result, we cannot differentiate or determine which molecules are working and how. Although this is not an ideal scenario for scientists, a lot of patients prefer to use the full raw cannabis plant as they deem it to be more effective than the modified and isolated compounds of cannabis.

The entourage effect is a relatively loose term that refers to the synergistic interplay between the key therapeutic components found within raw cannabis extracts versus refined isolated molecules. This phenomenon has been widely reported in the medical research of cannabis and is often referred to as the entourage effect. This is a relatively loose term that refers to the therapeutic synergy achieved from the use of a full- spectrum cannabis product. This powerful synergistic combination potently interacts with the ECS to exert these therapeutic effects. There is a maturing body of data that documents this synergistic effect. However, the challenge has been in understanding the intricate interactions that underly this phenomenon.
Although the impact of the entourage effect may sometimes be exaggerated, the synergy we often observe in the patient’ testimonies has a genuine basis (Ethan B. Russo, 2011; Baron, 2018; Ribeiro, 2018; Russo, 2019).

The fingerprint-like individuality of the human endocannabinoid system and the diversity of cannabis mean that the use of crude cannabis medicines may be somewhat of a matchmaking procedure. The complexity of these interactions significantly limits our ability to confidently state the effect and outcome of cannabis and thus the isolation of individual molecules has been preferred. This complexity provokes an ethical dilemma, full-spectrum cannabis extracts seem to be more potent, we just cannot standardize them or say with any certainty what all of the effects are or how they occur. The fundamental principle of medicine being, not harm, it is hard to say from a medical perspective whether we are doing more harm than good. An example of this being a breast cancer study in which a full spectrum cannabis product was used but referred to as a botanical drug preparation (BDP). The raw cannabis extract or BDP demonstrated higher potency than isolated THC for producing an antitumor response (Blasco-Benito et al., 2018).

The synergistic interplay between phytocannabinoids, flavonoids, and terpenes are can in part, be explained by several emerging properties that they share. Studies into the isolated effects of terpenes and flavonoids also have unique modulatory effects on the endocannabinoid system, even demonstrating the ability to alter the effects of THC (Ethan B Russo, 2011). To explore this, 6 major cannabis terpenes were explored but demonstrated no significant effect on the ability of THC to bind to the CB1 or CB2 receptor (Santiago et al., 2019). It is clear that there is a great deal still to be explored.

Terpenes have numerous applications and when inhaled, terpenes such as limonene and pinene have an absorption rate of up to 70% and 60%, respectively both rapidly metabolizing and redistributing throughout the body. (Falk et al., 1990; Filipsson et al., 1993). Another type of terpene - menthol- even shows activity at TRP Receptors from the endocannabinoid system (A. Farco and Grundmann, 2012; Janero and Makriyannis, 2014). It is almost certain that the dietary terpenes we consume daily through fruits and flowers have unregistered effects on our endocannabinoid system with terpenes and other phytochemicals having proven to suppress the generation of cancer (Rabi and Gupta, 2008). Flavonoids too have an attraction for cannabinoid receptors, and they are not to be forgotten in this chemical tapestry. Their activity at cannabinoid receptors means they are demonstrating a similar potential to cannabinoids as neuroprotectants, anti-inflammatories, and pain-relieving treatments (Korte et al., 2009). All this background interplay points towards an underlying system that once decoded will pave the way for the next generation of therapy and medicine.

The interactions of cannabis phytochemicals with the enzymes are not limited to those of the endocannabinoid system (Thors, Belghiti, and Fowler, 2008). One powerful group of enzymes known as cytochrome P450 (CYP450) enzymes are responsible for the activation, degradation, and chemical alteration of roughly 75% of all drugs used in medicine (Guengerich, 2008). A large number of cannabinoids interact and operate through this CYP450 as do many other conventional drugs (Zendulka et al., 2016). Interestingly, some of the furanocoumarin compounds in grapefruit negatively impact this CYP450 group and are known to inhibit and modify their activity (Fuhr, 1998). Flavonoids that naturally occur within the grapefruit also interact with these enzymes (Li et al., 1994; Bacanli, Başaran and Başaran, 2018). Terpenes utilize the same metabolic pathway for chemical detoxification and conversion into more easily water-soluble molecules (Janocha, Schmitz, and Bernhardt, 2015). This area of research is highlighting the vast potential to bioengineer these metabolic enzymes to increase the effectiveness of drugs.

The interplay between cannabinoids, flavonoids, and terpenes at various biological levels goes some way towards beginning to explain the depth of the entourage effect. This complex interplay between the compounds found in cannabis provides endless avenues for formulating safe and effective novel medicines. The case for utilizing this entourage effect is currently sufficiently strong as to suggest that one molecule is unlikely to match the therapeutic combination of cannabis phytochemicals or even the industrial potential of cannabis itself as a phytochemical factory (Russo, 2019).

Mainstream pharmacy demands purified substances but, this is not something that necessarily correlates to greater benefit for patients. Overall, it is difficult to justify the wide spread use of refined cannabis medicines in the short term when doctors have no training on their use or medical knowledge of their effects. The added dimension of raw cannabis is safe to use and difficult to overdose but highly illegal makes the laws surrounding cannabis the most dangerous element. This is an area that decriminalisation would support those in short term need who are currently under threat from the law.

