Can-na-bis (C. sativa L.) and humanity share a unique relationship that spans thousands of years.

We have internal biological systems that reflect this ancient relationship with can-na-bis.

These unique fingerprints are expressed in all human cells and point towards a new generation of health care.

With modern technology we can explore these fingerprints and their unique link to human health and disease.

Public opinion about C. sativa L. has varied tremendously over the past century. In recent decades, can-na-bis has been highly criminalised, nominally due to the focus on its potential to be abused as a psychotropic substance.

C. sativa L. in the hands of humanity possesses a universe of opportunity.

Can-na-bis and hemp are one in the same and have played an exceptional role in the development of humanity. Up until now, C. sativa L. has remained relatively 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 great passion, early C. sativa L. advocates lacked the 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 criminalisation of the plant.

In the past decade, medical support for C. sativa L. has been revitalised by an accelerating tide of data that is uncovering the fundamental science behind these age-old medical claims.

This modern research has identified an exciting biological link between humans and C. sativa L., forming the basis for a new branch of medicine.

The Endocannabinoid System (ECS) found in humans is a medical marvel, discovered through the scientific study of C. sativa L.

It is responsible for exerting the effects of C. sativa L. and its discovery marks the beginning of an entirely unexplored branch of medicine.

The use of C. sativa L. 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.

Contents

1.0 History of C. sativa L. 
1.1 Historical Uses 
1.2 Prohibition 
2.0 The C. sativa L. Plant 
2.1 Busting the Sativa vs Indica Myth 
2.2 Structure and Growth 
2.3 Seeds 
2.4 Stalks and Stems 
2.5 Flowers, Leaves and Trichomes 
3.0 Constituents of C. sativa L.
3.1 Terpenes 
3.2 Flavonoids 
3.2.1 Cannflavin A, B, and C 
3.3 Phytocannabinoids 
4.0 Cannabinoids 
4.1 Phytocannabinoids 
4.2 Endocannabinoids 
4.3 Synthetic Cannabinoids 
5.0 The Endocannabinoid System (ECS) 
5.1 Basic Biology 
5.2 Components of the ECS 
5.2.1 Endocannabinoids 
5.2.2 Enzymes 
5.2.3 Receptors 
5.3 Therapeutic Potential 
6.0 The Entourage Effect 
7.0 Absorption and Safety 
7.1 Fast Pharmacology 
7.2 Cannabinoid Pharmacology
8.0 Extracts and Oils 
8.1 C. sativa L. Products and Terminology 
9.0 Cannabinoid Safety and Tolerability 
9.1 Safety 
9.2 Drug Interactions 
10.0 International Perspectives and Storage 
10.1 Preservation and Longevity 
10.2 Conclusions 

1.0 History of C. sativa L.

To put the C. sativa L. 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 C. sativa L. have become criminalised 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).

C. sativa L. is a complex plant that contains an array of chemical compounds and properties.

These have been used creatively throughout human history, presenting rich opportunities to those exploring the vast potential 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 behaviour.

Ingestion and consumption of chemicals of this kind have been central to humanity for millennia.

Psychoactive substances are broken down into four major categories:

• Stimulants
• Depressants
• Opioids
• Hallucinogens.

We already have access to a range of psychoactive substances in the UK:

• Nicotine
• Caffeine
• 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 nicotine and caffeine have the potential to provoke numerous unwanted side effects and have addictive potential that can nurture 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 C. sativa L., psilocybin mushrooms, the peyote cactus and mescaline alter consciousness and perception within humans, primarily by mimicking human neurotransmitters and signalling molecules of the brain.

Contrary to their legal classification as class-A drugs, hallucinogens have a very low potential for addiction, psychological or physical dependence and are extremely safe when administered under clinical conditions. With the appropriate controls, adverse reactions are rare  (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 scrutinised and stigmatised 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.)

1.1 Historical Uses

Humans have a historic relationship with psychoactive herbal preparations.

These have been utilised medicinally for millennia, with ancient civilisation across the globe documenting cultural and spiritual ties to mind-altering plants.

Among these psychoactive shrubs is C. sativa L., one of the first crops to have been cultivated across East Asia.

Although its use has not been as apparent or pronounced in western culture, the C. sativa L. plant has long since been a part of society and has been utilised by humanity throughout the development of various civilisations, for everything from textiles to medicines.

Considering the failures of the war on drugs, perhaps our modern societies should look to the past and learn something from ‘the primitive’ so that we might find out how to both maximise potential benefits and minimise 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 C. sativa L. use by humans has been traced back to ancient China, where scientists have found hemp residues that were burned during mortuary ceremonies as far back as 500BC, some 2,500 years ago (Ren et al., 2019).

Archaeological findings from across the region have identified the remnants of C. sativa L. in various forms.

C. sativa L. is believed to have played a ritualistic role in ancient ceremonies when psychoactive compounds were consumed at high levels (Ren et al., 2019).

In a cemetery in North-West China, thirteen nearly whole hemp plants were found perfectly preserved in the form of a burial shroud, placed upon a male corpse. They were dated to be approximately 2,400-2,800 years old (Jiang et al., 2016).

Hemp, C. sativa’s more fibrous cousin, was famously a key crop in King Henry VIII’s British Navy (Mark A. R. Kleiman, 2011).

Although this ancient use of C. sativa L. may be somewhat disconnected from today’s modern society, not too long ago C. sativa was a common constituent found within many pharmaceutical preparations.

We need only look as far back as the 1960s and ‘70s, when cannabinoid research was rejuvenated mainly in response to the widespread recreational use of the drug (Pertwee, 2006).

In 1970, tincture of C. sativa L. was still a commercial product that was prepared from C. sativa grown in Pakistan and imported to the United Kingdom under license (Gill, Paton and Pertwee, 1970).

Catalogue image of the American Drug Syndicate’s C. sativa L. fluid extract, made with 60% alcohol. The syndicate was later purchased by the Drug Products Co. in 1958 (MEDICAL CANNABIS IN NEW YORK - The American Druggist Syndicate, no date).

1.2 Prohibition

Given the global use of C. sativa L. both culturally and industrially, how has it come to be that psychoactive plants, such as C. sativa L., have become so heavily criminalised 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 which retains these vested interests to this day.

Uncontrolled access, however, nurtured an opiate and drug abuse epidemic which escalated to the point that, on the 23rd of January 1912, the International Opium Convention was signed in The Hague (UNODC, 2009).

This legislation interrupted 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 C. sativa L. to be as potentially harmful as the opium poppy and coca bush, integrating it into the convention to restrict the supply of narcotic drugs (UNODC, 2008).

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 Drugs, listing all controlled substances and, in turn, creating the International Narcotics Control Board (INCB)(UNODC, 2008).

