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An Indian Perspective on Cannabis for Treatment of Pain

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An Indian Perspective on Cannabis for Treatment of Pain

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The history related to the use of medicinal Cannabis has been intimately intertwined with India since the beginnings of human civilization. Since its origin in the lower Himalayas, the diverse cultural, medical and religious uses of the Cannabis plant slowly disseminated around the world. After being outlawed as a narcotic drug in the 20th century, Cannabis has been rediscovered as a much needed medicine for chronically ill patients. Since 2000, a number of countries have initialized national programs to cultivate and distribute Cannabis for medical use, and to stimulate research and development to produce modern medicines from this ancient plant. Unfortunately and ironically, India has not benefitted from these developments, despite the countries’ claim to fame as a major source of information about the medicinal uses of Cannabis. In India untreated chronic pain is one of the major sources of patient’s sufferings and Cannabis medicine can prove to be a welcome alternative to the much more risky opioids derived from the Opium poppy. This review paper explores the origins of Cannabis medicine in India, its historical use as a treatment for chronic pain, and recent scientific developments with Cannabis and its main active constituents, the cannabinoids. Finally, the cannabinoids are compared to opioids for the treatment of pain, in order to make a recommendation for the reintroduction of Cannabis medicine for pain treatment in India today.
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e ISSN 2350-0204
International Journal
of Ayurveda and
Pharmaceutical
Chemistry
Volume 7 Issue 3 2017
www.ijapc.com
Greentree Group
Greentree Group
Received 20/08/17 Accepted 18/09/17 Published 10/11/17
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Int J Ayu Pharm Chem
REVIEW ARTICLE www.ijapc.com
e-ISSN 2350-0204
ABSTRACT
The history related to the use of medicinal Cannabis has been intimately intertwined with India
since the beginnings of human civilization. Since its origin in the lower Himalayas, the diverse
cultural, medical and religious uses of the Cannabis plant slowly disseminated around the world.
After being outlawed as a narcotic drug in the 20th century, Cannabis has been rediscovered as a
much needed medicine for chronically ill patients. Since 2000, a number of countries have
initialized national programs to cultivate and distribute Cannabis for medical use, and to
stimulate research and development to produce modern medicines from this ancient plant.
Unfortunately and ironically, India has not benefitted from these developments, despite the
countries’ claim to fame as a major source of information about the medicinal uses of Cannabis.
In India untreated chronic pain is one of the major sources of patient’s sufferings and Cannabis
medicine can prove to be a welcome alternative to the much more risky opioids derived from the
Opium poppy. This review paper explores the origins of Cannabis medicine in India, its
historical use as a treatment for chronic pain, and recent scientific developments with Cannabis
and its main active constituents, the cannabinoids. Finally, the cannabinoids are compared to
opioids for the treatment of pain, in order to make a recommendation for the reintroduction of
Cannabis medicine for pain treatment in India today.
KEYWORDS
Cannabis, Historical use, Analgesic, India, Opioids
An Indian Perspective on Cannabis for Treatment of Pain
Arno Hazekamp1,2*
1Scientific director, Bombay Hemp Company, Mumbai, India
2Independent consultant on medicinal Cannabis research and development, Hazekamp Herbal Consulting BV,
Leiden, The Netherlands
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INTRODUCTION
The history of India and the history of
Cannabis are intimately intertwined. For at
least the last 4600 years, Cannabis has been
continuously cultivated and used in
Northern India, according to archeological
findings1. Around 1000 BCE, the medicinal
use of Cannabis took definite root in Indian
culture. Then, from its origins in the lower
Himalayas, the Cannabis plant (Cannabis
sativa L.) gradually spread over the world.
(Figure 1).
Figure 1 The spreading of medicinal Cannabis use
around the world (Taken from Zuardi13)
Over the millenia, it has been used as a
source of fibre, food, (seed) oil and
medicine as well as for recreational,
religious and spiritual purposes. For
example, an ancient mystical sutra tells us
that Siddhartha (later known as lord
Buddha) survived for six years, prior to his
enlightenment, on a single Cannabis seed
per day2. Cannabis is believed to be the
favorite plant of Hindu god Shiva, and has
been an integral part of Hindu practice and
culture for ages3-9. Also, Muslims regarded
it as a holy plant and in Unani Tibbi (the
Muslim system of medicine) Cannabis was
used for treating numerous diseases10-12.
However, nowhere do the many applications
of the Cannabis plant become more apparent
than in the ancient tradition of Ayurvedic
medicine. Ayurveda, combining the Sanskrit
words for life and knowledge, is a system of
medicine typically based on complex herbal
compounds, often mixed with minerals or
metal substances. This system has survived
for over 3000 years and has been well
documented, making it one of the most
important sources of traditional knowledge
on medicine in the world. These days the
medicinal use of Cannabis is rapidly
becoming more accepted worldwide,
Ayurvedic knowledge on the risks and
benefits of this plant is more valuable than
ever. By combining traditional and cultural
knowledge about Cannabis use with the
modern demands of scientific research,
medicinal Cannabis may once again move to
the forefront of Indian medicine. After all,
no other country can boast such a wealth of
traditional use of Cannabis, combined with a
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well documented history of its risks and
benefits.
In fact, India is one of the few places in the
world with a true traditional use of
medicinal Cannabis; in most other places,
the only actual traditional use of Cannabis is
in fact its abuse as a narcotic drug. India has
the knowledge, tools and means to develop
new Cannabis-based medicines that can
embrace the best of two worlds viz., the
traditional preparations and administration
forms of the past (perhaps in combination
with other herbs and ingredients), and
modern-day clinical proof on safety and
efficacy. Bringing these sources of
knowledge together surely has the potential
to develop holistic Cannabis-based
medicines, fully supported by clinical trials,
but with low abuse potential. The most
promising area for the development of such
products is chronic neuropathic pain, a
medical indication that is severely
undertreated in India today. This paper
explores the different aspects and
implications of this idea.
