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Abstract

Cannabinoid-Based Medicine Knowledge & Attitudes

Confidential

Sébastien Béguerie , M.Sc. Ing. Plant Sciences.

Co-créateur de l'Union Francophone pour les Cannabinoides en Médecines

(UFCM)

http://www.ufcmed.org

Member of the International Association for Cannabis as Medicine (IACM)

http://www.cannabis-med.org

Associate Member of the Canadian Consortium for the Investigation of

Cannabinoids (CCIC)

http://www.ccic.net

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Table of Contents

General Introduction to the Research ..................................................................................................... 3

I. Literature study .................................................................................................................................... 5

1. Introduction ................................................................................................................................. 6

2. History of Cannabis ..................................................................................................................... 7

2.1 Historic Usage ....................................................................................................................... 7

2.2 Recent Usage ........................................................................................................................ 9

3. Cannabis Plants & Analysis ........................................................................................................ 11

3.1 Taxonomy ........................................................................................................................... 11

3.2 Phytocannabinoids ............................................................................................................. 13

3.3 Qualitative Analysis of Cannabis......................................................................................... 17

3.3.2. Types of Chromatography .............................................................................................. 20

4. Endocannabinoid system ........................................................................................................... 24

4.1 Introduction to the Endocannabinoid System .................................................................... 24

4.2 Cannabinoid Receptors ....................................................................................................... 26

4.3 Novel Cannabinoid Receptors ............................................................................................ 27

5. Potential of Cannabinoid-Based Medicine in Health and Disease ............................................ 29

5.1 Beneficial Effects of Cannabinoid-Based Medicine ............................................................ 30

5.2 Adverse Effects of Cannabinoid-Based Medicine ............................................................... 37

6. Legislation & the Dutch Government ........................................................................................ 41

6.1 Towards Legal Medicinal Cannabis ..................................................................................... 41

6.2 Legal Medicinal Cannabis : 2002-2011 ............................................................................... 41

6.3 International Law & Foreign Regulations ........................................................................... 46

6.4 Office of Medicinal Cannabis .............................................................................................. 48

7 ..................................................................................................................................................... 50

7.4 Legally available CBMs in the Netherlands ......................................................................... 50

7.5 Methods of Administration ................................................................................................ 51

7.6 Cost Coverage ..................................................................................................................... 51

8. Conclusion.................................................................................................................................. 55

Glossary ................................................................................................................................................. 57

References ............................................................................................................................................. 59

Appendices ............................................................................................................................................ 72

I. Tables Therapeutic Potential ................................................................................................. 72

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General Introduction to the Research

Cannabis sativa – better known as marijuana – has a long and controversial history. Used for

centuries for its high nutritional value and therapeutic properties, the plant was listed as an illicit

drug in the 1940’s after raised concern on its intoxicating effect and potential abuse (Kogan &

Mechoulam, 2007). Around the same time, more effective medicines were discovered and cannabis

was soon regarded as merely a scientific curiosity (Klein, 2005). However, since the early 90’s there

has been regained interest in its medicinal use, thanks to the discovery of the endocannabinoid

system (ECS). This system consists of endocannabinoids1, cannabinoid receptors, and related

enzymes that are present throughout the human body and interact with many other

neurotransmitter and neuromodulator systems (Klein & Newton, 2007; GWpharmaceuticals, 2010).

Recent studies have revealed that cannabis-derived compounds (so-called phytocannabinoids) and

their synthetic derivatives can act upon this system and exert various effects in the body. Currently,

evidence for the beneficial pharmacological effects of cannabis and its synthetic derivatives is

accumulating and there is ongoing debate on their clinical potential and their potential side effects

(Kogan & Mechoulam, 2007). Multiple sclerosis, cancer, AIDS, glaucoma, rheumatoid arthritis,

epilepsy and neurodegenerative disorders are just a few of the many disorders for which beneficial

effects of cannabinoids have been claimed (Dennert, 2009; Pizzorno, 2010).

Consequently, research into cannabinoids and the ECS has accelerated over the past years

and Cannabinoid-Based Medicines (CBM)2 are now available in several countries around the world. In

the Netherlands, several types of CBM are available on prescription of a physician, with medicinal

cannabis (dried flower tops grown under governmental supervision) being the most well-known

(NCSM website, 2011). These dried flower tops can be either smoked, inhaled using a mechanical

device or drunk as tea. Other CBMs are based on cannabinoid extracts from the cannabis plant

(herbal CBM) while others are based on synthetic analogues (synthetic CBM) (Dennert, 2009).

Currently, only 1,000-1,500 people, of an estimated 10,000-15,000 medicinal users in total in the

Netherlands, obtain medicinal cannabis legally via the pharmacy, at doctor’s prescription (Commissie

Evaluatie Medicinale Cannabis, 2005). Here, in approximately 70% of the cases, the initiative for

prescription comes from the patient (Pharmo, 2004). The other medicinal users are thought to obtain

their cannabis from the coffee shop. Since CBMs are not (yet) officially registered as medicines in the

Netherlands, prescription of medicinal cannabis and of herbal or synthetic CBMs occurs only

marginally (Pharmo, 2004). Together, these numbers indicate that CBM is not yet fully accepted as a

medicine.

The reasons behind this low acceptance are not completely understood. To gain insight into

these reasons, this project aimed to investigate the knowledge of and the attitudes towards CBM

1 Here, cannabinoids refers to all active substances of plant, animal, endogenous or synthetic origin

that work as agonist ligands at cannabinoid receptors of cells (Grotenhermen, 2003). Their carboxylic acids, analogs, and transformation products are the active ingredients found in hashish and marijuana (website Alpha Nova Pharma, 2011).

2 CBMs are considered to be: 1) dried flower tops (medicinal cannabis), 2) plant extracts (isolated

phytocannabinoids, or herbal CBM), and 3) synthetic analogues of these cannabinoids (synthetic CBM). In other words, all medicines that are direct or indirect based on cannabinoids (so as well natural as synthetic medicines).

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among Dutch health care professionals and patient organizations. Health care professionals, as well

as patient organizations, play an important role in the acceptance of CBM, as they are in the position

to prescribe and/or recommend the usage of this type of medicine. Their knowledge of and attitudes

towards CBM are at the basis of the acceptance of CBM as a medicine. Both knowledge and attitudes

were investigated, as knowledge might potentially influence a person’s attitude and, consequently,

his or her behaviour (e.g. prescription or recommendation) (Goodstadt, 1978).

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I. Literature study

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1. Introduction

As discussed in the general introduction of this report, firstly, a literature study was conducted to

obtain state-of-the-art knowledge of CBM, and the various aspects that relate to it. The obtained

knowledge was used for the development of the interview questions and as background knowledge

for the interviews. The latter to make sure that interviewers had an appropriate level of knowledge

of CBM when conducting interviews. The literature study contains various aspects related to CBM,

which are, in this study, subdivided into six topics:

a)The historical background on the usage of CBM

b)Taxonomy, phytocannabinoids, and qualitative analysis

c) The endocannabinoid system

d) Regulatory functions of endocannabinoid system in health and disease

e) Legislation on the use, production and sales of medicinal cannabis

f) Relation between CBM and patient population

Scientific databases, like PubMed, Scopus, Google Scholar and NCBI, were used to find relevant

literature. The following keywords were used, separately and in combination:

For a: cannabis history, marijuana history, ancient times, 19th century, 20th century, religion,

China, India, Europe, medicinal usage/use, scientific discovery/discoveries, Mechoulam,

endocannabinoid system, recreational usage.

For b: phytocannabinoids, resin glands, cannabis sativa, taxonomy, subspecies, strains, seeds,

morphology, cultivation, environment, Δ9-THC, cannabidiol, endocannabinoid system,

endocannabinoids, production, quantity, cannabis, secondary metabolites.

For c & d: cannabis, tetrahydrocannabinol, Δ9-THC , cannabinoid, endocannabinoid, CB1, CB2,

receptor, receptor system, function, therapeutic, therapeutic potential, medicinal cannabis, drug

effects, therapeutic use, smoking, pharmacology, Sativex, Cannador, dronabinol, multiple sclerosis,

palliative treatment, endocannabinoid system, THC, CBG, CBD, marijuana, marihuana, hashish, CBM,

rheumatoid arthritis, gilles de la tourette syndrome, chronic pain, chronic neuropathy, chronic

neuropathic pain, AIDS, acquired immune-deficiency syndrome, appetite stimulation, cancer,

epilepsy, spinal cord injuries, parkinson’s disease, glaucoma, nausea, antiemetic, analgesia,

Alzheimer.

For e & f: Bureau Medicinal Cannabis, BMC, cannabis, medicinal cannabis, marijuana, marihuana,

hashish, legislation, law, opium law, government, second chamber, the Netherlands, Holland, Dutch,

policy, Bedrocan, tolerance policy, France, Sweden, United States, New Zealand, international law,

drugs, narcotics, United Nations, application methods, tea, vaporizer, insurance, cannabinoid-based

medicine, patient, patient population.

In addition, snowballing via retrieved papers was used to discover other relevant papers as well as

other relevant terms. In this part of the report (part I), the results of the literature review are

presented and organized according to the subdivision that is stated above. At the end of this part,

conclusions are drawn based on the literature review.

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2. History of Cannabis

2.1 Historic Usage

Today, cannabis is best known for the recreational use of its most popular preparations; marijuana,

hashish and dagga (Di Marzo & De Petrocellis, 2006). However, cannabis was initially used for its

fiber and is actually one of the oldest herbs cultivated by man (Zuardi, 2006; Clarke & Watson, 2007).

The first archaeological evidence of cannabis use is found in China and dates back to Neolithic times,

around 4000 years B.C. The fibers that the Chinese obtained from the cannabis stems were used to

manufacture ropes, fish nets, paper, textiles and all kinds of other fabrics (Li, 1974). In Tibet,

cannabis paper was considered to be of such quality and durability, that monastic history was usually

written on it (Aldrich, 1977). Cannabis was also used as a food source during the Han dynasty. In fact,

its seeds were considered one of the “five grains”, together with rice, barley, millet, and soy beans

(Li, 1975). However, its importance as food source ceased with the introduction of new crops at the

beginning of this era (Keng, 1974). The same is true for its role as source of fiber, which diminished

after the introduction of cotton in the tenth-eleventh century (Li, 1974). Nevertheless, many

different varieties of cannabis can still be found in parts of China. The strains now cultivated in these

areas are among the tallest and have the lowest resin content (Li, 1974). Moreover, cannabis seeds

are still used as grain for cattle and even as an ingredient for kitchen oil in present-day Nepal (Fisher,

1975).

In addition to foods, fabrics and other applications of cannabis, the fruits, leaves and roots of

cannabis have also been used as medicine for millennia (Li, 1974). The therapeutic properties of

cannabis were first described in the famous Pên-ts’ao Ching, the world’s oldest accessible material

on Asian herbal medicine (Zuardi, 2006). Compiled during the late Han dynasty (c. 100 A.D.), this

pharmacopoeia is originally based on oral traditions that passed down from the legendary Chinese

emperor Shen-nung (c. 2700 B.C.) and perhaps from even more ancient times (Li, 1974). The book

classifies 365 species of roots, grass, woods, furs, animals and stones, and recommends the use of

cannabis as a therapeutic for rheumatism, intestinal constipation, disorders of the female

reproductive system and malaria, among others (Touw, 1981). Besides these applications, the

Chinese doctor Hua T’o (110- 207 A.D.) used a solution of cannabis, taken with wine, as an

Fig 1. a. Neolithic pottery bowl from Pan-p’o, Si-an, with imprints of cannabis cloth

(from Li, 1974) b. Shoes made of fine yellow cannabis cloth from a grave at Turfan,

Sinkiang, 721 A.D. (from Li, 1974) c. Illustration of cannabis with text describing its

functions from the Chêng-lei pên-ts’ao, 1234 A.D. (from Li, 1974)

a b c

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anaesthetic during surgery (Li, 1974). Although it was mainly the plant’s seeds that were used as

medicine – which are largely deficient in the main psychoactive ingredient, Δ9-tetrahydrocannabinol

(Δ9-THC) – the Pên-ts’ao Ching provides evidence that the Chinese were aware of the hallucinogenic

effects of cannabis: "ma-fen (fruits of hemp) . . . if taken in excess will produce hallucinations

(literally "seeing devils"). If taken over a long term, it makes one communicate with spirits and

lightens one's body" (Li, 1974, p. 446).

Apart from this, there are remarkably few written reports on the psychotropic effects of

cannabis in ancient Chinese texts. Most likely, cannabis was used during shamanistic rituals, which

were not meant to be shared by common people nor meant to be written down (Touw, 1981).

Indeed, a famous Toaist priest and physician of the fifth century A.D. wrote that the poisonous fruits

of cannabis were used by magicians “in combination with ginseng to set forward time in order to

reveal future events” (Li, 1974, p. 446). After the Han dynasty, shamanism gradually disappeared

from China and so did the knowledge of the medicinal use of cannabis (Li, 1974; Touw, 1981). In

contrast, shamanism remained an important cultural aspect within nomadic tribes and it was

probably via these people that cannabis spread to Central and Western Asia and India.

It was in India where the use of cannabis, both as a medicine and recreational drug, came

into full bloom. Cannabis is considered one of the “five sacred plants” in the Atharva Veda, a

collection of sacred Hindu texts, where it is described as a source of happiness, joy and freedom

(Touw, 1981). The plant was believed to be god-send and as such was used in numerous religious

rituals to overcome evil forces (Aldrich, 1977). Throughout the many different regions of India,

cannabis is also a favourite offer to give to passing sadhus (mystic monks or holy yoga masters) and

to the locally most worshipped God (Touw, 1981). Although the Indians used cannabis for religious

purposes for even a longer time, its medical application probably began around 1000 B.C. Initially

used as an analgesic, the list of its medical functions seems to be endless. For example, cannabis was

used – often in combination with other plants – as an anticonvulsant, tranquilizer, hypnotic, anti-

inflammatory, anesthetic, antibiotic, antiparasite, antispasmodic, appetite stimulant, digestive,

diuretic, antitussive, and expectorant (Zuardi, 2006). In fact, cannabis was regarded to be such an

important compound in Ayurveda (a system of traditional medicine and part of the Atharva Veda),

Fig 2. Age of the beginning of cannabis use as a medicine (from

Zuardi, 2006).

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that it has been referred to as “the penicillin of Ayurvedic medicine” (Touw, 1981, p. 6). For

recreational usage, cannabis was highly valued as an aphrodisiac. The Indians were well aware of the

psychotropic effects of cannabis and used its preparations in three different forms: Bhang (the

weakest type, consisting of dried leaves only), Ganja (a stronger type made of female flowering tops

alone), and Charas (the most potent preparation that consists of pure resin)(Touw, 1981). To

increase the hallucinogenic effects, these preparations were often used together with other

psychotropic products, such as opium, tobacco, wine, and some plants species within the genus of

Datura.

In contrast to India and China, there is only few written information on the use of cannabis in

the Himalayas and the Tibetan plateau (Touw, 1981). However, the plant was considered sacred in

Tibet and it was an important part of meditation in Tantric Buddhism (Aldrich, 1977). It is generally

thought that cannabis use was widespread in this region and Touw (1981) describes several

arguments that are in favour of this view. First of all, Indian medicine and Ayurveda in particular

greatly influenced Tibetan medicine (Kirilov, 1893). The Tibetans also borrowed their knowledge

from Chinese medicine, but this contribution was only secondary to Indian medicine. Second, botany

was an important aspect of the Tibetan pharmacopoeia (Meyer, 1977). Third, since cannabis was so

abundant in the region it is very likely that the plant was extensively used. Its sheer abundance might

also be the reason why cannabis has not been much discussed in the Tibeto-Himalayan region; the

plant might have been taken for granted. Furthermore, travellers frequently mentioned cannabis

plantations near settlements (Touw, 1981).

2.2 Recent Usage

After the description of its usage in ancient times, literature on cannabis ceased during several

hundreds of years. From the Christian Era to the nineteenth century, only few texts on the medicinal

properties of cannabis can be found, primarily in African and Arabian literature, which indicates a

spread in the use of cannabis. In Europe, however, the plant was exclusively used for the cultivation

of fibers (Zuardi, 2006). Only in the beginning of the nineteenth century, the first references to

cannabis and its intoxicating and medical properties appear in European literature (Mikuriya, 1969;

Zuardi, 2006). It has been hypothesized that the reintroduction of cannabis as a medicine was

initiated following a paper by dr. W.O. O’Shaughnessy in 1839 (Mikuriya, 1969). Dr. O’Shaughnessy

served in India for several years as a physician, where he got in touch with cannabis. Interestingly, he

did not only study the literature available on the plant, but also executed several clinical experiments

with success: he discovered that the plant could be used against rheumatoid arthritis, as well as to

treat convulsions (Mikuriya, 1969; Zuardi, 2006). In the later part of the nineteenth century over 100

articles were published on the therapeutic potential of cannabis. In addition, several pharmaceutical

companies marketed cannabis tinctures and extracts, and cannabis was allotted a place in the

Sajous’s Analytic Cyclopedia of Practical Medicine (1924). In this book, cannabis was described as

having three main properties: sedative or hypnotic, analgesic, and others, including appetite

enhancing properties (Zuardi, 2006).

After the initial surge, the usage of cannabis declined significantly in the first decades of the

twentieth century. Several hypothesis have been postulated to explain this decline, including a

difficulty to obtain scientific replicable effects, the introduction of other, more potent medication,

and the rise of the recreational use of cannabis (Mikuriya, 1969; Zuardi, 2006). Especially the latter

aspect has been thought to have contributed to the enactment of the Marihuana Tax Act Law in 1937

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in the United States, a restrictive law on the selling and usage of cannabis (Mikuriya, 1969). As a

result of the restrictive laws, the research in the area dwindled (Mikuriya, 1969). Interestingly,

though, recreational use surged in the second part of the twentieth century, especially among the

young generations (68% of the youth had indicated to have used cannabis at least once in 1980

versus 5% in 1967) (Zuardi, 2006). The discovery of the structure of Δ9-THC, however, by Gaoni &

Mechoulam in 1964 lead to a regained interest in the topic (Zuardi, 2006). This resulted in 1988 in

the discovery of the plasma membrane cannabinoid receptor system in the human body, (the

endocannabinoid system (ECS), see Chapter 4), followed by the discovery of the first

endocannabinoid; anandamide, in 1992 (Devane et al., 1988; Devane et al., 1992). Other landmark

discoveries of the last decades related to cannabis research were the cloning of two receptor-types

of the ECS, CB1 and CB2 in 1990 and 1992, and the identification of different types of

endocannabinoids (DiMarzo et al., 2004). Together, these discoveries have led to a renewed interest

in the medicinal properties of cannabis. As has been said: it seems like “A new cycle begins for the

use of cannabis” (Zuardi, 2006, p. 154).

