An Introduction

to Medicinal
Cannabis

Arno Hazekamp
 An Introduction to Medicinal Cannabis

Content
Introduction ............................................................................................ 2

1 | Standardization & Quality control .............................................. 5

1
2 | Chemical composition & Varieties .............................................. 9

3 | Methods of intake & Dosing ......................................................... 15

4 | Endocannabinoids & Mechanisms of action ............................. 21

5 | Clinical trials & Indications ........................................................... 25

6 | History, drug policy & The Dutch way ........................................ 35

Suggested Further Reading ................................................................ 42

Useful Websites .................................................................................... 42

ABOUT THE AUTHOR
Dr. Arno Hazekamp (1976) is an internationally acclaimed cannabis researcher, and Head of Research Colophon ................................................................................................ 43
and Education at Bedrocan BV - the official grower of medicinal cannabis in the Netherlands. Arno
earned his Bachelor’s degree in molecular biology, followed by an MSc degree in biopharmaceutical
sciences at Leiden University, the Netherlands. His PhD thesis was focused on the medicinal use of
cannabis, and the practical issues that prevent it from becoming part of modern medicine. Since 2002,
Arno has been involved in the Dutch national medicinal cannabis program as a specialist in quality
control, administration forms and chemical analysis. He is a board member of the International
Association for Cannabinoid Medicines (IACM), an active international lecturer and medicinal cannabis
advocate. His mission is to build a bridge between the needs of patients and the demands of modern
medicine through research and education.
Introduction
The world of medicine is strictly organized. Conventional medicines are carefully designed and developed
in a pharmaceutical lab and thoroughly tested for safety and efficacy, before being released onto the
market for a specific patient population. Cannabis is out of tune with this paradigm in multiple ways. For
example, it is a medicine pioneered and promoted by patients and their caregivers, instead of scientific
researchers or physicians. It is often consumed in its herbal form, using unconventional modes of
intake such as smoking, vaporizing, tea or brownies. Moreover, cannabis may be used to treat difficult
symptoms and improve quality of life for the chronically ill, but it also serves as a recreational drug that
affects the minds of millions. This situation is further complicated by a continuously growing attention for
cannabis by the media worldwide.

As a result, patients, physicians, regulators and scientists may find it hard to understand what is truly
medicinal about cannabis. Despite the fact that everyone seems to have an opinion about it, reliable
information on cannabis is still hard to find. Pharmaceutical researchers, traditionally focusing on
isolated active ingredients, have a hard time understanding cannabis in its complex herbal form. Clinical
trials, performed under strict conditions and regulations, are incapable of studying the unconventional 3
administration forms, the many cannabis varieties and the dosing regimens that experienced users
commonly use. And although a wealth of information seems to be available on cannabis through popular
websites, discussion forums and magazines, this is often based on single patient stories and assumptions.
Opinions and facts may get mixed up when seriously ill patients share their personal experiences with
others without the involvement of a medical professional.

As a result of all this, cannabis seems to be caught in the middle: too herbal for modern allopathic
medicine, and yet too potent for herbal or ‘alternative’ medicine. There is a need for balanced information,
clearly communicating the therapeutic but also the less desired effects of cannabis use. This publication
makes an effort to introduce the most important aspects of this fascinating and rapidly growing topic.
All basic concepts are shortly introduced, ranging from cannabis cultivation and quality aspects, to
administration forms and therapeutic effects. The information presented here is based on the authors’
involvement with the Dutch National medicinal cannabis program and his experience as a professional
cannabis researcher since 2002.

Please note that the information provided is meant for informational purposes only. The opinions
expressed in this publication are not intended to diagnose or treat any medical condition or disease. You
are advised to consult a medical professional before using cannabis as a medicine, and to be well informed
about the laws regarding cannabis in your location. No literature references were added to the text of
this publication because readers are encouraged to read more in the scientific literature to form their own There is a need for balanced
opinion. For this purpose, a list of suggested further reading and useful web sites has been added in the
back of this publication.
information, clearly communicating
the therapeutic but also the less
desired effects of cannabis use.
1 | Standardization & Quality control
A clearly defined composition is an essential requirement for medicines, because it prevents
unexpected surprises regarding its effects, potency or purity. For an herbal medicine like cannabis
this starts with tightly controlling and monitoring the conditions under which the plants are grown.
Cannabis plants exist in many different shapes and forms, also known as strains or varieties. Besides
obvious differences in plant shape and appearance, cannabis varieties differ by their specific content
of cannabinoids and terpenes (see chapter 2). The exact combination of these active components
present in a cannabis product defines its ultimate medicinal effect. This means that relatively small
changes in cannabis composition can have significant effects on the medicinal properties of cannabis.
Quality control by means of chemical characterization is the key for ensuring a reliable composition.
In the Dutch program, we make product information such as THC/CBD content, terpene profile and
moisture content openly available for all cannabis products. Independent laboratory analysis shows
each product to be free of contaminations such as pesticides, heavy metals or microbes. Complying
with industrial standards for hygiene and safety (HACCP), pharmaceutical requirements (GMP),
management system (ISO) and Good Agricultural Practice (GAP) is an integral part of all steps of the
production chain.
Standardized production
Cannabis plants intended for medicinal use are propagated by cloning, meaning that small parts
of a so-called ‘mother-plant’ are cut off and stimulated to grow into whole plants. Also known as
making cuttings, this same procedure is used by gardeners to multiply their favorite tomatoes, roses
or grapevines. Cloning ensures that all plants are genetically identical, and therefore will develop
the same desired and pleasing characteristics. For cannabis, it ensures that each plant has the same
potential for producing the desired blend of cannabinoids and terpenes.
into the mostly inactive CBN (see chapter 2). For that reason, each individual step from cultivation
to final use is equally important to monitor and control. At Bedrocan, all measured parameters
are carefully registered in logbooks, giving an overview of long-term trends over the course of
many years. The information gathered in this way is an important resource for further scientific
development programs.
Quality control
Cannabis medication must be reliable in order to be integrated in a normal active life: spending time
with friends and family, going to work, driving a car, etc. Bedrocan products are therefore tested by
independent and specialized laboratories to ensure they have the desired properties. In general, two
types of tests are applied to determine the quality of cannabis. One set of tests is performed to verify
that products have the desired composition regarding general appearance, cannabinoids, terpenes,
and moisture content. Another set of tests is applied to ensure that unwanted elements are absent:
adulterants, microbes, heavy metals, pesticides. When all results are in, they are summarized in
5
THC %

In the Dutch medicinal cannabis program cannabis is grown in batches of about 140 plants, each
batch taking a few months to fully develop for harvest. During this period, even small differences in
cultivation conditions may lead to significant changes in the final content of active components. Since
2002, in Bedrocan we have systematically studied the influence of such conditions on the quality
and composition of our cannabis plants. These studies included, for example, the intensity and type
of lights used, plant density, humidity and ventilation of the air, watering schedule, type of plant
nutrition used, and the effects of biological pest control. In this way we have learned how to carefully
monitor and control the development of our plants, leading to a highly standardized product (see Harvest date
figure 1-1).
Figure 1-1 Bedrocan produces a standardized product, which means that the chemical composition is
The responsibility of producing standardized cannabis medicine does not finish at harvest time.
always the same. This graph shows the measured THC content (%) in twenty different batches
All of the subsequent steps - drying, trimming, packaging, storage - may have an impact on the
of variety ‘Bedrocan’. The black lines indicate the allowed variation in content according to
final chemical composition as well. Terpenes may easily evaporate even at room temperature;
EU regulations for herbal drugs.
cannabinoids may degrade under the influence of light and heat, for example turning the active THC
a Certificate of Analysis, which is available for inspection by patients and doctors (see figure 1-2).
Cannabis can be called standardized when batches are consistently shown to be of the same high
quality over a longer period of time.
Figure 1-2 Certificate of Analysis as supplied with each batch of Dutch medicinal cannabis.
The cannabinoid composition is the most important aspect to measure for medicinal cannabis. When
referring to cannabis as a medicine (as opposed to a narcotic drug), THC is usually not considered
the only active component. There is mounting scientific evidence that Cannabidiol (CBD), and lesser-
known cannabinoids such as tetrahydrocannabivarin (THCV) or cannabigerol (CBG) may play a role
as well. Bedrocan products are therefore analyzed for a wide range of cannabinoids before they are
released for use by patients.
Additional tests evaluate the dutch products for general appearance (e.g. flower shape, absence of
hair or insects), moisture content and terpene profile. The abundantly present terpenes are thought
to influence the therapeutic effects of the cannabinoids in a myriad of ways, including enhancement
of cannabinoid uptake in the intestines or lungs, and influencing receptor binding or metabolism.
Many terpenes also have important properties by themselves, as discussed in chapter 2. cannabis from a reliable and official source, whenever available.
Potential contaminations in cannabis
Cannabis samples obtained from uncontrolled sources may be contaminated with various harmful
substances. In the media and medical literature, many cases have been identified where the
consumption of unsafe cannabis was the cause for hospitalization or severe health issues. Bedrocan
products are therefore tested to make sure that all the following contaminations are absent:
Because cannabis is grown under very warm and humid conditions, this creates the perfect conditions
for microbes to develop. Manure-based fertilizers or poor hygiene standards may infect plants with
intestinal (E. coli) bacteria, while contamination with fungi of e.g. Aspergillus or Penicillium species
may lead to life-threatening infections especially in immune-compromised patients. Not all of
these contaminations may be easily spotted by just looking at cannabis under a microscope. Some
microbes, or the toxic chemicals they produce, are resistant to heat and may be inhaled during the
smoking of a cannabis cigarette or while using a vaporizer. In order to guarantee the absence of
microbes, Bedrocan cannabis is disinfected by gamma-irradiation. This does not have an effect on the
chemical composition or the therapeutic effect of the cannabis plant.
Although pesticides are widely used in food agriculture, their use is always restricted to specific crops 7
in limited quantities. In the case of cannabis it is unclear which pesticides, if any, pose a threat to the
health of patients. Thus far, no studies have been conducted on the safety of pesticides as applied
to inhaled or ingested cannabis. Research has shown that many pesticides are inhaled intact when
contaminated cannabis is smoked. Bedrocan does not
use any chemical pesticides, but works with biological
pest control methods (predatory insects) only.
Patients are advised
to obtain medicinal
Heavy metals such as mercury, arsenic, cadmium or
lead are usually not applied to cannabis on purpose. cannabis from a reliable
However, they may be present in materials that come
into contact with the plant during cultivation, such as
and official source.
soil, water, or fertilizers. The cannabis plant is known
to very efficiently absorb heavy metals. After consumption, these heavy metals may accumulate in
body tissues causing harm to various organs over time. All materials used for cultivation of plants at
Bedrocan are specifically chosen for their safety regarding heavy metals.
Cannabis is sold by weight (per gram), and demands a higher price with increased potency. To
increase weight, adulterants such as sand or metal particles (lead, iron) may be added to herbal
cannabis. To increase the appearance of potency, finely ground-up glass or talcum may be added to
mimic the presence of glandular hairs ‘see chapter 2’. During quality control, Bedrocan cannabis is
always visually inspected to ensure the purity of all final products.
Clearly, inhalation or ingestion of any of these substances may lead to harmful situations by
infection, poisoning or damage to the lungs. Patients are therefore advised to obtain medicinal