The long history of Cannabis in
India
Cannabis is among the earliest plants
cultivated by mankind. The first evidence of
its use for medicinal or cultural purpose was
found in China, but there the medical use of
Cannabis never reached the importance it
did in India10,13. Nowadays, the strong
smelling annual herb is occurring
throughout the western Himalayas up to
2400m and is abundantly found throughout
the greater part of India.
The earliest written reference to Cannabis in
India may occur in the Atharvaveda, dating
to about 1500 BCE14,15. This ancient
document hails the bhang’ plant as one of
the five sacred plants and as a source of
happiness, donator of joy, and bringer of
freedom16 ; “We tell of the five kingdoms of
herbs headed by Soma; may it, and kusa
grass, and bhang and barley, and the herb
saha, release us from anxiety.” Grierson15
suggested this text to be part of an offering,
and ingestion or burning would both be
typical of ancient practices for this purpose.
In the Sushruta Samhita (meaning: the
verses of Sushruta), dating from around 500
BCE, Cannabis was recommended for
phlegm, catarrh and diarrhoea14,15. The
Sushruta Samhita is among the most
important ancient medical treatises, and one
of the foundational texts of the medical
tradition in India. The Rajanighantu, also
known as Abhidhana Cudamani, is the
famous work of Narahari Pandita, son of
Iśvarasuri, who was a resident of Kashmir
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around 1300 AD14,15. The manuscript
mentions Cannabis among various important
medicinal plants. It states that “its effects on
man are described as excitant, heating,
astringent; it destroys phlegm, expels
flatulence, induces costiveness, sharpens the
memory, excites appetite, etc.”
About two centuries ago the modern age of
Cannabis investigation began in India. In
1839, the seminal work of Sir William B.
O’Shaughnessy on Cannabis was written17,
and then republished in England a few years
later18. It was titled On the preparations of
the Indian Hemp or Gunjah’.
O’Shaughnessy served as a medical doctor
in India with the British and made his first
contact with Cannabis use there. Unlike the
European fiber Cannabis, these Indian
varieties did contain a significant amount of
bioactive chemicals called cannabinoids (see
below), as a result of the hot climate they
were growing in, and the genetic types of
Cannabis (varieties) present in India. He
studied the literature on the plant, described
many popular preparations, and evaluated its
toxicity in animals. O’Shaughnessy also
described various successful human
experiments using controlled doses of
Cannabis preparations for several common
diseases of the time. This work basically
constituted the first real clinical trials with
Cannabis. In his writings, Cannabis was
identified as potential treatment for a wide
range of disorders including cholera,
rheumatic diseases, rabies, and infantile
convulsions. For the first time in history,
miraculous recoveries were evidenced in a
series of tetanus victims, due to the
therapeutic properties of Cannabis19,20.
In 1877, the Bengal Government appointed
a special officer, named Babu Hem Chunder
Kerr, to make a full inquiry into the details
of cultivation of Cannabis in India. The Kerr
report submitted an extremely detailed
report encompassing history, religious
context, cultivation and employment of
Cannabis in all its preparations21. This
would form an important source for the
subsequent Report of the Indian Hemp
Drugs Commission16 which was
subsequently published in 1894 (Figure 2).
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Figure 2 Opening page of the report of the Indian
Hemp Drugs Commission16
Its findings exceeded 3000 pages after
exhaustive investigation and testimony, and
may be summarized as follows22 : (1)
Moderate use of Cannabis drugs had no
appreciable physical effects on the body. As
with all drugs, excessive use could weaken
the body and render it more susceptible to
diseases. Such circumstances were not
peculiar to Cannabis, however. (2) Moderate
use of Cannabis drugs had no adverse effect
on the brain, except possibly for individuals
predisposed to act abnormally. Excessive
use, on the other hand, could lead to mental
instability and ultimately to insanity in
individuals predisposed by heredity to
mental disorders. (3) Moderate use of
Cannabis drugs had no adverse influence on
morality. Excessive usage, however, could
result in moral degradation. Although in
certain rare cases Cannabis intoxication
could result in violence, such cases were few
and far between. The commission advocated
against governmental suppression of
Cannabis drugs. In the report12, many
positive statements accompanied
descriptions of their religious associations,
and particularly their legion medical usage,
both human and veterinary. The report
concluded that: “Cannabis indica must be
looked upon as one of the most important
drugs of Indian Materia Medica.”
Despite such nuanced recommendations, the
British Government of India finally
prohibited consumption of Cannabis resin in
India in the 1930’s. Since then the
cultivation and use of Cannabis has
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dwindled23. These decisions were closely
linked to developments that happened in
other parts of the world. At that time, the
active principle of Cannabis had not yet
been isolated and the drug was used in the
form of tinctures or extracts whose power
was dependent on different factors, such as
origin and age of the plant, and mode of
preparation19. Unfortunately, no laboratory
techniques existed at the time to check the
quality of Cannabis products. In addition,
various medications appeared in the early
20th century, with known efficacy for the
treatment of the same main indications that
Cannabis was typically used for. Fore
example, vaccines were developed for
various infectious diseases, such as tetanus.
Meanwhile, effective analgesics such as
aspirin appeared, and the recently invented
hypodermic needle allowed the injectable
use of morphine. As a narcotic and sedative,
Cannabis was rivalled by newly developed
substances such as chloral hydrate,
paraldehyde and barbiturates19. As a result,
from 1954 onwards the World Health
Organization (WHO) started proclaiming
that Cannabis and its preparations no longer
served any useful medical purpose and were
therefore essentially obsolete. In subsequent
years, the medicinal use of Cannabis
gradually disappeared from all medical
pharmacopoeias all over the world.