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3. Cannabis Plants & Analysis

3.1 Taxonomy

Even though cannabis is among the most widely disseminated and oldest cultivated plant species in

human history, its taxonomy is still being debated (Clarke & Watson, 2007). Cannabis was formerly

placed with nettles in the family of Urticaceae or with mulberries in the family Moraceae. Today,

hops (Humulus) are considered to be the closest relatives of cannabis and both genera are the only

representatives within the family of Cannabaceae (UNODC, 2009). Some botanists argue for a

polytypic classification of cannabis, and distinguish three different species which are geographically

isolated: Cannabis sativa, Cannabis indica, and Cannabis ruderalis (Schultes et al., 1975). Most

scientists however, consider cannabis to be a monospecific species consisting of different strains that

ultimately belong to one species: Cannabis sativa L. These different strains, or subspecies, include: C.

sativa spp. sativa, C. sativa spp. indica, C. sativa spp. ruderalis, C. sativa spp. spontanea, and C. sativa

spp. kafiristanca (Hill, 1983). Due to the extraordinary phenotypic plasticity and variability of

cannabis plants, their chemical and morphological composition not only depends on heredity factors,

but also on environmental conditions and cultivation methods (e.g. light, water, nutrients and space)

(Schultes et al., 1975; Clarke & Watson, 2007; UNODC, 2009). As a result, plants belonging to

different subspecies are often difficult to distinguish from each other. Furthermore, these different

subspecies can all interbreed. For these reasons, the name Cannabis sativa is often applied to all

cannabis plants (UNODC, 2009).

Most cannabis plants are dioecious, that is, they are either male (staminate) or female

(pistillate) (Clarke & Watson, 2007). Monocious plants, those with both male and female flowers, are

only occasionally found. While some plants may reach as high as six metres, most of them vary

between one and three metres in height. In general, female plants are more robust, yet shorter than

male plants (UNODC, 2009). Furthermore, female plants have the highest levels of the psychoactive

ingredient Δ9-THC, and they also produce seeds that are used as food source. Male plants on the

other hand, are more suitable for the production of fiber and seed-oil for fuel (UNODC, 2009). For an

overview of the separate parts of a cannabis plant, see Figure 3.

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Fig 3. Drawing of Cannabis sativa L. by Müller (1887).

A Inflorescence of male (staminate) plant 7 Pistillate flower showing ovary (longitudinal section)

B Fruiting female (pistillate) plant 8 Seed (achene*) with bract

1 Staminate flower 9 Seed without bract

2 Stamen (anther and short filament) 10 Seed (side view)

3 Stamen 11 Seed (cross section)

4 Pollen grains 12 Seed (longitudinal section)

5 Pistillate flower with bract 13 Seed without pericarp (peeled)

6 Pistillate flower without bract

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3.2 Phytocannabinoids

Cannabis sativa is a plant family with an unique composition: about 400-500 compounds have been

detected exclusively in these plants. Among them are approximately 70-80 terpeno-phenol

compounds which have collectively been named phytocannabinoids (Izzo et al., 2009; Fisar, 2009)

(note: exact numbers differ between reports). These phytocannabinoids are secondary metabolites of

the plant which are recognized by the bodily ECS, inducing the various bodily responses associated

with cannabis use (see also Chapter 4 and 5) (Morimoto et al., 2007; Fisar, 2009). These

phytocannabinoids should be distinguished from endocannabinoids (which are present in animals)

and synthetic cannabinoids (which are fabricated) (Fisar, 2009).

Based on their chemical structure, Elsohly & Slade (2005) divided the different plant

cannabinoids into eleven categories (see Table 1). Several well-identified examples of these groups of

phytocannabinoids are provided in Figure 4, showing also their chemical structure and effects. The

main constituents of cannabis are, however, Δ9-THC and cannabidiol (CBD) (Fisar, 2009). Δ9-THC is

most well-known for its psychotropic properties, acting upon both the CB1 and CB2 receptor types of

the ECS. In both from the cannabinol (CBN) and cannabichromene (CBC) subgroups, compounds are

thought to possess Δ9-THC-like effects (Fisar, 2009). CBD, on the other hand, is non-psychotropic and

has a low affinity for both receptor types, yet displays considerable potency in antagonizing CB1 and

CB2 agonists (Fisar, 2009). CBN-like and cannabigerol-like (CBG) compounds are other non-

psychotropic cannabis constituents. Cannabis plants contain also cannabinoid carboxylic acids, which

can be transformed to active Δ9-THC following heating (Fisar, 2009). As mentioned, there is an

extraordinary variety among cannabis plants, both in their chemical and morphological composition,

which is dependent on strain, environmental conditions, as well as cultivation methods (Schultes et

al., 1975; Clarke & Watson, 2007; UNODC, 2009). This variety is reflected in variations in the amounts

and presence of phytocannabinoids between different plants. Generally speaking, either Δ9-THC or

CBD is the main constituent and their concentrations in plants is, on average, of 1-12% (Frank &

Rosenthal, 1992). The fact that different cannabis strains and plants differ in their composition is

indicated with the term “chemotype”: a specific plant or strain has a certain chemotype with typical

quantities of specific phytocannabinoids (Frank & Rosenthal, 1992).

The phytocannabinoids are primarily produced in glandular tissues in the cannabis leaves and

stored in sticky droplets, called resin glands. These glands can be found on the surface of all parts of

Cannabis sativa, except for roots and seeds (Frank & Rosenthal, 1992). Generally speaking, resin

glands can be divided into three types: bulbous (15-30μm), capitate (25-100µm), and capitate-

stalked (150-500μm). The capitate-stalked resin glands are the only ones that can be seen with the

naked eye, the rest can be sensed as a sticky layer on top of, for example, the leaves (Frank &

Rosenthal, 1992). The reasons for the unique synthesis and storage of the phytocannabinoids are

unknown, but it has been hypothesized that they participate in physiologically relevant events such

as pathogen defense (CBD, CBG, and their acids are potent antibiotics) and plant-eating (via their

psychotropic actions) (Frank & Rosenthal, 1992; Morimoto et al., 2007). To obtain usable cannabis,

the flowers and leaves of the cannabis plant are first dried and then grinded or pressed into a dense

mass with a binding agent, yielding yellow or brown hashish (Fisar, 2009).

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Subgroups Compounds known

(approx. ~)

Cannabigerol (CBG) 7

Cannabichromene (CBC) 5

Cannabidiol (CBD) 7

Delta-9-trans-tetrahydrocannabinol (Δ9-THC) 9

Delta-8-tetrahydrocannabinol (Δ8-THC) 2

Cannabicyclol (CBL) 3

Cannabielsoin (CBE) 5

Cannabinol (CBN) 7

Cannabinoidiol (CBND) 2

Cannabitriol (CBT) 9

Miscellaneous 14

Table 1. Subgroups of phytocannabinoids identified. The number of

compounds is an approximation, indicating the size of the respective

groups (data from Elsohly & Slade, 2005).

Fig. 4. Different phytocannabinoids, their dates of isolations, and mechanisms of action (adapted from: Di

Marzo et al., 2004).

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3.3 Qualitative Analysis of Cannabis

The enormous number of cannabinoids that are found in Cannabis species have potential

applications in fields as diverse as medicine, recreation, and industry. However, to subject those

components to further research, all active substances have to be first identified, subsequently

separated and optionally purified. There are several methods which are implicated in cannabis

components identification. Here, a characterisation of the most commonly used is presented.

3.3.1 General Principles of Chromatography

The methods used for the analysis of the cannabinoid composition of a cannabis sample are usually

based on chromatography; a method for the separation of compounds in a mixture. A

chromatographic system consists of two phases, the mobile and stationary phase, which are

immiscible. The mobile phase passes a steady phase, the stationary phase. At the start of the

analysis, a sample with multiple compounds is introduced. These compounds are regularly shifting

between the stationary and the mobile phase, and the frequency at which these compounds switch

phases is dependent on the physical and chemical features of the compounds. If compounds

distribute differentially amongst the two phases, they will become separated because they will move

at a different pace. For example, if a compound is often present in the stationary phase it will move

slower through the chromatographic system than a compound that is often in the mobile phase

(Braam, 1994). There are many different types of chromatographic systems. These types differ in the

physico-chemical criteria for separation and in the way the separation is executed. Below, this

separation is discussed further.

There should be a difference between molecules present in a mixture, to create disparity in

distribution between mobile and stationary phase, and thereby separation. According to the choice

of matrix for the stationary phase, molecules can be separated based on their characteristics, for

instance by size, charge or hydrophobicity. Five different matrixes are discussed below.

a) Adsorption to a solid material

Compounds within the sample adsorb to a solid stationary phase. Here, adsorption is the adhesion of

atoms, ions and molecules to a surface. This adsorption can be due to hydrophobic , electrostatic and

“van der Waals” interactions. The mobile phase can be either a gas or a liquid (Braam, 1994).

b) Ability to dissolve in a liquid

The compounds dissolve in an immobilized layer of organic solvent. The mobile phase can be either a

gas or a liquid (Braam, 1994).

c) Ion exchange

If the mixture contains ionogenic components, these can adsorb to charged groups within the

chromatographic system (Figure 5). The stationary phase is formed by the positive charges bound to

the walls. With this technique, separation of, for instance, negatively charged amino acids from

positively charged amino acids is possible (Davis, University of California, 2011 )

d) Size of the compounds

This technique is used to separate molecules that differ in size. The mobile phase that contains a mix

of molecules passes through pores of various sizes. The small molecules pass through more pores

and therefore move slower in the desired direction (Figure 6).

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e) Biological affinity

By coating the system with a molecule for which specific components of a sample have a high

affinity, these specific components stay in the system while the other compounds are washed out.

Thereby separation and purification of these specific components is achieved. The affinity is based on

reversible protein-ligand interactions (Figure 7a). Usually the ligand is covalently bound to a matrix in

a column. The molecules bound to the ligands in the column can be eluted, i.e. detached, in two

ways. One specific fashion entails the addition of free ligand to the mobile phase. As a result, the free

ligand and the column-bound ligand compete for binding sites and the purified molecules detach

from the column and bind to the free ligand (Figure 7). Consequently, the free ligands with the

purified molecules are washed out of the column. Another, more general fashion for detaching the

bound molecules entails an adjustment of the pH of the mobile phase. This weakens the interaction

between the molecules and the column bound ligand. Some examples of ligands that can be used for

affinity chromatography and molecules that can be separated and purified with this technique are

given in Figure 7b.

Fig 5. Ion exchange chromatography.

a. The mix of amino acids flows through the surface with

immobilized cations. b. Negatively charged amino acids bind to

immobilized cation surface. c. Separation of negatively charged

amino acids. (from UC Davis (University of California), 2011)

a b c

Fig. 6. Size-exclusion

chromatography, used for size-

based separation (from Brian,

2011).

19 | P a g e

Fig 7. a. The bio affinity chromatography when the selective elution with ligand in the mobile phase is used

to detach the separated and purified molecules from the column (from Department Chemistry and

Biochemistry , University Arizona, 2011). b. Examples of ligands that can be used for affinity

chromatography and molecules that can be separated and purified with this technique (from Biochemistry

Department, Wageningen University, 2011).

a b

20 | P a g e

3.3.2. Types of Chromatography

Chromatography can be performed in two ways: column chromatography and Thin Layer

Chromatography (TLC). These are listed below.

Column chromatography

In this case, the separation takes place in a column. When a component has moved across the

complete column it is perceived by a detector. Two types of columns exist, namely: capillary columns

and packed columns. Capillary columns contain a layer of a stationary phase material on the inner

wall of the column, while packed columns are completely filled with granules, which either function

themselves as stationary phase material, or are bound to the stationary phase material. Capillary

column chromatography is usually applied for gas chromatography (Figure 8a) and packed column

chromatography is applied for both gas chromatography and liquid chromatography (Figure 8b and

8c). If the packing of the packed column chromatography consists of very small granules, high

pressure is required to force the mobile phase through the column. This is called High Pressure Liquid

Chromatography (HPLC). The technique is also called High Performance Liquid Chromatography,

because of the high quality separation that can be obtained (Braam, 1994).

Fig 8. a. A packed column, liquid chromatography (Kind Saud University, 2011) b. A capillary column

chromatography: overview of the instrument is illustrated with an enlargement of the capillary column in

which three compounds are separated, resulting in the subsequent peaks on the computer. c. Gas

chromatography: the multiple options for a cross section of a capillary column are depicted (form Linde,

2011).

c

b

a

21 | P a g e

Thin Layer Chromatography (TLC)

In TLC, the stationary phase is present in a layer, which is immobilised on a plate. The mobile phase is

a fluid that moves across the stationary phase due to capillary forces. In contrast to column

chromatography, the process is usually stopped when the separated components are still in the layer

(Figure 9). Improvements have been made with this technique resulting in High Performance Thin

Layer Chromatography (HPTLC) (Braam, 1994).

3.3.3 Analysis of cannabinoids

Analysis of the composition of a cannabis sample is generally based on either Gas Chromatography

(GC), HPLC, or TLC, as discussed below. For extraction of the cannabinoids from a sample, diverse

solutions can be used, for instance ethanol (Fischedick et al., 2009), petroleum ether, methanol,

benzene, a mixture of chloroform and methanol or a mixture of n-hexane and methanol (Raharjo &

Verpoorte, 2004).

Gas Chromatography

Cannabinoids are biosynthesized enzymatically within the plant as carboxylic acid forms. Neutral

cannabinoids are formed through decarboxylation of acidic forms by heat, exposure to light and

storage (Fischedick et al., 2009). Decarboxylation means the removal of carboxyl groups of the acidic

cannabinoids, converting them into neutral cannabinoids (Hazekamp, 2008). By injection of the

sample for a GC analysis, decarboxylation occurs automatically (Raharjo & Verpoorte, 2004). When

GC is used, derivatization is required to enable analysis of both neutral cannabinoids and cannabinoid

acids. Derivatization implies that certain components are either esterified, silanated or acetylated

(The Molecular Structures Group, University of Kansas, 2011). This is done to make highly polar

compounds sufficiently stable and volatile to facilitate GC analysis, without thermal decomposition

or conversions into derivatives (Scott, 2011). The detection methods commonly used for GC are

Fig 9. The principle of TLC

The left picture shows the situation before developing.

The applied samples are represented by the black dots

and the level of the mobile phase is below the sample

(blue line). Then the plate is developed (indicated by

the blue arrow). The right picture shows the plate after

development. Each dot represents a compound of the

sample (figure designed by authors).

22 | P a g e

Flame Ionization Detection (FID) or Mass Spectrometry (MS). FID is primarily sensitive to

hydrocarbons, like cannabinoids. The hydrocarbons within a flame give rise to ions, which make the

flame electrically conductive. This conductivity can be measured by placing two electrodes in the

flame. The measured conductivity differs between hydrocarbons. This measured difference is caused

by the fact that different size and different functional groups give rise to a distinguishable amount of

generated ions (Braam, 1994).

High Pressure Liquid Chromatography (HPLC)

With HPLC it is possible to measure acid and neutral cannabinoid forms simultaneously, without the

need for derivatization (Hazekamp, 2008). The mobile phase is generally a methanol-water gradient

with a linear increase in methanol concentration over time. This enables optimal separation of

cannabinoids. If acetic acid is added to the mobile phase, this facilitates separation of Δ9-THC and Δ9-

THC acid, so both can be detected simultaneously (Raharjo & Verpoorte, 2004).The separated

cannabinoids are detected with a UV- or photodiode array detector. This detector measures the

absorption of the chromophores, a light absorbing group of a molecule, present in cannabinoids

(Hezler, 2000). The resolution of separation for HPLC is lower than for GC and that results in

overlapping peaks as result of HPLC analysis. To overcome this problem, MS can be used to

distinguish between the overlapping peaks (Hazekamp, 2008). Another advantage of HPLC over GC is

that the limit of detection is often higher for analyses with HPLC (Raharjo & Verpoorte, 2004). An

disadvantage of HPLC compared to GC is that the procedure usually takes more time (Raharjo &

Verpoorte, 2004)

Thin Layer Chromatography (TLC)

HPLC and GC are methods that require complex and expensive equipment for the analysis. TLC, on

the other hand, can be performed with simple and inexpensive instruments. Nevertheless an

enhanced version exists, called HPTLC, which utilizes machines to obtain higher quality results and to

make the measurements more reproducible. HPTLC is performed for the analysis of cannabinoids.

The instruments used in this case are an automated sample applicator, to avoid variance in spot size

and location, and a densitometer and UV scanner for plate analysis (Fischedick et al., 2009).

Densitometry is used to quantify results (Fischedick et al., 2009). The densitometer measures the

optical density on the plate, which is higher if more light is absorbed. When it is desired to obtain

results on both neutral and acid cannabinoids, the sample should be measured two times, once with

and once without decarboxylation. The decarboxylation is done before the cannabinoids are

extracted (Fischedick et al., 2009). While these instruments enable higher quality measurements,

they are not required for TLC analysis.