All of the production steps
- growing, drying, trimming,
packaging, storage - may have
an impact on the final chemical
composition.
2 | Chemical composition & Varieties
It is sometimes said that cannabis is one of the most studied plants in the history of science. So far,
well over 10.000 scientific papers have been published, discussing the medical use as well as abuse
of cannabis. Already more than 500 chemical components - or constituents - have been identified
in cannabis plants and products from all over the world. Most well-known are the cannabinoids,
including the infamous THC. But many other groups of chemicals are also present, such as terpenes,
flavonoids and alkaloids. And every now and then, new constituents are still being discovered.
Because many of these constituents have never been properly characterized for their therapeutic
value, some scientists call the cannabis plant a “neglected pharmacological treasure trove”.
The most interesting constituents are found in the secretions of tiny glandular hairs that are present
all over the Cannabis plant. These hairs, known as trichomes, produce a sticky resin that accumulates
in little droplets at the tip of each hair. Trichomes are so small that they are only visible under a
microscope, as shown in figure 2-1. They can be found on male as well as female plants, but they are
most abundant in the female cannabis flowers. For that reason, cannabis growers focus on growing
female plants only. Ultimately, the medicinal value of a cannabis flower depends on the exact mixture 9
of constituents that it produces. Most scientists think that cannabinoids and terpenes are the most
relevant in this respect.
Figure 2-1 Microscope photograph of cannabis
trichomes (magnification ± 50 times).
Cannabinoids – the main active ingredients
Cannabinoids are considered to be the main therapeutically active constituents of the Cannabis
plant. They are unique to the cannabis plant and can be found nowhere else in nature. Currently over
100 cannabinoids have been identified, with chemical structures that closely resemble each other.
Additionally, many cannabinoid-like chemicals have been created artificially in pharmaceutical

THC CBD
CBG THCV
Figure 2-2 The chemical structures of some well studied cannabinoids.
laboratories. Cannabis grown indoors generally has higher levels of cannabinoids when compared
to outdoor grown plants. When grown under optimized indoor conditions, female flowers can be
obtained with a THC content of up to 30% of their dry weight.
The most famous cannabinoid of all is delta-9-tetrahydrocannabinol, more commonly known as
THC. In addition to the recreational feeling of ‘getting high’, THC is also responsible for many of the
medicinal effects of cannabis. This includes, among others, reduction of nausea, vomiting, pain and
muscle spasms, and improvement of sleep and appetite. The therapeutic applications of THC and
other cannabinoids are described in more detail in chapter 5.
Another cannabinoid that receives a lot of scientific attention is cannabidiol, or CBD. It has medicinal
effects but does not make a person feel “high”. To the contrary, CBD actually reduces some of
the unwanted effects that are caused by higher doses of THC. Studies indicate that CBD could be
effective in easing the symptoms of various difficult-to-control conditions, such as rheumatoid
arthritis, diabetes, PTSD, anxiety disorder, and antibiotic-resistant infections. Other examples of
medicinal cannabinoids include cannabigerol (CBG) which has potent anti-inflammatory effects, and
tetrahydrocannabivarin (THCV) which is being studied for treating epilepsy and Parkinson’s disease.
The chemical structures of these cannabinoids are shown in figure 2-2. Because of their very different
therapeutic properties, the specific mix of cannabinoids present in a cannabis flower has a major
impact on the medicinal properties it may cause. on. Based on such characteristics, two main types of cannabis are usually recognized: Cannabis sativa
Terpenes – fine tuning the therapeutic effect
The terpenes are the constituents that give cannabis its typical smell and taste. To date more than
120 different ones have been found in Cannabis. Unlike cannabinoids, all major terpenoids present
in cannabis (with pretty names such as myrcene, alpha-pinene, and beta-caryophyllene) can be
found abundantly in nature. Nonetheless, these terpenes display a wide range of effects that may
be involved in modulating some of the undesired effects of THC, for example by reducing short-
term memory loss or anxiety resulting from cannabis use. Terpenes may also produce their own
pharmacological effects; some of them are potent antibiotics, while others have analgesic or anti-
inflammatory properties, for example.
Because so many cannabis terpenes exist, there are many different combinations in which they can
be present in a cannabis plant. And just like with the cannabinoids, each specific mix of terpenes
may lead to a unique medicinal effect. Terpenes easily evaporate (which is the reason we can smell
them) and they are inhaled during smoking or vaporizing. Unfortunately, only very few studies have
been done on potential interactions between the terpenes and the cannabinoids. Nevertheless, it is
generally believed that each distinct type (variety, strain) of cannabis has its own unique composition
of cannabinoids and terpenes. 11
Varieties: what’s in a name Terpenes display a
Cannabis consists only of a single species, going by its
official botanical name Cannabis sativa L. This means (in wide range of effects
biological terms) that every cannabis plant can be crossed
with every other one. Its closest relatives in the plant
that modulate the
world are Hops (cousin) and Nettle (second cousin). Over
time, people worldwide have selectively grown cannabis
effects of THC.
for certain desired characteristics: narcotic effect, size,
bud shape, smell, you name it. When the resulting plant becomes sufficiently different from other
Cannabis plants, it is generally considered as a distinct variety. Dogs and tulips are other examples of
a single species with lots of different varieties.
As a result of centuries of such breeding and selection, a wide range of varieties (also known as
strains) has been developed. Varieties are commonly distinguished, by plant breeders, recreational
users, and patients, through the use of popular names such as White Widow, Northern Lights,
Amnesia, and Haze. Nowadays, well over 700 varieties have already been described and many
more are thought to exist. An obvious question is how the many names used for all these cannabis
varieties reflect an actual difference in medicinal properties. In other words: which varieties are most
important and useful to patients, and how many names do we really need to tell them apart?
The most common way generally used to classify Cannabis varieties is through ‘phenotype’, which
includes all characteristics that we can detect with our senses: plant shape, color, height, smell and so
 between Cannabis varieties could help to bridge the gap between the extensive knowledge on
Cannabis that exists within the community of recreational users, and the information needed by
Variety name THC CBD type medicinal users and health professionals.
Bedrocan ® 22 - sativa At Bedrocan we study a wide range of (potentially) active components in our plants, visualizing
Bedrobinol ® 13.5 - sativa up to 28 different cannabinoids and terpenes. By using this approach, we believe that the endless
Bediol ® 6.3 8 sativa number of popular varieties (also named ‘cultivars’) can be reduced to a more manageable number
of chemically distinct varieties (or ‘chemovars’). The varieties currently available from the Dutch
Bedrolite ® <0.4 9 sativa medicinal cannabis program are listed in table 2-3. Further studies into the chemical differences
Bedica ® 14 - indica Contents in % of dry weight and similarities between the most popular cannabis types may help medicinal users to accurately
and efficiently identify the cannabis variety they need most. Exchange of cannabis varieties and
information between researchers in different countries that allow medicinal cannabis use, including
Table 2-3 Composition of the cannabis varieties currently available from the Dutch medicinal cannabis program. the Netherlands, Canada and the USA, may greatly facilitate such studies.

and Cannabis indica. The sativa types of cannabis were originally grown in the Western world on an
industrial scale for fiber, oil, and animal feedstuff. They are characterized by tall growth with few, 13
widely-spaced, branches and long, thin leaves. In contrast, varieties of the indica type originated in
south Asia and are known historically as Indian hemp. They are characterized by shorter bushy plants
and broader leaves, typically maturing relatively fast. The two groups tend to have a different smell,
which likely reflects a different profile of terpenes. Most modern cannabis varieties available on the
drug market are in fact a hybrid (cross-breed) of sativa and indica ancestors. Cannabis ruderalis is
sometimes also recognized as a separate group. It is a smaller and “weedy” plant originally from
Central Russia. Originating from old hemp fields, this type is now rarely cultivated for THC content or
medicinal properties. Ruderalis plants have lost many of the traits they were originally selected for,
and have adopted themselves to their environment.