2.0 The C. sativa L. Plant

The global presence and influence of cannabis is historical.

Pollen fossil analysis has demonstrated extensive C. sativa L. cultivation by the Romans throughout Italy.

Primarily, the C. sativa plant’s success is explained by 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 C. sativa L. breeders were mainly interested in the fibrous stalks or the resinous flowers, cultivating two distinguished lineages referred to as “hemp” and “cannabis” but, both, botanically classified as C. 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 C. sativa L. remains classed as a single species (Small, 2015).

Marijuana is another term that you may have heard used to refer to C. sativa. It is a North American term for C. sativa, coined in the early 20th century to associate it with ethnic minorities.

Terms such as “marijuana” and “skunk” are not formally recognised in science; they are primarily utilised by media and law enforcement when referring to C. sativa L.

In regions of the world where a recreational C. sativa culture has developed, the narcotic subspecies has been classified in terms of its recreational effects. 

This recreational landscape has led to widespread hybridisation and cross-breeding, 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).

2.1 Busting the Sativa vs Indica Myth

The sativa vs indica terminology is something anyone entering the world of cannabis will encounter and, so, it is important to provide some clarity before any 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 the 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 C. sativa and C. indica.

The rate of diversification and the extensive crossbreeding between cannabis varieties 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 characterised by the International Code of Nomenclature for Cultivated Plants (ICNCP).

These terms have no taxonomic validity, making the sativa and indica distinctions almost meaningless (Pollio, 2016).

C. sativa is also sometimes referred to as C. sativa L. to denote Carl Linnaeus, the father of modern taxonomy, as the authority for the first use of the C. sativa species name.

To complicate the debate further, there exists a third classification, C. ruderalis.

First described by Russian botanist D. E. Janischewsky in 1924, it is generally accepted as a subspecies of C. sativa, but a feral breed of the plant that is much smaller than common C. sativa plant and with a visible difference in flowers and leaves (Hillig and Mahlberg, 2004). 

2.2 Structure and Growth

C. sativa 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 C. sativa 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 has been explored and successfully used to decontaminate heavy metal polluted soils (Linger et al., 2002; Kumar et al., 2017; Husain et al., 2019).

This exciting property means that it is even being considered as a solution to the nuclear waste surrounding Chernobyl and Fukushima.

The growth of C. sativa has nine distinct stages, each with their own substages of development. They include;

1. Germination and sprouting
2. Leaf development
3. Formation of lateral shoots
4. Stem elongation
5. Inflorescence emergence
6. Flowering
7. Development of fruit
8. Ripening of fruit
9. Asenescence 

(Mishchenko et al., 2017).

2.3 Seeds 

C. sativa is a robust and high-yielding crop that lends a great deal of its success to the physiology of its seeds.

The seeds have unique properties and themselves have a great deal of potential for scientific exploration.

The seed is ellipsoid, slightly compressed, smooth, 2-6mm in length and 2-4mm in diameter.

It is light-brown to dark grey, and, 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 fibre, vitamins and minerals (Callaway, 2004).

Hemp seed 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).

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, C. 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 hemp seed to beneficially influence heart disease (Rodriguez-Leyva and Pierce, 2010).

2.4 Stalks and Stems

Hemp is a highly fibrous plant known for the low density and high tensile strength of its fibres.

These fibres are contained within the woody stems and stalks of the C. sativa 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 fibres and a low-cellulose high-lignin core containing short fibres (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 fibres 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). 

2.5 Flowers, Leaves and Trichomes

In drug varieties of C. sativa, the flowers of the plant are highly resinous, containing a cocktail of therapeutic compounds.

The flowers of C. sativa L. are the primary constituent of what has been labelled ‘medical cannabis’, also referred to popularly in the UK media as ‘sk-unk’.

These resinous flowers have been the primary concern of authorities.

It is the molecules within this C. sativa 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, making mass production of C. sativa inflorescences extremely difficult to standardise in large quantities (Tipple et al., 2016).

Within the flowers, hundreds of specialised 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 the flowers and leaves.

The specifics of the plant’s trichome genes determine the medicinal, psychoactive and sensory properties of C. sativa products (Livingston et al., 2020).

The word trichome comes from the Greek word trikhōma, which means ‘growth of hair’.

Trichomes emerge as the C. sativa 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 phytochemical potency (Wagner, 1991).

Within this covering of trichomes, chemical compounds are synthesised and secreted, supporting 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.

Hemp trichome types. (A) Unicellular non-glandular trichome; (B) Cystolithic trichomes; (C) capitate sessile trichome; (D) capitate-stalked trichome; (E) simple bulbous trichome; (F) complex bulbous trichome (Andre, Hausman and Guerriero, 2016).

These secretions are produced most abundantly by the capitate stalked family of terpene (Image D), which produce the three key chemical constituents of C. sativa, 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 standardisation of C. sativa particularly difficult.

3.0 Constituents of Can-na-bis

Like all plants, C. sativa L. contains a spectrum of elements that contribute to the plant’s 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 C. sativa have made it particularly difficult to legislate for. Fortunately, this has not stifled research.

Recent advances in technology have made C. sativa L. analysis easier than ever, enabling this recent surge in C. sativa research and development.

Overall, at least 545 unique compounds have been isolated from the C. 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 varieties; terpenes, flavonoids and cannabinoids.

There are, however, a plethora of other compound classes including: 50 identified hydrocarbons, 34 sugars, 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.

3.1 Terpenes 

Terpenes are one of the three key classes of therapeutic compounds found within C. sativa.

They are a diverse class of aromatic compounds found universally across the plant kingdom and also key communication molecules for insects (Breitmaier, 2006).

Terpenes are some of the key ingredients found in essential oils as well as other products utilised in perfumery and aromatherapy (Omar et al., 2016).

Generally regarded as safe (GRAS) by the Food and Drug Administration (FDA), 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 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 varieties of C. sativa have been given different recreational names.

These aromatic molecules exert their own effects within the body and have been suggested to work synergistically with phytocannabinoids, amplifying the therapeutic effectiveness of C. sativa.

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

The five most prevalent terpenes found in C. sativa and effects according to aromatherapy.

Over 150 terpenes have been documented in cannabis varieties, each of which is uniquely produced or exaggerated by certain strains contributing to the users’ preferences in fragrance (Booth and Bohlmann, 2019).

These unique terpene ratios may be used as chemical markers for the chemical categorisation of C. sativa strains (Elzinga S et al., 2015; Aizpurua-Olaizola et al., 2016).

Further research is anticipated to optimise the breeding of strain-specific synergistic ratios of cannabinoids, terpenes and other phytochemicals for more predictable user effects and characteristics, along with improved symptom and disease-targeted therapies (Baron, 2018). 