Without truly understanding the endocannabinoid system it is extremely difficult to accurately prescribe cannabis to patients but also to commercialize and industrialize a substance we do not fully understand. For this reason, companies have been falling over themselves to develop basic THC and CBD sprays, tinctures, and medicines which utilize various ratios of THC to CBD to create a simple medical product. These are simple products which we can show are safe but ones we still do not truly understand. They absolutely have their applications but are far from efficient when they come with such cost and confusion, all of which negatively impact the patient. The decriminalization of cannabis would be the fastest was to enable patient access, through which education and awareness could lead. At this point, many of the risks, costs, and delays could be forgone. The safety and practicality of using cannabis in its many forms will be discussed in the following chapter.

8.0 Absorption and safety

As shown throughout this book so far, Cannabis Sativa is an extremely safe, non-toxic, and valuable drug plant. Plants and herbs have been the foundations for medical preparations throughout human history. The long-standing common misconception that cannabis causes mass schizophrenia is as about as outdated as the belief that cigarette smoke is positive for lung health. There numerous drug plants are known to science. The tobacco plant, the opium poppy, the coca plant, Cannabis Sativa is just one. As such, the drug groups abundant in cannabis follow the same pharmacological laws as the drugs found in other drug plants. The plant as it stands is extremely safe. It is the phytocannabinoid compounds in cannabis that cause controversy and debate. The safety and tolerability of phytocannabinoids are well documented and so too are the effects of these drugs in humans, but very little is known about how these drugs produce these effects once within humans. Pharmacology is the study of this field and it explores the uses, effects, and modes of action of drugs, which is integral to 21st-century medicine. The illegality of cannabis has meant that very little research has been done into the pharmacological flow of cannabinoids through humans.

Given that this area of cannabinoid medicine is still developing, medical researchers are left with some fundamental questions that are so far unanswered. How long are these medicines active for? How should these drugs be dosed to achieve the desired effect? How do they interact with existing medications? For this chapter, we will outline the current understanding of how drugs such as phytocannabinoids flow through the body. We will also explore how the various administration routes effects of drugs serve different purposes. By giving you a brief induction into pharmacology, we aim to demonstrate the complexity of the cannabis discussion and the factors to be considered when administrating cannabinoids.

8.1 Fast Pharmacology

The effects of phytocannabinoids are well documented, the challenge herein lies in understanding how exactly these effects are exerted. Like all drugs, phytocannabinoids and their partner constituents have multiple administration routes, and therefore there are lots of ways in which the consumption methods can be tailored to the needs of the user. Drugs can be inhaled, consumed orally (tablet/solution), applied dermally (skin), suppositories (rectally), and absorbed into the bloodstream, injected into muscle tissue or directly into the bloodstream, intravenously.

Depending on the chemical properties of the drug and method of consumption, the absorption of drugs into the bloodstream can be highly variable. A drug's lifecycle as it passes through the body is comprised of four distinct processes, Absorption, distribution, metabolism, and excretion (ADME). A common misconception is that when a drug is consumed it should immediately take effect and enter the bloodstream. Often only a portion of the drug consumed enters the bloodstream and becomes active. A process is known as bioavailability. The bioavailability of drugs is highly variable and based on the chemistry of the drug, the method of administration, and the individual consuming it.

Typically, intravenous administration is the most efficient method of administering a drug with near 100% bioavailability. For phytocannabinoid research, intravenous THC was utilized as an administration strategy for exploring the isolated effects of high concentrations of THC on humans (Englund, M. Stone, and D. Morrison, 2012).

Following absorption into the bloodstream, drug compounds are then distributed to the body’s various tissues where they initiate their effects. Once their function has been served, the body’s focus is to facilitate the safe secretion of the drug by increasing the solubility of the compounds, a process known as metabolism. We know in the case of endocannabinoids we know this degradation occurs through the endocannabinoid system enzymes (such as MAGL), we are unsure as to the full metabolic blueprint of phytocannabinoids. Early work shows phytocannabinoids share some major degradation processes with other drugs, including the CYP450 enzyme, whilst also interfering with secondary metabolic pathways (Zendulka et al., 2016). The presence of phytocannabinoids has been known to alter endocannabinoid pathways as well as interact with other drugs that rely on p450 enzymes (Zendulka et al., 2016). These pathways are chains of communication, and these subsequent interactions and interferences in this communication are the key unknowns for phytocannabinoid medicine and the underlying reason for our hesitation in adopting cannabis into our medical system.

In addition to the overlap in signalling pathways, phytocannabinoids converge in the liver where they are metabolized by digestive enzymes. Following their expenditure and use, they are then excreted by the body. The excretion phase of drug pharmacology is the removal of drugs from the body, typically by the kidneys, which filter out toxins. This excretion rate can vary from person to person and is dependent on many factors including age and additional use of medication. This occurs in the form of urine, but also through sweat, tears, saliva, respiration, feces, and milk. These diverse ways through which we excrete drugs is one of the reasons we discourage pregnant and breast- feeding women from drug use as these can be easily transferred through excretions.