Alpha Nova Pharma developed an analysis kit, called CAT kit, for determination of

cannabinoid composition of cannabis samples. This kit is a form of TLC. It is developed because no

scientific background and no expensive instruments are needed to perform the analysis. Therefore it

can be used by anyone who would like to analyse the composition of their cannabis, for instance

breeders, pharmacists, coffee shops and patients. A fingerprint, which is a qualitative result, can be

obtained without decarboxylation. But when quantitative results are preferred, each sample should

be measured twice, once with and once without decarboxylation. This decarboxylation can be

performed by placing the sample on aluminium foil in the oven for approximately four minutes. If the

23 | P a g e

sample is left in the oven for too long, degradation products will be formed. In contrast, if the sample

is left in the oven too short, the decarboxylation is not completed and quantification will not be

feasible. An exemplary result is visualized in Figure 10a. Instead of the automated sample applicator,

the kit contains capillary tubes which take up 2µl when they are placed on a piece of cotton that was

dipped in the sample. With the capillary tube the sample is spotted on the plate, one centimetre

from the bottom and at least half a centimetre from the edge. The plate is placed in a developing

chamber with three millilitres of developing solution, this is the mobile phase. The plate develops in

approximately twenty minutes (Alpha Nova, 2011). The detection is done with a dye, selective for the

visualization of cannabinoids. The cannabinoids that can be detected with this kit are THC, THV, CBD,

CBN, CBG, CBC and their corresponding acids. Every cannabinoid reacts differently with the dye

resulting in distinctive colours. The exact list of detectable cannabinoids and respective colours are

presented in Figure 10b (Alpha Nova, 2011).

Fig 10. a. The cannabinoid composition profile of a cannabis sample, obtained using the analysis

kit (from Alpha Nova Pharma, 2011) without (#1) and with (#2) decarboxylation. b. Cannabinoids

that can be detected with the CAT kit; the Rf value in the second column indicates the location of

the spot on the plate while the colours are listed in the third column (from Alpha Nova, 2011).

a b

24 | P a g e

4. Endocannabinoid system

4.1 Introduction to the Endocannabinoid System

Although cannabinoids have been used for millennia for treating pain and other symptoms, their

mechanisms of action remain obscure. With the discovery that the active components of cannabis

have a great impact on the ESC in our body, cannabis plants became attractive again from a medical

point of view. The ECS seems to be essential in most, if not all, physiological processes in the human

body, including appetite, pain-sensation, mood, memory and forgetting. The first annotation about

the ECS appeared in late 80s, when putative cannabinoid agonists were created for further research

on endocannabinoid receptors (Matsuda et al., 1990). In 1990 the cannabinoid-1 (CB1) receptor was

cloned and its role in influencing central nervous system (CNS) was verified (Matsuda et al., 1990).

Just three years later, the cloning and characterization of the second receptor, named CB2,

succeeded (Munro et al., 1993). The ECS is present in many species of animals within diverse groups,

including mammals, birds, fish, and reptiles (McPartland and Glass 2003).

The ECS comprises three main elements: cannabinoid receptors, endocannabinoids and

enzymes which synthesize and degrade the endocannabinoids (Di Marzo et al., , 2004). The most

important element is represented by receptors, responsible for an adequate transduction of

signalling molecules into the signalling events inside the cell. The endocannabinoid receptors are

embedded in the plasma membrane, thus extracellular molecules perception is feasible. The

cannabinoid receptors are divided into two distinct group: (1) metabotropic cannabinoid receptors

(MCRs) and (2) ionotropic cannabinoid receptors (ICRs) (See Textbox 1) (Akopian et al., 2009). The

second element of the ECS is represented by signalling molecules, referred to as the endogenous

ligands or endocannabinoids. The ligand molecules are able to bind to the receptor and thereby

stabilize the receptor conformation. The stable conformation of the receptor leads to activation or

inhibition, depending on the receptor and ligand type, as well as other proteins associated with the

recognition event. Generally, ligands which activate receptors are called agonists, whereas the ones

inhibiting the receptors are called antagonists (Demuth and Molleman, 2005). The ligands are

secreted by specialised cells of mammalian bodies. Four types of endogenous ligands (agonists) have

Textbox 1. Glossary

Iononotropic receptors: Channel-like receptors, a subclass of transmembrane receptors that are opened

by agonist binding and through which ions such as Na+, K+ and/or Ca2+ can very selectively pass.

Ionotropic receptors located at synapses convert the chemical signal of presynaptically released

neurotransmitter directly and very quickly into a postsynaptic electrical signal.

Metabotropic receptors: Seven-transmembrane receptors that couple to G proteins, starts some

intracellular biochemical cascade after its activation by an agonistic ligand. They modulate pathways

such as cyclic AMP–protein kinase A (via Gs or Gi), diacylglycerol–protein kinase C (via Gq) and inositol

1,4,5-trisphosphate–Ca2+ (via Gq).

Voltage-dependent calcium channel (VDCC): the calcium-permeable channels found in excitable cells, so

those that can be stimulated to create a tiny electric current (like muscle fibers and neurons).

Transient receptor potential (TRP) channels: a large family of plasma membrane cation channels of

numerous human and animal cell types. They function as a receptor able to perceive a variety of

sensations like the feeling of pain, different kinds of tastes, pressure, and vision. Moreover, they are

used as molecular thermometers to sense hot or cold.

Retrogate messengar: The phenomena in which the signaling molecule (signal) travels from

postsynaptic neuron to a presynaptic one.

25 | P a g e

been described to so far: (1) anandamide (AEA, arachidonoylethanolamide), (2) 2-

arachidonoylglycerol (2-AG), (3) virodhomine (o-arachidonoyl-ethanolamine) and (4) N-

arachodonoyl-dopamine (NADA) (Jiang et al., 2007).

To produce the endogenous cannabinoids and to degrade them after receptor activation,

enzymes are needed to carry out and regulate ligand synthesis, transport and degradation. These

enzymes are therefore the third main element of the ECS (Di Marzo et al., , 2004). Besides

endogenous ligands, plant active components as well as synthetic components resembling the

endogenous ligands can bind to the receptors. Thus, the active components of Cannabis plant can act

as modulators of the ECS. The first identified family of cannabinoid receptors were the metabotropic

(see Textbox 1) G protein-coupled receptors (GPCRs), which have seven transmembrane spanning

domains (Howlett et al., 2002) and contain CB1, CB2, GPR55 (Ryberg et al., 2007), and possibly

GPR119 (Godlewski et al., 2009) and peroxisome-proliferator-activated receptors (PPARs) (Pertwee,

2010). GPCRs comprise a large protein family of transmembrane receptors that sense extracellular

molecules and activate inside signal transduction pathways and, eventually, cellular responses. G

protein-coupled receptors are found only in eukaryotes, including yeast and animals. There are two

principal signal transduction pathways involving the G protein-coupled receptors: the cAMP signal

Fig 11. The endocannabinoid neuromodulatory signalling in

brain. (Adapted from: Guzman, 2003, p. 747).

Abbreviations: NT, neurotransmitter; mR, metabotropic

receptor; iR, ionotropic receptor; T, unidentified membrane-

transport system; FAAH, fatty acid amide hydrolase; AEA,

anandamide; 2-AG, 2-arachidonoylglycerol; AA, arachidonic

acid; Et, ethanolamine

26 | P a g e

pathway and the phosphatidylinositol signal pathway (Demuth and Molleman, 2006). Cyclic AMP,

produced when the activated membrane enzyme adenylyl cyclase catalyzes the ATP molecules, is an

important second messenger in cellular metabolism.

Metabotropic receptors CB1 and CB2 are Gi/o coupled (inhibitory regulative G-protein)

through who’s α subunit they inhibit adenylyl cyclase and stimulate mitogen-activated protein

kinases. Moreover, CB1 is coupled to inhibition of voltage-activated Ca2+ channels and stimulation of

inwardly rectifying K+ channels (Mackie et al., 1995). The CB1 receptor is expressed in high

abundance within certain regions of the brain. Hence, CB1 receptors have been isolated in the

hippocampus, basal ganglia (striatum, substantia nigra, globus pallidus), cerebral cortex

(predominantly in the prefrontal cortex), amygdala and cerebellum (Herkenham et al., 1990; Glass et

al., 1997; Tsou et al., 1998; Eggan and Lewis, 2007). The brain expression of CB1 indicates the role of

the ECS in brain neuromodulation (Guzmán, 2003). Postsynaptic neurons synthesize (membrane-

bound) endocannabinoid precursors and specialized enzymes cleave them to release active

endocannabinoids, either AEA or 2-AG (Guzmán, 2003). Endocannabinoids subsequently act as

retrograde messengers (see Textbox 1) by binding to presynaptic CB1 cannabinoid receptors, which

activation leads to the inhibition of voltage-sensitive Ca2+ channels and the activation of K+

channels. This decreases membrane depolarization and exocytosis, thereby inhibiting the release of

neurotransmitters (including glutamate, dopamine, acetylcholine and GABA). The inhibition of

physiologically important neurotransmitters affects, in turn, the processes such as learning,

movement and memory. The degradation of endocannabinoids is conducted by well-characterized

fatty acid amide hydrolase (FAAH) (Cravatt et al., 1996). Due to fact that degradative enzymes are

located in postsynaptic neutrons, the endocannabinoid ligands must be translocated first to those via

the membrane transport system. For the graphical depiction of the mechanisms, see Figure 11

(Guzman, 2003).

4.2 Cannabinoid Receptors

Peripherally, CB1 receptors have been identified in the spleen and tonsils (Galiegue et al., 1995), the

guinea-pig small intestine (Pertwee et al., 1996a), the mouse urinary bladder (Pertwee & Fernando,

1996), the mouse vas deferens (Pertwee et al., 1996b), sympathetic nerve terminals (Ishac et al.,

1996; Vizi et al., 2001), hamster smooth muscle cells (Filipeanu et al., 1997), cat vascular smooth

muscle cells (Gebremedhin et al., 1999) and at very low levels in adrenal gland, immune system cells,

vascular tissue, heart, prostate, uterus and ovary (Gerard et al.,1991; Galiegue et al., 1995; Liu et al.,

2000). The peripheral nervous system expression is implicated in processes such as peripheral pain

perception (peripheral nociceptors), vascular tone, intraocular (De Petrocellis & Di Marzo, 2010). For

instance, as the CB1 is expressed in cholinergic nerve terminals of the stomach, duodenum and

colon, the inhibition of the receptor blocks the acetylcholine release (Di Carlo & Izzo, 2003). In the

peripheral nervous system, acetylcholine activates muscles and it is a major neurotransmitter in the

autonomic nervous system. Thus, the blockage of the acetylcholine release might be linked to muscle

relaxation and might have a physiological role in the control of emesis (vomiting) (Darmani, 2010).

The expression level of CB1, however, is age-dependent (Heng et al., 2011). The evidence for

expression change were shown for cortex exclusively, and is the highest in juveniles and drops

thereafter toward adult levels (Heng et al., 2011).

CB2 was first considered to be the “peripheral cannabinoid receptor”, with exclusive CB2

expression on the immune system cells at an expression level much higher than that of CB1. It was

27 | P a g e

found that the CB2 receptor was expressed in spleen, tonsils and the thymus gland (Sylvaine et al.,

1995) and on immune cells such as monocytes, macrophages, B-cells, and T-cells (Miller and Stella,

2008). However, multiple recent reports question the absence of CB2 in the CNS. For instance, it is

now well accepted that CB2 is expressed in brain microglia during neuroinflammation. Moreover,

CB2 receptor mRNA has been reported in cerebellar granule cells (Skaper et al., 1996), in cultured

cerebrovascular endothelium (Golech et al., 2004) and in very low level in periaqueductal grey (PAG),

thalamus, striatum, cortex, amygdala and hippocampus (Ibrahim et al, 2005). However, the extent of

CB2 expression in neurons has remained controversial (Atwood & Mackie, 2010). Due to specific

expression, the CB2 receptor activation has been shown to be devoid of CNS-mediated side effects,

such as catalepsy, hypothermia and reduced locomotion that result from CB1 receptor activation

(Malan, 2001). For that reason, CB2 receptors represent an alternative site of action for non-

psychotropic therapeutic interventions. The activation of the receptors trigger a sustained activation

of ceramide biosynthesis, which has an impact on body weight regulation, energy expenditure, and

the metabolic syndrome (Yang et al., 2009).

It has been hypothesised that after nerve injury (stimulation), CB1 and CB2 receptors are

synthesised in dorsal root ganglion cell bodies and rapidly transported out to nerve terminals where

they are activated (Wotherspoon et al., 2005). Therefore, the peripherally located CB1 and CB2 act as

a nociceptors. A nociceptor is a sensor that responds to potentially damaging stimuli (detect

mechanical, thermal or chemical changes above a set threshold) by afferent activity in the peripheral

and central nervous system. This process, called nociception, usually causes the perception of pain

(Kreitler et al., 2007). The mechanism of pain release is explained by receptor expression on

presynaptic GABAergic terminals, and the activation reduces the probability of neurotransmitter

release. As a direct consequence of GABA decrease, the glutamate release seems to be increased,

resulting in induced anti-nociception which is known as a behavioural analgesia (Palazzo et al., 2010).

4.3 Novel Cannabinoid Receptors

Further research shows that the system is even more complicated. Studies demonstrate that many

cannabinoid effects cannot be attributed merely to the CB1 and CB2 metabotropic GPCRs. Additional

receptor types should exist to explain for the distinct ligands affinity and the diverse mechanisms of

signalling. Moreover, constitutive activation of some receptors was shown, which is thought to be

the result of coupling to different G proteins (Demuth and Molleman, 2005). A candidate receptor

GPR55, also referred to as the orphan receptor GPR55, is coupled to Gα13 (Ryberg et al., 2007). Only

few known ligands can activate the receptor. The activation was the highest when the CP 55940 (the

synthetic cannabinoid which mimics the THC molecule) was applied. The receptor regulates the

activation of several proteins that are involved in diverse array of cellular events, such as control of

cell growth and cytoskeletal reorganization (Ryberg et al., 2007). Moreover, some receptors, like the

human orphan receptor GPR119, has a close phylogenetic proximity to the CB1 and CB2 receptors

(Godlewski et al., 2009). GPR119 is coupled to Gs, thus leading to increase in intracellular cAMP,

stimulation of adenylyl cyclase and enhancement of protein kinase A activity (Godlewski et al., 2009).

GPR119 is activated mainly by the agonist oleylethanolamide (OEA). OEA has been shown to activate

other cannabinoid receptors, like type-1 vanilloid receptor (discussed later), however, there is no

evidence that they activate the CB1 and CB2 receptors (Ambrosini et al., 2010). The CNS is protected

from damage or infection by microglia, a type of glial cell with a reservoir of macrophages of the

brain and spinal cord. The activated microglia undergo directed migration towards affected tissue.

28 | P a g e

Interestingly, the ECS controls microglial migration via CB2 receptors and the “abnormal cannabidiol”

receptor, known as the GPR18 (Franklin & Stella, 2003). GPR18 is expressed significantly in

hematopoietic cell lines and lymphocyte subsets (Kohno et al., 2006). Remarkably, both CB1 and

GPR18 bind the natural ligand N-arachidonylglycine (NAGly), the carboxylic analog of the

endocannabinoid anandamide (Huang et al., 2001).

Many terminals, such as sympathetic axons and hippocampal mossy fibers, are regulated by

both metabotropic (GPCRs) and ionotropic cannabinoid receptors (ICR) (Guzmán, 2003). Thus, the

second family of cannabinoid receptors, next to the metabotropic family, is represented by ICRs. To

date, the ICR family consists of at least five cannabinoid receptors. Those receptors are members of

the TRP family of channels (see Textbox 1). The TRP channels are a broad family of ligand-gated ion

channels that generate an inward flow of cations upon activation. The majority of ICRs are found in

nociceptive sensory neurons, which perceive and respond to harmful stimuli, such as mechanical,

thermal and chemical stimuli (Akopian et al., 2009). Therefore, the sensory neuron activation by

plant-derived cannabinoids, gating of inward currents generated by these ICRs, might result in

nociception and, ultimately, pain perception (Akopian et al., 2009). However, the molecular

mechanism(s) for these effects remains obscure.

TRPV1 and TRPA1 are the most known ionotropic receptors. They are activated by nM–μM

concentrations of distinct cannabinoids, while the metabotropic CB1 and CB2 are activated by aa

concentration starting at a threshold of 1nM (Table 2) (Akopian et al., 2009). Further research to

obtain a better understanding of the ECS functionality is needed.

Table 2. The action of cannabinoids (endogenous, plant and synthetic types) on the ionotropic

and metabotropic cannabinoid receptors (data from Akopian et al., 2009).

Abbreviations: ICR, ionotropic cannabinoid receptor, MCR, metabotropic cannabinoid receptor,

NADA, N-arachidonoyl-dopamine, ACEA, Δ9-THC, delta(9)-tetrahydrocannabinol.

Cannabinoid Type Action on ICR Action on MCR Currenta

Anandamide Endogenous TRPV1>0.3 μMb CB1; CB2>10 nM

200–500

pA

NADA Endogenous TRPV1>10 nM CB1; CB2>100 nM 300–700

pA

ACEA Synthetic TRPV1>5 μM CB1>1 nM 300–700

pA

Δ9-THC Plant TRPV2; RPA1>10 μM CB1; CB2>10 nM

100–200

pA

Cannabidiol Plant TRPV2; TRPA1>10 μM non-applicable 50–100

pA

a: approximate value of current magnitudes in sensory neurons

b:The values given represent the threshold concentrations of cannabinoids to activate the

receptors

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5. Potential of Cannabinoid-Based Medicine in Health and Disease

The described ECS in the previous section, exerts an important neuromodulatory function in different

brain areas and is also known to be involved in the regulation of other peripherally located organs,

such as the heart, gastrointestinal track, uterus and ovary. More importantly, modulating the activity

of the ECS turned out to hold therapeutic promise in a wide range of disparate diseases and

pathological conditions, starting from mood and anxiety disorders, neuropathic pain, multiple

sclerosis and spinal cord injury, to cancer, atherosclerosis, myocardial infarction, raised intra-ocular

pressure, glaucoma, metabolic syndrome, and osteoporosis, to name just a few. An obstacle to the

development of widely accepted CBM has been the socially objectionable psychoactive properties of

plant-derived or synthetic agonists, mediated by CB1 receptors. However, this problem does not

arise when the therapeutic goal is obtained by treatment with an antagonist of a CB1 receptor, such

as in obesity. The psychoactive properties may also be absent when the action of endocannabinoids

is improved indirectly through blocking their metabolism or transport. The use of selective CB2

receptor agonists, which lack psychoactive properties, could represent another promising possibility

for certain conditions. Nowadays, several CBMs are used in clinical trials (see Textbox 2). In this

Chapter we provide an overview of regulatory functions of the ECS in health and disease.

Textbox 2. List of CBMs that are used in the clinical trials (Adapted from: Hazekamp & Grotenhermen,

2010)

Cannabis (dried flower tops of female plant): cannabis used for medical purposes is mostly standardized.