A corner of the industry is exploring the matching of C. sativa terpene profiles to diseases and symptoms.

Without more robust knowledge of the endocannabinoid system there will remain many limitations to these procedures.

3.2. Flavonoids

Another class of key therapeutic family found in C. sativa are flavonoids.

The flavonoid pigments are responsible for most flower colours present in nature and responsible for giving the C. sativa L. plant its trademark deep green colouring.

They are found within the flowers, leaves, twigs and pollen of the 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 C. sativa offer great medical benefits to humans.

This branch of C. sativa molecules is among some of the least researched molecules within the chemical soup of C. sativa L., with little known as to the full potential they possess.

3.2.1. Cannflavin A, B, and C

Flavonoids have a similar range in variety as cannabinoids.

In total, nearly 20 different flavonoids have been identified in C. sativa (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, we will briefly touch on the key flavonoids, cannflavins (Panche, Diwan and Chandra, 2016).

The primary flavonoids found uniquely in C. sativa are cannflavin A and B.

They are unique to C. sativa and as yet have not been found anywhere else in nature (Fornaro et al., 2016).

Cannflavin C has only been a recent discovery, in 2008 (Radwan et al., 2008). Very little is known about these molecules.

Cannflavins A and B are 30 times more prevalent than aspirin.

Hemp seeds are highly nutritious, with cannflavins A and B 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).

3.3 Phytocannabinoids

The most abundant class of phytochemicals in C. sativa are phytocannabinoids.

Like many drug classes, phytocannabinoids are derived from the 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 C. sativa.

While exploring what it was within C. sativa L. that produced its psychoactive effects, an entirely new class of drugs was discovered.

Phytocannabinoids. The initial discovery of these C. sativa-derived cannabinoids and the reason for the ‘phyto’ prefix is that their discovery has led to the identification of several families of cannabinoids.

All of these are referred to as cannabinoids but distinguished by the prefixes: phyto, endo and synthetic. These cannabinoids are also discussed in chapter 4.

4.0 Cannabinoids

‘Cannabinoid’ is a very broad term, referring not only to a class of molecules derived from C. 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 synthesised the primary psychoactive component C. sativa L., the infamous tetrahydrocannabinol (THC) (Gaoni and Mechoulam, 1964).

Until the synthesis of THC, little was known about what it was within C. sativa 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 have 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 C. sativa-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 body's.

Humans and almost all life utilise 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 C. sativa L. 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 are either produced in nature or synthesised 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 utilising for various effects throughout our existence.

Scientists observing these phenomena can synthesise 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.

4.1 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 C. sativa.

Phytocannabinoids are to C. sativa L. 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 C. sativa 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 C. sativa 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 C. sativa L. 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 can-na-bis are explored in chapter 5.

The variety in the phytocannabinoids present within C. sativa (Morales, Hurst and Reggio, 2017).

How are they created?

The production of phytocannabinoids is governed by the chemical soup produced within C. sativa, which constantly evolves throughout the plant’s life cycle.

These phytocannabinoids are produced in varying quantities in the trichomes of the plant (Mahlberg and Eun, 2004).

The unique chemical ingredients in C. sativa L. provide the necessary elements for a chemical cocktail of ingredients that, when combined, create molecules. These precursor molecules combine like ingredients within the plant.

The binding and conversion of molecules are facilitated by small chemical factories known as enzymes.

Enzymes are the universal synthesisers of chemical reactions made up of large numbers of amino acids and proteins.

The enzymes that produce these molecules in C. sativa are known as synthase enzymes.

These enzymes synthesise 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 faced by those retail groups that may be required to shelf and store can-na-bis products for extended durations.

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, C₂₁H₃₀O_2.

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 substance, as well as nicotine and caffeine.

THC and CBD have a similar molecular life cycle and both drugs share 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 C. sativa 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, a process where molecules lose a carbon dioxide (CO₂) molecule from their structure.

In C. sativa L., 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).

Activating the contents like this is one key reason why C. sativa has historically been smoked.

These cannabinoid acids have similarly exciting anti-inflammatory and neuroprotective properties and share many of the same therapeutic properties as 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.

The chemical difference between THC and CBD.

Interestingly, this degradation can be measured to indicate the age of a C. sativa sample (Ross and ElSohly, 1999).

The potential for degradation further complicates the regulatory process, as it is difficult to guarantee the content of these products following the initial testing and packaging.

The contents of any CBD product may be very different from the actual content at the time of purchase and use. This is another challenge facing the cannabis industry. 

4.2  Endocannabinoids

Similar to C. sativa L., we humans produce our own cannabinoids, i.e. endocannabinoids.

These are utilised by the body as communication compounds, which are exchanged between cells in a constant chemical dance that maintains your body and health.

These molecules are produced naturally by our cells.

This phenomenon was first identified while exploring the effects of C. sativa.

The pioneers of C. sativa L. research speculated that for THC to exert its effect, it has 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 rise to 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. 

The chemical structures of endocannabinoids found within humans (Battista et al., 2012).

A series of studies that analysed porcine (pig) brains through mass spectroscopy in 2008 gave birth to the study of endogenous cannabinoids.

A certain molecule in the samples 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.

These endocannabinoids are key modulators of physiological processes such as pain.

An incredible example of this is the extraordinary and well televised case of a woman whose body produces higher than average levels of AEA due to a genetic mutation and a long history of undergoing surgical procedures without the need for anesthetics (Habib et al., 2019).

The full 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 role in maintaining human health.

So far, the most researched endocannabinoids are anandamide (arachidonoylethanolamide; AEA) and 2-arachidonoylglycerol (2-AG).

Yet the endocannabinoid family also includes 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 5.

4.3 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. 

An overview of isomers and the many structural variations molecules of the same chemical formula can take.

A big problem with C. sativa-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 C. sativa use and consumption of C. sativa 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 or isolated 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 ways of exploring and utilising these compounds.

Medicine vs legal highs

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 C. sativa 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” 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 cousin can be created and distributed.

This means that they have become a stealthy and potent alternative to C. sativa L.

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, pose a greater risk to the public than the naturally occurring C. sativa.

Evidence has found using synthetic cannabinoids to increase the relative risk of needing emergency medical treatment by 30 times that of regular C. sativa users.

These are not to be considered safer alternatives to herbal C. sativa 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). 

5. The Endocannabinoid System (ECS)

The endocannabinoid system (ECS) could be considered one of the greatest medical discoveries of the early 21st century.

The ECS is the entire basis for C. sativa and its use as a medicine.

This is the communication system through which the phytocannabinoids in C. sativa L. 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).