8.2 Cannabinoid Pharmacology.

The diverse properties and interactions that cannabis compounds have on the body provide multiples hurdles in the form of gaps in our knowledge. Phytocannabinoids are hydrophobic compounds, meaning they do not dissolve in water, but lipophilic meaning that they can be dissolved in fats and oils (Sharma, Murthy and Bharath, 2012). For this reason many cannabis products are diluted in a fat based carrier oil. As a result, the bioavailability of phytocannabinoids is notoriously poor. These fat-soluble properties mean cannabis metabolites can be stored in fat tissue. As a result of this phytocannabinoids can be detected in fat. Metabolites such as THC, can be found in the blood for extended periods which can be used as a determining marker for the regularity of cannabis use (Musshoff and Madea, 2006; Sharma, Murthy and Bharath, 2012). This low bioavailability has been crudely sidestepped by humans who have historically smoked cannabis. Smoking cannabis has long since been the preferred form of crude consumption and knowingly or not, inhalation is the fastest way to absorb most drugs of a low bioavailability (Ann Tronde, 2002). Contrary to popular belief, phytocannabinoids and in particular THC, have a poor incorporation rate into skin and hair and so cannabis is difficult to detect through these means without high powered analytical equipment (Musshoff and Madea, 2006; Khajuria and Nayak, 2014). THC can be incorporated into the hair in minusculecule quantities from consumption, but contamination from cannabis users can also cause this THC incorporation (Moosmann, Roth and Auwärter, 2015). Transfer of phytocannabinoids into the hair of non-cannabis users can occur from sweat, hand to hand, or through cannabis smoke (Moosmann, Roth and Auwärter, 2015).

In addition to the low bioavailability, accurately studying cannabis in humans poses several additional challenges. Standardization of the cannabis growth is extremely difficult, the variability of THC and other compounds in plant material (0.3% to 30%) leads to variability in tissue THC levels from inhalation. When smoking, THC bioavailability averages 30%, oral THC is only 4% to 12% bioavailable and absorption is highly variable based on individual (McGilveray, 2005). We can manage this variation in bioavailability through varying the routes of administration already used in pharmacology and medicine but most of the research is yet to look beyond THC. The hundreds of other phytocannabinoids also then require a great deal of mapping to accurately state the dose and response relationship between phytocannabinoids and humans.

These areas are likely to have been explored privately for specific cannabis medical products, but this knowledge would not be publicly accessible for some time. A recent study by a very talented group at The university of Nottingham explored the research on the dosing CBD, the primary phytocannabinoid retailed across the UK. A review of 792 published cannabis research papers showed just 24 articles explored the pharmacological parameters of cannabidiol showing little work has been done to explore the issue (Millar et al., 2019). This similar absence of data is true for THC. The study concluded that research in this field was sparse and warranted far greater exploration. Given that we have a readily accessible over the counter CBD market, should we not have a medical understanding of these drugs before enabling widespread commercial consumption?

The key now is translating what knowledge we do have into human data. We can be tailoring the administrative methods to the ailment so that the symptom or tissue being targeted receives optimal dosing. Our medical system relies heavily on the pharmaceutical industry for products and research, and it is worrying that much of this is industry lead and funded. This means that the human element of medicines is often left unexplored and only the efficacy cost-effectiveness of medical products researched. Rat research models have shown the successful transdermal application of cannabidiol to reduce the inflammatory and arthritic pain but clarity is needed as to how this occurs (Hammell et al., 2016). The benefit of an animal study is that it helps us predict what medical outcomes we can expect in patients. This animal research in many cases just does not translate as these studies are often poorly designed conducted and analysed (Bracken, 2009).

Much of cannabis research is animal based in vivo (in life) or takes place in vitro (in glass) in a petri dish. Humans are infinitely more complex than these models and so it is difficult to generalise what is published. Significant time is required to now begin upgrading and translating this research to humans and human tissue. Animal models have been used to demonstrate the vast and exciting therapeutics effects that can be potentially achieved in humans, exhibiting treatments for almost all major diseases. These studies now need to mature. Animal models have highlighted the impact not just of cannabis but the complex interactions of these molecules with the ECS and other elements of human physiology. Our knowledge is very much in its infancy and so although we know these molecules until we know how they work, we are purely speculating as to the true impact and effect. The entourage is another dimension that further complicates the mapping process for researchers. Valuable though it is therapeutically, you can begin to see the scale of the challenge researchers face. Entirely new branches of pharmacology and medicine need to be established and explored. Human trials of the level required currently insufficient, held back primarily by the decades of cannabis prohibition when it was deemed to have no medical value.

9. Extracts and Oils

The UK cannabis market relies on a synergy between sciences. Engineering is a massive component of cannabis industry that possesses remarkable potential for innovation and development. The extraction of cannabinoids is a key process in this synergy and a sector that draws much of its technology from existing industries. Using extraction lessons from the perfumes industry as well as from black-market cannabis industry techniques, engineers have developed a multitude of methods for removing the valuable drug compounds from the plant biomass.

Following on with our theme of diversity, cannabis compounds demonstrate similar diversity in the methods that can be used to extract target molecules. These can then be used as the basis for cannabis products, being later diluted and formulated to specific requirements. Cannabinoid extraction is a science of its own and a world of hidden techniques and innovations. Crude extraction methods have been utilized successfully by cannabis users for several decades to create highly concentrated cannabis oils using little more than a bucket and some ethanol. These oils can contain hundreds of compounds, very little is known about what is present within the oil. Low-quality extraction of hemp for example, can result in the heavy metals that are absorbed by the plant being extracted and concentrated alongside the phytocannabinoids. Hemp produces low levels of phytocannabinoids, and so a great deal more concentration is required to increase the strength of the extracts. Lacking regulation and oversight, has enabled corner-cutting in this phase of production, meaning the heavy metals are often forgotten about or not tested.

Inappropriately prepared extracts have exhibited wide-ranging contaminations. A Californian cannabis study screened 57 cannabis extract samples from the American market, for cannabinoid content and the presence of residual pesticides or solvents. Over 80% exhibited contamination of some form with THC concentrations ranging from 23.7% to 75.9% (Raber, Elzinga and Kaplan, 2015). In another study of the Washington cannabis market, 22 out of 26 samples tested positive for pesticides which included over 45 distinct chemical agents that were being readily purchased by American consumers (Russo, 2016). These studies highlight the need for strict commercial regulation and awareness around the contamination risks associated with improper cannabis cultivation and extraction.