The Sativa-Indica dilemma

Several scientific attempts have been made to classify Cannabis varieties based on cannabinoid
composition. For forensic and legal purposes, the most important classification is that of the drug-
type (marijuana) or the fiber-type (hemp). Existing classification systems consider the content of THC
and CBD, and sometimes additional cannabinoids as well. But unfortunately, the various terpenes
have not been included in these classification attempts. For a clearer understanding of the medicinal
properties of the Cannabis plant, a better classification system is needed that includes all the known
cannabinoids and terpenes.

By a tedious process of trial and error, patients in many countries have found a cannabis variety that
The popular distinction
works optimally for treatment of their medical condition. The popular distinction between sativa and between sativa and indica
indica types is an important help for patients during this search. However, it has never been properly
studied if and how the medicinal properties of cannabis are correlated in any way to the distinctions
types is an important
made between sativa and indica. It is clear that a better understanding of chemical differences help for patients.
 3 | Methods of intake & Dosing
Cannabis can be used in several different ways. Although smoking is the most commonly known
method of intake, it is surely not the only - or the healthiest - one. Other methods commonly tried by
medicinal users of cannabis include:
∙∙ Inhalation with the use of a special vaporizing device
∙∙ Preparing tea or cookies containing cannabis
∙∙ Concentrated extracts
∙∙ Consuming raw cannabis as a vegetable, or by juicing it

Because many of these preparations have never been properly studied by medical scientists, most of
what we know about them is based on experiences by actual patients.

Depending on the choice of administration form, many changes to the original chemical profile of the
plant material may occur. For instance, a common factor of most administration forms is a heating
step, which is essential for conversion of the cannabinoid-acids into their pharmacologically more 15
active form (explained in more detail below). Overheating may lead to the formation of degradation
products such as Cannabinol (CBN) and Delta-8-THC, both of which have potential pharmacological
properties of their own. Volatile components such as the terpenes may easily get lost by evaporation,
for example during the boiling of tea, or while concentrating an extract by evaporating the solvent.

On top of this, each preparation comes with its own efficiency of uptake (by intestines or the lungs)
and its own set of specific metabolites formed upon consumption. Especially the difference between
oral (ingested) and pulmonal (inhaled) preparations are of importance here. After all, inhaled
cannabinoids and terpenes enter directly and unaltered through the lungs into the bloodstream,
while ingested compounds are significantly delayed and altered by the actions of the intestines and
the liver. The combination of all these factors may result in a different type and duration of effects for
each cannabis medicine, even when the same type of cannabis is used in their preparation.

Acidic and neutral cannabinoids

THC and CBD are the two most famous cannabinoids, but contrary to popular belief they are not
actually present in fresh cannabis plants. The reason is that the plant produces all its cannabinoids
Medicinal cannabis in a slightly different form known as acidic cannabinoids or cannabinoid-acids. When sufficient
heat is applied, cannabinoid-acids will quickly convert to their so-called ‘neutral’ counterparts by a
can be used in several process called decarboxylation. So when cannabis is burned for smoking, baked for edibles, or boiled

different ways, for tea, THC-acid turns into its neutral form THC, CBD-acid turns into CBD, and so on for all other
cannabinoids. This process is visualized in figure 3-1. Decarboxylation also spontaneously takes place
including vaporizing in aging cannabis samples as a result of storage and exposure to light or room temperature, but at a
much slower rate.
and preparation of tea.
 Vaporizing
THC-acid THC Vaporizing is a technique aimed at heating cannabis to a high temperature without burning the plant
material. In this way cannabinoids and terpenes are released in the form of a vapor, which can be
inhaled directly. Vaporizing offers all the advantages of inhaled administration (rapid effect, accurate
dosing) while avoiding the risks related to smoking. Although many different vaporizer devices
are available on the market, only a few of them have been subjected to any quality testing. The
Volcano® Medic vaporizer (figure 3-2) is currently the only one that has a status of approved medical
Figure 3-1 Decarboxylation: the conversion of THCA into THC is shown as example. device (in Canada and Germany), showing that it is a reliable and efficient device for administering
Under the influence of heat, light or prolonged storage the cannabinoid-acids turn cannabinoids. The miniVap ® is another vaporizer that is currently undergoing quality testing.
into their neutral counterparts by releasing carbon dioxide. Because plant material is not burned during vaporizing, no active ingredients are lost and the full
potential of the cannabis can be used.

For a long time, scientists considered cannabinoid-acids to be the ‘inactive’ form of cannabinoids.
The oral route: tea and edibles
After all, they don’t make you feel high and do not bind to the cannabinoid receptors (see chapter 4). When cannabis is taken orally, it takes at least 30 to 90 minutes before any effects occur. Effects
But at present it is known that also the acidic cannabinoids may have important medicinal properties. peak usually after two or three hours, and wear off in about four to eight hours. Cannabis tea and
For example, CBD-acid has a potent antimicrobial activity and shows promising anti-inflammatory edibles (cookies, brownies, candies etc.) are two very common ways of consuming cannabis orally. 17
effects, while THC-acid was found to have a potent effect on the human immune system. And Because these products typically don’t look or smell like cannabis, they allow the user to consume
perhaps most interestingly, some acidic cannabinoids appear to slow the growth of certain cancers, it in a public space (e.g. at work, family visit) without drawing much unwanted attention. The
at least in laboratory tests. For some types of patients the cannabinoid-acids may therefore not be slow onset of effects, combined with a long duration, makes oral administration mainly suitable
inactive at all. for treating chronic complaints that need a constant dose of cannabis throughout the day. Oral

The inhaled route: smoking and vaporizing

When inhaled, cannabinoids and terpenes are rapidly absorbed by the lungs and distributed through-
out the body. First effects generally occur within a few minutes, and gradually wear off over three
to four hours. Inhalation may therefore be most suited for patients dealing with symptoms that
suddenly flare up and need to be addressed rapidly, such as certain types of pain, spasms associated
with MS or epilepsy, or nausea and vomiting. It is fairly easy to control the dose by inhaling; when
the effect is insufficient after several minutes, you can simply take another puff until you achieve the
desired effect or start feeling side effects. Cannabis can be inhaled in two main ways, smoking and
vaporizing.