5.1 Basic Biology

The human body is composed of many trillions of cells that form a vast, constantly adapting network of communications. 

Each of us is a delicate biological machine 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 throughout the body.

Scientists refer to this signalling as ‘cellular communication’.



The basics of cellular communication

The ECS is responsible for providing chemical feedback for these 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 extremes 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.

Single-cell communication route and the true scale of communication in humans. 

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 for the cell to thrive.

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 through the 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 and hair growth.

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 email 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 of stimulatory signals begin to oversaturate the target with information.

Endocannabinoid system 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 have the means to communicate through 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.

These are new buttons that can be pushed and used to control disease and improve health. 

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 C. sativa 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.

It may even be that we move away from conventional drugs and pharmaceuticals to explore novel technologies that utilise the diverse communication abilities of cells. This could even be vibrational or bioelectrical.

5.2 Components of the ECS

The three components of the ECS: endocannabinoids, cannabinoid receptors and synthesizing and degrading enzymes.

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 C. sativa, 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’s experience of C. sativa L. 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 realising 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.

5.2.1 Endocannabinoids

One of the key elements that make up the endocannabinoid system are endocannabinoids.

These are the chemical messages or ligands 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 C. sativa 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).

5.2.2 Enzymes

Enzymes are microscopic proteins made up of uniquely coiled chains of amino acids and 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 in order to rapidly supply or deny cellular information to build endocannabinoids, such as anandamide, from precursors and then 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 synthesised on demand by a collection of enzymes;

• AEA is catalyzed 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, although 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).

Example of enzymatic activity and the catalytic process. These enzymatic processes can be mimicked synthetically at industrial scale, biomimetically.

5.2.3 Receptors

Cannabinoids were initially thought to work non-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.

Some beautiful nanotopographical images of immune cells that have had their receptors fluorescently stained. The receptors have been stained blue and can be seen scattered across the cell surface (Franke et al., 2019).

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 cell's surface, similar to the dimples on a golf ball.

This cell surface comprises numerous other receptor types and so this blueprint of receptors 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 receptors (GPR’s)
• 5-hydroxytryptamine receptors(5-HT) 
• 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 PPARs 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 behaviors and mood disorders (Garcia-Garcia, Newman-Tancredi, and Leonardo, 2014).

The TRPV family of receptors are heavily involved in the transmission of inflammation and pain of various sorts and, as such, is a target 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.

The ECS has afforded medicine a new lens through which we can view health and disease. 

This a a once-in-a-century discovery and something that humanity should take great notice of.

Examples of receptor variation across a selection of fluorescently stained immune cells, captured with nanotopography (Franke et al., 2019).

Since their identification, the receptors of the ECS 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 communications, 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.

Some of the key constituents of the endocannabinoid system that have been identified to date.

5.3 Therapeutic Potential

What we are discovering in cannabinoid medicine is that the ECS 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 synthesising and degrading enzymes, or changes in the prevalence and distribution of receptors.

We are realising that in disease states, this regulatory system suffers a loss of function and certain elements become exaggerated or degenerate.

In diseases such as cancer, healthy cells and cancerous cells show very different ECS patterns (Chen et al., 2015).

This altered fingerprint may present in several ways and may be caused by factors that we are slowly beginning to understand.

A strong example of this ECS alteration can be observed in 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 epileptic people’s hippocampus (Ludányi et al., 2008).

The significance of this is that THC, the most abundant compound in C. sativa, targets and activates the CB₁ receptor.

The basic principle is that the binding of THC to CB₁ initiates this anti-epileptic effect.

The effect though is highly dependent on the fingerprint of the individual’s ECS.

This points us in the direction of personalised cannabinoid medicine.

The CB₁ distribution across the neuronal tissues is highly variable and, as a result, underlying alterations 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 the types of neurons in the brain and so 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 C. sativa, medicines and policy.

It is the ECS that offers the greatest therapeutic potential but our knowledge of it is still in its infancy. As this knowledge matures, so will the treatment potential of the ECS (Pertwee, 2005).

Ignoring the ECS would be comparable to ignoring mechanics and engineers when making automotive policy or directing industry. The fundamentals cannot be ignored.

Although crude C. sativa consumption works very well for some people, it is by no means the future of medicine and is still very much the equivalent of consuming raw opium.

C. sativa L. lacks the specificity of conventional medicines but is arguably far safer than some treatments we administer legally.

C. sativa has tremendous potential across the board for general symptom management and relief.

In terms of what can be achieved medically, the ECS and its targeted manipulation hold truly revolutionary potential.

Synthetic cannabinoids modulate the endocannabinoid with more precision, creating 21^st 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 ability to reprogramme and re-coordinate this dysregulated cellular communication that is fundamental in most diseases.

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

6.0 The Entourage Effect

The diverse range of therapeutic constituents make C. sativa L. a therapeutic dream for researchers but a nightmare for regulators as it is challenging to place in our rigid institutional framework.

It is a plant of over a thousand molecules, each of which possess diverse therapeutic properties.

As such, its crude use has typically generated tremendous symptoms and disease relief.

We are living in the past in more ways than one with C. sativa but we are slowly seeing the readoption of traditional crude consumption.

Cannabinoid medicine could be many decades ahead and we should be benefiting from next generation endocannabinoid medicines had it not been for prohibition.

As such, we are now readopting the traditional methods of C. sativa consumption as our medical capacity and proclivity to utilise C. sativa L. catches up.

As discussed in chapter 3, the three major chemical groups of C. sativa (phytocannabinoids, terpenes and flavonoids) all possess therapeutic properties.

The combined consumption of these three groups through the crude use of can-na-bis has allowed early users to gain the highest degree of symptom relief possible.

When studying can-na-bis, 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 C. sativa extract, increasing the efficiency of C. sativa medicines and reducing unwanted side effects.

What we discovered was that isolated phytocannabinoids such as CBD do have therapeutic value.

Ultimately, for a vast number of patients seeking relief, crude C. sativa 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 vaporisation does seem to be the most effective.

For patients who need it most, this is all that matters.

For many, this is why they break the law, despite the availability of CBD products. 

Due to the potent medicinal properties of cannabinoids, terpenes, flavonoids and other phenolics found within the C. sativa L. plant, the whole C. sativa plant represents a more effective crude medicine than isolated or synthesised compounds.

Through researching can-na-bis and its applications as a crude medicine, we have had to map the therapeutic spectrum of the individual molecules to understand how exactly can-na-bis 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 C. sativa-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).

When applied in complex combinations however, it is almost impossible to determine which molecules are producing which effects.

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 C. sativa plant as they deem it to be more effective than the modified and isolated compounds of C. sativa L.