In the absence of standardized procedures and approved methods of extraction in the UK, it is invariably likely that a significant portion of products in the UK contain unwanted compounds and contaminants. The world of extraction is home to the cannabis industry's finest chemical engineers. Despite this, a large degree of amateur extraction takes place. The reason this problem has emerged is, extraction equipment and solvents are relatively none descript and accessible, so almost anyone can purchase the equipment and begin experimenting, and not always in the safest way.

Extracting phytocannabinoids using liquid solvents is one of the most encountered methods for crudely extracting cannabis compounds. The process involves running the liquid solvent through the cannabis plant matter where the phytochemicals are stripped away and dissolved into the solvent. Ethanol, butane, and hexane or some of the most common solvents that are utilized, leaving a mixture of phytochemicals and solvent. The residual solvent is then evaporated, and the concentrated combination of phytochemicals left in a concentrated oil form. This can then be further refined and filtered to further remove any potential residues. The presence of solvents and flammable liquids, if incorrectly prepared, can turn what seems like a simple process into an extremely dangerous procedure. The danger of solvents such as these has already been documented in the short few years of its existence.

The rise of amateur extraction in areas such as Colorado, and the using techniques such as this that rely on the flammable solvents, has resulted in an unexpected rise in flash burns and hospital admissions associated with the production of cannabis extracts (Bell et al., 2015).
CO2 extraction is a more industrial method of extraction which relies on similar to the use of solvents but instead using pressurized liquid CO2 to remove the phytochemicals. The condensed CO2, commonly known as dry ice, is pumped through the plant matter where it strips the phytochemicals in a similar manner to the stronger solvents. The mixture of liquid CO2 and Cannabis oils is separated in a separate chamber where the pressures and temperatures are altered to the CO2 becomes a gas, depositing the cannabis oils in the bottoms of the pressurized chamber. The benefits of this method are that CO2 is a less damaging solvent that reduces the risk of harmful solvents being left in the extract. Butane and hexane residues are also known to pooling in enclosed spaces, where all that is needed is a spark often causing fires and explosions (Al-Zouabi et al., 2018).

The slight differences in the boiling points of the phytocannabinoids mean that careful manipulation of the pressures and temperatures can isolate certain cannabinoids from the plant. These more refined chemical processes provide numerous avenues for refinement and wider exploration into cleaner and more efficient technologies. The combination of CO2 extraction with microwaves and ultrasound is being trialled to further refine these processes (Lewis-Bakker et al., 2019). Despite some fantastic engineering, extraction can also be achieved simply using oils and heat, a method that dates back hundreds of years.

We mentioned early in this book that cannabis compounds are lipophilic and readily dissolve in fats and oils. Extraction can also be achieved by submerging the plant matter in oil and heating the mixture, the plant cannabinoids seep out of the plant matter and into the oil. The warming of this mixture activates the phytocannabinoids converting them from acids to their active form. For example, THCA and CBDA would be converted into their active form’s THC and CBD. This procedure is not quite as efficient as the industrial procedures but something that has been crucially useful to early cannabis users. Given the potential health implications of low-quality extraction and the dangers it poses to users it is important to understand the variability in methods for cannabis product production. This should illustrate to you why cannabis products should be sourced responsibly and the need for regulated high quality production. This highlights too the crucial need for testing and quality assurance to limit these contaminations, which will ultimately be increasing the standards of products and the consumers exposure to variability and contamination. As the UK industry develops industry bodies and international cannabis companies will put forward their preferences on the outlook of the UK market, it is important that these discussions are scientifically led and not controlled by private companies.

Cannabis products and terminology
Ever the creatives, we humans have developed a diverse number of methods utilizing the therapeutic components of cannabis. Depending on the production method and its quality, the products may contain single isolated compounds or entire cannabis phytochemical spectrums. In this chapter, we will break down the major products and derivatives that you will likely come across when exploring cannabis. What should these extracts contain and what is the difference between them?

Whole Plant/Crude – An unrefined extract considered low quality, it contains all parts of the cannabis plant including unnecessary waste material like waxes, fats and chlorophyll.

Full-spectrum – A refined cannabis extract that contains as many valuable compounds from the cannabis plant as possible. The product typically contains THC, multiple cannabinoids and all cannabis compound groups such as terpenes and flavonoids.

Broad-spectrum – A refined extract that contains many valuable compounds found in cannabis; it too has multiple cannabinoids but not quite all of the cannabinoids that are found in a full-spectrum extract. Broad-spectrum extracts have been refined further to remove THC, CBN and THCV; drugs that are still controlled and deemed illicit by the UK government. Other than this they are the same as full spectrum.

Narrow-Spectrum – A refined extract, it usually contains just one (CBD) or possibly two cannabinoids but still contains other beneficial compounds from the cannabis plant.

Concentrates and extracts – These are purified and highly concentrated forms of the oil that are typically inhaled through vaporisation or “dabbing”. These extracts can be anywhere from 50% up to 90% purity and can come in a dense, wax-like oil or a crystalline powder.

Isolates – Isolates are purified 99% forms of isolated cannabinoids. Isolates can be added to a variety of products. Pharmaceutical grade isolates are used for cannabinoid medical research and are the basis for many basic cannabis medicines.