Smoking Figure 3-2 The Volcano® Medic vaporizer,

Smoking is by far the most commonly used method of consuming cannabis worldwide, either in pure the only cannabis vaporizer that
form or in combination with tobacco. Smoking enables the user to directly use the cannabis of his has received approval as medical
choice with minimal effort or cost. However, inhalation of toxic compounds during cannabis smoking device, and has been used in
may pose serious health risks due to the release of byproducts such as tar, ammonia and carbon clinical studies.
monoxide. In many countries, the stigma attached to smoked cannabis poses a major obstacle for
approval of herbal cannabis as a medicine by public health authorities. For all these reasons, smoking
is not advised for the medicinal use of cannabis.
cannabis may also be preferred for aiding sleep, because its effect potentially last all night. A major
disadvantage of oral administration is the large variability in uptake by the intestines, because the
type of food you eat can have a significant influence on the absorption of the active substances.
Moreover there is the inconvenience of taking oral medication in case of e.g. nausea, vomiting or
lack of appetite. Dosing with oral cannabis medicine should be done carefully and slowly, because
overdosing more easily occurs than with inhaled administration.
Tea
Herbal cannabis can be consumed by boiling it with water, also referred to as ‘cannabis tea’. Actual
methods used for cannabis tea preparation by patients are largely unknown, and many variations
may exist. In the Netherlands, patients are advised to prepare cannabis tea by adding 1 gram of
cannabis to 1 liter of boiling water, letting it simmer for 15 minutes, and finally filtering out solid
parts by using a tea-strainer or filter paper. Studies have shown that an average cup of cannabis tea
contains about 5 times more THC-acid than THC. The reason is that boiling water is not as hot as the
heat applied for baking, smoking or vaporizing of cannabis. Cannabis tea should therefore not just
be considered as a weak administration form of THC (which it is), but rather as an entirely different
medicine, because of the presence of high amounts of acidic cannabinoids.
Edibles
Self-medication with cannabis in ingested forms, such as cookies, brownies or oil, seems to
be particularly popular among North-American patients. Unfortunately, there currently are no
scientifically approved methods available for the analysis of cannabinoids and/or terpenes in edibles
containing herbal cannabis or extracts. As a result, no good scientific data is available on the potency,
composition or consistency of edibles. Theoretically, issues that are likely to occur with edibles
include proper mixing (ensuring one cookie has the same potency as the next), and stability of these
products during storage. Consequently, the use of standardized recipes and procedures is probably
even more important for edibles than for the other administration forms discussed in this chapter.
Because they are so different from modern medicines, these kind of cannabis preparations are
usually not used in any research projects.
New kids on the block: tinctures, concentrates and raw juice
According to a recent international survey among almost 1000 patients, the most common problems
associated with cannabis medicine are bad taste, drowsiness, uncontrollable appetite (often referred
to as the ‘munchies’), and mental effects (getting high). The study also suggested that different
administration forms may be preferred in the privacy of ones’ home and in public. In order to address
such issues, self-medicating patients frequently experiment with new administration forms, some of
which may then gather significant popularity through web forums, magazines and social media. Not
surprisingly, most of these new and unconventional administration forms have never been tested for
any form of quality or safety. Two of these uncommon preparations discussed below are Cannabis oil
and consumption of raw cannabis.
Cannabis oil and raw juicing
Cannabis oil is a concentrated extract obtained by solvent extraction of the buds or leaves of the
cannabis plant. It is not actually an oil, but derives its name from its sticky and oily appearance.
Some patients firmly believe that cannabis oil is capable of curing cancer, a claim often backed
up with several anecdotal patient stories. Laboratory studies do indeed show a potential effect of
cannabinoids on isolated cancer cells in a petri-dish and in lab animals, but it is too early to claim that
consumption of cannabis medicine may cure cancer in the much more complex situation of human
cancer.
Various solvents have been recommended for making cannabis oil, such as petroleum ether, naphtha,
alcohol and olive oil. A recent study comparing five commonly used preparation methods for cannabis
oils found significant differences in cannabinoid and terpene composition of the final products. Also,
the presence of residual solvent was found to be a significant concern, particularly in the case of
using naphtha for extraction. The final conclusion of the study was to prepare extracts directly in olive
oil, heated in a boiling water bath for an hour or two; this guarantees the highest recovery of active
compounds, and no risk of organic solvent residues.
19
An interesting new development is the use of raw cannabis buds and leaves, prepared as a drink by
juicing them in a blender with water of fruit juice, or consumed directly as a salad. In contrast to the
other administration forms mentioned above, this preparation does not undergo any form of heating,
and therefore contains all cannabinoids in their original (acid) form. The possible effects of this
interesting administration form have not yet been studied in any way.
General hints for dosing
No matter what administration form is preferred, patients should be careful not to accidentally
overdose on cannabinoids. Especially to those who have no prior experience with cannabis, the
feeling of getting high may be disturbing or frightening. Other overdosing effects may cause a patient
e.g. to fall (dizziness), throw up (nausea), or become disoriented. See chapter 5 for more information
on effects that may be expected after consumption of cannabis medicine.
It is important to find your own proper dose in order to fully benefit from the medicinal properties of
cannabis. Most unwanted side effects of cannabis may be prevented by following just a few simple
guidelines. The first one is to start with a low dose. It is better to take several small doses in a day
that add up to a perfect result, than to experiment with one single large dose that may turn out to be
too much. Second, it is important to have patience and wait for the effects (if any) to appear. Clearly,
this can be frustrating in the case of acute symptoms such as strong pain, nausea or spasms, but
remember that cannabis may have a different effect on each patient. In order to really evaluate what
cannabis does to your medical condition, it is best to use the same (low) dose for several days, and
monitor any effects that may occur. In this period you will be better able to recognize positive as well
as unwanted effects. Finally, you can start to increase the dose slowly after a few days. Again: do
not suddenly or quickly increase or change the dose, but take it slow and take a few days after each
increase to monitor progress. In about 1-2 weeks, you should be able to find your own, personalized
dose that gives you the most medicinal effect with minimum side effects.
Table 3-3 summarizes the average times needed to experience first, maximum, and final effects. If
you think you need an extra dose of cannabis medicine, you should at least wait until the time for
maximum effect has passed: about 15 minutes for inhaled cannabinoids (vaporizing and smoking),
and 2 hours for ingested cannabinoids (tea, extract or edibles).
First effects: Maximum effect: Maximum duration:
Inhalation 5 min 15 min 3-4 hr
Oral 30-90 min 2-3 hr 4-8 hr
Table 3-3 Table comparing different methods of intake, and the timing of their effects (approximate).
It is important to have
patience and wait for The human endocannabinoid system
the effects to occur.
4 | Endocannabinoids & Mechanisms of action
Until quite recently it was unknown how cannabis caused its effects on the brain. Initially it
was assumed that cannabinoids such as THC simply dissolve in cell membranes in the brain,
thereby disrupting the function of brain cells, similar to the way alcohol makes you feel drunk.
Then something revolutionary happened; in the 1990’s the human endocannabinoid system was
discovered, and we learned that many of our own bodily functions are controlled by cannabis-like
substances produced in the brain, immune system and other organs. In this chapter we will look in
more detail at how that actually works.
Receptors: how cells communicate
A receptor is a large molecule found on the surface of a cell. Here it receives chemical or physical
signals from outside the cell. This is the most important way for a cell to respond to changes in its
environment. Hundreds of different receptor types are found on an average cell. Each receptor type
binds only certain substances.
A substance that binds to a receptor is called a ligand. In general, ligands are small molecules such 21
as a neurotransmitter (e.g. dopamine), hormone (testosterone), pharmaceutical drug (beta-blockers),
toxin (from a virus or bacteria), or… a cannabinoid like THC. When a ligand binds to its corresponding
receptor it changes the receptor’s setting, quite similar to how a lock requires a specific key to open
it. When this happens, the received signal urges the cell to do ‘something’ that is specifically linked
with that receptor, such as grow (e.g. to heal a wound), die (e.g. make place for new cells), produce
chemicals (e.g. to digest food, to fight infection), or allow specific substances to enter the cell (e.g.
building materials for the cell).
Because the biological effect of many (pharmaceutical) drugs takes place through interaction with
receptors, it makes sense that the psychoactive effects observed for THC led to the scientific hunt
for specific cannabinoid receptors. This finally resulted in the identification of Cannabinoid-Binding
receptor type 1 (CB-1, 1990), soon followed by discovery of a type 2 receptor (CB-2, 1993). Currently,
there is even speculation about a possible CB-3 receptor, but this has not yet been fully confirmed.
Cannabinoid receptors can be found all over the body, but they are more prominent in some organs.
The CB-1 receptor is predominantly present in the central nervous system (brain and spinal cord),
particularly in those brain regions that regulate functions we typically associate with the use of
cannabis: sleep, appetite, perception of time and pain, memory etc. Overstimulation of the CB-1
receptor leads to a feeling of intoxication, also known as being ‘high’ or ‘stoned’. The CB-2 receptor
is present mainly on the cells of our immune system where it can influence pain, inflammation and
tissue damage.
The discovery of cannabinoid receptors prompted scientists to search for its natural ligands, which
should be produced somewhere in the human body. Finally, a single compound could be isolated, it is not entirely unique; just think of the opiates
with a strong binding to the CB1 receptor. This compound (arachidonic acid ethanolamide) was named (morphine, codeine etc.) that are produced by the
Anandamide, from the Sanskrit word for ‘‘eternal bliss’’. A few years later, a related compound was poppy (opium) plant. These opiates interfere with
isolated with an affinity for both cannabinoid receptors; it was identified as 2-arachidonyl glycerol, our system of opioid receptors, which are part
abbreviated as 2-AG. The structures of these two compounds are shown in figure 4-1. In more recent of our nervous system and are meant to help us
years, a wide range of compounds with endocannabinoid activity have been isolated or synthesized. deal with intense pain, danger and other forms
of severe stress. Thanks to scientific study of the
poppy plant we have access to potent painkillers
Anandamide 2-Arachidonylglycerol and anesthetics that help us get through a
surgery or severe accident. Thus, turning a
narcotic plant into valuable medicine has been
done before, and cannabis may follow the same
way to modern medicine.