6.1. Phytocannabinoid, Terpene and Flavonoid Promiscuity

The entourage effect is a relatively loose term that refers to the synergistic interplay between the key therapeutic components found within raw C. sativa extracts versus refined isolated molecules (i.e. the use of a full-spectrum C. sativa product).

This powerful synergistic combination potently interacts with the ECS to exert therapeutic effects.

A maturing body of research is supporting this synergistic effect.

The challenge has been in understanding the intricate interactions that underlie this phenomenon.

Although the impact of the entourage effect may sometimes be exaggerated, the synergy we often encounter in patient testimonies has a genuine basis (Ethan B. Russo, 2011; Baron, 2018; Ribeiro, 2018; Russo, 2019).

The fingerprint-like individuality of the human ECS and the diversity of C. sativa L. mean that the use of crude C. sativa 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 C. sativa and thus the isolation of individual molecules has been preferred.

This complexity provokes an ethical dilemma.

Full-spectrum C. sativa L. extracts seem to be especially potent.

We cannot standardise them or say with any certainty what all of the effects are or how they occur. Because the fundamental principle of medicine is to prevent harm, it is hard to say from a medical perspective whether we are doing more harm than good.

As an example: in a breast cancer study in which a full spectrum C. sativa product was used but referred to as a botanical drug preparation (BDP), the raw C. sativa L. extract or BDP demonstrated higher potency than isolated THC for producing an antitumor response (Blasco-Benito et al., 2018).

The isolated effect of isolated phytocannabinoids such as THC versus the combined strength of many phytocannabinoids, terpenes and flavonoids.

The synergistic interplay between phytocannabinoids, flavonoids and terpenes can, in part, be explained by several emerging properties that they share.

Studies into the isolated effects of terpenes and flavonoids show that they have unique modulatory effects on the ECS, even demonstrating the ability to alter the effects of THC (Ethan B Russo, 2011). 

To explore this,  six major C. sativa 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 metabolise and redistribute throughout the body (Falk et al., 1990; Filipsson et al., 1993).

Menthol, another type of terpene, even shows activity at TRP receptors from the EDS (A. Farco and Grundmann, 2012; Janero and Makriyannis, 2014).

The dietary terpenes we consume daily through fruits and flowers almost certainly have unregistered effects on our ECS, 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 C. sativa phytochemicals with enzymes are not limited to those of the ECS (Thors, Belghiti, and Fowler, 2008).

One particularly powerful group of enzymes, known as cytochrome P450 (CYP450), play a key role in processing C. sativa L. compounds.

CYP450 enzymes are predominantly found in the liver and 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, prescription medication users are typically told to avoid grapefruit.

The reason for this is that the furanocoumarin (flavonoid) compounds in grapefruit can affect this CYP450 group and are known to inhibit and modify their activity, potentially provoking toxic effects (Fuhr, 1998).

Flavonoids that naturally occur within the grapefruit also interact with these enzymes (Li et al., 1994; Bacanli, Başaran and Başaran, 2018).

Terpenes are also involved in the mix and utilise this same metabolic pathway for chemical detoxification and conversion into more easily water-soluble molecules (Janocha, Schmitz, and Bernhardt, 2015).

This area of research highlights 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 C. sativa provides endless avenues for formulating safe and effective novel medicines.

The case for utilising this entourage effect is sufficiently strong as to suggest isolated molecules are unlikely to match the therapeutic combination of C. sativa phytochemicals or even the industrial potential of C. sativa itself as a phytochemical factory (Russo, 2019).

Mainstream pharmacy demands purified substances but this is not something that necessarily correlates to greater relief for patients.

Overall, it is difficult to justify the widespread use of refined C. sativa L. medicines in the short-term when most doctors have no prior training on their use or medical knowledge of their effects.

Overdosing from C. sativa consumption is very difficult to do and, if anything, the laws surrounding C. sativa are the most dangerous aspect of the whole situation.

Decriminalisation would support those in short-term need who are currently under threat from the law and support the continued growth of the UK industry.

Without truly understanding the ECS, prescribing C. sativa L. accurately, along with the industrialising or commercialising of the products, is extremely difficult.

For this reason, companies have been falling over themselves to develop basic THC and CBD sprays, tinctures and medicines that utilise various ratios of THC to CBD.

These are simple products that we can show are safe but still not medicines we truly understand.

Medicines of this kind 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 decriminalisation of C. sativa, along with the appropriate education, would be the fastest way to enable patient access.

At this point, many of the risks, costs and delays could be forgone.

The safety and practicality of using C. sativa in its many forms will be discussed in the following chapter.

7.0 Absorption and Safety

As we have shown, C. sativa is an extremely safe, non-toxic and valuable drug. Plants and herbs have been the foundations for medical preparations throughout human history. The common misconception that C. sativa causes mass schizophrenia is as mythical as the belief that cigarette smoke is positive for lung health.

Numerous drug plants are known to science. The tobacco plant, the opium poppy and the coca plant are just some of the many other plants that are utilised by medicine. C. sativa is another exciting option. As such, the drug groups abundant in C. sativa follow some of 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 C. sativa L. 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 they are in humans.  Pharmacology is the study of this field and it explores the uses, effects and modes of action of drugs. The illegality of C. sativa 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 serve different purposes. By giving you a brief induction in pharmacology, we aim to demonstrate the complexity of the C. sativa discussion and the factors to be considered when administering cannabinoids.

7.1 Fast Pharmacology

The effects of phytocannabinoids are well-documented.

The challenge 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 match the needs of the user.

Drugs can be inhaled, consumed orally (tablet/solution), applied dermally (skin), via suppositories (rectally), injected directly into the bloodstream (intravenously) or into muscle tissue (intramuscularly).

Depending on the chemical properties of the drug and the method of consumption, the absorption of drugs into the bloodstream can be highly variable.

A drug’s lifecycle as it passes through the body consists of four distinct processes:

• absorption
• distribution
• metabolism
• 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.

This is a process known as bioavailability.

The bioavailability of drugs is highly variable and based on the chemistry of the drug, the method of administration and the absorption capacity of 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 utilised 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 that this degradation occurs through the endocannabinoid system enzymes (such as MAGL), but 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, while 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 communications 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 C. sativa into our medical system.

Examples of the movement of drugs into and through the body and organs following consumption.

In addition to the overlap in signalling pathways, phytocannabinoids converge in the liver where they are metabolised 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, faeces 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.

7.2 Cannabinoid Pharmacology

The diverse properties and interactions that C. sativa L. compounds have on the body provide multiple hurdles in the form of gaps in our knowledge.

Phytocannabinoids are hydrophobic compounds (they do not dissolve in water) but, are instead, lipophilic, meaning that they can be dissolved in fats and oils (Sharma, Murthy and Bharath, 2012).