CBD oil – A non-descript term used to refer to cannabis products containing a high portion of CBD alongside other phytocannabinoids. This term is often used interchangeably and used to refer to legal, broad-spectrum and narrow-spectrum products. Improperly prepared and illegal CBD oils will contain the illicit compounds THC, CBN and THCV.

Hemp Oil/ Hemp seed oil – Regularly falsely retailed as CBD or Cannabis oil. It is extremely cheap to produce and is visually very similar to other cannabis oils, and therefore a popular tool for snake-oil salesmen. It may contain trace amounts of cannabinoids, terpenes or flavonoids but is instead a highly nutritious cooking oil contains a large amount of Omega 3 and 6 similar to olive and rapeseed oil but does not contain any functional quantities of cannabinoids or CBD.

Cannabis extracts are some of the safest compounds in medicine. Current concerns are predominantly around the chronic crude use of highly concentrated unregulated extracts. We hope to limit public exposure to the unregulated, untested and irresponsibly sourced cannabis. Cannabis is extremely safe, the dangers arise from lacking understanding and awareness of users, the public, and politicians. Education is a key tool in strengthening this industry and arming consumers with the knowledge they need to safely navigate the industry and its hurdles.

10.0 Cannabinoid Safety and Tolerability

In this chapter, we aim to provide you with as much practical information as possible regarding cannabis product safety. Science has a foundational knowledge of cannabinoids and a sufficient understanding of the impact and interactions CBD has with certain enzyme signalling pathways within the body. CBD intertwines with many established areas of medicine and as such there are some vital bits of knowledge that people with existing health conditions and medications should be aware of. Fundamentally cannabis is a drug plant and contains drugs in the form of cannabinoids. Therefore, the safety of cannabis is best perceived in the context of other widely accessible drugs that are readily available. Before we delve into this evidence, let’s quickly review our knowledge of cannabis and how its molecules react within the body.

As we mentioned before, certain enzymes are prevalent in metabolism. These same enzymes are involved in the metabolism of many conventional other medications. There are potential interactions that should be considered by those who rely on these prescription drugs. Fortunately, modern medicine is familiar with the pharmacology of these existing medications and so we shall outline briefly what some of the most common interactions are and highlight the key risks that cannabis consumers should be aware of. By educating the population aware of these interactions and potential risks we can continue to make cannabis products use even safer. This is especially key for those who rely on prescription medications to support their chronic or acute health conditions. The key to reducing these risks is awareness and reducing the likelihood of its unintentional combination with existing medications, and its impacts on their bioavailability. This is a trend that should be followed for all drugs, harm reduction through education.

10.1 Safety

The key focus here is that cannabis is extremely safe to use for most people. In the context of deaths, allergies, and risks, Cannabis is many times safer than our cultural favourite, alcohol, which causes numerous overdoses each year. MOE which stands for margin of exposure, is a scale used to classify the relative risk of drugs. MOE is calculated by a ratio of two different factors; the benchmark dose, which is the amount of drug needed to become harmful, and the other being the amount consumed by the population. Although it may seem counteractive, the smaller the MOE is the higher risk it carries to society (Dirk W. Lachenmeier and Rehm, 2015). A recent study categorized alcohol as a high-risk drug based on the ratio of intake to toxicity, exhibit an MOE of less than ten, more dangerous than heroin. Cigarettes fell into the risk category with an MOE of less than 100. All other drugs including opiates, cocaine, ecstasy and amphetamines exhibited MOE of greater than 100, safer than alcohol and cigarettes. Cannabis exhibits an MOE of over 10,000, classifying it as exceptionally low risk in comparison to other commonly consumed drugs (Dirk W Lachenmeier and Rehm, 2015).

Interestingly, drugs that we consider to be everyday staples such as paracetamol and caffeine are easy to overdose and mix with other medicines which is responsible for a large number of hospital admissions each year. Paracetamol, also known as acetaminophen, can be consumed every 4-6 hours in doses up to 60mg per kilo of body weight (mg/kg) reaching toxicity at 140mg/kg or 10g/day (Ye et al., 2018). It is the second most common cause of liver transplantation worldwide and responsible for 56,00 emergency department visits and 500 deaths per year in the US (Caparrotta, Antoine and Dear, 2018; Kennon-McGill and McGill, 2018). The average caffeine consumption is 140-180mg per day(~2mg/kg) with a lethal dose of approximately 367 mg/kg in rats and oral doses over 2000mg require hospitalization on (Fulgoni, Keast and Lieberman, 2015; Adamson, 2016; Willson, 2018). Mixing paracetamol and caffeine with other prescription medicines can be similarly dangerous as doing so with cannabis and so public education on these factors is critical (McCarthy, Mycyk and DesLauriers, 2008). As you can see these commonly available drugs do have toxic thresholds, but we are rarely educated on the dangers of alcohol, coffee, or paracetamol.

Early cannabis toxicity research explored the impacts of extremely high, one-time oral doses of cannabinoids in rats, dogs and monkeys. Rats showed a slightly weaker tolerance to doses of highly concentrated THC, which exhibited lethality at doses of 225-3600mg/kg, typically dying from hypothermia 36-72 hours post-administration (Thompson et al., 1973). Monkeys and dogs demonstrated even higher tolerability with single doses of THC at concentrations as high as 3000 to 9000mg per kilogram of body weight proving non-lethal (Thompson et al., 1973). This would be comparable to a human who weighs 80kg having to orally consume 250,000mg to 720,000mg of concentrated THC in one oral dose. A dose that would equate to between 250 and 750g of pure THC. Studies have highlighted anywhere between 14.6 and 66.3mg of THC being found in each gram of cannabis (Sheehan et al., 2019). To reach this lethal dose threshold through cannabis smoking 3770g of cannabis at once, that’s using a high THC estimate of 66.3mg/g of cannabis and 250,000mg as a lethal dose. Although it is rare for doses as high as these to be experienced, these are key signs of a THC overdose and the potential side effects which this may cause.