Despite these challenges, Cannabis use
remained common in 20th-century India. As
recent as 1957, two authorities in India
noted in their review paper The use of
Cannabis drugs in India’ that23; “Cannabis
undoubtedly has remarkable therapeutic
properties; …the drug has no constipating
action, it does not depress the respiratory
centre (as opioids do); and there is little or
no liability to addiction formation”. In 1965,
Dwarakanath24 listed the names of 48
modern Ayurvedic and eight Unani Tibbi
formulas containing Cannabis for a wide
range of indications in a Report to the
United Nations. The author felt that a
legitimate role for Cannabis products
persisted, stating that: “these drugs should
be allowed to be used by Ayurvedic and
Unani physicians until such time as the
benefits of modern medicine are extended to
rural areas. Banning their use by the large
mass of Ayurvedic and Unani physicians for
therapeutic purposes may create a vacuum
which may not be easily filled for a long
time to come.” Unfortunately, the vacuum
left by banning Cannabis, particularly for
the treatment of severe pain, has still not
been filled sufficiently by other medications
even today25,26.
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Presently, the plant is popularly known in
India mainly as a source of narcotics in
various forms and names, such as bhang,
charas, ganja, marijuana, hashish, weed,
grass etc. It is illegal to produce,
manufacture, possess, sell, purchase,
transport, use, consume, import or export
any narcotic drug or psychotropic substance
except for medical or scientific purposes
under the Narcotic Drugs and Psychotropic
Substances Act in India27. Nevertheless,
cultural use remains common in various
parts of India and in surrounding countries
such as Nepal26. Efforts for research and
cultivation of varieties of Cannabis called
industrial hemp are increasingly being
undertaken in many countries across the
world. Hemp is a type of Cannabis with no
abuse potential, but with an excellent quality
of fibers and very nutritious seeds. Hemp
grows very well in India and is currently
being reintroduced as an agricultural crop
e.g. for local manufacturing of textiles (e.g.
Bombay Hemp Company;
www.boheco.org).
Cannabis as a well-known remedy
for pain
In recent years, self-medicating patients
from around the world have ascribed a long
list of therapeutic effects to Cannabis, but
many of these claims have not yet
undergone rigorous clinical testing in
humans. In fact, the limited evidence
available today on the risks and benefits of
medicinal Cannabis remains a major
obstacle for its acceptance by medical
professionals28. More studies are certainly
needed in order to use Cannabis responsibly,
but the large number of Cannabis products
in use today, combined with the many
medical indications that Cannabis could
potentially be beneficial for, make it nearly
impossible to decide which studies should
be funded and executed first. When deciding
which medical claims seem to be most
reliable, and should therefore be further
investigated in modern studies, a look at
historical records may help us in the right
direction.
Throughout history, one of the most
persistent medical uses of Cannabis is the
treatment of intense pain. Indeed, the
application of this plant as a potent analgesic
has been described in many ancient texts
and traditional practices. The uses range
from drinking milk medicated with
Cannabis, to applying an external compress
and fumigation for pain relief29. Based on its
narcotic properties Cannabis seems to have
been used as an anaesthetic by the ancient
Indian and Chinese surgeons, sometimes in
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combination with alcohol30. It was used as a
household remedy and by Hakims (Unani
physicians) and Vaidyas (Ayurvedic
physicians) as pain-reliever as well as
appetizer, aphrodisiac, antispasmodic,
antidiarrheal and diuretic23. The 18th
century Persian medical text Makhzan-al-
Adwiya, written by M. Husain Khan (as
described by O’Shaughnessy18), was
extremely influential in the Unani Tibbi, or
Arabic-tradition medicine on the Indian
subcontinent. In it, Cannabis was described
in its various preparations as an intoxicant,
stimulant and sedative, but also as treatment
for inflammations and neuralgic pains.
After the introduction of Cannabis from
India into Europe in the mid-19th century, a
number of medical practitioners both in
India and in Great Britain soon noted
success in the use of Cannabis for treatment
of migraine, as well as neuropathic and other
pain conditions31,32. As a result, in 1860 the
first clinical conference about Cannabis took
place in America, organized by the Ohio
State Medical Society33. In the second half
of the 19th century, over 100 scientific
articles were published in Europe and the
United States about the therapeutic value of
Cannabis34. However, the climax of the
medical use of Cannabis by Western
medicine occurred in the late 19th and early
20th century. Many famous laboratories
marketed extracts or tinctures containing
Cannabis, including Merck in Germany,
Burroughs-Wellcome in England, and
Bristol-Meyers Squibb, Parke-Davis and Eli
Lilly in the United States19. Many of those
products were focused on treating various
types of pain. The scientist Dymock, in
Europe around 1890, illustrated such use of
Cannabis quite well when he stated35 : “I
have given the [Cannabis] extract in doses
of from 1/2 to 1 grain to a large number of
hospital patients suffering from chronic
rheumatism; it entirely relieved the pains”.
In India, treatment of pain conditions with
Cannabis products extended well into the
20th century. For example, the use of
Cannabis in Unani medicine around the
1950s included treatment of insomnia,
migraine, neuralgic pains, asthma, etc.23. In
a 1962 book about medicinal plants of
India36, the author stated: “Cannabis resin is
a valuable narcotic, especially in cases
where opium cannot be administered; it is of
great value in malarial and periodical
headaches, for migraine, anaesthetic in
dysmenorrhea, neuralgia, severe pains of
various kinds of corns, etc.” And in 1965,
Dwarakanath24 maintained that Cannabis
was employed in Indian folk medicine in
aphrodisiacs and as treatment for pain.