For this reason, many C. sativa products are diluted in a fat based carrier oil.

As a result, the bioavailability of phytocannabinoids is notoriously poor.

These fat-soluble properties mean C. sativa 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 C. sativa use (Musshoff and Madea, 2006; Sharma, Murthy and Bharath, 2012).

This low bioavailability has been crudely sidestepped by humans who have historically smoked C. sativa.

Smoking C. sativa L. has long since been the preferred form of crude consumption and, whether knowingly or not, inhalation is the fastest way to absorb most drugs of a low bioavailability (Ann Tronde, 2002).

Contrary to popular belief, phytocannabinoids, in particular THC, have a poor incorporation rate into skin and hair and so C. sativa 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 minuscule quantities, but contamination from C. sativa users can also cause this THC incorporation (Moosmann, Roth and Auwärter, 2015).

Transfer of phytocannabinoids into the hair of non-C. sativa users can occur from sweat, hand to hand, or through C. sativa smoke (Moosmann, Roth and Auwärter, 2015).

In addition to low bioavailability, accurately studying C. sativa L. in humans poses several additional challenges.

True standardisation of C. sativa 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%; when orally consumed THC is only 4-12% and absorption is highly variable based on the 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 C. sativa medical products, but this knowledge would not be publicly accessible for some time.

The key now is translating what knowledge we do have into human data. We can start to tailor the administrative methods to the ailment so that the symptom or tissue being targeted receives optimal dosing.

Tissue libraries could be used to catalogue the human endocannabinoid system to build human models for higher level research.

Our medical system relies heavily on the pharmaceutical industry for products and research; and it is worrying that much of this is industry-led and funded.

The human element of medicines is often left unexplored and only the efficacy and cost-effectiveness of medical products is researched.

Great volumes of animal (in vivo) research, especially in rats, have shown the transdermal application of cannabidiol to reduce inflammatory and arthritic pain. More clarity, however, 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.

The difficulty is that animal research, in many cases, just does not translate as these studies can often be poorly designed, conducted and analysed (Bracken, 2009).  

Much of C. sativa 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 or translate the findings that have been 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 therapeutic 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 C. sativa but the complex interactions of these molecules with the ECS and other elements of human physiology.

Our knowledge is very much in its infancy. Until we know how these molecules work, we are speculating as to their true impact and effect.

The entourage effect 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 are currently insufficient, held back primarily by the decades of C. sativa L. prohibition where it was deemed to have no medical value.

As we embark upon the 21^st century, our technological advancements will amplify our ability to explore this field and lead to incredible new breakthroughs for medicine and health.

8.0 Extracts and Oils

The UK C. sativa market relies on a synergy between sciences.

Engineering is a massive component that possesses remarkable potential for innovation and development.

The extraction of cannabinoids is a key process 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, engineers have developed a multitude of methods for removing the valuable drug compounds from the plant biomass.

Following on with our theme of diversity, C. sativa L. compounds demonstrate similar diversity in the methods that can be used to extract target molecules.

These can then be used as the basis for C. sativa 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 utilised successfully by C. sativa users for several decades to create highly concentrated C. sativa 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 leaving them within the end product.

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 heavy metals are often forgotten about or not tested.

Inappropriately prepared extracts have exhibited wide-ranging contaminations.

A Californian C. sativa L. study screened 57 can-na-bis 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 C. sativa 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 C. sativa L. cultivation and extraction.

In the absence of standardised procedures and approved methods of extraction in the UK, it is likely that a significant portion of products in the UK contain unwanted compounds and contaminants.

The world of extraction is home to the C. sativa industry’s finest chemical engineers.

Despite this, a large degree of amateur extraction takes place.

This problem has emerged because extraction equipment and solvents are relatively nondescript and accessible, leading to unsafe experimentation.

The illegal status of C. sativa access also encourages a great deal more amateur cultivation and processing as users want to avoid attention from and engagement with the black market.

Extracting phytocannabinoids using liquid solvents is one of the most commonly encountered methods for crudely extracting C. sativa L. compounds.

The process involves running the liquid solvent through the C. sativa L. plant matter where the phytochemicals are stripped away and dissolved into the solvent.

Ethanol, butane and hexane are some of the most common solvents that are utilised, 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 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 techniques that rely on the flammable solvents, has resulted in an unexpected rise in flash burns and hospital admissions associated with the production of C. sativa extracts (Bell et al., 2015).

CO₂ extraction is a method most associated with industrial extraction, which relies on similar use of solvents but instead using pressurised liquid CO₂ to remove the phytochemicals.

The condensed CO₂, commonly known as dry ice, is pumped through the plant matter where it similarly strips the phytochemicals like the stronger solvents.

The mixture of liquid CO₂ and C. sativa oil is separated in a separate chamber where the pressures and temperatures are altered until the CO₂ becomes a gas, depositing the C. sativa oils in the bottoms of the pressurised 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.

Comparable solvents such as butane and hexane residues are known to pool 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 undergoing trials to further refine these processes (Lewis-Bakker et al., 2019).

Despite some fantastic engineering, extraction can also be achieved simply by using oils and heat, a method that dates back hundreds of years.

We mentioned earlier that C. sativa 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 forms THC and CBD.

This procedure is not quite as efficient as the industrial procedures but crucially useful to early C. sativa users.

Given the potential health implications of low-quality extraction and the dangers it poses, it is important to understand the variability in methods for S. sativa L. product production.

This should illustrate why C. sativa products should be sourced responsibly and the need for regulated high-quality production.

Testing and quality assurance are needed to limit contaminations, increasing the standards of products and the consumers’ exposure to variability and contamination. As the UK industry has developed, industry bodies and international C. sativa L. companies have put forward their preferences on the outlook of the UK market.

What is crucial is that these discussions be scientifically led and reviewed rather than overseen by private companies.

8.1 C. sativa L. products and terminology

Ever the creatives, we humans have developed a diverse number of methods utilising the therapeutic components of C. sativa.

Depending on the production method and its quality, the products may contain single isolated compounds or entire C. sativa phytochemical spectrums.

Here, we will break down the major products and derivatives that you will likely come across when exploring C. sativa L.

What should these extracts contain and what is the difference between them?

Whole-Plant (crude) Extract

Botanical – Refined from the flowers, sugar leaves, fan leaves and stalk.

Contains: Controlled cannabinoids, non-controlled cannabinoids,
terpenoids, flavonoids, fats, waxes, chlorophyll and additional plant
compounds.

Flower-Only Extract

Botanical – Refined from the flowers and sugar leaves.