The main way (also medically) of administration is by smoking.

THC (delta-9-tetrahydrocannabinol): pharmacologically and toxicologically most important cannabinoid.

Is mainly used for its palliative effect by inhibiting chemotherapy-induced nausea and vomiting, such as

in cancer patients. Nabilone® is a synthetic analogue of THC that is used for the treatment of chemically-

induced nausea and vomiting that has not responded to conventional antiemetics.

Dronabinol: international non-proprietary name of the naturally occurring (-)-trans-isomer of THC.

Marinol® is a synthetic version of dronabinol that is formulated as a capsule containing sesame oil.

Marinol® is used to treat severe weight loss associated with anorexia, patients with AIDS and patients

that suffer from nausea and vomiting as a result of cancer chemotherapy.

CBD (cannabidiol): major non-psychotropic cannabinoid found in cannabis that has shown anti-epileptic,

anti-inflammatory, anti-emetic, muscle relaxing, anxiolytic, neuroprotective and anti-psychotic activity

and reduces the psychoactive effects of THC.

Sativex®: a cannabis-based oromucosal spray containing THC and CBD in a 1:1 ratio. This pharmaceutical

product has been approved in Canada as adjunctive treatment for neuropathic pain in adults with MS

and for pain in cancer patients.

Cannador®: an oral capsule containing whole plant extract with standardized THC and CBD content. This

THC:CBD ratio has a fixed narrow range of 2:1. Several clinical trials have found a beneficial effect of

Cannador® on muscle stiffness, spasms and associated pain in MS, for cachexia in cancer patients and for

post-operative pain management.

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5.1 Beneficial Effects of Cannabinoid-Based Medicine

Evidence for the medicinal properties of cannabis or single cannabinoids in certain diseases is

accumulating. Approximately 110 clinical studies that involved a total number of over 6,100 patients

suffering from various diseases have been conducted in the period of 1975 to 2009. The next

paragraphs summarize the most important findings of different CBMs on various diseases over the

last 34 years.

5.1.1 Nausea and Emesis

Many conventional cytotoxic drugs that are often used in cancer chemotherapy are strongly emetic

(i.e. they cause vomiting and nausea). Recreational cannabis smokers that received chemotherapy

have informed their doctors of the relieving effects on nausea. Subsequently, many studies have

been conducted to the anti-emetic effects of both natural and synthetic THC. It was found that both

forms of THC are superior to placebo and equivalent or better than anti-emetics that were available

in the 1970s and 1980s. Patients receiving chemotherapy generally preferred THC and Nabilone®

(synthetic analogue of THC) over conventional drugs, even though they were accompanied by several

adverse effects (Table A-I in Appendix I). During studies to the anti-emetic effects of THC, sedation

and psychotropic symptoms were commonly reported, though they were usually rated mild to

moderate and resolved quickly after discontinuation. The most commonly reported side effects were

somnolence, dry mouth, ataxia, dizziness, dysphoria, and ortostatic hypotension. Meta-analysis

suggested that an optimal balance of efficacy and adverse effects is reached with THC or Nabilone®

doses of 7 mg/m2 or less. Several studies showed that low-dose preventive treatment gives better

results than targeting established vomiting (Robson, 2001). A recent study (2007), that compared the

efficacy of dronabinol with ondansetron, found both to be similarly effective for the treatment of

chemotherapy-induced nausea and vomiting. However, a combination-therapy was not more

effective than either agent alone (Meiri et al., 2007; Hazekamp & Grotenhermen, 2010). In Canada,

dronabinol and Nabilone® are indicated for chemotherapy-induced nausea and vomiting (Wang et

al., 2008). These recent findings advocate that the cannabinoids possess broad-spectrum antiemetic

properties. Mechanism of the effects of cannabinoids on chemotherapy-induced nausea and

vomiting has been investigated since the discovery of the CB1 and CB2 receptors. Cannabinoids used

in clinical trials act as agonist antiemetic drugs via the activation of cannabinoid CB1 receptors

mainly, whereas endocannabinoids possess both pro- and antiemetic actions. A multitude of

experimental findings indicate that both cannabinoid CB1 and CB2 receptors, as well as TRPV1

receptors, and their endogenous ligands, are found in the brainstem and gastrointestinal tract

circuits. This can affect gastrointestinal tract motility, secretion and function, which would ultimately

affect emesis. Thus, the secretion of peripherally- and/or centrally-acting emetogens (agents

possessing the capacity to induce emesis, such as serotonin, dopamine, substance P and

prostaglandins) is inhibited by cannabinoid receptors agonists and antagonist, depending on the

receptor involved (Darmani, 2010).

5.1.2 Appetite Regulation

The past decade has seen considerable advances in our understanding of endocannabinoid‐mediated

control of feeding behaviour. Recently, the link between the appetite regulation and

endocannabinoid level was demonstrated. AEA and 2‐AG levels in the rat brain (specifically in limbic

forebrain, hypothalamus and cerebellum) were quantified in three feeding states: fast, feeding

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moment and satiation after food intake (Kirkham et al., 2002). AEA and 2‐AG levels were significantly

elevated by food deprivation in the limbic forebrain while 2‐AG concentration was significantly

reduced in the hypothalamus during the feeding state, but significantly increased during the deprived

state. The hypothesis suggests that elevated endocannabinoid levels in brain areas during food

deprivation play an important role in motivating animals towards food. The decrease of 2‐AG levels

in the hypothalamus during feeding moment proposes that 2‐AG synthesis is actively inhibited during

feeding, to facilitate satiation after food intake. Recently, the AEA and 2-AG preferentially increased

taste responses to sweet over salty, sour or bitter (Yoshida et al., 2010).

Cancer- and AIDS patients often experience significant weight loss, muscle atrophy, fatigue,

weakness and loss of appetite. AIDS patients have claimed that smoking marijuana relieves nausea,

improves appetite, reduces anxiety, relieves aches and pains, improves sleep and inhibits oral

candidiasis. Oral administration of THC, as well as other agonists of CB1 receptor, has been shown to

improve appetite and to slow down weight loss, thereby showing hyperphagic (polyphagic)

properties. However, several side effects, including dizziness, disassociation, confused thinking, panic

and feelings of disturbance have led to withdrawals in open studies. Several studies have found that

dronabinol might be implicated in helping to stimulate the appetite of cancer and AIDS patients, and

even improve the sense of taste in this population (Hazekamp & Grotenhermen, 2010; Brisbois et al.,

2011). Since CB2 receptors have recently been localized in the CNS (Morgan et al., 2009) and the

expression of this receptor has not been found in feeding pathways, little research has considered

CB2 receptor to have an effect on appetite regulation. Therefore, the exploration of the CB2 receptor

may result in development of a new generation of CBM.

On the other hand, CBM can be used as medicine to decrease food intake. Obesity poses one

of the most serious public health problems of the 21st century. Obesity is thought, at an individual

level, to be caused by a combination of excessive caloric intake and a lack of physical activity. A

limited number of cases are due primarily to genetics, medical reasons, or psychiatric illness. While

the food intake increase can be obtained by agonists of CB1 receptor application, the decrease has

been shown after the CB1 receptor antagonists usage. One of the first used antagonists was

Rimonabant®. Rimonabant® was approved in Europe as an supplement to diet for the treatment of

obesity by the European Commission on 19 June 2006 (European Medicines Agency, 2009). However,

due to severe side effects and lower effectiveness of Rimonabant® in real-world experience that in

initial clinical trials, European Medicines Agency suggested the suspension of the promotion of

Rimonabant. The phytocannabinoid Δ9-tetrahydrocannabivarin (Δ9-THCV) was suggested to be a

novel cannabis-derived component with hypophagic properties and an eventual treatment for

obesity (Riedel et al., 2009). The recent finding showed that CP-945,598, the selective antagonist of

CB1 receptor, enhanced weight loss and supported weight loss maintenance in both diabetic and

non-diabetic patients. Importantly, the CP-945,598 seems to be safe and efficient even in the long-

term treatment (Aronne et al., 2011).

Although the current state of knowledge implicates that cannabinoid receptors modulate

appetite regulation, the recent research of Yoshida on CB1- knocked out mice did not show any

correlation between the ECS and appetite regulation (Yoshida et al., 2010).

5.1.3 Pain Relief

As it was described in previous chapter, the CB1, CB2 and presumably TRPV1 function as nociceptors.

For CB1 and CB2 receptors, which are expressed on presynaptic GABAergic terminals, the

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mechanisms of pain relieve is explained by inhibition of neurotransmitter relieve in case of the

receptors activation. Additionally, the TRP1 belongs to the family of transient receptor potential

channels. Their main function is to perceive variety of sensations, including pain. However, there are

a lot of different kinds of pain, and understanding what type might be treated with cannabis is

crucial. The classification of The International Association for the Study of Pain (IASP) defines pain

according to five categories: duration and severity, anatomical location, body system involved, cause,

and temporal characteristics (intermittent, constant, etcetera) (Kreitler, 2007). Cannabinoids have

been proven to be effective in the relieve of a wide range of pain problems, mainly somatogenic

pain, which is divided into nociceptive and neuropathic pain. Subsequently, both of them are divided

into acute and chronic pain. An acute nociceptive pain is triggered by the stimulation of peripheral

nerve fibers. However, the stimulation threshold must exceed harmful intensity, potentially

dangerous for tissue. Thus, the acute nociception is associated with nerve damage caused by trauma,

diseases such as diabetes, Herpes zoster, irritable bowel syndrome, late-stage cancer or

chemotherapy. A chronic pain, however, serves no biologic function as it is not a symptom of a

disease but is a disease process itself. There are two types of chronic pain which can be treated with

cannabis: inflammatory nociceptive pain and neuropathic pain. Inflammatory nociceptive pain is

associated with tissue damage and the resulting inflammatory process. Neuropathic pain is triggered

by damage to neurons in the peripheral and central nervous systems. Neuropathic pain often seems

to have no evident cause, but, some common causes of neuropathic pain include diabetes, HIV

infection or AIDS, multiple sclerosis (MS), chemotherapy and many others.

Indeed, for the diseases mentioned above, the therapeutical potential of cannabis have been

shown by many academic research and clinical trials. A study by Wilsey et al. (2008), to the pain-

relieving effects of smoked cannabis, found significant improvement of neuropathic pain in patients

with complex regional pain syndrome, spinal cord injury, peripheral neuropathy, or nerve injury

(Wilsey et al., 2008). MS patients that smoke cannabis have reported improvements in night-time

spasticity and muscle pain (91-98%); night leg pain, depression, tremor, anxiety, spasms on walking,

paraesthesiae (80-89%); leg weakness, trunk numbness, facial pain (71-74%); impaired balance

(57%); constipation (33%); and memory loss (31%). Several studies on the efficacy of THC on muscle

spasm reported a relieve in spasticity, nocturia and general well-being with doses of five to ten mg.

Nabilone® (Hazekamp & Grotenhermen, 2010). Besides the alleviating properties, recent studies

have suggested that cannabinoids may have immunomodulating and inflammatory properties as

well. Indeed, recent experimental evidence suggests an effect of cannabinoids on more fundamental

processes besides pain that are important in MS, with evidence for anti-inflammatory effects

(Hazekamp & Grotenhermen, 2010; Bakera et al., 2010), and encouragement of remyelination and

neuroprotection (Zajicek and Apostu, 2011). Anti-inflammatory properties are believed to be

regulated mainly through the activation of the CB2 receptor. Activation of this receptor seems to

cause a shift from Th1 to Th2 cells. It is generally believed that MS is an autoimmune condition,

which then would involve Th1 cells. The detailed information about the pain treatment using

cannabinoid-based medicine was reviewed by Rahn and Hohmann (2009). Several studies support

the consideration that cannabinoids have a higher efficacy in chronic- than in acute pain conditions

(Mensinga et al., 2006).

Although the analgesic properties of cannabis are beyond any doubt, the clinical use of CBM

is limited due to their psychoactive properties, presumably mediated by cannabinoid receptors

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expressed in the CNS. The mostly used dronabinol reduces spontaneous pain intensity (Svendsen et

al., 2004). However, treatments with dronabinol have been accompanied by several dose-related

side effects, including slurred speech, sedation and mental clouding, blurred vision, dizziness and

ataxia. Besides dronabinol (and other THC-related drugs) numerous CBM have been developed for

patients suffering from MS and (MS)-related neuropathic pain. Cannabidiol is a natural components

in cannabis characterised by low affinity to CB1 and CB2 receptors. CBD competes with cannabinoid

agonists (like Δ9-THC) for cannabinoid receptor binding sites, thereby minimizing psychoactivity of

drugs that employ a combination of Δ9-THC and CBD. CBD's antinociceptive properties have

additionally been attributed to inhibition of anandamide, endogenous cannabinoid, degradation

(Rahn and Hohmann, 2009). Recently, the research has been concentrated on the role of the CB2

receptor in modulating nociception (Guindon and Hohmann, 2008). A novel ethyl sulfonamide THC

analogue, O-3223, selectively binds to and activates CB2 receptors. It reduces nociception in

neuropathic and inflammatory mouse models of pain (Kinsey et al, 2011). Development of O-3223

gives a promising candidate for future pain treatment.

5.1.4 Multiple Sclerosis and other Disorders Characterized by Spasticity

Spasticity is characterized by stiff or rigid muscles with exaggerated, deep tendon reflexes. The

condition can interfere with walking, movement, or speech. Spasticity is one of the major symptoms

in MS, cerebral palsy, spinal cord and head injury, damage to the brain causing limited oxygen

accessibility, and metabolic diseases such as adrenoleukodystrophy, amyotrophic lateral sclerosis

(Lou Gehrig's disease), and phenylketonuria. Recently, the studies released the close connection

between inflammation and neurodegeneration in MS patients. However, the treatment with

conventional medicine has a low efficacy due to anti-inflammatory drugs’ inability to access the CNS.

During the last years, a vast amount of literature on cannabinoids has provided strong evidence on

their abilities as neuroprotective agents under different pathological states. This was first

demonstrated in experimental brain ischemia in 1994 (Bar-Joseph et al., 1994). Ever since, there are

numerous studies showing the potency of CBM as an effective protective drug for MS patients

(Arévalo-Martín et al., 2003; Sánchez et al., 2006; Peterson et al., 2007; Kubajewska et al., 2010). The

mechanism in which CBMs are used as an anti-inflammatory and protective drug is explained by the

specific expression of cannabinoids receptors. The CB2 receptor is mainly expressed on the cells of

the adaptive and innate branches of the immune system, thus cannabinoids exert a very wide

spectrum of actions on cells, both in the periphery and the CNS. The activation of CB2 receptors by

agonists reduces the inflammatory insult against neuroaxonal structures. Inside the CNS, other well-

defined actions protect neurons against damage, and they are mediated mainly through CB1

receptor activation. Most studies show that cannabinoids induce a Th2 shift (Sánchez, A. García-

Merino, 2011). However, the exact mechanism is complex and there is disagreement between the

detailed reports (Klein et al., 2000; Yuan et al., 2002; Sacerdote et al., 2005). The role of anandamide

is not clear in MS, however the increased level of AEA was measured in CNS of MS patients (Stock et

al., 2006).

Although some of the results of the above mentioned studies are contradictory, Sativex®

spray, from Bayer Schering Pharma UK, is indicated as an add-on treatment for patients with

moderate to severe spasticity associated with MS. It is used for patients who do not respond

adequately to other anti-spasticity medicines and who show a clinically significant response during an

initial trial of the Sativex® treatment. Sativex® does not cause the psychoactive side effects

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associated with smoking cannabis. The active components are present in the blood at much lower

concentrations when used as spray. Moreover the combination of THC and CBD in equal quantities

causes CBD to compete with THC for receptor binding sites. Reported side effects of Sativex® include

dizziness and fatigue, although these are mild and usually improve within a few days (Kmietowicz,

2010).

5.1.5 Cell-cycle Regulation and Cancer Treatment

Recent studies have shown that the ECS could offer an attractive anti-tumor target. A tremendous

amount of studies have revealed the molecular mechanisms of cannabinoids, providing knowledge

on how to modulate the activity of specific cannabinoid receptors in order to apply CBM as

chemotherapeutic agents. To date, it was found that CBM inhibits tumor cell growth and induces

apoptosis by modulating different cell signalling pathways. The anti-tumor properties were observed

in gliomas by induction of oxidative stress (Massi et al., 2010), lymphomas by activation of p38

mitogen-activated protein kinases involved in cell differentiation and apoptosis (Gustafsson et al.,

2006), prostate cancer by CB1R-mediated tumor cell proliferation inhibition (Nithipatikom, et al.,

2011), breast cancer by extracellular signal-regulated kinase (ERK) and reactive oxygen species

modulation (McAllister et al., 2010), lung cancer by inhibition of phosphorylation of AKT by agonists

of CB1 and CB2 receptors (Preet et al., 2011), skin cancer (Luca et al., 2009), pancreatic cancer cells

(Carracedo et al., 2006) by the mechanisms involving activation of ceramide that function as cellular

regulators of differentiation, proliferation, programmed cell death and apoptosis (Chowdhury et al.,

2009). The studies have been performed using a range of different cannabinoids, from

endocannabinoids, AEA and 2-AG,synthetic agonists of either CB1 or CB2 or both receptors,

Win55,212-2, JWH-015, ACEA and JWH-133, to natural cannabis components THC and CBD.

Interestingly, It has been demonstrated that GPR55 is expressed in various cancer types in an

aggressiveness-related manner, suggesting a novel cancer biomarker and a potential therapeutic

target (Hu et al., 2011). An explanation of the exact mechanism of CBM-mediated regulation of cell

signalling pathways is depicted in the Figure 12. However, this goes beyond the scope of this report

and we therefore refer to the review paper by Sarfaraz et al. (2008).

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5.1.6 Neurological Disorders

Only a handful of clinical trials have shown the effects of CBM on the symptoms of neurological

disorders other than multiple sclerosis. The majority of these studies are too small to be considered

conclusive, and their results are far from promising. However, due to ineffective conventional

treatments for movement disorders, epilepsy, autoimmune encephalomyelitis, Tourette's syndrome

and Alzheimer's disease, no potential medicines should be overlooked.