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Around the same time, Sanyal37 observed
that: “They also used the fumes of burning
Indian Hemp (Cannabis Indica) as an
anaesthetic from ancient times…”. In 1977,
Sharma11 noted that “even today [Cannabis]
is used with restraint and judgment by
students of Indian medicine. There are
reports claiming the value of Cannabis in the
treatment of high blood pressure, migraine
headaches, and even cancer.” Interestingly,
the use of concentrated Cannabis extracts for
the treatment, and possibly even curing, of
cancer is once again in the spotlights, after
recent studies showed a remarkable effect of
isolated cannabinoids on a range of cancer
cell types in vitro and in vivo38.
In 1996 an interesting scientific experiment
took place, when Indian native Cannabis
was extracted and used to treat cancer pain
in a modern clinical trial with 42 human
subjects39. Although some patients felt no
analgesia with doses of 25 mg of extract, the
majority of patients experienced more than
50% pain relief with no use of adjunctive
medicine. By any modern standards this is
an impressive and significant therapeutic
effect. Since the mid-1990s, many of the
traditional claims made for Cannabis have
been investigated in modern studies around
the world, and some even have become
accepted as a proven treatment. As a result,
fully regisered products such as Marinol®
(containing synthetic THC in sesame oil),
Nabilone® (a synthetic analogue of THC)
and Sativex® (a mixture of THC- and CBD-
rich Cannabis extracts) were developed and
these are now available on prescription in
many countries.
In the neurological realm, the ability of
Cannabis to treat severe pain is the subject
of a great deal of current research. Results to
date are very encouraging, in terms of basic
understanding of the biochemical pathways
involved40,41 as well as the benefits seen in
clinical trials42,43. Cannabis seems to be
most efficient in the treatment of
neuropathic types of pain, which means that
the source of the pain originates from
damage of the nervous system itself. In
contrast, acute types of pain do not seem to
respond as well to cannabinoid treatment44.
The safety profile of cannabinoids was
found to be very acceptable when used in
doses appropriately for medical treatment45-
47.
Based on modern pharmacology, it is now
understood that the analgesic effects of
cannabinoids are caused by their interaction
with the endogenous cannabinoid
(endocannabinoid) system48. In short, plant-
derived cannabinoids are able to interact
with the body’s own endocannabinoids, by
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binding to so-called cannabinoid-binding
(CB) receptors, of which currently two types
are known. CB1 receptors modulate
neurotransmitter release in the brain and
spinal cord, where they are present in high
densities in certain parts of the central
nervous system49. They are also present in
nociceptive and nonnociceptive sensory
neurons of the dorsal root ganglion and
trigeminal ganglion50, as well as in defense
cells such as macrophages, mast cells, and
epidermal keratinocytes51. CB2 receptors are
expressed at considerable levels in cells of
the immune system52, where they regulate
neuroimmune interactions and can interfere
with inflammatory hyperalgesia. Other
receptors are believed to respond to
(endo)cannabinoids a well, including the
orphan receptor GPR55, and the vanilloid
receptor TRPV153. These receptors have
become an important target for the
development of a new generation of pain
medication53,54.
Comparing cannabinoids to opioids
Severe pain can have a wide range of
sources, including infection, injury, cancer
or auto-immune disease. Throughout
medical history the various origins of pain
have been notoriously difficult to classify
and to treat. Because pain cannot be directly
measured on an objective scale, it is
important to believe the patient when he
describes his level of pain. In medical
research, pain intensity is therefore scored
using a Visual Analogue Scale (VAS) or a
Numeric Rating Scale (NRS) where patients
indicate their pain on a scale typically
ranging from 0 (no pain at all) to 10 (worst
pain imaginable)55. However, the subjective
nature of pain makes it difficult to
accurately determine the exact effect of any
pain medication on a patient.
The "pain ladder", or analgesic ladder, was
created by the World Health Organization
(WHO) as a guideline for the use of drugs in
the management of pain (Figure 3).
Figure 3 The ‘pain ladder’, as developed by the
World Health Organization
Originally published in 1986 for cancer
pain, it is now widely used by medical
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professionals for the management of all
types of pain56. The three-step approach is
inexpensive, in terms of cost of medicine,
and 7090% effective when used properly.
The general principle is to start with drugs
described for the initial step, and then to
climb the ladder if pain remains present. The
medications range from common, over-the-
counter drugs such as aspirin at the lowest
step (level 1) to powerful opioids including
methadone, morphine and oxycodone at the
highest (level 3). For severe pain conditions
only strong opioids are currently available to
achieve relief of suffering, short of moving
on to more invasive techniques such as
surgery or temporary degeneration of the
affected nerves (e.g. neurolysis)56. To help
calm fears and anxiety, adjuvant drugs may
be added at any step of the ladder.
It must be noted that there is no standardized
dosage in the treatment of pain; every
patient will respond differently. The correct
dosage is one that will allow adequate relief
of pain, resulting in acceptable quality of life
for the patient. The dosing regimen should
therefore be adapted to achieve the best
balance between the analgesic effect and the
side effects. That means analgesics should
be prescribed with a constant concern for
detail. But when pain medication needs to be
taken daily, at regular intervals, patients
must be able to use such drugs in a home
setting. Unfortunately, many policymakers
and medical professionals consider opioids
too risky to be used or prescribed in such a
liberal manner.
In India, an estimated one million people
with cancer, plus an unknown number of
people with other incurable and disabling
diseases, need opioids for pain relief. But
despite the fact that India is one of the
world’s largest producers of medicinal
opioids, only a tiny proportion of the
population in need have access to them,
mainly in the form of morphine26. Important
barriers that prevent access include
cumbersome regulatory and licensing
procedures for physicians and hospitals that
want to prescribe opioids, combined with
harsh punishments in case the regulations
are not correctly followed. Through decades
of strict regulation, medical professionals
developed an increasing fear of morphine;
they would not use it and taught their
medical students to avoid it. Also, over
decades, scientific advances in medicine
have resulted in an overemphasis on ‘‘cure’’
and a downturn in the practice of symptom
control or palliative care, including pain
relief25. This climate has made the medical
community in India shy away from the use
of opioid drugs to treat their patients, even
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in the absense of proper alternatives for
treating severe pain26. As a result, the vast
majority of patients suffering from severe
pain in India remain undertreated today57.