External cannabinoids, present in the cannabis

plant, are able to interact with our internal
Figure 4-1 Chemical structure of the two main endocannabinoids: Anadamide and 2-AG.
endocannabinoid system and cause a variety of 23
effects. However, cannabis is a potent medicine
and may not be suitable for all patients. In
Cannabinoid receptors and their natural ligands together constitute what is referred to as the endo- some cases (depending on e.g. cannabis variety,
cannabinoid system. This cannabinoid signaling system is present in almost every imaginable animal dose and administration form), the effects may
life form, ranging from humans to cats and birds, down to fish and even primitive sea creatures such be therapeutic, while under other conditions
as the Hydra (see figure 4-2). This finding shows the evolutionary importance of such a system for unwanted effects may occur. When too much is
basic survival and functioning of species. It should be noted that not all of the effects of cannabinoids consumed a state of intoxication will occur. Figure 4-2 Predatory sea creature called
can be explained by receptor-binding alone, and it is believed that at least some effects are caused Although for some people this may be pleasant the Hydra, one of the most
through other mechanisms. and even part of the therapeutic effect, concerns primitive organisms with an endo-
have been raised about the potential for long- cannabinoid system (size ca. 5 mm)
The cannabis mode of action term cannabis consumption to increase risk for
In pharmacology, the term mode of action refers to the specific biochemical interaction through which schizophrenia, psychosis, bipolar disorders and
a drug substance produces its medicinal effect. So, an important question is, how can substances major depression. In some way you could say that recreational users of cannabis are purposely
from the Cannabis plant help in combatting different diseases; what is its mode of action? Scientific overdosing a medicine, because they like the side-effects of it. By looking at the issue in this way, it
studies clearly show that endocannabinoids play an important role in keeping our bodies balanced, may be easier to see the difference between medicinal use and the recreational use of cannabis.
especially during a state of illness. One cannabinoid researcher described it in this way: the
The terpenes may be involved in all this in several possible ways: by helping cannabinoids to cross
endocannabinoid system helps your body to “feel less pain, control your movement (spasms), relax,
from the blood stream into the brain, or perhaps by changing the binding of cannabinoids to their
eat, forget (posttraumatic stress), sleep and protect your nervous system”.
receptors. Some terpenes also have their own effects, completely independent of the cannabinoid
It has now been scientifically established that the cannabis plant produces substances called receptors. However, there are too many terpenes and too many different modes of action to discuss
cannabinoids that can interfere with our endocannabinoid system. This interaction provides many them all here. At present various studies have shown that whole plant preparations of cannabis
opportunities for treating difficult diseases and for the development of new medicines. In other often have a better medicinal effect than just THC alone. The way all the cannabis compounds work
words, the endocannabinoid system presents a set of new pharmacological ‘locks’ that can be together to cause a medicinal effect is called synergy. More research is needed to fully understand
opened or closed with the help of natural or synthetic cannabinoids. This is exciting information, but how these interactions works.

Clinical studies with cannabis
were often inspired by positive
anecdotal experiences of
patients using herbal cannabis
products for self-treatment
5 | Clinical trials & Indications
According to statistics there are well over 100 million frequent users of cannabis worldwide, but
it is unclear how many of them could be considered, or consider themselves, as medicinal users.
Currently, most information available on the effects of cannabis comes from studies on the
recreational use of cannabis, with the result that new medicinal users and their physicians are
easily concerned with typical abuse risks, such as addiction, overdosing and intoxication (feeling
‘high’). Physicians find it hard to get reliable information on therapeutic cannabis use. Cannabis and
cannabinoids are rarely discussed in medical school, and even the existence or the function of the
endocannabinoid system (chapter 4) is largely unknown among medical professionals. Cannabis
seems stuck in the middle; on the one hand too potent to be regulated as an herbal (or alternative)
medicine, on the other hand too herbal to be regarded as conventional medicine. As a result, there is
no clear consensus on where the line should be drawn between the appropriate medical use of the
cannabis plant, and its use as a recreational drug.
Randomized, placebo-controlled, and double-blinded clinical trials are the current gold standard for
determining the efficacy and safety of medicines. Such studies are costly and very time-consuming, 25
but by weighing the benefits versus the risks, they help us decide where and when the use of a new
medical treatment is appropriate and responsible. Clinical trials performed to determine the effects
of cannabinoids often show significant limitations, such as a focus on isolated cannabinoids (e.g.
Marinol) rather than on herbal cannabis, and the use of low doses because of fear of overdosing the
patients. On top of that, clinical researchers often have a hard time obtaining the licenses needed
to study cannabis, finding standardized cannabis products suitable for research, and dealing with
practical problems related to studying unconventional preparations such as smoking, vaporizing or
edibles.
In contrast, self-medicating patients can often choose from a wide range of cannabis products
(even though this may be illegal), from which they pick the optimal cannabis variety, dose and
administration form by a process of trial and error. Additional reasons that can explain why people
choose medication with herbal cannabis over conventional therapy include cost issues, distrust in
modern healthcare, or an interest in ‘green’ medicine. Many patients have heard about cannabis
medicine from other patients or from recreational users. Sometimes cannabis is more effective than
pharmaceutical drugs and/or people use cannabis to help them cope with the side effects of, or to
replace, these medications. Because of all these reasons, experienced patients may actually know
more about the advantages and disadvantages of treatment with cannabis than clinical researchers
do. An important way of finding out the medicinal value of cannabis is therefore by performing
surveys among large groups of patients. According to the most recent and largest-ever survey among
953 patients worldwide, the top 5 symptoms for using cannabis were chronic pain (29.2% of those
surveyed), anxiety (18.3%), loss of appetite and/or weight (10.7%), depression (5.2%), and insomnia
or sleeping disorder (5.1%). Several other studies have identified the same symptoms, specifically
chronic pain, as leading reasons for using cannabis medicine. In this chapter we will discuss in more
detail what medical conditions might be treated with cannabis, and what could be the mechanisms
behind those effects.
Physiological effects of cannabis
The fact that cannabis has a clear effect on humans does not necessarily make it a medicine. After
all, alcohol and tobacco have clear effects too, but not many consider them to be medicinal. So let’s
first explore the most prominent physiological effects of cannabis. Most of these effects are the direct
result of the THC present in cannabis, but we increasingly understand how other components such as
CBD and the terpenes add to the medicinal effects as well. Table 5-1 summarizes the wide range of
physiological as well as mental functions effects that have been observed for THC.
One of the best known effects of cannabis is euphoria, commonly known as ‘feeling high’ or ‘being
stoned’. Besides that people may feel relaxed, have an impairment of short term memory, an
increase in heart rate, may have uncontrollable fits of laughter, and experience changes in their
awareness of the surroundings. Colors seem brighter, sounds are enhanced, and even mild visual
and auditory hallucinations may occur. Often this is accompanied by a dry mouth and reddened eyes.
In a medicinal setting these symptoms are mostly mild and disappear rapidly. For inexperienced
users or after the consumption of high doses these symptoms can be more severe and may induce
uncontrollable movements, anxiety, or derealization/depersonalization, but without the classic
withdrawal symptoms. In virtually all cases these effects will disappear spontaneously and without
intervention within a few hours.