Conventional pharmaceuticals used in the treatment of epileptic seizures, referred to as

anticonvulsants, do not establish a desired effect for up to 30% of epileptic patients and they are

known to produce disabling or even life-threatening side effects. Cannabidiol is suggested to be a

powerful anticonvulsant free of tolerance. However, its efficacy varies between species in animal

Fig. 12. “Schematic representation of signalling pathways associated with cannabinoid receptor activation induced by its agonists. Upon receptor binding, cannabinoid receptor agonists inhibit cell proliferation through inhibition of cAMP-dependent protein kinase, which activates mitogen-activated protein kinases (MAPK). Stimulation of ceramide synthesis via activation of serine pamitoyltranferase (SPT) up-regulates p8, leading to the subsequent induction of apoptosis. Cannabinoid receptor agonists also activate MAPKs and PI3K/AKT pathways; sustained activation of ERK1/2 leads to the induction of cyclin kinase inhibitor p27/KIP1 with modulation of cell cycle regulatory molecules, resulting in G1 arrest and apoptosis. The proposed mechanisms are based on the available literature and are cell specific, and not all pathways are triggered simultaneously” (from Sarfaraz et al., 2008, p. 340).

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models. Cannabinoids appear to be anti-convulsive in patients and animal models of temporal lobe

epilepsy (Bhaskaran & Smith, 2010). The temporal lobe epilepsy is caused by pathological changes of

neural network in dentate gyrus. The cannabinoids (WIN 55,212-2, AEA, or 2-AG) used in the trial

relieved some epileptic symptoms, however, the mechanisms of this effect is not known. According

to one hypothesis, the activation of CB1 receptor present on nerve terminals can suppress recurrent

excitation in the dentate gyrus of mice (Bhaskaran & Smith, 2010). Recently, it was shown that

phytocannabinoid cannabidiol reduces seizure severity and lethality, suggesting that earlier, small-

scale clinical trials examining CBD effects in epileptic subjects warrant renewed attention (Jones et

al., 2011). This research showed that CBD in a dose of 100 mg per kg decreased the percentage of

animals experiencing the most severe seizures, decreased median seizure severity and showed a

strong trend to reduced mortality. These results extend the anticonvulsant profile of CBD, when

combined with a reported absence of psychoactive effects. The evidence presented by Jones (Jones

et al., 2011) strongly supports CBD as a therapeutic candidate for a diverse range of human

epilepsies.

From unverified reports and preliminary controlled studies it is suggested that - at least in a

subgroup of patients- cannabinoids are effective in the treatment of Tourette's syndrome (TS)

(Müller-Vahl, 2009). While most patients report beneficial effects when smoking marijuana, available

clinical trials have been carried out using THC. To date, it is unknown whether other cannabinoids

that interact with the endocannabinoid receptor system might be more effective in the treatment of

TS than smoked marijuana or pure THC (Müller-Vahl, 2009).

There is also growing evidence that the endocannabinoids are lipid mediators involved in the

control of neuron survival (Galve-Roperh et al., 2008). Therefore, different mechanisms have been

associated with cannabinoid receptors and their role in neuroprotection (Van Der Stelt & Di Marzo,

2005). As discussed later, antioxidative, antiglutamatergic and antiinflammatory effects are now

recognized as derived from cannabinoid action and are known to be of common interest for many

neurodegenerative diseases. Thus, these features make cannabinoids promising candidates for the

development of novel therapeutic strategies. The perspective for cannabinoid-based treatment in

neurodegenerative diseases are reviewed in detail by Romero and Martínez-Orgado (2009).

5.1.7 Schizophrenia

Many controversial data has been published discussing the relation between schizophrenia and

cannabis. The main component of cannabis, THC, is proven to be responsible for the majority of the

psychotomimetic effects of the plant. Several studies have indicated that THC elevates levels of

anxiety and psychotic symptoms in healthy individuals. In contrast to THC, cannabidiol has anxiolytic

and antipsychotic properties and is suggested to have a neuroprotective effect in humans. Cannabis

that is obtained from coffee shops is known to contain a high THC content. It is also known that a

large proportion of schizophrenic patients acquire cannabis from coffee shops and often claim to feel

better when they are “high”. However, research has indicated that cannabis use among

schizophrenic patients induces psychotic symptoms and that they are prone to develop psychological

dependence. Preliminary data suggest that smoking strains of cannabis containing cannabidiol, in

addition to Δ9-THC, may have a protective effect against psychotic-like symptoms induced by Δ9-THC

alone, however, more research is necessary (Morgan & Curran, 2008). To date no scientific study has

investigated the impact of the CNS on measureable phenotypic features in schizophrenia in relation

to cannabis abuse. However, cannabis abuse may lead to increased white matter volume deficits and

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cognitive impairment, which could in turn increase schizophrenia risk, especially for genetically

susceptible individuals (Ho et al., 2011).

5.1.8 Raised Intra-ocular Pressure

Glaucoma is an eye disorder caused by raised intra-ocular pressure. Many anecdotal reports have

indicated that street marijuana can relieve glaucoma symptoms. Randomized controlled trials

confirmed that oral, injected or smoked cannabinoids can decrease intra-ocular pressure and that

this effect is dose-related. THC, Δ8-THC and 11-hydroxy-THC were reported to be more effective than

cannabinol. Cannabidiol did not show any effect on intra-ocular pressure. Instead, a study by Tomida

et al. (2006) found a transient elevation of intra-ocular pressure at a higher doses (40 mg). A

randomized-controlled trial found a reduction of intra-ocular pressure upon smoking cannabis.

However, this study was accompanied by alterations in mental status. THC eye drops have reported

to reduce the intra-ocular pressure with minimal side effects. The untreated eye showed parallel

reductions in intra-ocular pressure, suggesting a systemic rather than a local mode of action. It is

suggested that cannabinoids can reduce intra-ocular pressure by influencing aqueous humor

production and outflow through the activation of the CB1 receptor (Hazekamp & Grotenhermen,

2010). Although topical administration by means of eye drops would be ideal for glaucoma-

treatment, they have been associated with irritation and corneal damage (Robson, 2001). In 2010,

Canadian Ophthalmological Society did not agree on the policy to recommend the medicinal use of

marijuana for glaucoma patients. They explained their discussion to be the result of a lack of

scientific evidence showing a beneficial effect on the progress of the disease, undesirable

psychotropic and other systemic side effects, and a temporary duration of action (Buys & Rafuse,

2010).

5.1.9 Other Disorders with potential CBM Application.

There are a lot of other potential targets for CBM use. Since reviewing of all of them is impossible,

only the most significant were presented. For some diseases the research has started recently, thus

more time is needed for detailed investigation. Only in Great Britain, there are an estimated 50,000–

100,000 people with diabetes using cannabis, of which an unknown number uses the drug for self-

medication. Indeed, experimental studies indicate that the ECS has a role in mechanisms central to

diabetes. Therefore, studies that try to gain insight into the relationship between cannabis,

cannabinoids and diabetes are emerging (Frisher et al., 2010). Clinical trials of cannabis extracts for

the treatment of bladder dysfunction bring promising hope for patients suffering from problems with

their lower urinary tract (Ruggieri, 2011). However, a much greater understanding of the

mechanisms of action of cannabinoid receptors in the human body is necessary to facilitate

development of novel cannabinoid medicines.

5.2 Adverse Effects of Cannabinoid-Based Medicine

5.2.1 Immediate Adverse Effects

The table A-I (in Appendix I) present the therapeutic use of CBM for specific disorders. As indicated,

CBM administration was associated with several adverse effects observed in a studied population.

The effects varied in relation to the form of CBM (smoked marijuana, extracted plant active

components, synthetic drugs used nowadays in clinical research) and the dosage. The most common

observed side effects were fatigue, sleepiness, anxiety, sedation, disorientation, confusion, and

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dizziness (Sylvestre et al., 2006; Abrams et al., 2007; Ellis et al., 2009). The cannabis extract

containing both purified Δ9-THC and CBD compounds triggers mildly psychotropic side effects in

patients (Tomida et al., 2006). The commercially available CBM, dronabinol, when used in a

concentration higher than 20 mg daily, evokes several side effects, like dizziness and fatigue,

although these are mild and usually improved within a few days (Meiri et al., 2007; Kmietowicz,

2010). The additional side effects, like headache, nausea and over-intoxication were observed when

the dose exceeded 30 mg of the drugs per day. No side effects were observed when the dose of the

drugs did not exceed 20 mg per day (Esfandyari et al., 2007). The administration of Sativex® did not

trigger any side effects, when the concentration of the drug was lower than 25 mg per day (Collin et

al., 2007; Aragona et al., 2009; Conte et al., 2009). However, nausea, dizziness, weakness, fatigue and

headache were reported when the dose exceeded 25 mg per day (Wade et al., 2006; Rog et al.,

2007). The data reported here were collected during numerous clinical studies on patients suffering

from many neurological and physiological diseases or ailments, and stand for immediate side effects

observed during the treatment and after a few hours.

The elucidation of precise adverse effects of CBM on long-term users seems problematic,

since the research done so far mainly presents data on recreational marijuana users. The recreational

marijuana users, however, deal with cannabis that comes from the coffee shop and it is not seen as

the one having therapeutical properties. Therefore, it is crucial to distinguish the recreational

marijuana users from potential CBM patients. Moreover, an observed tendency is that scientific

papers do not publish what exact marijuana chemotype was used in a particular experiment. Since

chemotypes differ from each other with respect to the active compounds composition, the

marijuana used for research should always be analyzed first. Moreover, the dosage of marijuana

used in particular research is often not reported (Kavia et al., 2006; Freeman et al., 2006; Ellis et al.,

2009; Buckner et al., 2011).

5.2.2 Dependency

Dependency, in relation to drugs, means that a person needs a certain substance to function

normally. If drug administration is ceased abruptly, withdrawal symptoms occur. Drug addiction is

the uncontrollable use of a substance, despite its negative or dangerous effects. Drug abuse can lead

to drug dependence or addiction. People who use drugs for pain relief may become dependent,

although this is uncommon. It has been proposed that regular and long term use of cannabis might

induce several adverse effects such as dependence syndrome (Morioka et al., 2010). Δ9-THC

stimulates brain-reward areas through the activation of CB1 receptors and induces drug-seeking

behaviour. However, there is no direct evidence showing the dependency amongst patients using

CBM. Tolerance to the behavioural and pharmacological effects of cannabis can occur within days or

weeks after repeated usage. Several studies reported cases of tolerance to the effects of cannabis on

mood, memory, psychomotor performance, sleep, EEG, heart rate, arterial pressure, body

temperature and anti-emetic effects. Dose and frequency of administration are important indicators

for the rate of onset and the degree of tolerance. It is therefore difficult to predict the degree of

tolerance in an individual or to predict the extent to which a particular task is impaired by a given

dose of cannabis or THC. Withdrawal syndromes can be developed after chronic use. The prevalence

of withdrawal symptoms among chronic cannabis users is estimated between 16% and 29%. More

detailed information has been reported by DSM items (American Psychiatric Association, 1994).

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5.2.3 Psychosis and Schizophrenia

By now several data support the link between psychosis, schizophrenia and cannabis use (Veen et al.,

2004; Green et al., 2005; Gonzalez-Pinto et al., 2008). Cannabis can cause an acute toxic psychosis,

which is a non-specific acute brain syndrome that can occur with other intoxicants as well. Symptoms

that are commonly seen in acute toxic psychosis are delirium with confusion, prostration,

disorientation, derealisation and auditory and visual hallucinations. Although relatively uncommon,

acute paranoid states, mania or hypomania with persecutory and religious delusions and

schizophrenic form psychosis may also occur. However, only a very small percentage of the

population exposed to cannabinoids develops a psychotic illness, which suggests that patients with

genetic vulnerability are more susceptible for psychiatric effects of cannabis (D'Souza et al., 2009).

Many studies indicate aggravation of schizophrenia by cannabis and that cannabis can antagonize the

therapeutic effects of anti-psychotic drugs in previously well controlled schizophrenic patients. It is

however not clear if cannabis can actually cause schizophrenia in patients that would otherwise not

have developed it.

Animal studies and molecular research suggest that cannabinoids may affect normal brain

development during adolescence, increasing the risk for schizophrenia (Fernandez-Espejo et al.,

2009). This can be explained by the fact the cannabinoid receptors expression profile differs in

juveniles and adults (Heng et al., 2011). Therefore, cannabis can activate schizophrenia at earlier

lifetime in vulnerable individuals. In addition, experimental data indicate that stimulation of CB1

receptors lead to a facilitation of dopamine release in the mesolimbic system and a disregulation of

dopaminergic activity, which is critical in the mechanism of schizophrenia (Fernandez-Espejo et al.,

2009).

5.2.4 Effects on Cognition and Memory

In the general scientific literature, impairment of memory is often cited in association with cannabis

administration. Ranganathan and D’Souza (2006) found that acute usage of cannabis deteriorate

immediate and delayed free recall of information, while Fletcher and Honey (2006) also gave an

evidence for “difficulties in manipulating the contents of memory, failure to use semantic processing

and organisation to optimise episodic memory encoding, and impaired retrieval performance” (p. 6).

Despite the observation of memory problems, the exact mechanism of how cannabis effects

cognition is not yet defined (Solowij & Battisti, 2008). There is an increasing amount of evidence that

long-term cannabis users can develop functional changes in the brain, which is manifested by subtle

aggravation in cognitive function. These changes however depend on the dose and the duration of

administration. To elucidate the nature of memory deficits in cannabis users, more studies are

needed.

5.2.5 Effects on Mood

One of the most commonly experienced effects of cannabis is euphoria, a feeling of great happiness

or well-being that is mostly exaggerated and not necessarily well-founded. Euphoria is mostly not

experienced as an adverse effect but as a pleasant effect instead. Dysphoria reactions to cannabis

use are the most common adverse psychological effects of cannabis use. Dysphoria may include

anxiety and panic, unpleasant somatic sensations and paranoid feeling, mania or depression. People

who have experienced dysphoria may relive this feeling several weeks or months later without

further exposure to the drug (Sanches &Marques, 2010). Moreover, cannabis exerts a generalized

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CNS-depressant effect, resulting in drowsiness and sleep after an initial period of excitement

(Sanches & Marques, 2010). For certain disorders however, for example anxiety, these effects may

be beneficial. Schofield et al. (2006) found that “boredom, social motives, improving sleep, anxiety

and agitation associated with negative psychotic symptoms or depression were the most important

motivators of cannabis use” (abstract, p.570) and subsequently the factors mentioned above were

overcome by cannabis administration.

5.2.6 Effects on Motor Function

Anecdotal reports describe functional improvement in motor function (e.g. more legible

handwriting). Indeed, during surveys of patients with MS and tremor (which is usually cerebellar in

origin), respondents often report clinical benefit after using cannabis (Brust, 2010). However, acute

cannabis consumption may initially increase motor activity and is followed by a state of physical

inertia with ataxia, dysarthria and general incoordination, which may last several hours depending on

the dosage (Muller-Vahl et al., 1999).

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6. Legislation & the Dutch Government

6.1 Towards Legal Medicinal Cannabis

The process towards legalisation of medicinal cannabis in the Netherlands started in 1996 with a

request of minister Borst of Public Health, Welfare, and Sport (Volkgezondheid, welzijn, & sport,

hereafter referred as the ministry of VWS) to the Health Council of the Netherlands

(Gezondheidsraad). In this request, the minister demanded advice from the council on the status of

the medicinal application of cannabis. The minister did this, because a growing patient population

worldwide indicated to benefit from cannabis usage, but the Opium Law, at that time, did not allow

the usage of cannabis as such (Ministerie van VWS, 1996; Commissie Evaluatie Medicinale Cannabis,

2005). In their report, the Health Council indicated that there was insufficient evidence to support

the medicinal usage of cannabis and cannabinoids, partially due to an inadequacy and insufficiency in

the clinical research up to that point (Gezondheidsraad, 1996). As a result, the minister indicated that

no measures would be taken to legalize medicinal cannabis, but that she was positive towards well-

conducted clinical research on the medical application of cannabis (Kamerstukken II, 1997).

In order to further clinical research, the minister indicated in 1998 that she would like to

found a national bureau, which is an official requirement under international law for policy changes

related to narcotic drugs (see Chapter 6.4). At this point the founding of a national bureau and the

cannabis supply were primarily meant for medical and clinical research (Commissie Evaluatie

Medicinale Cannabis, 2005). This national bureau, the Office of Medicinal Cannabis (Bureau voor

Medicinale Cannabis, hereafter referred to as BMC), was founded in 2000 and functions as the

executive branch of the ministry of VWS (Staatscourant, 2000). One of its first tasks was to alter the

Dutch Opium Law, to provide the office and its tasks with a lawful basis (Commissie Evaluatie

Medicinale Cannabis, 2005).

Even though in first instance the prime function of the BMC was to stimulate scientific

research in the workings of cannabis, in 2001 it became clear that the development and registration

of cannabis as a medicine would need at least another five years. Since it was known that a number

of patients obtained cannabis from the coffee shop, illegal organizations, or illegally from

pharmacies, with quality standards considered to be doubtful, the Second Chamber and the ministry

considered waiting for another five years too long. In addition, the Second Chamber and the ministry

acknowledged that in the illegal circuit no guidance could be given by doctors or pharmacies. As a

result, it was decided in 2001 to legalize the usage of cannabis for medicinal usage (by patients), in

addition to usage for medical and clinical research (Kamerstukken II, 2001; Commissie Evaluatie

Medicinale Cannabis, 2005). From 2003 onwards, medicinal cannabis can be obtained from the

pharmacy with a prescription.

6.2 Legal Medicinal Cannabis : 2002-2011

Over the past eight years medicinal cannabis can, thus, be obtained by patients for medical purposes,

thanks to a change in the Opium Law. As this measure was considered to be politically sensitive at

the time, and the mandate of the BMC is only guaranteed for periods of five years, it is interesting to

consider the opinions of the Dutch government and the First and Second Chamber on this topic over

the past nine years (Commissie Evaluatie Medicinale Cannabis, 2005). In total 117 official,

governmental documents were found within the period of January 2002 – March 2011 with the

search term ‘medicinale cannabis’ (medical cannabis). In the period of 2002-2003 these are primarily

42 | P a g e

clarifications on the execution of the Opium Law and the workings of the BMC by the ministry to the

chambers, as well as financial overviews of the ministry of VWS. In 2004, the publications are

primarily characterized by questions from members of the Second Chamber to the former minister of

VWS, dhr. Hoogervorst. Hereof, it became, among others clear that the Dutch government does not

subsidize clinical research on cannabis, does support the higher prices demanded by the pharmacies

compared to regular illegal cannabis, is aware of the former surplus, and would recommend patients

to use the official, legal medicinal cannabis (among others, Kamervragen (Aanhangsel) 1281, 1313,

2035).