The basis of this behavior is a widespread
fear of the effects of opioid use. The general
public, including government officials,
associates morphine with inevitable
addiction and are reluctant to accept the
drug for medical needs. Such fears have
been fueled to a large extent by the rapid
increase in the use of medical opioids such
as Percocet, Vicodin and OxyContin in the
United States. As a result of overprescribing
of opioids by physicians and pharmacists,
overdose deaths in the US have currently
reached record levels, also known as the
‘opioid epidemic’58. Hence, the suggestion
by WHO to prescribe and use as much
painkillers as needed to effectively treat the
pain, may be at odds with a realistic worry
about drug abuse and overdose morbidity
and mortality.
Cannabis may provide a solution to this
difficult medical and ethical dilemma. The
main active constituents of the Cannabis
plant, the cannabinoids THC and CBD, have
already shown to be effective in a wide
range of pain models and in clinical
trials42,43,59. While these cannabinoids exert
some of the same potent analgesic effects as
the opioids, they are vastly more acceptable
in their potential side effects. Most
importantly, opioids may lead to respiratory
depression which is a major cause of death
from opioid overdosing60. In contrast,
cannabinoids do not have lethal potential
even at very high concentrations, due to a
lack of cannabinoid receptors in brain areas
that control critical physiological functions
such as heartbeat and breathing61,62.
Moreover, the addictive potential of
Cannabis is directly related to its content of
the psychotropic component THC. Other
cannabinoids, such as CBD and THCV, do
not show any such potential and have been
found safe and well-tolerated even at very
high dose63,64. Interestingly, cannabinoids
and opioids work very well together in the
treatment of pain; clear synergistic effects
between the two have been observed, and
the combined use makes it safer, because it
allows the opioid dose to be significantly
reduced65. This means that an increase of
pain patients using Cannabis or
cannabinoids may directly result in a
lowered need for the more risky opioids, as
has been witnessed in several US states that
have legalized the medicinal use of
Cannabis48. In fact, the addictive potential of
Cannabis is believed to be so much lower
compared to opioids, that cannabinoids are
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considered a target treatment for combatting
opioid addiction and withdrawal66.
While the drawbacks of opioids are
becoming increasingly more clear, the more
mild effects of Cannabis and its
therapeutically active cannabinoids are
becoming more attractive. Medicinal
Cannabis, for example in the form of a
standardized oral tablet or extract, may
fulfill many of the roles currently played by
opioids, and would fit very well in step 2 or
3 of the WHO pain ladder mentioned above.
Based on the latest meta-analyses of clinical
evidence, it has been been concluded that
there is conclusive or substantial evidence
that Cannabis is effective for the treatment
of chronic pain in adults48,59. Meanwhile, the
side effects caused by medicinal Cannabis
use are believed to be generally mild and
manageable, the most commonly observed
side effects being dizziness, dry mouth,
euphoria, disorientation, and drowsiness67.
Although these data are encourraging for
further exploration of Cannabis as an
analgesic, it is important to also highlight
the need for more research to better
understand the efficacy, dose-response
effects, routes of administration, and side
effect profiles for the many different
Cannabis products that are commonly used
today28,48. Because the exact balance
between long-term risks and benefits of
Cannabis use is still unclear, its medicinal
application should be recommended only for
treatment-resistant patients, who do not
sufficiently respond to conventional drugs
and treatments.
Separating recreational from
medicinal use of Cannabis
It goes without saying that Cannabis is not
just a benign medicinal herb. Just like the
Opium poppy (Papaver somniferum L.),
Cannabis can be used as a source of
narcotics as well as medicine. In fact,
Cannabis is the world’s most widely abused
narcotic drug68, and may cause various
undesired effects when used without
restraints. Long term effects may include
impaired cognition, dependence, or the
development of psychosis in genetically
vulnerable individuals28. But unlike e.g.
opioids, using a high dose of Cannabis will
not kill or permanently harm the user. Based
on its lack of acute life-threating effects69,
Cannabis has been called a 'soft drug' in
some jurisdictions such as The
Netherlands70. Because of these, and other,
reasons, several countries have
decriminalized the use of Cannabis for
recreational use in recent years71.
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According to the report The Use
ofCannabis Drugs in India23 the uses of
Cannabis drugs in the Indian sub-continent
can be described under the following
categories: 1) medical and quasi-medical use
(therapeutic use); 2) use in connection with
religious and social customs (cultural use);
and 3) euphoric purposes (recreational use).
Unfortunately, it is the use or abuse for
euphoric purposes which causes public
commotion, fear and indignation in the
minds of many, often obscuring the
medicinal and religious significance of
Cannabis in India. Interestingly, historical
documents and traditional Indian scriptures
may be of help in formulating a balanced
message about the appropriate use of
Cannabis as a medicine to the public. For
example, Hindu scriptures have not
encouraged recreational use, intoxication
from, or abuse of Cannabis. In fact, the
scriptures warn against the over-use of
alcohol and other intoxicants such as
Cannabis, and they teach against using any
substances for intoxication72.
While a cultural understanding of Cannabis
may aid in its appropriate use, the main key
for applying Cannabis responsibly as a
modern medicine lies in a proper
understanding of its main active ingredients.
The sticky resin produced by the flowers
and top leaves of the plant contains a
number of substances called cannabinoids of
which delta-9-tetrahydrocannabinol (THC)
is the most important. THC is the only
psychoactive compound present in
Cannabis; all others may have therapeutic
effects but do not have any significant
potential of making the user feeling ‘high’.