What we know from clinical trials

Psyche and perception: fatigue, euphoria,
enhanced well-being, dysphoria, anxiety,
reduction of anxiety, depersonalization,
increased sensory perception, heightened
sexual experience, hallucinations, alteration of
time perception, psychotic states.
Cognition and psychomotoric
performance: fragmented thinking, enhanced
creativity, disturbed memory, unsteady
gait, ataxia, slurred speech, deterioration or
amelioration of motor coordination.
Nervous system: analgesia, muscle
relaxation, appetite stimulation, vomiting, anti-
emetic effects, neuroprotection in ischemia and
hypoxia.
Body temperature: decrease of body
temperature.
Cardiovascular system: tachycardia,
enhanced heart activity and increase in oxygen
demand, vasodilation, orthostatic hypotension,
hypertension (in horizontal position), inhibition
of platelet aggregation.
Table 5-1 Overview of the main physiological effects of THC for inhaling cannabis (chapter 3). It is reasonable to assume that future clinical trials will utilize this
Taken with permission from: Grotenhermen F, Russo E, eds. Cannabis and cannabinoids. Pharmacology, alternative delivery method more frequently.
toxicology, and therapeutic potential. Binghamton/New York: Haworth Press, 2002.
Eye: injected (reddened) conjunctivae, reduced
tear flow, decrease of intraocular pressure.
Respiratory system: bronchodilation,
hyposalivation and dry mouth.
Gastrointestinal tract: reduced bowel
movements and delayed gastric emptying.
Hormonal system: influence on LH, FSH,
testosterone, prolactin, somatotropin, TSH,
glucose metabolism, reduced sperm count and
sperm motility, disturbed menstrual cycle and
suppressed ovulation.
Immune system: impairment of cell-mediated
and humoral immunity, anti-inflammatory and
im¬munestimulating effects.
Fetal development: malformations, growth
retardation, impairment to fetal and postnatal
cerebral development, impairment of cognitive
functions.
Genetic material and cancer: antineoplastic
activity, inhibition of synthesis of DNA, RNA and
proteins.
In the period from 1975 to 2012, at least 139 clinical studies were published on herbal cannabis
or pure cannabinoids, together including about 9000 patients suffering from a wide range of
medical conditions. Based on this wealth of data it has been confirmed that cannabinoids exhibit
a therapeutic potential mainly as analgesic for chronic neuropathic pain, as appetite stimulant and
anti-emetic for debilitating diseases (e.g. cancer, AIDS, Hepatitis C), as well as in the treatment of 27
various symptoms of multiple sclerosis. Additionally, cannabinoids show promising results in the
symptomatic treatment of spinal cord injuries, intestinal dysfunction, Tourette’s syndrome, hyper-
activity and anxiety disorders, allergies, epilepsy and glaucoma. Perhaps one of the most exciting
recent findings is that cannabinoids may be effective in the treatment of some forms of cancer, by not
just ameliorating symptoms but actually attacking and killing cancer cells. However, more studies are
needed before cannabis should be recommended for cancer, as explained in more detail below.
Clinical studies with cannabis or cannabinoids have often been inspired by positive anecdotal
experiences of patients using herbal cannabis products for self-treatment. For example, the
antiemetic, appetite enhancing, analgesic and muscle relaxant effects, and the therapeutic use of
cannabinoids in Tourette’s syndrome, were all discovered or rediscovered because patients kept
telling scientists and politicians about it. This clearly indicates the critical role that collecting data on
actual patient experiences has played - and may continue to play – in our evolving understanding of
cannabis effects.
It is interesting to note that in recent years some well-designed studies on the effects of smoked
cannabis have been published, mainly in studies on HIV/AIDS. This is of specific interest because
most patients self-medicating with cannabis administer their medicine by smoking, while virtually no
clinical trial has dared to study this controversial administration form. Such studies particularly show
a benefit on neuropathic pain and appetite. Obviously, the noxious byproducts (tar, carbon monoxide,
ammonia, etc.) released through combustion remain a reason to advice against smoked cannabis.
Specific herbal vaporizers have been developed to provide a safer and more efficient delivery system
The Dutch approach
In the Dutch medicinal cannabis program, a number of medical indications have been selected as
the primary target for cannabis treatment (listed in table 5-2).The reason is that for these conditions
the most extensive clinical proof is available. Many patients suffering from these diseases cannot be
helped sufficiently by conventional medicine either because there is too little effect or the side effects
are too severe. These conditions will be discussed in more detail below.

In general, medicinal cannabis does not cure these disorders, but it can relieve the symptoms
associated with them or stop progression of the disease. Co-medication with cannabis may also
enhance the effects of other medication, and/or reduce harmful side effects associated with them.
In the Netherlands, it is up to physicians to determine whether treatment with medicinal cannabis
Medicinal cannabis
would benefit a patient, depending on the specific diagnosis, symptoms and circumstances. In this, does not cure these
they are not limited to the list of conditions given below. A physician will usually only prescribe
medicinal cannabis if the standard treatments and registered medicines are not having the desired disorders, but it can
effect or are causing too many side effects.
relieve the symptoms
29
Chronic pain
Severe chronic pain seems to be the major reasons why patients use cannabis medicinally. There
associated with them
are many types of pain and not all of them respond the same to cannabis. The therapeutic effects or stop progression
of cannabinoids seem to be most pronounced in neuropathic types of pain, meaning that the pain
originates from damage or disease that affects the sensory nerves. This is the case for example in of the disease.
multiple sclerosis (MS), where the patients’ nerves are being attacked by his own immune system;
or fibromyalgia, where the nerves become hypersensitive and record even a mild touch as pain. In
contrast, studies measuring the effects on acute pain (e.g. postoperative pain) often show no effects.
Most likely, this difference can be explained by the different role the endocannabinoids (chapter 4)
play in both types of pain.

Studies on severe pain indicate that the majority of cannabinoid side effects are preferable over the
side effects caused by the prolonged use of high doses of conventional opioid medication. Chronic
neuropathic pain is a common and difficult to treat condition that has limited treatment options. As a
consequence, even modest therapeutic effects of cannabinoids may be relevant to suffering patients.
It is interesting to note that a selective beneficial effect on women was observed in some chronic pain
studies. This may be an indication that certain cannabinoids can help alleviate chronic pain conditions
which predominantly affect women, such as fibromyalgia.

Because chronic pain is so difficult to treat with any single medicine, cannabinoids have often been
studied in combination with other pain medication, including strong opioids such as morphine. It was
found that cannabinoids and opioids can work together, in such a way that their combined effect is
stronger than may be expected. This effect is called ‘synergy’. As a result, addition of cannabinoids
can often result in a lowering of the dose of opioids needed, thereby reducing the potentially severe
side effects (e.g. respiratory depression) of opioid medicines.

• Chronic pain (mainly pain associated with the nervous system, for example patients with HIV/AIDS. Besides that, Marinol has also been approved as an antiemetic for cancer
caused by a damaged nerve, phantom pain, facial neuralgia or chronic patients undergoing chemotherapy. Some study results suggest that the addition of THC directly
pain which remains after the recovery from shingles);
• Pain and muscle spasms or cramps associated with multiple sclerosis or spinal One well-known effect of cannabis consumption is the strong stimulation of appetite, also known as
cord damage;
• Nausea, loss of appetite, weight loss and debilitation due to cancer or AIDS;
• Nausea and vomiting associated with chemotherapy or radiotherapy used in Although other drugs may be available to treat nausea, vomiting or lack of appetite, the combined
the treatment of cancer, hepatitis C or HIV infection and AIDS;
• Gilles de la Tourette syndrome;
• Therapy-resistant glaucoma.
Table 5-2 Main indications for cannabis treatment in the Dutch medicinal cannabis program
Multiple sclerosis
Many patients worldwide use cannabis to alleviate pain and muscle spasms or cramps associated
with multiple sclerosis or spinal cord damage. Indeed, most clinical trials with cannabinoid-based
medicine have been focused on MS. Standard therapy often provides inadequate relief and can be
limited by side effects of the medication used. As a consequence, patients suffering from multiple
sclerosis have historically experimented with many alternative therapies, including cannabis, to
improve their quality of life. Nowadays, there is much scientific proof that cannabis and cannabinoids
have beneficial effects on disease-related pain, bladder symptoms, tremor, and spasticity. Sleep also
improves significantly by using cannabis, resulting in both deeper and longer sleep.
MS is one of the few medical conditions where long-term effects of cannabinoids have been studied
(mainly in the form of the pharmaceutical product Sativex®). These results have shown that patients
do not seem to develop a tolerance for the medicinal effects, and they do not need to increase their
doses in order to get the same therapeutic result over time. Although the medical proof supporting
cannabis use for MS is still somewhat limited, it is important to note that the same is true for most
conventional MS medications.
Nausea, vomiting and appetite
Cannabis can have strong effects on nausea and vomiting associated with chemotherapy or
radiotherapy used in the treatment of cancer, hepatitis C and HIV infection or AIDS. Already since
1986, THC – under the product name Marinol® - has been approved by the US Food and Drug
Administration (FDA) as appetite stimulant in the case of anorexia associated with weight loss in
before and after chemotherapy may offer more benefit than conventional medication alone.
‘having the munchies’. Mostly this is a desire for foods with high fat or sugar content. For patients,
this high caloric intake may contribute to weight gain or even simply to absorb enough nutrients,
which may be crucial in combatting some medical conditions such as AIDS related wasting syndrome.
effect of cannabis on all these symptoms at once make it a particularly potent drug for improving
the quality of life of patients. Moreover, there is the inconvenience of taking oral medication in case
of nausea or vomiting. Because cannabis can be inhaled (chapter 3) it is more convenient and works
more rapidly than oral medication.
Tourette syndrome
Tourette syndrome is a strongly inheritable neuropsychiatric disorder, characterized by physical 31
(motor) as well as vocal (phonic) tics. Many anecdotal reports have provided evidence that cannabis
might be effective not only in the suppression of such tics, but also in the treatment of associated
behavioral problems such as obsessive-compulsive behavior (OCB). Clinical trials investigating the
effect of (pure) THC in the treatment of Tourette syndrome showed a significant tic reduction without
causing significant adverse effects. Because the highly visible tics have an enormous impact on
Tourette patients’ social life, even a small effect of cannabis could be considered as relevant. THC may
therefore be recommended for the treatment of Tourette syndrome in adult patients, when first line
treatments failed to reduce the tics.
Therapy-resistant glaucoma
In glaucoma patients a progressive increase of pressure inside the eye causes a gradual loss of vision,
resulting in total blindness if untreated. Studies in the 1970s already showed that cannabis, when
smoked or eaten, effectively lowers eye pressure as much as standard medications. Because of this
effect, cannabis medication may be able to save the eye from becoming permanently damaged.
Although currently many treatment options are available, glaucoma is still one of the leading causes
of irreversible blindness worldwide. In case conventional treatments do not have the desired effects,
the use of cannabis may be advised. The duration of the pressure-lowering effect is typically in the
range of several hours, so the cannabis medicine would need to be taken with regular intervals.
Other indications
Outside the view of their doctors, patients self-medicate with cannabis for a wide range of medical
condition. Based on the available scientific evidence, three potential uses of medicinal cannabis that
deserve some further attention are cancer, epilepsy and psychiatric disorders.
Cancer Limitations and risk factors
As discussed above, cannabinoids exert palliative effects in cancer patients by reducing nausea, Just like any other medicine, cannabis is not totally harmless. Below the most important risk factors
vomiting and pain, by stimulating appetite, and by improving the quality of sleep. But in addition, will be shortly discussed.
laboratory studies on lab animals and isolated cancer cells have shown cannabinoids to be capable,
under some conditions, of inhibiting the development of cancer cells in multiple ways. As a result Psychosis
of such exciting findings, a growing number of amateur videos and reports have appeared on the
In rare occasions, cannabis use can induce a state of psychosis in those individuals that have a
internet arguing that cannabis can cure cancer. But although research is on-going around the world,
genetic predisposition for it. As a result, patients with a (family) history of psychotic disorders,
there is currently no solid evidence from clinical trials to support such claims. It should be noted,
particularly schizophrenia and bipolar disorder, should be under careful psychiatric monitoring when
however, that the potential effects of terpenes (chapter 2) on cancer, either alone or in combination
using cannabis.
with cannabinoids, have not yet been addressed in laboratory studies. Indeed, the combined effects
of cannabinoids and terpenes are often claimed to be the major difference between ‘holistic’ herbal
preparations of cannabis and pharmaceutical products based on single cannabinoids. Moreover, Heart disease
self-medicating patients often use extraction methods and/or administration forms that are quite Cannabinoids can have a strong, but temporary, effect on heart rate and blood pressure. Patients with
different from conditions used in laboratory or hospital studies. Because of this gap between clinical a history of heart disease or receiving any type of heart medicine should use cannabis under careful
research and real-life experiences, the curative potential of herbal cannabis preparations for the supervision by a medical doctor.
treatment of different cancer types remains unclear.
Pregnancy 33
Epilepsy There are indications that use of cannabis during pregnancy can affect the development of the
Although epilepsy may be well controlled by existing medication, up to a significant number of people unborn child. Because certain components of cannabis - including THC - are excreted in breast milk,
with epilepsy do not have adequate control of their seizures. Although surgery may be considered the use of medicinal cannabis is not advised while breastfeeding.
for difficult cases, this is a delicate, complicated operation with severe risk to the brain. For such Liver disease
patients, the use of cannabis may seem an interesting alternative to try first. As early as 1979, studies
on rats already confirmed the anticonvulsant effects of (pure) CBD. In various subsequent animal and
After the use of cannabis, the liver is the main There are certain
organ involved in chemically altering the
(small-scale) human studies on epilepsy, CBD in several administration forms was able to reduce the cannabinoids as part of its function to remove conditions where the risks
frequency and severity of seizures. Combined with an absence of psychoactive effects, these results
indicate the potential of CBD as a therapeutic candidate for a diverse range of human epilepsies.
external substances from the body (metabolism).
The effects of cannabis may therefore be associated with using
Psychiatric disorders
significantly different in patients with a liver
disease.
medicinal cannabis may
Another upcoming, but only partially understood, application of cannabinoids is in the treatment
of psychiatric disorders such as schizophrenia, anxiety and bipolar disorder. Although long-term
be increased.
Addiction
consumption of high doses of THC has actually been identified as a risk factor for the development It is unlikely to develop an addiction when
of such mental illnesses, other cannabinoids seem to have the reverse effect. In particular the non- cannabis is used as a medicine. The recommended dose for medicinal use is often lower than
psychoactive cannabinoid CBD has shown potential in this respect, and cannabis varieties (chapter 2) that for recreational use, and a medical professional should be involved in monitoring the patient.
high in CBD are being developed in many places around the world. Researchers believe that CBD may Patients should take particular care, however, if they have been addicted in the past. High dosages
exert its effects on the brain by interacting directly with the endocannabinoid system (chapter 4). In a of medicinal cannabis taken over a longer period may lead to addiction. Quitting may then cause
study using pure CBD, it was found this mechanism may lead to substantial antipsychotic properties withdrawal symptoms, such as mild forms of restlessness, irritability, insomnia and nausea.
in acute schizophrenia with an efficacy comparable to the standard drugs.