In the beginning of 2005, a more extensive question and answer session in the Second

Chamber was published. From this, it becomes clear that in the first two years, the BMC did not

function optimally. Losses were made, as the amount of patients that would allegedly use the legal

medicinal cannabis turned out to be lower than expected. This was thought to be due to several

reasons: the legal medicinal cannabis was more expensive than cannabis from the coffee shop (about

2-3 euros per gram), a limited range of types was available, the expenses were largely uncovered by

the insurance, doctors are sceptical on the prescription of medicinal cannabis, the quality of the

cannabis was not yet steady, and cannabis usage has a bad image in society (Ministry of VWS, 2005).

Together, this lead to the consideration of the government to stop with the legal provision of

medicinal cannabis (Timmer & Van der Ham, 2005). Consequently, an evaluation report by the

ministry of VWS was issued (Commissie Evaluatie Medicinale Cannabis, 2005). In this report, the road

towards legalised medicinal cannabis is described, as well a description of the current status of

medicinal cannabis in the Netherlands. The main conclusions were that the introduction has been

appropriate according to the law, that it was successful both for research and medicinal purposes,

that the Dutch government has successfully stimulated the movement towards registration of

cannabis as a medicine, and that the BMC did not reach its break-even requirement. Also several,

critical footnotes had to be made, among which the apparent non-acceptance of medicinal cannabis

by Dutch health practitioners. These footnotes should be given more consideration in future times,

according to the committee (Commissie Evaluatie Medicinale Cannabis, 2005).

Interestingly, in 2005, the Second Chamber also demanded a research into the possibility to

legalise the production and supply of cannabis to coffee shops. It was concluded, however, that such

a legalisation would be in contradiction to European and International Law (TMC Asser Instituut,

2005). In 2006, there were plans by the city of Groningen to introduce a cannabis pharmacy. This

idea was supported by the Dutch government, though strict regulation was demanded and has

eventually been executed (Kamerstukken 2006, 915). In 2006, former minister Hoogervorst also

informed the Second Chamber on his decision on the continued provision of medicinal cannabis.

Firstly, he notes that he would like to put further effort into the registration of cannabis as a

medicine, by working together with a consortium of Dutch enterprises. In his opinion, there is still

sufficient interest in medicinal cannabis, among others from foreign countries (Canada, Italy,

Germany), as well as from foreign enterprises. This marketing potential led the minister to decide to

prolong the legalisation of medicinal cannabis with one year (with an option for five years), with the

aim to make medicinal cannabis more profitable, cheaper, and a registered medicine in this period

(Ministry of VWS, 2006). By the new minister, in 2007, this notion was reinforced, formalizing the

allowance for the following five years, with the remark that in the case of the registration of a

comparable medicine, this decision could be challenged (Ministry of VWS, 2007).

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In 2009, an initiative memorandum was formulated by a member of the Second Chamber, Van der

Ham. On the bases of several cases, he formulated five problems with the current medicinal cannabis

policy, as well as giving four possible solutions (Van der Ham, 2009) (See Table 3 and Table 4). The

responses of the minister to this memorandum are added in the Table 4, where appropriate (Van der

Ham, 2009b; Ministry of VWS, 2009). Also, a meeting was organized to discuss this nota, of which

three outcomes were formulated, followed by a reaction of the minister (Ministry of VWS, 2010).

Firstly, a meeting was organized for insurance companies, with the aim to show them the benefits of

medicinal cannabis. Secondly, it was requested to reassess the potential to get medicinal cannabis

approved as a rational pharmacotherapy. The ministry and the BMC are, together, with the

Committee for Pharmaceutical Help (CFH) working on this. Thirdly, it was asked whether cannabis, as

a plant, could be registered as a medicine. In principle, the minister noted, that this is possible, but a

large variety of trials and tests need to be performed to achieve this registration (Ministry of VWS,

2010). In response to this memorandum, thus a variety of issues were clarified. After the mentioned

publications, no new data on medicinal cannabis has been made available. Questions that remain

are, whether cannabis can be approved as a rational pharmacotherapy, what the progress on official

registration of cannabis as a plant is, and what will happen to the medicinal cannabis policy in 2012 –

five years after the prolongation of the mandate by former minister Klink (2007). An overview of the

abovementioned procedures can be found in Figure 13.

Table 3. Problems with the Dutch policy towards medicinal cannabis, identified by Van der Ham, 2009.

Problem Explanation

Unclarity about application and shortage of

research

Doctors do not know exactly for what diseases they can

prescribe medicinal cannabis, nor are they aware that cannabis

does not necessarily need to be smoked. In addition, there is

insufficient research on the potential medicinal usage of

cannabis. There is a role for the BMC here, according to Van der

Ham.

Shortage of available cannabis types Different types of cannabis have different cannabinoid contents

and yield, therefore, different bodily responses. For different

diseases, different cannabis types are needed. Currently, there

are only three types available, forcing people into the illegal

circuit and self-cultivation.

Costs The prices of medicinal cannabis are much higher than for illegal

cannabis (8,90 Euro, vs. 7,70 Euro for Dutch marijuana, and 4,30

Euro for imported marijuana). For regular users, this comes

down to a difference of several thousands of Euros a year. Also,

medicinal cannabis is not yet reimbursed by all insurance

companies.

Self-cultivation Self-cultivation is a solution sought by several patients.

Cultivation, however, to meet the needs for medicinal usage are

in contrary to the Opium law.

Quality of medicinal cannabis vs. Illegal

cannabis

The medicinal cannabis was, in an independent research found

to be of much higher quality than illegal cannabis. The fungi,

metals, and pesticides in illegal cannabis can pose a risk to

people with a weak overall health.

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Table 4. Potential solutions to the problems with the Dutch policy towards medicinal cannabis, as identified by

Van der Ham, 2009. Responses by the Minister of VWS, Ab Klink, are added (Ministry of VWS, 2009).

Solution Explanation Response Minister

Better information

provision and more

research

The ministry of VWS should get in

touch with patient organizations and

doctor organizations to inform them

about medicinal cannabis and its

applications. Also, the BMC should

invest into research into cannabis

usage.

It is not the role of the government to

inform doctors or stimulate research in

this area. The minister sees a role here

for pharmaceutical companies.

Expansion of the amount of

available cannabis types

In consultation with patient

organizations, the need for new or

other cannabis types should be

investigated. According to American

specialists, a variety of seven to ten

types is necessary to cover the needs

of all patients.

Possible, but only on indication of

patient organizations. If these

organizations indicate a need for a

substantial amount of patients, the

BMC will consider the introduction of a

new sub-type (note: in 2011 a new sub-

type was added as an experiment).

Medicinal cannabis should

become cheaper

It is proposed to put medicinal

cannabis in the basis insurance.

The minister agrees that cannabis

should be part of the basis insurance.

However, in the basis insurance only

registered medicines can be

reimbursed. Cannabis is not a

registered medicine yet. A Dutch

company is working on a CBM, for

which registration would be requested.

This product was, at the point of

writing, in clinical trials.

Allowance of self-cultivation

to patients

In consultation with a doctor, a

patient could be allowed to cultivate

more than the current maximum

quantity on medicinal grounds. This

would entail a change in the Opium

Law, but would be in accordance

with a recent decision by the Dutch

High Court (Hoge Raad).

The Dutch government does not want

to support self-cultivation by patients,

as it is contrary to Dutch and

international law. The decision of the

High Court was an exception.

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1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012

1996: Request for advice on medicinal cannabis to health council by Ministry of VWS

1998: Idea for a national bureau on cannabis to further clinincal research

2000: Start up of National Bureau (the BMC).

2001: Decision that the BMC would not only stimulate clinical research, but would also produce medicinal cannabis for patients.

2005: Publication of Evaluation Report

2005: Production only by Bedrocan.

March 2003: Growing of cannabis officially allowed to Bedrocan and SIMM

2002: Official changes in Opiuml aw

September 2003: Cannabis officially allowed to be prescribed by doctors and supplied by pharmacies.

2006: Decision to prelong the supply of medicinal cannabis with 1 year.

2007: Decision to prelong the supply of medicincinal cannabis with 5 years.

2009: Initiative memorandum on the accessibility of medicinal cannabis

2011: Availability of fourth subtype (Bedica)

2012: Probable reconsideration of the

Note: In the period between 2002-2011 a relatively critical attitude could be observed in the Dutch Second Chamber, shown by the nature and amount of questions asked by members of the Second Chamber.

Fig. 13. The governmental process towards the legalisation of medicinal cannabis, and the process from the legalisation to now. Described are the major decisions and date

in the recent history of medicinal cannabis in the Netherlands.

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Psychoactive drugs and narcotics are in the Opium law divided in two categories, list I and II.

Currently, hennep and hashish are on list II of the Opium law, which means they are considered to be

soft drugs. Tetrahydrocannabinol, however, one of the active components in hennep and hashish is,

when isolated, considered to be a hard drug and is, as such, placed on list I due to its psychoactive

properties. On which list the drug is present indicates also how high the punishments are when the

Opium law is not abided to. The Dutch Opium law is famous for its associated “gedoogbeleid”. This

means, among others, that for specific drugs people are allowed to carry with them small quantities

of drugs for personal usage. For hennep and marijuana this limit is set at five grams (Openbaar

Ministerie, 2000). The regulations with respect to the policy on coffee shops are also described in the

Opium law. Coffee shops are tolerated (“gedoogd”) to sell soft drugs under specific regulations: no

advertisement, no access for anyone below the age of eighteen, only soft drugs can be sold, no

public disturbance, and no more than five grams of marijuana can be sold per person. Interestingly,

even though the selling of marijuana is permitted, the production and delivery of the compound is

prohibited, making the coffee shop business half legal/half illegal. Lastly, in the Netherlands, a person

is tolerated (but again, not allowed) to grow cannabis plants for personal usage, with a limit set at

five plants a person (Openbaar Ministerie, 2000).

6.3 International Law & Foreign Regulations

The current Opium law and the regulations surrounding medicinal cannabis in the Netherlands are

based on the Single Convention on Narcotic Drugs of 1961 (United Nations, 1961). This convention is

an international treaty which prohibits the production and supply of specific drugs, as well as

describing drugs for which a license can be given for specific purposes, such as medical treatment or

research. In this convention, drugs are classified under schedule I till IV. According to article 3, a new

drug should be scheduled as I or II when it is a “substance liable to similar abuse and production of

similar ill effects as the drugs already in Schedule I or II, or is convertible into a drug”. In comparison,

of new drug would be in Schedule III when “the preparation, because of the substances which it

contains, is not liable to abuse and cannot produce ill effects; and the drug therein is not readily

recoverable”. A drug is scheduled as IV when it was in Schedule I, but appears to be “particularly

liable to abuse and to produce ill effects, and no such liability is offset by substantial therapeutic

advantages”. Whereas drugs as methadone and opium are scheduled in I, cannabis is considered to

be a Schedule IV type of drug. Even though requests have been filed to reschedule

cannabis/marijuana, the drug is officially still considered to be a Schedule IV (United Nations, 1961).

The classification of cannabis has had a substantial influence on the regulations on medicinal

cannabis in the Netherlands. In article 23 it is mentioned, for example, that to permit cultivation of

opium poppy or the production of opium, one or more government agencies should be installed to

carry out specific, regulatory functions. In article 28 it is mentioned that this regulation also applies

to cultivation of the cannabis plant. The BMC is founded in accordance to this regulations and

distributes licences for the production, distribution, sterilisation, and quality control.

Art. 23. - 1. A Party that permits the cultivation of the opium poppy for the production of opium shall

establish, if it has not already done so, and maintain, one or more government agencies (hereafter in

this article referred to as the Agency) to carry out the functions required under this article.

The Agency shall designate the areas in which, and the plots of land on which, cultivation of the

opium poppy for the purpose of producing opium shall be permitted.

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Only cultivators licensed by the Agency shall be authorized to engage in such cultivation.

Each license shall specify the extent of the land on which the cultivation is permitted.

All cultivators of the opium poppy shall be required to deliver their total crops of opium to the Agency.

The Agency shall purchase and take physical possession of such crops as soon as possible, but not

later than four months after the end of the harvest.

The Agency shall, in respect of opium, have the exclusive right of importing, exporting, wholesale

trading and maintaining stocks other than those held by manufacturers of opium alkaloids, medicinal

opium or opium preparations. Parties need not extend this exclusive right to medicinal opium and

opium preparations.

Art. 28. - 1. If a Party permits the cultivation of the cannabis plant for the production of cannabis or

cannabis resin, it shall apply thereto the system of controls as provided in article 23 respecting the

control of the opium poppy.

Other international laws to which the Dutch Opium Law adheres are the Convention on

Psychotropic Substances (1971) (to cover newly discovered psychotropic drugs), and the Joint Action

of 16 June 1997 adopted by the Council on the basis of Article K.3 of the Treaty on European Union,

concerning the information exchange, risk assessment and the control of new synthetic drugs. Both

are, however, of lesser interest to the present report as they do primarily regulated new

psychotropic and synthetic drugs.

Outside the Netherlands, an increased tolerance to medicinal cannabis and cannabis in

general has been observed (Ministry of Justice, 2002). Even though the coffee shop policy executed

by the Dutch government is still considered to be contrary to the Single Convention of Narcotic

Drugs, more countries seem to follow the example of the Netherlands. Countries such as Italy,

Luxemburg, Portugal, and Spain are known to tolerate the possession of cannabis for personal use

and only impose administrative sanction on the buying, selling or possession of cannabis, in general

(Ministry of Justice, 2002). Similarly, countries like Germany, Finland, and Italy appear to import

Dutch cannabis for medicinal purposes (Drugtext, 2007).

In general, however, it is difficult to get a good overview of the current status of medicinal

cannabis tolerance and legalisation worldwide. The recent changes in the field are extensive and

countries just have, or plan to update their regulations on the subject. Even on the site of the

International Association for Cannabinoid Medicines (IACM) the information is not up to date and

information dates back, in many cases, to 2008 (IACM website, 2011). Greater tolerance towards the

medicinal use of cannabis has, however, been observed over the past years in Switzerland, the

United Kingdom, Luxemburg, Portugal, Finland (after 2008), Germany (2007 onwards), Israel, Spain,

United States, and Canada (IACM website, 2011; Ministry of Justice, 2002; Drugtext, 2007; Pudney,

2010; IACM bulletin, 2009). In the United States, the regulation is quite exceptional, as the usage is

allowed in certain states, but not in others (12 of the 50 states) (IACM USA, 2008; NCSM website,

2011). Also in France, there is a possibility to obtain medicinal cannabis, however, this is only

possible after approval by the Authorisation Temporaire D’utilisation (ATU) (Michka, 2009). In

Sweden, on the contrary, the medicinal usage of cannabis is not accepted at all: for example, in 2004

and 2008 people were sent to prison due to the usage or growing of cannabis for personal, medicinal

purposes (IACM Sweden, 2008). Great differences are also seen between what is accepted. In certain

48 | P a g e

countries, for example, only synthetic derivatives or herbal isolations are allowed (for example,

Sativex®), whereas in other countries patients are able to import, for example, Dutch grown cannabis

(Ministry of Justice, 2002; IACM website, 2011).

6.4 Office of Medicinal Cannabis

Following the requirement of articles 23 and 28 in the Single Convention on Narcotic Drugs, a

governmental agency regulating the cultivation, licensing, distribution, import and export, and stocks

of cannabis for medical purposes was implemented, the Office of Medicinal Cannabis (BMC). This

office was founded in 2000 and is only concerned with medical and scientific applications and

regulations of cannabis, such as the provision of legal medicinal cannabis to pharmacies, universities,

and hospitals (BMC website, 2011; Commissie Evaluatie Medicinale Cannabis, 2005). The office works

as a sub-division of the Ministry of VWS .

The official goal of the office is to investigate whether or not cannabis or cannabinoid products can

be used as medicines, leading to the potential official, medical registration of such products. Several

associated goals were identified (Ministry of VWS, 2000):

- The development of a product for research

- The development of an appropriate administration method.

- The execution of clinical trials

- The production of legal cannabis for research and medicine production (plus regulation

and distribution).

For the first three goals, a more stimulatory role was envisioned by former minister Borst,

This has also been executed as such. The BMC has not directly sponsored or subsidized cannabis

related research, but does encourage the development of cannabis related products, administration

methods, and clinical trials (Ministry of VWS, 2000). The main responsibilities of the BMC lie,

therefore, in the field of supervising the production and distribution of legal cannabis for medical and

scientific purposes, via the contracting of growers and the controlling of the stocks. In first instance

(in 2000), the provision of medicinal cannabis to patients was not envisioned. This aspect only

became integrated in the policy in 2002, where after also the demand that the office needs to

operate break-even was formulated (Commissie Evaluatie Medicinale Cannabis, 2005). Therefore,

the BMC also provides information to doctors, pharmacies, and patients on the applications and

regulations of the usage of medicinal cannabis in the Netherlands. Thanks to its monopoly position,

the BMC is also the only organization which is legally allowed to import and export cannabis and

hashish to and from other countries.

When a pharmacy or research institute wants to supply or work with medicinal cannabis, a

so-called opium-exemption needs to be requested from the BMC. This exemption allows the

pharmacy or research institute to work with cannabis, hashish, hennepoils, or preparations of these

products and to maintain a limited stock. An exemption can be given for the reasons: public health,

health of animals, research, and trade. The request for exemption requires the payment of a

compensation to the BMC of €1225,-, followed by a yearly due amount of €350,-. An exemption is

provided for a period of five years. After obtaining the exemption, a pharmacy or research institute is

legally allowed to work with and supply cannabis (BMC website, 2011).

In line with its goals and legal obligations, the BMC has to select specific growers for the

cultivation of legal cannabis. These growers need to meet specific regulations. For example, these

growers need to possess a certificate of good conduct and need to agree to sell their full harvest to

49 | P a g e

the BMC. Also, excess remnants need to be destroyed directly. These regulations are put in place to

ensure that no agency-produced cannabis will enter the illegal circuit (Ministry of VWS, 2000).