• Drowsiness
• Tremors
• Mild hypothermia
• Salivation
• Hyperreactivity to stimuli
• Anaesthesia
• Characteristic huddled posture
• Slow movements
• Abnormal eating procedures
• Sedation

The effects of cannabinoids are typically more potent in females (Thompson et al., 1973). As you can see phytocannabinoids were proven to be extremely safe compared to other drugs and it would be difficult to overdose on THC.

10.2 Drug interactions

There are several potential drug interactions that prospective cannabis product users should be aware of. Orally consumed cannabinoids the same route of absorption as medicines, food, and drink. Most orally consumed drugs travel through the stomach and gut where they are absorbed alongside fats and oils inside the intestines. From the intestines, the body extracts the key nutrients from the contents of the gut and transports them through the bloodstream to the liver for processing. Enzymes within the liver are responsible for the processing and metabolism of drugs in the bloodstream and those on prescribed medication should make several considerations before using cannabinoid-based products. These considerations should be made by those utilizing prescription medication many of these drugs relay on the same enzymes for their metabolism. One group in particular, the cytochrome enzyme is responsible for metabolizing 75% of all drugs used in medicine (Guengerich, 2008). These medications should be monitored as CBD and THC have the potential to increase or decrease the levels of these prescription medications when combined (Watanabe et al., 2007). The interactions abundant and so we shall overview cannabinoids and the best understood metabolic interactions that will be relevant to those interested in cannabis.

Cannabinoids have a strong metabolic relationship with two other major cytochrome groups CYP3A4 and CYP2C9 enzymes among several others (Yamaori et al., 2011; Stout and Cimino, 2014; Bouquié et al., 2018) These two enzymes metabolise a large number of drugs such as anti- depressants, anti-histamines and anti-cancer drugs. CBD is an inhibitor of the CYP2C19 subfamily, concomitant administration of CBD significantly changed serum levels of topiramate, rufinamide, clobazam, eslicarbazepine, and zonisamide in patients with treatment-resistant epilepsy (Gaston et al., 2017).

CYP3A4 enzymes - The cytochrome enzymes are responsible for roughly 60% of prescribed drug metabolism with CYP3A4 responsible for around half of that (Zanger and Schwab, 2013). CBD’s ability to inhibit the activity of this enzyme may increase serum concentrations of macrolides, calcium channel blockers, benzodiazepines, cyclosporine, sildenafil, antihistamines, haloperidol, antiretrovirals, and some statins (Arellano et al., 2017). Interestingly, other substances such as grapefruit juice can also interfere with CYP3A4’s activity (Bailey et al., 1998).

CYP2D6 enzymes - Metabolizes many antidepressants, but is inhibited by CBD, THC and CBN may, therefore, increase serum concentrations of SSRIs, tricyclic antidepressants, antipsychotics, beta-blockers and opioids (including codeine and oxycodone) (Yamaori et al., 2011). Opioids such as codeine are also metabolized by CYP2D6 which has seen it become a target for the treatment of codeine dependence (Romach et al., 2000). This relationship with the cytochrome group may explain how the consumption of opioids can also be impacted by cannabis. In a study exploring the effects of cannabis in 176 patients with treatment-resistant chronic pain, patients reported improvements in pain and a 44% reduction in opioid requirement on average (Haroutounian et al., 2016).

The most common drugs in society today have the potential to interact with cannabinoids through their shared cytochrome activity. Nicotine utilizes this same cytochrome P450 group of enzymes which is potentially altered in long term users and already a target site for smoking cessation drugs (Anderson and Chan, 2016). Alcohol is another drug that relies heavily on P450 enzymes. Long-lasting alcohol consumption causes chronic activation of the immune system, which can cause long term alterations in the P450 enzymes (Djordjević, Nikolić and Stefanović, 1998). In instances such as this, chronic immune system activation results in chronic inflammation within organs, which is a key contributor to cancer. Preliminary research demonstrates the clinical promise of CBD in treating alcohol use disorder (AUD), which can directly reduce alcohol intake (De Ternay et al., 2019; Turna et al., 2019). Clarity on these metabolic processes will provide opportunities for new therapies that leverage these enzymatic pathways.

Cannabinoids on their own are very safe but in combination with the wrong medications and substances can alter absorption of already-prescribed medication provoking more serious complications. These complex pharmacological interactions are best navigated with your doctor so that your medication can be adjusted accordingly where necessary. This information is provided as a harm reduction measure to ensure that readers of this book are aware of the potential harms that cannabis can pose to populations with already compromised health. Although we are unclear on the full extent to which cannabinoids interact with the endocannabinoids system, cannabinoids on their own are very safe and non-toxic. In combination with the wrong medications or substances cannabinoids can have very different interactions potentially exacerbating existing conditions that rely on specific dosing strategies. These are complex pharmacological interactions that are best navigated with your doctor so that the medication can be adjusted where necessary. Another piece of information to add to the jigsaw is the emerging relationship between CYP enzymes and endocannabinoids (Chen et al., 2008; Zelasko, Arnold and Das, 2015). These enzymes even manipulate your hormones (Wang, Napoli and Strobel, 2000).