Pharmacological studies have identified
specific receptors for cannabinoids as part of
a so-called endocannabinoid system in the
human body and these receptors have shown
to be present in various tissues and organs,
including the brain and immune system73, as
described above. Indian charas (Cannabis
resin) of good quality is said to have a THC
content of up to 30%74,75, and even higher
concentrations can be achieved with modern
techniques of processing Cannabis flowers.
Among the many claimed therapeutic
indications of THC, its anti-emetic, appetite
stimulant, and analgesic effects, as well as
relief of symptoms of multiple sclerosis, are
the most well established59,76. Various other
cannabinoids are also under investigation,
including cannabidiol (CBD), which has
increasing evidence for therapeutic effects
particularly in epilepsy, insomnia, anxiety,
inflammation, brain damage (as a
neuroprotector), psychosis, and others59,77.
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Historically, the intoxicating effects of
Cannabis were well-known in India, which
is reflected in the three major types of
preparation. The weakest type, Bhang,
consists of dry leaves from which flowers
are carefully removed. A stronger type,
Ganja, is prepared with the flowers of
female plants only. The strongest of them all
is Charas, made exclusively of the resin that
covers female flowers10. These forms of
preparation guarantee the presence of active
cannabinoids such as THC and CBD, which
explains the intoxicating as well as
medicinal effects it has to the user. Indian
traditional manuscripts on medicinal plants
often have a strong focus on safety and
toxicity. Therefore, it is no surprise that
Ayurveda has long recognized the
intoxicating effects of Cannabis, and has
labelled it as a ‘toxic’ herb.
In Ayurveda, toxic drugs are used for
therapeutic purposes only after a treatment
called Shodhan’, which is a
decontamination procedure to reduce their
undesired effects29. In one particular study78
the scientific basis of various Shodhan
treatments was evaluated, by looking at their
effect on the chemical composition of
Cannabis leaves. Treatments included
washing the herbal material in cold water,
frying in ghee, soaking in milk, and boiling
in the decoction of a specific tree bark. The
study clearly indicated the utility of Shodhan
techniques in reducing narcotic content of
Cannabis, as a considerable reduction of
THC content (up to 85%) was observed. A
modern understanding of the chemistry of
Cannabis explains these reductions by the
washing away of trichomes where
cannabinoids are produced (washing in cold
water), the partial extraction of active
compounds with lipophilic solvents (milk,
ghee) or evaporation of active compounds
by heat (frying).
Despite treatments to reduce their potency,
many traditional administration forms of
Cannabis have considerable abuse potential,
because they are consumed in the form of
tasty foods or drinks that may stimulate the
consumer to use too much. Examples are the
mixing of Cannabis with honey, milk, butter
and/or spices14. Moreover, because of a lack
of quality control and potency testing, the
consumer never knows the strength of a
product he is consuming. Already in 1982,
in a treatise entitled Indigenous Drugs of
India79 the authors noted the requirement of
proper dose titration due to increasingly
inconsistent Cannabis preparations.
Although performing Shodhan procedures to
remove THC and other cannabinoids
reduces the narcotic strength of Cannabis
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preparations, it simultaneously destroys the
majority of the medicinally active
ingredients. Clearly, a proper balance should
be found between reducing abuse potential,
versus maximizing therapeutic strength of
Cannabis products.
A solution to this dilemma may be the
development and application of modern
dosing techniques and administration forms,
to control or limit the intake of
pharmacologically active cannabinoids. For
example, a Cannabis extract with limited
poteny can be made available on
prescription through pharmacies only. Or
Cannabis medicine can be offered in
metered-dose inhaler systems that monitor
the total daily intake80. Another idea is that
the traditional preparation of the typically
Indian Bhang could be modernized to
develop a standardized and quality-
controlled, but low potency product that
physicians can legally prescribe.
Another approach focusses on the
composition of the Cannabis plants that are
allowed to be used in the preparation of
medicinal products. It is possible to develop
Cannabis varieties with a reduced inherent
potential for intoxication, for example types
that contain a higher proportion of CBD to
counteract the psychotropic effects of THC
present in the same plant81,82. Also, the
content of THC in Cannabis plants may be
limited to a certain maximum percentage.
Such an approach has already been
discussed in Canada, where a maximum
THC content of 9% was suggested for
medicinal use, based on available clinical
study data83. As an added benefit, limiting
the THC content helps to make sure that the
balance between the various components in
the Cannabis plant (cannabinoids, terpenes,
etc.) remains more comparable to natural
Cannabis plants grown in India in historical
times. Cannabis plants grown indoors under
completely artificial conditions may easily
turn into ‘supercrops’ with cannabinoid
contents that are far removed from the
traditional medicines that India got used to
over millenia of use.
Cannabis according to the TKDL
and the CCARS
Looking for descriptions of Cannabis
medicine in ancient handbooks written in
nearly forgotten languages may be a tedious
and nearly impossible job for any scientist.
Luckily, such endeavours are not needed
any longer. The Traditional Knowledge
Digital Library (TKDL) is a unique Indian
digital database of traditional knowledge,
established in 2001 as a collaboration
between the Council of Scientific and
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Industrial Research (CSIR) and the Ministry
of AYUSH. The objective of the library is to
protect the ancient and traditional
knowledge of the country from exploitation
through biopiracy and unethical patents, and
is especially focused on medicinal plants
and formulations used in Indian systems of
medicine. As of 2010, it had transcribed 148
books on Ayurveda, Unani, Siddha and
Yoga, into 34 million pages of information.
Data on 80,000 formulations in Ayurveda,
1,000,000 in Unani and 12,000 in Siddha
has already been collected in the TKDL84.
The TKDL describes Cannabis as an
important drug of various Indian systems of
medicine. The resource contains many
formulations with Cannabis mentioned as
the principle component (e.g Bhang) or
being used as a polyherbal formulation (e.g.