Selected growers are visited regularly by representatives of the Inspection of Healthcare and

employees of the BMC.

At the start, the BMC contracted two growers, the Stichting Institute for Medical Marijuana

(SIMM) and the company Bedrocan. After a conflict with the head of the SIMM, the contract with

this company was suspended in 2004 (Ministry of VWS, 2004). Bedrocan produces cannabis in a

standardized manner, using climate control and specific cultivation procedures for different cannabis

subtypes. Every two weeks fresh cannabis is yielded, which is then dried, the leafs and stems are

removed, cut, and packaged in sets of 250g. Every package is gamma-irradiated to ensure the

absence of fungi and other disease causing agents. Also, every harvest is tested for the presence of

pesticides and heavy metals, as well the amount of active compounds present, by an independent

laboratory, appointed by the BMC. These procedures ensure the quality of the legal medicinal

cannabis (Bedrocan website,2011).

Bedrocan is currently supplying three different types of cannabis, Bedrocan, Bedrobinol,

Bediol. A fourth one was added to this list in April, 2011 (Bedica). These products have different

percentages of cannabinoids and, therefore, different properties. All of these products are registered

as official medical materials, but have not been qualified as rational pharmacotherapies. According to

American specialists, this variety is not sufficient to cover the needs of all patients. Hereto, a number

of seven to ten varieties should be available (Van der Ham, 2009). The ministry of VWS, the ministry

responsible for the BMC, responded that when patients, via patient organizations would indicate the

need for an additional subtype, this would be taken into consideration (Ministry of VWS, 2009).

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7

7.4 Legally available CBMs in the Netherlands

With respect to medicinal cannabis, there are currently three (and from April onwards four) types of

medicinal cannabis available at Dutch pharmacies. These four types differ in their contents of THC

and CBD (see Table 5). Duo to its different composition (a relatively low THC and high CBD content),

Bediol is thought to be especially suitable for MS patients, as this combination might help to relieve

pain and spasms (cramps). Besides, CBD does not only reduce cramps, but also reduces inflammation

In addition, CBD has a less psychoactive effect on the brain and is, therefore, also used by other

patients (BMC website; medicinal cannabis).

Table 5. Different types of Medicinal Cannabis in the Netherlands and their respective composition and

strengths. (Adapted from: BMC website; medicinal cannabis, 2011)

Bedrobinol and Bedrocan are available as dried flower tops, whereas Bediol and Bedica are available in a

grounded form. The latter form is said to be easier in administration to patients. * Excluding 6% VAT. ** The

difference between Bedica, the most recent medicinal cannabis types, and Bedrobinol, Bedrocan, and Bediol, is

the plant subtype used. There consists three main cannabis subtypes: sativa, indica, and ruderalis. The

company Bedrocan claims that the difference between these two subtypes can be found in the quantity of

terpenes present. For example, Bedica has a higher percentage in myrceen, a compound with a calming effect

(Bedrocan website, 2011).

So far, no other cannabis-based medicine have been registered or approved in the Netherlands (only

medicinal cannabis is registered as a precursor medicine). Sativex® (a plant extract containing THC

and CBD), which is marketed by the British GW Pharmaceuticals as a treatment for, among others,

MS and muscular spasms, has been officially approved in the United Kingdom, Canada, Spain and

New Zealand (GW Pharmaceuticals). It is not registered yet in the Netherlands, which is interesting,

as one of the first approval procedures was commenced in the Netherlands in September 2006

(IACM, 2007). Marinol (synthetic THC), from Solvay Pharmaceutics, is a dronabinol (THC) based

medicine, which is only available outside the Netherlands. With a doctor’s prescription and

permission of the IGZ it is, however, available at the specific pharmacies (Service Apotheek

Oudewater, 2011). Other CBMs that are worldwide (almost)available are:

- Namisol® (a THC extract from cannabis plants): purified THC from cannabis plants. It will

be produced in a tablet form. The first clinical trials with this medicine have started in

2010.

- Cannador® (standardized extract of THC and CBD (2:1)): oral capsule. Clinical trials have

already been conducted for this capsule (Hazekamp & Grotenhermen, 2010). Also

Content (%) Price* Plant subtype

Dronabinol (THC) Cannabidiol (CBD) Per 5 grams

Bedrobinol approx. 12 <1 € 41,25 Sativa

Bedrocan approx. 19 <1 € 41,25 Sativa

Bediol approx. 6 approx. 7,5 € 43,50 Sativa

Bedica approx. 14 < 1 € 45,00 Indica **

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Cannador® can be imported with a doctor’s permission and IGZ approval (Commissie

Evaluatie Medicinale Cannabis, 2005).

- Nabilone® (a synthetic analogue of THC): has been approved in Canada, but not in

Netherlands. It can be imported to the Netherlands with a special doctor’s description

and approval of the IGZ.

7.5 Methods of Administration

The most well-known method of administration of cannabis is, obviously, smoking. However, the

smoking of cannabis is just as harmful as the smoking of cigarettes and carries along the associated

health risks, such as lung complaints and even cancer (Abrams et al., 2007). For terminally ill patients,

however, these are not main concerns and smoking has remained a prime method of administration

(Pharmo, 2004). The advantages of smoking are that the cannabis starts to work immediately on the

body and that it is, therefore, easy to dose. Thanks to these benefits, a search for a better, safer

delivery system was demanded, possessing the properties of making cannabis easy to dose, as well

as safe (Joy et al., 1999). This resulted in the development of the vaporization technique.

Cannabis vaporization occurs by heating the cannabis to a temperature of ~185-200 degrees

Celcius. At these temperatures, the cannabinoids in the cannabis vaporize, whereas combustion and

the vaporization of smoke toxins are avoided (Adams et al., 2007; BMC website, 2011). With this

method, thus, cannabinoids can be inhaled without the toxic by-products of smoking. Several

different types of vaporizers are available on the market, of which one, the Volcano Vaporizer® is the

only one that has been scientifically tested (Hazekamp et al., 2006; Adams et al., 2007). These results

indicate that usage of the Volcano vaporizer is a safer method of administration than smoking,

thanks to a reduction in the respiratory disadvantages, whereas the final pulmonal uptake of the

cannabinoids is comparable (Hazekamp et al., 2006; Adams et al., 2006). Per time, approximately

200mg cannabis should be put into a vaporizer. It is recommended to wait five to fifteen minutes

after an inhalation, to see whether the wanted effects occur (or potential unwanted side effects)

(BMC website, 2011). An advantage of inhalation is the rapid onset of the effects. This makes

inhalation a good method of usage for acute (pain) complaints.

Another method of administration is via the consumption of tea. Even not as popular as

smoking, a substantial amount of patients takes their cannabis like this. The effects of drinking tea

are mild, since the concentration of cannabinoids is low. This is due to the relatively insolubility of

cannabinoids in water (Hazekamp et al., 2006) . In addition, the effects have a slow onset, but remain

for several hours. Therefore, making cannabis tea is a usable method for people more chronic

complaints (NCSM website; cannabis thee, 2011). To make cannabis tea, one gram of cannabis needs

to be dissolved in one litre of boiling water. When coffee milk or chocolate milk powder is added, this

tea can be preserved for about five days. To increase the concentrations of cannabinoids, people can

add a little bit of butter or oil to the tea – to dissolve the cannabinoids (NCSM website, 2011).

Of the other available CBMs, Sativex® needs to be administered as an oromucosal spray, whereas

Marinol® is a gelatin capsule, Namisol® is/will be available in tablet form, and Cannador® and

Nabilone® are available as capsules.

7.6 Cost Coverage

In the Netherlands, the Health Care Insurance Board (College van Zorgverzekeringen, CVZ)

determines which threatments and medicines are included in the basic health insurance (at:

52 | P a g e

www.cvz.nl). In 2003 the Ministry of VWS asked the CVZ to assess the therapeutic potential of

medicinal cannabis. The conclusion of the report of CVZ was that there was insufficient evidence for

the therapeutic potential of cannabis in any disorder so far (van Luijn, 2003). Therefore the CVZ

advised to not include medicinal cannabis in the basis health insurance. This does not mean that

medicinal cannabis cannot be included in the basis health insurance, but every health insurance

company is free to determine their own reimbursement policy for medicinal cannabis (NCSM, 2009-

a).

In 2009 the NCSM researched the reimbursement policies for medicinal cannabis of fourteen

of the largest health insurance companies in the Netherlands. A summary of the results of this

research can be found in Table 6.

As can be seen in Table 6, ten out of the fourteen health insurance companies reimburse (a

part of) the costs for medicinal cannabis. FBTO is the only insurance company that includes

medicinal cannabis in the basis insurance. In all the other insurance companies, medicinal cannabis is

included in additional policies or in so called “coulance” policies. A coulance insurance means that

medicinal cannabis can be reimbursed in some special cases. A written motivation of a doctor is

needed which states why a patient needs medicinal cannabis (NCSM, 2009). Azivo even has a

questionnaire that has to be filled in by the doctor in charge. Then, a specialist or doctor within the

insurance company will assess if, based on the motivation of the doctor, (a part of) the costs are

reimbursed or not. Interpolis only accepts requests for medicinal cannabis that are submitted by a

medical specialist, in this case a neurologist, oncologist or pain specialist. Salland and Azivo state

explicitly that medicinal cannabis is only reimbursed when other medications are not sufficient, do

not work or have many side effects. In two insurance companies, CZ and Delta Lloyd, the opinion of

the doctor who prescribes the medicinal cannabis is decisive. In that case there is no need for the

insurance company to assess the motivation of the prescribing doctor (NCSM, 2009).

The percentage of the costs that is reimbursed is often fixed per insurance company. Looking

at the table, the insurance companies cover 75% or 100%. But the maximum amount of money that

is reimbursed is not always fixed, even not within one insurance company. In case of an additional

insurance, a more expensive insurance covers in general more costs for medicinal cannabis (NCSM,

2009). For example in Delta Lloyd, the maximum reimbursement varies from 150 Euros per year to

no maximum, depending on how extensive additional packages the patient has. CZ has the highest

set maximum, but they emphasize that a very extensive additional insurance is needed which only

little people have (NCSM, 2009). Vaporizers are only reimbursed in CZ and Delta Lloyd.

Table 6. Summary of NCSM report: The reimbursement of medicinal cannabis by Dutch health insurance

companies (From NCSM, 2009-b). a) FTBO can ask for a contribution of the patient. b) Azivo does not

reimburse vaporizers, only in rare cases. c) The cannabis has to be obtained from the Azivo pharmacy. d)

Salland looks at every individual case to determine the amount of money that is reimbursed. e) Salland

does not comment on this.

53 | P a g e

Reim

bu

rsem

ent o

f med

icinal

cann

abis?

Type o

f Insu

rance p

olicy

Am

ou

nt o

f reimb

urse

men

t

(%)

Maxim

um

amo

un

t

reimb

ursed

ann

ually (Eu

ros)

For all in

dicatio

ns?

Op

inio

n o

f do

ctor d

ecisive?

Reim

bu

rsem

ent o

f

vapo

rizers?

On

ly cann

abis fro

m th

e

ph

armacy?

Agis yes additional 75% € 200 - 600 no no no

FBTO yes basic 100%

no maximum

a yes no no yes

Interpolis yes coulance 100% € 900 yes no no yes

Zilveren Kruis -

Achmea yes coulance 75% € 900 yes no no yes

Azivo yes coulance 75% € 45 p.m. yes no no b yes c

CZ yes additional 100% € 4.500 yes yes yes yes

Delta Lloyd yes additional 100%

€ 150 - no

maximum yes yes yes yes

Menzis yes coulance 75% € 45 p.m. no no yes

OHRA no no

ONVZ yes additional 100% no no yes

Salland

yes coulance var. d

depends on

individual

case

no ? e

Univé no no

Trias no no

VGZ no no

In most cases only medicinal cannabis from the pharmacy is reimbursed. There is one

exception, Agis also reimburses cannabis from the coffee shop that is used for medicinal purposes.

The choice of pharmacy is free for the patient. Again, there is one exception, Azivo. Azivo reimburses

only medicinal cannabis from a Azivo pharmacy. Some insurance companies defined indications for

which medicinal cannabis is reimbursed. Both Agis and Menzis reimburse medicinal cannabis for

certain indications only. Agis reimburses for three indications, namely: sleeping problems because of

Amyotrophic lateral sclerosis (ALS), spasms in MS, and extreme pain in cancer. Menzis reimburses

for four indications: severe pain in cancer, severe cramps in MS, neuropathic pain, and severe nausea

and decreased appetite in AIDS (NCSM, 2009).

The four insurance companies that do not reimburse medicinal cannabis, also do not

reimburse vaporizers. In the past, till 2005, Univé did reimburse medicinal cannabis (NCSM, 2009). It

is not stated why Univé changed their policy. VGZ based their no reimbursement policy on the report

of the CVZ. The same is applicable for OHRA, who states that medicinal cannabis is not a registered

medicine and therefore not included in their insurances. OHRA only reimburses medicines that are

listed in the Geneesmiddelen Vergoedingssysteem (Medicine Reimbursement System, GVS) of the

government (NCSM, 2009). It has been shown that, in general, patients are satisfied with the

54 | P a g e

reimbursements that they obtain, however, they do note that it would be more appropriate to fully

reimburse the costs. Also, they find it strange that the government does ensure the provision of this

medicine, but does not ensure the cost coverage (Commissie Evaluatie Medicinale Cannabis, 2005).

The interviewed patients note that this lack of full reimbursement might contribute to the relatively

low number of legal users (Commissie Evaluatie Medicinale Cannabis, 2005).

55 | P a g e

8. Conclusion

A lot of aspects related to CBM are discussed. The extended literature research presented here was

conducted on, among others, history, the ECS, therapeutic potential, and legislation, related to CBM.

This resulted in an overview of the state-of-the-art knowledge on CBM. Results obtained from the

literature study were a basis for the qualitative study (Part II). Therefore, issues that were of specific

interest for the qualitative study, are described in this chapter.

As discussed, cannabis is among the most widely disseminated and oldest cultivated plant

species in human history, however, its taxonomy is still being debated. About 400 to 500 compounds

have been detected in these plants, of which there are an estimated 70 to 80 phytocannabinoids,

which are recognized by the bodily ECS. A specific plant or strain has a certain chemotype with

typical quantities of specific phytocannabinoids. However, to subject those chemotypes to further

research, all active substances have to be first identified, subsequently separated and optionally

purified.

The ECS exerts an important neuromodulatory function in different brain areas and is also

known to be involved in the regulation of other peripherally located organs. The first annotation

about the ECS appeared in late 80s, when possible cannabinoid agonists were synthetized for further

research on endocannabinoid receptors. An obstacle for the development of widely accepted CBM

has been the socially objectionable psychoactive properties of plant-derived or synthetic agonists,

mediated by CB1 receptors. However, this problem does not arise when the therapeutic goal is

obtained by treatment with an antagonist of a CB1 receptor. The psychoactive properties may also

be absent when the action of endocannabinoids is improved indirectly through blocking their

metabolism or transport. The use of selective CB2 receptor agonists, which lack psychoactive

properties, could represent another promising possibility for certain conditions. Moreover, studies

demonstrate that many cannabinoid effects cannot be attributed merely to the CB1 and CB2

metabotropic GPCRs. Additional receptor types should exist to explain for the distinct ligands affinity

and the diverse mechanisms of signaling. Moreover, constitutive activation of some receptors was

shown, which was thought to be possibly due to coupling to different G proteins.

Evidence for the therapeutic properties of cannabis or single cannabinoids in certain diseases

is accumulating. Approximately 110 clinical studies, that involved a total number of over 6,100

patients suffering from various diseases, have been conducted in the period of 1975 to 2009. But also

more recently, a considerable number of studies reported on the therapeutic potential of cannabis.

This implies that, currently, there is a great interest in the application of cannabis as a medicine, and

many researchers expect a great potential. The beneficial effects of CBM on certain diseases and

symptoms cannot be disputed anymore, e.g. in pain relief, appetite regulation and nausea, whereas

the beneficial effects of CBM on other diseases is still a rather controversial topic, e.g. in

schizophrenia and Tourette’s Syndrome treatment. In addition to the beneficial potential, CBM is

associated with various adverse effects. It has been proposed that regular and long- term use of

cannabis might induce several adverse effects such as dependence syndrome and drug-seeking

behaviour. However, there is no direct evidence showing the drug dependency amongst patients

using CBM. In addition, tolerance to the behavioural and pharmacological effects of cannabis can

occur within days or weeks after repeated usage. In general, an observed tendency is that scientific

papers do not publish what exact chemotype, or the dosage used, in a particular experiment. Taking

56 | P a g e

this all together, there is a need for more clinical trials on the effects of CBM on specific disorders,

especially related to the specific chemotypes of CBM.

Studying the legal aspects of CBM showed that from 1996 onwards, CBM, in particular

medicinal cannabis, has been a controversial topic of discussion among several government bodies.

With the founding of the BMC, and the legalization of medicinal cannabis under the Dutch Opium

Law in 2003, medicinal cannabis can now be obtained from the pharmacy. Four different types of

medicinal cannabis are available, but have not been qualified as rational pharmacotherapies. It is

stated that the current variety of four types, is not sufficient to cover the needs of all patients.

Currently, in the Netherlands, an estimated 10,000-15,000 people use cannabis as a

medicine. An estimated 1,000-1,500 people use legal, doctor-prescribed medicinal cannabis, with the

number of users declining. The majority of the patients proposes this possibility to their GP

themselves (~60-70%). Only in a limited amount of cases, the initiative appears to come from GPs

themselves. Among specialists, such as neurologists, pain specialists and internists, the initiative for

prescription to patients appears to be even lower (2-17%). Among insurance companies, every

insurance company is able to set up an individual reimbursement policy. Some insurance companies

do not reimburse it at all, whereas others reimburse (part of the) costs for CBM via an additional or

so called coulance policy.