6 | History, drug policy & The Dutch way
Cannabis most likely originates from Central Asia, as archeological evidence indicates it was
cultivated in China for food and fiber already 10.000 years ago. Also in ancient Egyptian mummies
clues have been found for the use of cannabis as food or medicine. In fact, cannabis is one of the
oldest known medicinal plants and is described in almost every ancient handbook on plant medicine,
most commonly in the form of a tincture or a tea. Some religions were closely related with the
properties of the cannabis plant. For example, in Hindu legend cannabis is believed to be the favorite
food of the god Shiva, because of its energizing properties. As cannabis spread from Asia towards the
West, almost every culture came into contact with this versatile plant.

Nowadays, cannabis can be found in all temperate and tropical zones, except in humid, tropical
rainforests. As a fiber plant cannabis is also known as Hemp. It produces some of the best and most
durable fibers of natural origin. For a long time in history these fibers were used to produce sails
for sea-ships, paper, banknotes and even the first Levi’s jeans. The oil that can be pressed form the
hempseed is very nutritious and is considered as a good alternative to fish oil as a source of the
healthy kind of fatty acids. 35
Despite the fact that cannabis has been grown for centuries on a large scale in most countries, the
recreational use as a narcotic remained uncommon in Europe or the United States until relatively
recently. People were largely unaware of the psychoactive properties of cannabis and it is unlikely
that early cultivars, selected mainly for their fiber qualities, contained significant amounts of the
psychoactive compound THC. The medicinal use of cannabis was only introduced in Europe around
1840 by a young Irish doctor called William O’Shaughnessy. He served for the East India Trading
Company in India, where the medicinal use of cannabis was widespread. Unlike the European fiber
cannabis, these Indian varieties did contain a reasonable amount of THC. In the following decades
cannabis knew a short period of popularity both in Europe and the United States. At the top of
its popularity, dozens of different medicinal preparations were available with cannabis as active
ingredient, which were recommended for indications as various as menstrual cramps, asthma, cough,
insomnia, support of birth labor, migraine, throat infection and withdrawal from opium use. See
figure 6-1 for some examples of old cannabis medicine.