Tiryaaq afiyun). The indications mentioned
in the TKDL that Cannabis can resolve, or
beneficial effects it can have, are: gout,
catarrh, coryza, mastitis, analgesic, mania,
diphtheria, poisoning, iatrogenic agent,
rheumatism, cholera, malaria, pyrexia,
spermatorrhea, aphrodisiac, inspissant, atony
of bladder, bleeding piles, nausea, vomiting,
anorexia, indigestion, dyspepsia,
cough/bronchitis, hyperacidity, Incurable,
sprue/malabsorption syndrome, curable
disease of severe nature, acute diarrhoea,
dyspnoea, anaemia/hyperbilirubinemia,
intellect promoting, semen promoting,
immuno potentiators, anti-oxidant, anti-
ageing and strength promoting.
According to a recent review paper by the
Central Councel for Research in Ayurvedic
Sciences (CCRAS), different pharmacopoeia
of Ayurveda report about 191 formulations
of 13 different dosage form having Cannabis
(Vijayā) as an ingredient85. Cannabis has
been attributed with different
pharmacological properties i.e Tika Rasa,
Laghu Tkṣṇa Guna, Uṣṇa Vrya and Kau
Vipāka. It pacifies Kapha and Vāta Doas,
increases Pitta Doa and has Dpana,
Pācana, Rocana, Madakārἷ and Vyavāyἷ
action. According to the review paper,
Cannabis may be useful to combat more
than 29 disease conditions including
intestinal disorders, fever, diarrhoea,
dyspepsia, urinary disorder etc. According
to the authors, Cannabis fulfils the criteria of
a good and effective drug, as recommended
in the classical texts of Ayurveda. The main
part of Cannabis used, for medicinal
purpose, is its leaf in processed form
(Shodhan, see above) in a typical dose of
125-250 mg.
Usually, texts related to medicinal plants
systematically record the part used,
pharmacological properties, shodhana
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(processing) procedures, actions, medical
indications and contraindications of the
plant drug. In Ayurveda, different
traditionally used names, known as Paryāya
(synonyms) are often attributed to a single
plant to define its morphological description,
habitat, and pharmacological characters. For
Cannabis, there are about 40 synonyms
attributed to describe its morphological and
pharmacological characters in various
classical texts written over time (Table 1)85.
Many synonyms are of mythological origin,
indicating its frequent uses and close
relation with various aspects of society
during the ancient period. Clearly, this may
complicate the search for preparations
containing Cannabis in older manuscripts,
because we must be very careful in assuring
that Cannabis is indeed the plant mentioned.
A complicating factor in the use of
traditional sources of information is that
diseases and their cures may be described
and classified very differently compared to
modern medicine. Therefore, a major
challenge lies in translating between the
two, so that we may learn e.g. how
neuropathic pain is defined in Ayurveda and
other systems, and how that relates to the
way medical science classifies and treats
neuropathic pain today.
Table 1 Indian names used to describe Cannabis in
Sanskrit and Hindi (taken from Russo14)
Indian name
ajaya
ananda
bahuvadini
bhang, bhanga
bhangini
bharita
capala
capta
chapala
charas
cidalhada
divyaka
dnayana vardhani
ganja
ganjakini
gatra-bhanga
harshani
harshini
hursini
Indrasana
jaya
kalaghni
madhudrava
madini
manonmana
matulani
matkunari
mohini
pasupasavinaini
ranjika
sakrasana
samvida manjari
sana
sarvarogaghni
sawi
Shivbooty
siddha
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sidhamuli
siddhapatri
siddhi
siddhidi
sidhdi
suknidhan
tandrakrit
trailokya vijaya
trilok kamaya
ununda
urjaya
vijaya
vijpatta
virapattra
vrijapata
Modernizing an old medicine - the
Indian way
Ayurvedic medicine has recognized the
importance of Cannabis for millennia, but
modern science is only now proving its
wisdom. In fact, many ideas now commonly
accepted for the production or the use of
medicinal Cannabis have originated in India.
For example, the most potent forms of
Cannabis available today are derived from
Cannabis varieties known to botanists as
Cannabis indica, or Indian hemp. And
ancient Indian documentation on Cannabis
production emphasizes the necessity of
removing male plants by the “ganja doctor”
to prevent fertilization of the female
plants16. This treatment significantly
increases the production of the medicinal
resin. Contemporary growers know this
method as ‘sinsemilla’ (from the Spanish:
‘without seeds’) and virtually all medicinal
(as well as most recreational) Cannabis in
the world is currently produced in this
manner.
Also in the research field of the
endocannabinoid system, Indian influences
are visible. The discovery of the human
endocannabinoid system73 and the rapidly
unfolding therapeutic potential of the
cannabinoids - ranging from inflammation
and epilepsy to chronic pain and even cancer
- are quickly opening up a whole new field
of medicine. As a result, the number of
scientific papers published on the medicinal
properties and applications of Cannabis and
its cannabinoids has been growing at an
exponential rate since the early 1990’s
(Figure 4).
Figure 4 Number of scientific papers published on
Cannabis (in PubMed, per 5 year interval)
0
2000
4000
6000
8000
10000
55-59
60-64
65-69
70-74
75-79
80-84
85-89
90-94
95-99
00-04
05-09
10-15
Scientific papers published
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Many of these cannabinoid researchers to
some degree have acknowledged the integral
role that Indian culture has played in our
understanding of Cannabis. Thus, the first
endocannabinoid ever discovered (chemical
name: arachidonyl-ethanolamide) was
dubbed anandamide (ananda is Sanskrit for
‘bliss’)86. In a likewise manner, one of the
identified endocannabinoids, chemically
known as O-arachidonylethanolamine and
acting as a cannabinoid receptor antagonist,
has been nicknamed virodhamine (virodha
is Sanskrit for ‘opposition’)87.