Contains: Controlled cannabinoids, non-controlled cannabinoids,
terpenoids, flavonoids.

Contains: Lower levels of fats, waxes, chlorophyll and additional plant
compounds compared to Whole-Plant extracts.

Full-Spectrum Extract

Botanical – Refined from a Whole-Plant or Flower-Only extract.

Contains: Controlled cannabinoids, non-controlled cannabinoids,
terpenoids, flavonoids.

Trace: Fats, waxes, chlorophyll and additional plant compounds

Broad-Spectrum Extract

Botanical – Refined from a Full Spectrum Extract.

Contains: Non-controlled cannabinoids, terpenoids, flavonoids.

Trace: Controlled cannabinoids, fats, waxes, chlorophyll and
additional plant compounds

Narrow-Spectrum Extract

Botanical – Refined from a Full Spectrum Extract.

Contains: Non-controlled cannabinoids

Trace: Controlled cannabinoids, terpenoids, flavonoids, fats, waxes,
chlorophyll and additional plant compounds

Single-Spectrum / Isolate

Botanical – Refined from a Full Spectrum Extract.

Contains: Single cannabinoid

No-Spectrum / Isolate Synthetic

Not from the plant.

Contains: Single cannabinoid

CBD Oil

A non-descript term used to refer to C. sativa products containing a high portion of CBD alongside other phytocannabinoids.

This term is often used interchangeably 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 C. sativa oil.

It is extremely cheap to produce and is visually very similar to other C. sativa oils and, therefore, a popular tool for snake-oil salesmen.

It may contain trace amounts of cannabinoids, terpenes or flavonoids, but is really a highly nutritious cooking oil that contains a large amount of Omega 3 and 6, similar to olive and rapeseed oil.

It does not contain any functional quantities of cannabinoids or CBD.

Conclusion

C. sativa extracts are some of the safest compounds in medicine.

Concerns predominantly surround the chronic crude use of highly concentrated unregulated extracts.

We hope to limit public exposure to contaminated and irresponsibly sourced C. sativa, as well as low quality or scam products.

C. sativa L. is extremely safe – the dangers arise from a lack of understanding and awareness from users, politicians and the wider public.

Education is a key tool in strengthening this debate and in arming consumers with the knowledge they need to safely navigate this burgeoning industry and its hurdles.

9. Cannabinoid Safety and Tolerability

In this chapter, we aim to provide you with as much practical information as possible regarding C. sativa product safety.

Science has a foundational knowledge of cannabinoids and a sufficient understanding of the impact and interactions CBD has with certain enzymes and signalling pathways within the body.

CBD intertwines with many established areas of medicine and, as such, there is some vital knowledge that would-be C. sativa users and people with existing health conditions and prescriptions should be aware of.

Fundamentally, C. sativa L. is a drug plant that contains drugs in the form of cannabinoids.

Therefore, the safety of C. sativa is best perceived in the context of other widely accessible drugs that are readily available.

Before we delve into this evidence, let us quickly review our knowledge of C.sativa 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 pharmacological pathways of these existing medications.

We shall outline briefly what some of the most common interactions are and highlight the key risks that C. sativa L. consumers should be considering before use.

By making the population aware of these interactions and potential risks, we can continue to make C. sativa product use even safer.

This is especially important for those who rely on prescription medications to support their chronic or acute health conditions.

The key is to reduce the likelihood of the product’s 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. 

9.1 Safety

The key focus here is that C. sativa is extremely safe to use for most people.

In the context of deaths, allergies and risks, C. sativa L. is many times safer than alcohol, our cultural favourite drug, which causes numerous overdoses each year.

Margin of exposure (MOE) is a scale used to classify the relative risk of drugs.

It is calculated by a ratio of two different factors:

• the benchmark dose, which is the amount needed to become harmful
• the amount consumed by the population

Although it may seem counteractive, the smaller the MOE number is, the higher risk it carries to society (Dirk W. Lachenmeier and Rehm, 2015).

A recent study categorised alcohol as a high-risk drug based on the ratio of intake to toxicity.

The findings revealed 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.

C. sativa L. 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).

Drugs that we consider to be everyday staples, such as paracetamol and caffeine, are easy to overdose or mix with other medicines, accounting 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 10grams per day (Ye et al., 2018).

It is the second most common cause of liver transplantation worldwide and responsible for 56,000 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 367mg/kg in rats and oral doses over 2,000mg requiring hospitalisation in humans  (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 C. sativa, yet public knowledge of this is low (McCarthy, Mycyk and DesLauriers, 2008).

Clearly, these commonly available drugs do have toxic thresholds, but we are rarely educated on the dangers of alcohol, coffee or paracetamol.

Early C. sativa 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 225-3,600mg/kg; the rats 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 3,000- 9,000mg/kg 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-720,000mg of concentrated THC in one oral dose; a dose that would equate to between 250-750g of pure THC.

Studies have highlighted anywhere between 14.6 and 66.3mg of THC being found in each gram of C. sativa L. (Sheehan et al., 2019).

Although the subjective effect of this hypothetical scenario would be quite overwhelming and highly unlikely, it would be no small feat to consume such extreme quantities.

To reach this lethal dose threshold through C. sativa smoking, 3,770g of C: sativa at once, that is using a high THC estimate of 66.3mg/g of C. sativa 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.

9.2 Drug Interactions

Beyond the immediate safety of THC, there are several potential interactions that these drugs could have that prospective users should be aware of.

Orally consumed cannabinoids take 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.

Many of these prescription drugs rely on the same enzymes for their metabolism.

One group in particular, the cytochrome enzyme, is responsible for metabolising 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 are abundant and so we shall overview cannabinoids and the best understood metabolic interactions relevant to those interested in C. sativa L.

Cannabinoids have a strong metabolic relationship with two other major cytochrome groups, the 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 antidepressants, antihistamines 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: This group of enzymes metabolise many antidepressants, but are inhibited by CBD, THC and CBN.

They 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 metabolised 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 C. sativa.

In a study exploring the effects of C. sativa L. 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).

Effects of inhibition of enzyme activity on drug concentration and availability.

10.0 International Perspectives and Storage

Across the globe, we are slowly beginning to integrate C. sativa 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 favour of harm reduction and decriminalisation.

The gradual adoption of evidence-based approaches is encouraging progressive policymakers to remove the criminality of drug use, instead viewing drug use as a public health issue.

Portugal is an example where drug use has been decriminalised, allowing drug users to engage with public health in a clinical setting with aim of breaking the cycle of drug abuse along with underlying mental and social issues.

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 ACEs are predisposed to 4-12 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).

Ongoing poor health in later life from the effects of ACEs is often compounded by drug use.

Meeting these individuals with punishment through criminalisation only encourages the cycle, further marginalising people.