57 | P a g e

Glossary

AA arachidonic acid

AEA anandamide

2-AG 2-arachidonoylglycerol

AKT alpha serine/threonine-protein kinase

ALS myotrophic lateral sclerosis

ATP adenosine triphosphate

ATU Authorisation Temporaire D’utilisation

BMC Bureau Medicinale Cannabis (Office of Medicinal Cannabis)

cAMP cyclic adenosine monophosphate

CB-1 cannabinoid-1 (receptor)

CB-2 cannabinoid-2 (receptor)

CBC cannabichromene

CBD cannabidiol

CBE cannabielsoin

CBG cannabigerol

CBL cannabicyclol

CBM cannabinoid-based medicine

CBN cannabinol

CBND cannabinoidiol

CBT cannabitriol

CFH Committee for Pharmaceutical Help

CNS central nervous system

CVZ College van Zorgverzekeringen (Health care Insurance Board)

ECS endocannabinoid system

ERK extracellular signal-regulated kinase

Et ethanolamine

FAAH fatty acid amide hydrolase

FID Flame Ionization Detection

GABA gamma-aminobutyric acid

GC Gas Chromatography

GPCR G protein-coupled receptor

GVS Geneesmiddelen Vergoedingssysteem (Medicine Reimbursement System)

HPLC High Pressure Liquid Chromatography

HPTLC High Performance Thin Layer Chromatography

IASP International Association for the Study of Pain

IR ionotropic receptor

ICR ionotropic cannabinoid receptor

MAPK mitogen-activated protein kinases

MCR metabotropic cannabinoid receptor

mR metabotropic receptor

mRNA messenger ribonucleic acid

58 | P a g e

MS Mass Spectrometry

MS Multiple Scleroris

NADA N-arachodonoyl-dopamine

NAGly N-arachidonylglycine

NT Neurotransmitter

OEA oleylethanolamide

PAG periaqueductal grey

PPER peroxisome-proliferator-activated receptor

SFK Stichting Farmaceutische Kengetallen (Foundation of Farmaceutical Key Figures)

SIMM Stichting Institute for Medical Marijuana

SPT serine pamitoyltranferase

T unidentified membrane-transport system

THC tetrahydrocannabinol

THCV tetrahydrocannabivarin

TLC Thin Layer Chromatography

TRP transient receptor potential

TS Tourette's syndrome

VDCC voltage-dependent calcium channel

59 | P a g e

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en informatiebeleid voor de komende jaren. Kamerstuk 24077, nr. 200.

Ministry of VWS (2009): Toegankelijker medicinale cannabis; brief minister met reactie op

initiatiefnota ‘Toegankelijker medicinale cannabis’. Kamerstuk 32159, nr. 3.

Ministry of VWS (2010): Toegankelijker medicinale cannabis; brief regering; toezegging gedaan tijdens

het algemene overleg over medicinale cannabis. Kamerstuk 32159, nr. 6.

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http://www.ncsm.nl/artikel/288+Wet+en+regelgeving.html (Accessed at: March 31, 2011)

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(Accessed at: April 6, 2011)

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rapport; uitgevoerd in september 2009. At:

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Openbaar Ministerie (2000): Aanwijzing opiumwet. Nr. 2000A19.

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=1234&Letter=M (Accessed at: April 4, 2011)

Staatscourant 4 september 2000, pag. 11.

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behoeve van de bevoorrading van coffee shops – Internationaalrechtelijke en Europeesrechtelijke aspecten’.

Kamerstuk 24077, nr. 175

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Appendices

I. Tables Therapeutic Potential

Study Country Indication Type of study Product Concentration Patients assessed Efficacy Adverse effects

Skrabek et al. (2008)

Canada Fibromyalgia Randomized, doubleblind, placebo-controlled trial

Nabilone (oral)

Up to 1 mg BID 40 fibromyalgia patients having continued pain despite the use of other oral medications.

Nabilone improved symptoms and was well-tolerated.

drowsiness, dry mouth, vertigo and ataxia

Wilsey et al. (2008)

United States

Neuropathic pain

Double-blind, placebocontrolled, crossover study

Cannabis (smoked)

3.5% and 7.0% cannabis

38 patients with complex regional pain syndrome (CRPS type I), spinal cord injury, peripheral neuropathy, or nerve injury.

Significant improvement of neuropathic pain.

Clear undesirable effects; however, no drop-outs.

Narang et al. (2008)

United States

Chronic pain Phase I: randomized, single-dose, doubleblind, placebo-controlled, crossover trial; Phase II: extended openlabel titrated trial.

Dronabinol (oral)

10 or 20 mg 30 patients with severe chronic noncancer pain, taking stable doses of opioid analgesics for longer than 6 months

THC (in combination with opioids) reduced pain & pain bothersomeness, and increased satisfaction. No difference was observed between 10-20mg THC

Dry mouth, tiredness, sleepiness, and drowsiness

Frank et al. (2008)

Great Britain

Chronic neuropathic pain

Randomised, double blind, crossover trial

Nabilone (oral)

2 mg 96 patients with chronic neuropathic pain Dihydrocodeine provided better pain relief Nabilone

Sickness

Nurmikko et al. (2007)

Great Britain

Neuropathic pain, allodynia

Randomised, doubleblind, placebo-controlled, parallel-group trial

Sativex (sublingual)

Self-titrating regimen. Given in addition to existing stable analgesia.

125 patients with a current history of unilateral peripheral neuropathic pain and allodynia

Significant improvement in pain

Problems with GI-tract and central nervous system- or topical related problems.

Holdcroft et al. (2006)

Great Britain

Postoperative pain

Multicenter doseescalation

Cannador (oral)

Single dose of 5, 10 or 15 mg

65 Postoperative patients experiencing at least moderate pain, after stopping patient controlled analgesia

The optimal dose was 10 mg Cannador, effectively reducing postoperative pain without serious side effects

Non-persisting effect on central nervous or cardiovascular systems.

Pinsger et al. (2006)

Austria Chronic pain Placebo-controlled, double-blind pilot stud

Nabilone (oral)

Up to 1 mg per day

30 patients with chronic therapy-resistant pain in causal relationship with a pathologic status of the skeletal and locomotor system

Given in addition to standard treatment Nabilone caused a significant reduction in pain and improvement of quality of life

dizziness, fatigue, dry mouth and sleepiness

Blake et al. (2006)

Great Britain

Pain in rheumatoid arthritis

Placebo-controlled, randomized, doubleblind, parallel group study

Sativex (sublingual)

Not reported 58 patients with active arthritis not adequately controlled by standard medication

Sativex produced improvements in pain and sleep

Mild transient dizziness

Ware et al. (2006)

Canada Chronic pain Randomized, controlled, crossover trial

Cannabis (smoked)

Various concentrations

8 experienced and authorized (Canada) cannabis users with chronic pain

Medical cannabis users can appreciate differences in herbal cannabis products

Not discussed

Table A-I. Studies on Therapeutic Potential (Adapted from: Hazenkamp & Grotenhermen, 2010)

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Seeling et al. (2006)

Germany Postoperative pain

Randomized, double blind trial

THC (oral) Eight doses of placebo or 5 mg THC

100 patients after radical prostatectomy. No synergistic or additive interaction between THC and piritramide.

Not discussed

Beaulieu (2006)

Canada Postoperative pain

Double-blind, randomized, placebocontrolled, parallelgroup pilot trial

Nabilone (oral)

Three doses with 1 or 2 mg within 24 hours after surgery

41 patients undergoing gynecologic, orthopedic or other surgery

Nabilone did not reduce 24h morphine consumption or improve effects of morphine. Nabilone did increase pain scores.

dry mouth, nausea and vomiting, respiratory depression, sedation and pruritus

Study Country Indication Type of study Product Concentration Patients assessed Efficacy Adverse effects

Kraft et al. (2008)

Austria Acute inflammatory pain and hyperalgesia

Double-blind, placebocontrolled, crossover study

Cannador (oral

4% THC cannabis 18 healthy female volunteers without a history of cannabis use.

No analgesic or antihyperalgesic activity observed for the cannabis extract.However, Cannador did lead to hyperalgesic effect

Hyperalgesic effect

Redmond et al. (2008

Canada Experimental heat pain

Double-blind, placebo controlled, crossover study

Nabilone (Oral)

Single dose of 0.5 and 1.0 mg

17 healthy volunteers.

Nabilone failed to produce analgesic effect, and it did not interact with descending pain inhibitory systems. Significant difference was observed in effects between men and women.

Dry mouth, red eyes, mild sedation, and euphoria

Wallace et al. (2007)

United States

Pain: capsaicininduced and hyperalgesia

Randomized, doubleblind, placebocontrolled, crossover trial

Cannabis (smoked)

2%, 4% and 8% THC cannabis

15 healthy volunteers.

A medium dose of cannabis reduced pain, while a high dose increased pain induced by capsaicin (might be caused by another compound in cannabis).

Increased in capsaicin-induced pain with 8% THC dose

Roberts et al. (2006)

United States

Analgesia, synergy with morphine

Double-blind, four treatment, four period, four sequence, crossover trial

THC (oral) 5 mg THC or placebo. After 90 minutes0.02 mg/kg morphine (intravenously) or placebo

13 healthy volunteers.

There was a synergistic effect between THC and morphine on the affective component of pain but not on the sensory component.

Mild euphoric or dysphoric effects, but no serious or unexpected toxicities occurred.

Study Country Indication Type of study Product Concentration Patients assessed Efficacy Adverse effects

Ellis et al. (2009)

United states

Neuropathic pain

Phase II, double-blind, placebo-controlled, crossover trial

Cannabis (smoked)

Not reported 28 patients with documented HIV infection and neuropathic pain refractory to a least two previous analgesics.

Significant pain relief with cannabis.

concentration difficulties, fatigue, sleepiness or sedation, increased duration of sleep, reduced salivation,

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and thirst. Haney et al. (2007)

United states

HIV: caloric intake, mood, sleep

Placebo-controlled within-subjects study

Dronabinol (oral); Cannabis (smoked)

Dronabinol: doses up to 30 mg.

10 patients taking at least 2 antiretroviral medications, currently under the care of a physician for HIV management, and smoking marijuana at least twice weekly for the past 4 weeks.

THC and cannabis caused an increase in caloric intake and weight.

At highest dose (30 mg): headache, nausea and overintoxication.

Abrams et al. (2007)

United states

HIV: sensory neuropathy

Prospective randomized placebo-controlled trial

Cannabis (smoked)

Cannabis or placebo cigarettes 3x daily, 5 days, containing 1-8% THC.

50 patients with HIV infection and symptomatic HIV-associated sensory neuropathy.

Smoked cannabis was well tolerated and effectively relieved chronic neuropathic pain from HIV-associated sensory neuropathy.

anxiety, sedation, disorientation, confusion, and dizziness. No withdrawals.

Haney et al. (2005)

United states

HIV: caloric intake, mood

Randomized, withinsubject, staggered, double-dummy design

Dronabinol (oral); Cannabis (smoked)

Dronabinol (up to 10 mg daily) and smoked cannabis (up to 3.9% THC

30 HIV-positive patients smoking marijuana.

THC and cannabis cause increased caloric intake.

No clear reported adverse effects.

Study Country Indication Type of study Product Concentration Patients assessed Efficacy Adverse effects

Aragona et al. (2009)

Italy MS: psychopathological and cognitive effects

Double-Blind, placebocontrolled, crossover trial

Sativex (sublingual)

22 mg THC per day

17 cannabis-naïve MS patients

Cannabinoid treatment did not induce psychopathology and did not impair cognition in cannabis-naïve patients

No clear adverse effects

Conte et al. (2009)

Italy

MS: pain Randomized, doubleblind, placebocontrolled, cross-over study

Sativex (sublingual)

8 sprays daily (ca. 20 mg THC and CBD)

18 patients with secondary progressive MS

Results provide objective neurophysiological evidence that cannabinoids modulate the nociceptive system in patients with MS

No clear adverse effects

Collin et al. (2007)

Great Britain

MS: spasticity Randomized, placebo-controlled trial

Sativex (sublingual)

Self-titration; mean dose of ca. 25 mg of THC and CBD

189 MS patients with spasticity.

Significantly reduction in spasticity. No clear reported adverse effects

Rog et al. (2007)

Great Britain

MS: neuropathic pain (Open label extension of Rog 2005)

Uncontrolled, open-label trial

Sativex (sublingual)

Self-titration; mean of ca. 25 mg of THC

63 MS patients with central neuropathic pain.

Sativex was effective, with no evidence of tolerance, in these select patients with CNP and MS who completed approximately 2 years of treatment (n = 28). Ninety-two percent of patients experienced side effects, the most common of which were dizziness and nausea.

Nausea, dizziness, weakness, and fatigue

Kavia et al. (2006)

Great Britain

MS-associated Detrusor overactivity

Double blind, randomized, placebo-controlled parallel group trial

Sativex (sublingual)

Not reported 135 MS patients with an overactive bladder.

Sativex has a beneficial effect on the symptoms of overactive bladder.

Dizziness, urinary tract infection, and headache

Freeman et al. (2006)

Great Britain

MS: urge incontinence

Multicentre, randomised placebo-controlled trial

Cannador (oral); dronabinol (oral)

Not reported 630 MS patients with muscle spasticity.

Cannabis and THC caused a significant reduction in incontinence.

No clear reported adverse effects

Wissel et al. (2006)

Austria

Spasticity related pain

Double-blind placebocontrolled cross-over trial.

Nabilone (oral)

Not reported 11 patients with chronic upper motor neuron syndrome (UMNS).

Significant reduction of pain, but not of spasticity, motor function, or activities of daily living.

Mild, easy tolerable symptoms

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Wade et al. (2006)

Great Britain

MS: spasticity (Open label extension of Wade 2004)

Open label continuation after placebo-controlled study

Sativex (sublingual)

Self-titration; mean of 30 mg THC (11 sprays)

137 MS patients with symptoms not controlled satisfactorily using standard drugs.

Long-term use of an oromucosal CBM (Sativex) maintains its effect in those patients who perceive initial benefit. The precise nature and rate of risks with longterm use, especially epilepsy, will require larger and longer-term studies.

Adverse effects were common but rarely troublesome.

Katona et al. (2005)

Great Britain

MS: cytokine profile

Randomised, placebocontrolled trial at 33 UK centers

Sativex (sublingual)

Not reported

100 MS patients with muscle spasticity.

No evidence for cannabinoid influence on serum levels of cytokines.

Not reported

Study Country Indication Type of study Product Concentration Patients assessed Efficacy Adverse effects

Tomida et al. (2006

Great Britain

Glaucoma: intraocular pressure

Randomized, double-blind, placebo-controlled, 4 way crossover study

2 cannabis extracts rich in THC or CBD (sublingual)

Single dose cannabis extracts containing 5 mg THC, 20 mg CBD, 40 mg CBD or placebo

6 patients with ocular hypertension or early primary open angle glaucoma.

Significant reduction of intraocular pressure

Mildly psychotropic side effects in one patient

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Study Country Indication Type of study Product Concentration Patients assessed Efficacy Adverse effects

Esfandyari et al. (2007)

United States

Colonic motor and sensory functions

Randomized, placebo-controlled study

Dronabinol (oral)

Single dose of 7.5 mg

52 healthy volunteers

THC relaxes the colon and reduces postprandial colonic motility.

Not reported

Esfandyari et al. (2007)

United States

Gastrointestinal transit and postpandrial satiation

Double-blind, randomized, placebo-controlled, parallel group study

Dronabinol (oral)

Three doses of 5 mg 30 healthy volunteers Dronabinol retards gastric emptying in humans; effects are gender-related. Dronabinol also increases fasting gastric volumes in males.

Not reported

Study Country Indication Type of study Product Concentration Patients assessed Efficacy Adverse effects

Meiri et al. (2007)

United States

Chemotherapy-induced nausea and vomiting

Double-blind, placebo-controlled study

Dronabinol (oral)

Increasing dose of up to 20 mg daily, either alone or in combination with ondansetron

64 patients receiving moderately to highly emetogenic chemotherapy.

Dronabinol or ondansetron was similarly effective for the treatment of CINV. Combination therapy with dronabinol and ondansetron was not more effective than either agent alone. Active treatments were well tolerated.

Dizziness and fatigue in patients receiving combination therapy

Strasser et al. (2006)

Switzerland

Cancer: anorexia-cachexia

Multicenter, phase III, randomized, double-blind, placebo-controlled clinical trial

Cannador (oral); THC (oral)

Cannador (standardized for 2.5 mg THC and 1 mg CBD) or THC (2.5 mg) twice daily for 6 weeks.

164 patients with advanced cancer, Cancer-Related Anorexia-Cachexia Syndrome, and severe weight loss

Insufficient difference between Cannador, THC and placebo on appetite or quality of life.

Minority of adverse effects linked to study medication.

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Study Country Indication Type of study Product Concentration Patients assessed Efficacy Adverse effects

Leweke et al. (2007)

Germany Schizophrenia Double-blind, controlled clinical trial

CBD (oral), amisulpride (oral)

Not reported 42 patients suffering from acute paranoid schizophrenia and schizophreniform psychosis.

CBD significantly reduced psychopathological symptoms of acute psychosis. CBD was as effective as amisulpride, a standard antipsychotic.

EPS, increase in prolactin, weight gain. These effects are stronger with amisulpride than with cannabidiol.

D'Souza et al. (2005)

United States

Schizophrenia Double-blind, randomized, placebocontrolled study

THC (intravenous)

up to 5 mg 13 stable, antipsychotic-treated schizophrenia patients

THC is associated with transient exacerbation in core psychotic and cognitive deficits in schizophrenia. These data do not provide a reason to explain why schizophrenia patients use cannabis in self-treatment.

perceptual alterations, cognitive deficits, and medication side effects associated with schizophrenia

Study Country Indication Type of study Product Concentration Patients assessed Efficacy Adverse effects

Guzmán et al. (2006)

Spain Cancer: recurrent glioblastoma multiforme

Pilot phase I trial THC (intra-tumoral)

Not reported 9 patients with recurrent glioblastoma multiforme

THC inhibited tumour-cell proliferation in vitro and decreased tumour-cell Ki67 immunostaining when administered to two patients

Not reported

Sylvestre et al. (2006)

United States

Hepatitis C Prospective observational study

Cannabis (smoked)

Modest dose 71 patients, being recovering substance users

Modest cannabis use may offer symptomatic and virological benefit to some patients undergoing HCV treatment by helping them maintain adherence to the challenging medication regimen

Study limitations that warrant caution in the interpretation of this study

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