Unfortunately, difficulties with the supply from overseas and varying quality of the plant material
made it difficult to prepare a reliable formulation of cannabis. Because, at that time, no tools existed
for quality control it was impossible to prepare a standardized medicine, so patients often received a
dose that was either too low, having no effect, or too high, resulting in serious side effects. Moreover,
cannabis extract was not water-soluble and therefore could not be injected, while oral administration
was found to be unreliable because of its slow and erratic absorption. Because of such drawbacks
the medicinal use of cannabis increasingly disappeared in the beginning of the twentieth century. Its
place was largely taken over by opium based drugs such as morphine and codeine. When finally a
high tax was imposed on all cannabis-based products (seeds and fibers excluded) and increasingly
restrictive legislation was introduced for cannabis abuse, the medicinal use of cannabis gradually
disappeared from all Western pharmacopoeias in the period from 1937.
Only since the flower-power-time of the 1960s, the smoking of cannabis as a recreational drug
has become a widely known phenomenon in the Western world. From then on, import of stronger
varieties from the tropics, combined with a growing interest in breeding, initially most notably among
American Vietnam war veterans, led to a steady increase in psychoactive potency. Contemporary
recreational cannabis has increasingly become a high-tech crop, grown indoors under completely
artificial conditions.
The Single Convention
As from 1954, the World Health Organization (WHO) started claiming that cannabis and its
preparations no longer served any useful medical purpose and are therefore essentially obsolete.
This decision was made under pressure of increasing reports by the newly created Federal Bureau of
Narcotics that cannabis was a drug dangerous to society. Up to that moment, cannabis legislation
had been based on a large number of international conventions, causing considerable legal confusion.
It was therefore proposed to combine all legislation into a single international convention, the draft of
which was finally accepted by the United Nations in 1961. Under this “Single Convention on Narcotic
Drugs” cannabis and its products were defined as dangerous narcotics with a high potential for abuse
and no accepted medicinal value. It reflected the belief that cannabis was a narcotic with a threat that
was equal to heroin, ecstasy and LSD. In following years several complementary treaties were made
to strengthen the convention. These laws have been an important basis for the ‘War on Drugs’.
Since the Single Convention was introduced, the potential danger of recreational cannabis use
has been much higher on the political agenda than any of its benefits as a source of fiber, food or
medicines (see chapter 7). According to the American president Nixon, cannabis was a secret weapon
of the communists, being spread by the Jews to destabilize the Western world. This cannabis-related
fear has been the base for the legislation that is nowadays obstructing the rediscovery of cannabis as
a medicine. Although our scientific understanding of cannabis has increased significantly over the last
years, these insights are only slowly and reluctantly incorporated into new legislation.
In the coming years, a large variety of scientific and clinical data is expected to become available,
further showing the medicinal effects of cannabinoids and the endocannabinoid system. Several
Western countries are already providing medicinal cannabis products to patients, and some steps are
even taken towards decriminalization of recreational cannabis use in a few countries. These shifts
signal that the Single Convention, and the punishment-based prohibition that goes with it, may start
to reach its expiry date. The legislation that follows it will depend for a large part on the quality of the
scientific research available. Although no formal rules prohibit cannabis smoking in public places, such as bars, restaurants or
Drug policy of The Netherlands
Whereas most countries of the world have traditionally followed an approach of punishment-based
prohibition on cannabis and other drugs, the Netherlands have instead focused on harm-reduction.
The basic principles of the Dutch drug policy were largely formulated in the mid-seventies. This policy
does not moralize, but is based on the assumption that drug use is an undeniable fact in society and
must be dealt with as practically as possible. The most important objective of this policy is therefore
to prevent or to limit the risks and the harm associated with drug use, both to the user himself and
to society at large.
The cornerstone of this policy is the law known as the Opium Act, which is based on two key
principles. Firstly, it distinguishes between different types of drugs on the basis of their harmfulness,
with cannabis, hashish and psychedelic mushrooms on the one hand, and drugs that represent an
“unacceptable” risk on the other. The terms ‘soft-drugs’ and ‘hard-drugs’ refer to this distinction.
Secondly, the law differentiates on the basis of the nature of the offence, such as the distinction
between possession of small quantities of drugs intended for personal use versus possession
intended for sales and distribution. Personal use of a drug itself is not an offence.
37
Cannabis cultivation, sales and use are formally illegal according to Dutch law. However, through
the famous outlets known as “coffeeshops” the sales of small quantities of cannabis is tolerated
(condoned) under strict conditions. There are currently about 600 of such coffeeshops in the
Netherlands, with the majority located in the bigger cities. Tolerance is a typically Dutch policy
instrument which is based on the power of the Public Prosecutor to refrain from prosecuting offences.
This principle is formulated in the law and is called the “expediency principle”. The small-scale sales
carried out in the coffee shops are thus a legal offence from a legal viewpoint, but under certain
conditions it is not prosecuted. These conditions are: no advertising, no sales of hard-drugs, no
nuisance must be caused in the neighbourhood, no admittance of and sales to minors (under the
age of 18), and no sales exceeding 5 grams of cannabis per transaction. The stock of the coffeeshop
should not exceed 500 grams of cannabis. If these rules are violated, the shop can be closed down by
the municipal authorities. Currently, a new requirement is proposed stating that coffeeshops should
be at least 350 meters removed from any school.
The main philosophy behind the Dutch policy towards the coffeeshops is that of harm reduction. This
is based on the argument that if small-scale cannabis sales and use is not prosecuted under certain
conditions, the users – mainly young people experimenting with the drug – are not criminalized (they
do not get a criminal record). Also, they are not forced to move in criminal circles, where the risk that
they will be pressed to try more dangerous drugs such as heroin is much greater. Tolerance does
not mean that cannabis smokers can just light up a smoke anywhere they like outside a coffeeshop.
train stations, very few people do so. If they do no sanctions are applied, but the person is likely to be
asked by the staff to put out the cannabis cigarette.
 Starting a medicinal cannabis program
Based on their liberal drug policy it may not be surprising that the Dutch have been among the
first to start an official Government program for medicinal cannabis. In fact, it was Health Minister
Els Borst (1994-2002) who first officially acknowledged that a lot of patients were using cannabis
Figure 6-2 Informal Dutch sign indicating
obtained through coffeeshops for medicinal purposes. However, in coffeeshops patients cannot get
that smoking of cannabis is
any guarantees on the quality, composition or origin of the cannabis. In order to supply patients with
not appropriate in this location
a safe and reliable source of high quality cannabis, and to involve physicians and pharmacists in the
(public park, playground etc.).
medicinal use of cannabis, the Minister made it possible to start a national program. As a result, the
Office of Medicinal Cannabis (OMC) was established as a National agency in 2000.
® Copyrights: KochxBos Studio Amsterdam
The OMC is part of the Ministry of Health, responsible for the production of cannabis for medical and
scientific purposes. By setting up a National agency the Dutch cannabis program is in full agreement
with the Single Convention, which allows the medicinal use of cannabis under strict conditions.
Medical grade cannabis finally became available in Dutch pharmacies in September 2003, and
since then it can be obtained on doctors’ prescription. Besides supplying it to Dutch patients, the
OMC also provides cannabis for scientific research, for development of cannabis-based medicine by
39
pharmaceutical companies, and for export to other countries with a medicinal cannabis program if
those authorities issue an import license.

Right from the start, a reliable source of high quality cannabis materials was considered crucial for
the success of the Dutch medicinal cannabis program. Therefore, a skilled breeder was contracted
for the cultivation of plants under highly standardized conditions, resulting in a product with a
reliable and consistent composition. The
whole process of growing, processing
and packaging of the plant material are
performed according to pharmaceutical

Figure 6-1 Some examples of cannabis medicines of the past standards, all supervised by the OMC.
Collection Hash Marihuana & Hemp Museum, Amsterdam. The quality is guaranteed through regular
testing by specialized and certified
laboratories (see chapter 1).

The absence of formal regulations for the use of cannabis has opened the way for these informal Based on the availability and quality of
norms, and their existence and effectiveness is an aspect of Dutch drug policy that is often clinical data and scientific literature, a
underestimated and difficult to grasp by foreigners. For example, tourists who visit Amsterdam selection of indications was made by the
commonly make the mistake of thinking they can smoke cannabis ‘everywhere’. In response to this OMC for treatment with its medicinal
and other problems with public cannabis use, the city of Amsterdam has even invented a new traffic grade cannabis (see chapter 5).The
sign (see figure 6-2). It must be noted that the majority of the Dutch population, especially senior product is finally delivered to patients in
citizens, have never consumed cannabis and do not know much about cannabis regulations or habits. 5 gram packages, as shown in figure 6-3.
Figure 6-3 Dutch medicinal cannabis is available to patients
through pharmacies in 5 gram packages.
Photo: Bedrocan
SUGGESTED FURTHER READING
A very short selection of the scientific literature:
Ben Amar M (2006) Cannabinoids in medicine: A
review of their therapeutic potential. Journal of
Ethnopharmacology, 105(1-2), 1-25
Hazekamp A (2006) An evaluation of the quality
of medicinal grade cannabis in the Netherlands.
Cannabinoids, 1(1), 1-9
Hazekamp A and Grotenhermen F (2010) Review
on clinical studies with cannabis and cannabinoids
2005-2009. Cannabinoids, 5(special issue), 1-21
Hazekamp A and Fischedick JT (2012) Cannabis
- from cultivar to chemovar. Towards a better
definition of cannabis potency. Drug Testing and
Analysis, 4, 660-667
Hazekamp A and Heerdink ER (2013) The
prevalence and incidence of medicinal cannabis on
prescription in The Netherlands. European Journal
of Clinical Pharmacology, 69(8), 1575-1580.
Hazekamp A, Ware MA, Muller-Vahl KR, Abrams
D, Grotenhermen F (2013) The medicinal use of
cannabis and cannabinoids; an international cross-
sectional survey on administration forms. Journal
of Psychoactive Drugs, 45(3), 199-210
Izzo AA, Borrelli F, Capasso R, Di Marzo V,
Mechoulam R (2009) Non-psychotropic plant
cannabinoids: new therapeutic opportunities from
an ancient herb. Trends in Pharmacological Sciences,
30(10), 515-527
Russo EB (2011) Taming THC: Potential cannabis
synergy and phytocannabinoid-terpenoid
entourage effects. British Journal of Pharmacology,
163, 1344-1364
Skaper SD, Di Marzo V (2012) Endocannabinoids in
nervous system health and disease: the big picture
in a nutshell. Philos Trans R Soc Lond B Biol Sci,
367(1607): 3193-3200
USEFUL WEBSITES
41
Dutch Office of Medicinal Cannabis (OMC)
www.cannabisbureau.nl
Bedrocan BV
www.bedrocan.com
Dutch Foundation for Cannabis and its
Constituents as Medicine (NCSM)
www.ncsm.nl Colophon
© 2013, Dr. Arno Hazekamp
International Association for Cannabinoid
Medicines (IACM) This is a Self-publishing book.
www.cannabis-med.org Thanks to Bedrocan BV for support.
International Cannabinoid Research Society Text: Dr. Arno Hazekamp
(ICRS) Photos: Floris Leeuwenberg, Lex van Lieshout
www.icrs.co and Eppo Karsijns.
Design: Marion Fischer, Papyr
Canadian Consortium for the Investigation of
E-mail: ahazekamp@rocketmail.com
Cannabinoids (CCIC)
www.ccic.net Nothing from this document may be copied, saved in an
authorised database or be made public in any form, whether
Americans for Safe Access (ASA)
it be electronically, mechanically or through photocopies
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without prior consent from the publisher.