Following prosecution and incarceration, people are dropped 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 it through interventions can reduce the secondary costs of drug abuse to public services.

Through 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 ACEs, further facilitating prevention, resilience building, and ACE-informed service provision (Hughes et al., 2017).

Although this global shift towards a harm reduction landscape is building momentum, massive variability exists between international and regional tolerance and policy towards C. sativa L.

Safe though it is, C. sativa still retains a great deal of stigma from the ‘war on drugs’, which has only served to further drug use and abuse and also strengthened the black market.

The varying international perspectives on drug use make travelling with C. sativa L. products particularly risky, something that we strongly do not recommend.

Although C. sativa 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 C. sativa L. products.

In the United States, these drug laws can vary from state to state, making the legal landscape extremely difficult to navigate for C. sativa users seeking to travel nationally and internationally.

10.1 Preservation and Longevity

C. sativa phytochemicals possess several chemical properties that should be factored into your cannabinoid product storage strategy to protect its longevity.

Above all else, it should be emphasised that these products should be kept out of the reach of children and pets.

C. sativa L. products are non-essential but carry a great number of therapeutic properties that can be tapped into.

Now beyond protecting these products from children, cannabinoids require a degree of protection from several elements that can lead to degradation of the chemical structures within.

C. sativa L. products are perishable and do degrade overtime.

The primary instigators of this degradation are UV light, heat and atmospheric oxygen (Lindholst, 2010).

Each of these factors encourage weaknesses and alterations in the bonds between the atoms in the phytocannabinoid compounds.

Degradation of phytocannabinoids by heat (Hazekamp et al., 2007).

By avoiding sunlight and favouring storage in the dark, the risk of degradation can be significantly reduced and the shelf-life prolonged by ~50% (Lindholst, 2010).

Interestingly, cannabinoids can be preserved for decades.

C. sativa 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 C. sativa products, a typical lifespan of up to 15 months can be expected if they are stored in refrigerated conditions, compared to roughly a three-month shelf-life under standard room conditions (Peschel, 2016; Mazzetti et al., 2020).

Darkened and light protective bottles are typically the best storage vessels for oils and extracts. Glass is typically the safest.

The absence of consistent consumer information already makes finding reliable products across the C. sativa market complicated for consumers.

In such an under-developed field, there is little to no education on good practices or consistency of storage techniques and so even well produced products could degrade if stored improperly.

As a result, it is harder to guarantee the product’s cannabinoid content at any other point in the product’s lifespan than at the time of testing.

Up to date test certifications (known as Certificates of Analysis or COAs) are therefore highly important and at least give the consumer 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 C. sativa consumers to navigate.

The variances in shelf-life highlight the need for strict standardised 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.

Professionalism very much underpins the purity of the product entering the diluent and the degree to which this has been preserved and passed onto the consumer.

With the barrier-to-entry being so low for over-the-counter products at this early stage, these products can be extremely variable and, for this reason, travel risks with any C. sativa L. products should not be taken.

Furthermore, there is tremendous variability in testing accuracy and methodology, which also blurs the line as to the contents of some of these products.

11.0 Conclusion

Our relationship with cannabinoids extends to the point that our cells even rely on endogenously produced cannabinoids to coordinate and manage our health and wellbeing.

We are many years from fully understanding the many complexities of C. sativa L. and the endocannabinoid system, but for those with exceptional need, we know more than enough to enable access by decriminalising drug use.

Is the continued criminalisation of C. sativa possession in the public’s best interests and does this criminalisation really protect our communities?

Given that a growing number of constabularies are choosing to deprioritise C. sativa L. and other drugs in favour of more constructive harm reduction measures, it would seem not.

It will be many more years before refined endocannabinoid medicines will be fully researched and even longer still before medical professionals who still need to be trained in how to use them.

Given this delay, it seems naïve to expect the public to just wait until this future scenario develops.

For those with life-threatening conditions, waiting is not an option and so we should look towards relaxing enforcement of C. sativa laws until we can informedly produce new ones fit for the 21st century.

Perhaps the answer is less legislation and more education?

Throughout this whole process, governments have been anxious 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.

Our policies and our systematic failure to take the appropriate action are encroaching on the borders of negligence, breach of duty and incompetence.

We must swiftly learn that we cannot legislate for everything and that science is not black and white.

Until we address drugs as a public health problem instead of a criminal matter, it will be impossible for the conversation to evolve beyond subjective good vs bad.

The savings in costs of both time and resources would be tremendous, but if we continue to use the same stale thinking, we will only produce the same stale results.

As the age old saying goes, if you put garbage in, you get garbage out.

How can the consensual use of a naturally occurring product of the planet be a criminal act?

Does this really warrant jailing and prosecution.

The limiting of debate to CBD as a medicine and THC as a dangerous drug has detracted from the whole basis for this law change, correcting the unnecessary criminalisation and persecution of C. sativa-using patients.

Perhaps we should be looking towards making less low level arrests and looking towards high priority organised crime.

We have a large volume of superficial data which fails to dig down into the depths of what we need to know to keep our legal system at the forefront of the modern world.

We must be open to exploration and improvement otherwise we brush over fundamental cracks in this system where we are brewing inefficiencies, inequalities and systematising problems.

At these early stages no one is truly informed or qualified enough to give precise medical advice to patients on how or when to use C. sativa.

Guidance is important, but what should take priority is the independence of health and access to C. sativa L. for those who wish to try it.

This is the 21st century.

This sentiment is widely accepted in most first world countries, so why not the UK?

The UK needs to think ahead and realise just how much is being overlooked.

We can explore the scientific realm of possibilities.

Science removes the arbitrage and ideological interruption in favour of informed, objective, open debate.

Exploring science allows us to take a glimpse at how the world could look by 2050 and beyond.

Adopting educational policies can lay the foundation for our future, but this requires an open political landscape that seeks to understand the depth and opportunity of C. sativa L.

At this stage, some may point out that these delays in progress hint towards the protection of vested interests that would be shaken by relaxing our C. sativa laws.

By broadening this debate with science and education, we can highlight the true scale of this debate, as well as some of the key issues impacting our communities.

Small perspective shifts can be powerful in positively impacting the lives of millions.

Cannabinoids and C. sativa are not words to be feared but words to be excited about.

In this day and age, we have the infrastructure and expertise to develop global centres for C. sativa L. excellence and endocannabinoid exploration to lead the world forward with cutting edge science and technology.

We hope that by dispelling many of the conventional misnomers and myths around C. sativa through educational materials such as this, we will be able to move towards a scientifically driven society.

This is our opportunity to lay the foundations of the 21st century. There is an exciting future ahead!