We have provided this information as a harm reduction measure to ensure that our readers are aware of the potential harm cannabis can pose to these already at-risk populations. In the future we may be able to use cannabinoids synergistically with existing medication to increase their effectiveness and reduce their side effects. For now, this is very much a guessing game. This area of research needs tremendous exploration. There are many years to go before we can informedly apply this knowledge to patients through the NHS.

11.0 International Perspectives and Storage

Across the globe, we are slowly beginning to integrate cannabis into our society. This has been reflected in the relaxations of our laws and our greater medical acceptance of cannabinoids. Nations are gradually adopting a less prohibitionist view of drugs in favor of harm reduction and decriminalization. The gradual adoption of evidence-based approaches is encouraging progressive policymakers to remove the criminality of drug use instead of viewing drug use as a public health issue. Portugal is an example where drug illicit drug use has been decriminalized. This allows drug users to engage with public health to then work with drug users in a clinical setting. The aim of this to break the cycle of drug abuse to address the underlying mental and social issues that typically underly problematic drug use.

Adverse childhood events (ACE’s) are experiences that cover the breadth of childhood exposure to emotional, physical, or sexual abuse and household dysfunction. People exposed to four or more ACE’s are predisposed to between 4- and 12-times greater risk of alcoholism, drug abuse, depression, and suicide. These vulnerable individuals are 2 to 4 times more likely to smoke or have poor self-rated health and suffer later in life from adult health conditions such as lung disease and ischaemic heart attack (Hughes et al., 2017; Felitti et al., 2019). The ongoing poor health in later life often seen as a result of the downstream effects of these ACE’s is often compounded by drug use. Meeting these individuals with punishment through criminalization of their behaviour only encourages a cycle of criminality. This further marginalizes these people, directing them to the fringes of society. Prosecution and incarceration therein lead to their later release, dropping these vulnerable people back into society with very little support or counsel only to recommit the same crimes. Problematic drug users often repeat this cycle many times through their lifetime. Breaking this cycle through interventions can reduce the secondary costs of drug abuse to the public whilst also reducing the burden on emergency services. Through these evidence-based approaches, we can sustain improvements in public health with small perspective changes around drug use and people who use drugs. Harm reduction can enable this vital communication and raise awareness for the existence of ACE’s further facilitating prevention, resilience building, and ACE informed service provision (Hughes et al., 2017).

Although we are seeing this global shift towards a harm reduction landscape, massive variability exists between international tolerance and policy towards cannabis. Safe though it is, cannabis still retains a great deal of stigma from the great “war on drugs” which has only furthered drug use and abuse and in practical terms, only strengthened a highly fruitful Black-market. The varying international perspectives on drug use, make traveling with cannabis products particularly risky, and something that we strongly recommend against. Although cannabis can be freely purchased in some countries, in other countries it may result in a death penalty. Drug laws are renowned for their inconsistency and so we advise removing the risks of prosecution altogether by avoiding international travel with any cannabis products. In the United States, these drug laws can vary from state to state making the legal landscape extremely difficult to navigate for cannabis users seeking to travel nationally and internationally.

11.1 Preservation and longevity

There are several chemical properties that cannabis phytochemicals exhibit that should be factored into your cannabinoid storage strategy. Before all else, it should be emphasized that these products should be kept out of the reach of children and pets who are inherently inquisitive. Beyond this, though Cannabinoids require a degree of protection from several elements that can lead to degradation of the phytocannabinoids within. The primary instigators of this degradation are UV light, heat and atmospheric oxygen (Lindholst, 2010). Each these factors encourage weaknesses and alterations in the bonds between the atoms in the phytocannabinoid compounds.

By avoiding sunlight and favouring storage in the dark, this degradation can be significantly reduced and the self-life prolonged by ~50% (Lindholst, 2010). Interestingly cannabinoids can be preserved for decades. Cannabis samples obtained from the Pitts-River Museum in Oxford, dating from around 1896-1905, still contained measurable levels of CBN and THC (Harvey, 1990).

For most over the counter cannabis products, you can typically expect longevity of up to 15 months if stored in refrigerated conditions compared to roughly a 3 months shelf life under standard room conditions (Peschel, 2016). Darkened and light protective bottles are containers are typically the best storage vessels for oils and extracts, glass is typically safest. The absence of consistent information in this space already makes finding standardized products across the cannabis market complicated for consumers. With this being such an under-developed field, there is little to no data on the consistency of storage techniques for cannabis products. Due to this disconnect, the cannabinoid content cannot be guaranteed at any other point than the time of testing. Up to date test certifications (known as Certificates of Analysis or COA’s) are therefore key if purchasing cannabis products. These certificates at least give you an idea of the contents at that initial point in their shelf life. These certificates are at times even fraudulently produced and so there is a clear minefield for first-time cannabis consumers to navigate. These variances in shelf life highlight the need for strict standardized preparation protocols to assure the consistency of products in the months following production (Pacifici et al., 2017). Due to these variables, the contents presented on the label, either as a percentage or as a quantity in milligrams, may then not reflect the contents of the bottle. It very much depends what the purity of the product entering the diluent and the degree to which this has been preserved. These products can be extremely variable and for this reason, travel risks with any cannabis products should not be taken.