Naturally, there are concerns that Cannabis
use is not all benign, and that there are
negative health and social consequences
from its use for some consumers. Clearly,
just the fact that the Cannabis plant once
was a valuable part of traditional medicine is
not reason enough for its re-inclusion into
modern medicine. Scientific drug
development is a rigorous process and
regulatory bodies have stringent
requirements to be fulfilled before drugs are
approved for marketing28. But with the
growth of scientific interest for Cannabis, its
therapeutic effects as well as its risks are
now studied with increasingly accurate
scientific methods. Recent experiences in
various countries such as Israel, Canada,
The Netherlands and several US states with
legalization of Cannabis for therapeutic or
recreational purposes indicate that it does
not pose an unacceptable threat to public
health and safety88-101, even though much
remains to be learned102. Interestingly, even
after more than a century, such conclusions
are closely in line with the 1894 Hemp
Drugs Commission in India. In their
extensive report16, already discussed above,
the commission did not oppose the moderate
use of Cannabis for social and medicinal
practices in the Indian sub-continent, even
though excessive consumption was regarded
as injurious.
As a result of these new insights, various
countries have been revamping their
national policies for supporting use of
Cannabis for therapeutic purposes. Those
countries already include Canada, The
Netherlands, Israel, Australia, Germany,
Italy, many US States, as well as various
South-American countries. Cannabis-based
medicine is already approved for the
treatment of pain and spasticity caused by
multiple sclerosis in many places103, and its
potential role in the treatment of e.g.
epilepsy104, rheumatoid arthritis105, and
cancer106 is actively being explored. Based
on these developments around the world,
Indian regulators would not be out of line
when encouraging and facilitating scientists
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to explore the potential of their versatile
native plant while the world already benefits
from it. For too long, there have been no
clear guidelines and jurisdiction for
obtaining a license for medical or scientific
research. This has made research extremely
difficult in most states of India.
It is true that the existent safety and efficacy
data for cannabinoids is still incomplete28.
However, the treatment of chronic
neuropathic pain in India represents an
excellent case for further expanding our
knowledge in this field, for a population
much in need of new treatment options. The
essence of this development would be to
copy the useful aspects of traditional
Cannabis use but remove its more risky
aspects by applying principles of modern
medicine. In short: be traditional when we
can, and modern when we must. This
approach fits very well within the principles
of the phytopharmaceutical drug regulations
that have already ushered various Indian
traditional medicines into the modern world.
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Apart from having been used and misused for at least four millennia for, among others, recreational and medicinal purposes, the cannabis plant and its most peculiar chemical components, the plant cannabinoids (phytocannabinoids), have the merit to have led humanity to discover one of the most intriguing and pleiotropic endogenous signaling systems, the endocannabinoid system (ECS). This review article aims to describe and critically discuss, in the most comprehensive possible manner, the multifaceted aspects of 1) the pharmacology and potential impact on mammalian physiology of all major phytocannabinoids, and not only of the most famous one Δ(9)-tetrahydrocannabinol, and 2) the adaptive pro-homeostatic physiological, or maladaptive pathological, roles of the ECS in mammalian cells, tissues, and organs. In doing so, we have respected the chronological order of the milestones of the millennial route from medicinal/recreational cannabis to the ECS and beyond, as it is now clear that some of the early steps in this long path, which were originally neglected, are becoming important again. The emerging picture is rather complex, but still supports the belief that more important discoveries on human physiology, and new therapies, might come in the future from new knowledge in this field.
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Background: According to the 2014 WHO Global Atlas of Palliative Care, there is insufficient access to palliative care services worldwide, with the majority of unmet need in low- and middle-income countries. In India, there are major disparities in access to palliative care, with the majority of services being offered by non-governmental organizations (NGOs) scattered throughout the country. The barriers to expanding palliative care services in India are common to many lower- and middle-income countries-a lack of financial resources, a paucity of trained staff, and a focus on curative rather than comfort care. In this paper, we describe a model of palliative care being used by CanSupport, a non-governmental organization based in Delhi that was formed in 1996. They offer home-based services provided by multidisciplinary teams consisting of a physician, nurse, and social worker who are trained in palliative care. Methods: Data on patient demographics, services provided, and outcomes were collected retrospectively for patients treated by CanSupport for the year 2009-2010. Sources include CanSupport's population data and direct discussions with CanSupport staff. Results: During the year 2009-2010, CanSupport served 746 patients, with an average of 10 home visits per patient. Only 29% of patients were referred from hospitals or physicians, with the rest being self-referred or referred from CanSupport's help line. Pain scales were administered on each visit and 31% of patients received morphine. Of the 514 patient deaths, 76% occurred at home and a majority of families received bereavement counseling for up to 6 months. Conclusions: CanSupport has shown that a home-based care model can be successful in India and is desired by patients at the end of life or with chronic illness. Their model of care saves the patients the cost of a hospital visit while still providing evaluation by staff with training in palliative care. In addition, the multidisciplinary nature of the teams allows for symptom management and emotional counseling for both the patients and their families. CanSupport has developed a way to provide reliable, cost-effective palliative care to patients that can serve as a model for building palliative care capacity in low- and middle-income countries.
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The Netherlands has seen an increase in Δ9-tetrahydrocannabinol (THC) concentrations from approximately 8% in the 1990s up to 20% in 2004. Increased cannabis potency may lead to higher THC-exposure and cannabis related harm. The Dutch government officially condones the sale of cannabis from so called ‘coffee shops’, and the Opium Act distinguishes cannabis as a Schedule II drug with ‘acceptable risk’ from other drugs with ‘unacceptable risk’ (Schedule I). Even in 1976, however, cannabis potency was taken into account by distinguishing hemp oil as a Schedule I drug. In 2011, an advisory committee recommended tightening up legislation, leading to a 2013 bill proposing the reclassification of high potency cannabis products with a THC content of 15% or more as a Schedule I drug.