Product Volume Milligram per millilitre (mg/mL) Percent concentration
10ml 500mg/ 10ml 5%
10ml 1000mg/10ml 10%
30ml 3000mg/30ml 10%
An evidence-based approach is needed to best address cannabis as a plant rather than creating ways to legislate only for CBD. Cannabis compounds are fluid, and as we have seen can transform and metabolize into other compounds once within the body. The government has tasked itself with an impossible job of segregating THC and CBD the perception that THC is psychoactive and causes psychosis and CBD is non-psychoactive and therefore does not cause psychosis. The Irony of the scheduling is that both THC and CBD psychoactive are near identical molecules that are both formed from CBGA (Zirpel, Kayser and Stehle, 2018). Cannabinoids and CBD have a complex array of metabolic pathways, CBD consumption and absorption is a complex process with a wide variety of overlapping and intertwining pathways and metabolites. There is little concrete evidence of any kind and so detailed legislation is not feasible. Holistic, big picture conversations are required. The debate must be broadened. For example, a study exploring the metabolism of orally consumed CBD identified that in an acidic environment, such as the stomach, CBD can be converted into two forms of THC, Delta 9 and Delta 8 (Merrick et al., 2016). Would the consumer then be breaking the law by unknowingly digesting these molecules into controlled substances? The law is a complex science in itself but a build-up of stories and precedent, the cannabis story and stagnation of reform has been largely built upon misinformation and fear. We now have an opportunity to gel our societal laws with our scientific laws to leverage endocannabinoid science and research to create a new evidence-based 21st century story.

11.2 Conclusions

By publishing this book, we aim is to broaden the discussion around cannabis show you the beautiful intricacy behind the plant and its relationship with humans and health. Placing the cannabis conversation in the wider scientific conversation helps provide context to debate. Progress thus far has been hindered by stigmatization of open cannabis discussion, primarily due to limited cannabis knowledge and abundant misinformation. Through this book, we wish to give you a glimpse into the full potential of cannabis as the science is suggesting and highlight the limitations of our knowledge and the potential future once this knowledge grows. There is a huge amount that we do and do not know about cannabis. Through this, we hope to break this deadlock by outlining the full impact of cannabis reform for humanity. We hope this has demonstrated the disparity between the cannabis framework as it stands and the reality of cannabis its compounds which are, in terms of toxicity, some of the safest drugs on the planet. Our relationship with cannabinoids extends to the point that our cells even rely on cannabinoids to maintain our health. We are many years from fully understanding the many complexities of cannabis and the endocannabinoid system, but for those with exceptional need, we know more than enough to enable access. In the meantime, is it in the publics’ best interest that the masses are still criminalized for its possession given these properties?

It will be some years before our knowledge is refined enough to truly understand the depth of these questions. It will be more years still before refined cannabis medicines will be researched and accessible to medical professionals who still need to be trained on how to use them. Given this delay, it seems naive to expect the public to just wait until this fully informed scenario develops. For those with life-threatening conditions, there is no waiting, and so we should look towards relaxing enforcement of cannabis laws until we can informedly produce new ones. Perhaps the answer is less legislation and more education. Throughout this whole process, the governments have been eager not to make a mistake, choosing instead to tread cautiously. Sometimes failing to act is the greatest mistake of all and one that ultimately leads to the most damage.

Until we address drugs as a public health matter instead of a criminal matter it will be impossible for us to legislate efficiently for cannabis. This focus on the misuse of cannabis a drug has detracted from the whole basis for this law change, stopping the unnecessary criminalization of cannabis-using patients. No individual can informedly advise patients how or when to use cannabis. So, should it not upon the individual or guardian to have this sovereign choice over their health and when to use such a safe botanical drug? Guidance is important but what should take priority is the independence of health and safe access to cannabis for those who wish to use it. Something that is widely accepted in most first world countries, so why not the UK?

The absence of cannabis clarity and coherence makes the industrial and societal landscapes risk to navigate. This has not only exposed consumers to countless risks but in turn deterred a great deal of serious business. Evidence-based business and policy will always emerge and ultimately prevail as it removes a much of the guesswork whilst grounding the conversation in the realms of possibility. This removes arbitrage and ideological oversight in favour of informed, evidence based debate. Adoption of these policies ultimately takes a mature, apolitical landscape that seeks understand the complexity and opportunity of the cannabis conversation. The war on drugs is gradually coming to a close, which presents an abundance of opportunities from which to build collaborative and sustainable methods to provide safe and consistent access. Perhaps the real enemy here is the 1971 Misuse of Drugs Act which is still saturated with antique perceptions and loose terminology that criminalizes drug users by outlawing a substance. The evidence points towards relaxing our criminal view of drugs in exchange for regulation. This would bring safety to the drug market limiting the influence of organized crime and thereby reducing the harms around drug use and promoting information and awareness.

By broadening this debate with referenced scientific studies, we hope we have highlighted to you the true scale of this debate and the key issues holding back wider accessibility and progress. Until our laws adjust, hemp farmers will continue to have to throw away their CBD rich hemp flowers to focus on the harvesting of the woody stalks. Cannabis users will continue to be discriminated against. And patients will continue to be caught the fray. Cannabinoids and cannabis are not words to be feared but words to be excited about. In the 21st century we have the infrastructure and expertise to develop global centers for cannabis excellence and endocannabinoid exploration. We hope that by dispelling many of the conventional misnomers and myths around cannabis through educational materials such as these, we will be able to move towards scientifically driven society. This is our opportunity to reshape the 21st century.

*The citations provided in this book each refer to a published scientific paper that has been reviewed and approved by academic professionals and verified for their accuracy.

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