ChapterPDF Available

Cannabinoids and anxiety

Authors:
(( 3. Umbruch 4.4..2005 ))
Milestones in Drug Therapy
MDT
Series Editors
Prof. Michael J. Parnham, PhD Prof. Dr. J. Bruinvels
Senior Scientific Advisor Sweelincklaan 75
PLIVA Research Institute Ltd NL-3723 JC Bilthoven
Prilaz baruna Filipovic´a 29 The Netherlands
HR-10000 Zagreb
Croatia
Cannabinoids as
Therapeutics
Edited by R. Mechoulam
Birkhäuser Verlag
Basel · Boston · Berlin
Editor
Raphael Mechoulam
Medical Faculty
Hebrew University
Ein Kerem, Jerusalem 91010
Israel
Advisory Board
J.C. Buckingham (Imperial College School of Medicine, London, UK)
R.J. Flower (The William Harvey Research Institute, London, UK)
G. Lambrecht (J.W. Goethe Universität, Frankfurt, Germany)
P. Skolnick (DOV Pharmaceutical Inc., Hackensack, NJ, USA)
A CIP catalogue record for this book is available from the Library of Congress, Washington, D.C.,
USA
Bibliographic information published by Die Deutsche Bibliothek
Die Deutsche Bibliothek lists this publication in the Deutsche Nationalbibliografie; detailed biblio-
graphic data is available in the internet at http://dnb.ddb.de
ISBN 3-7643-7055-6 Birkhäuser Verlag, Basel - Boston - Berlin
The publisher and editor can give no guarantee for the information on drug dosage and administration
contained in this publication. The respective user must check its accuracy by consulting other sources
of reference in each individual case.
The use of registered names, trademarks etc. in this publication, even if not identified as such, does not
imply that they are exempt from the relevant protective laws and regulations or free for general use.
This work is subject to copyright. All rights are reserved, whether the whole or part of the material is
concerned, specifically the rights of translation, reprinting, re-use of illustrations, recitation, broad-
casting, reproduction on microfilms or in other ways, and storage in data banks. For any kind of use,
permission of the copyright owner must be obtained.
© 2005 Birkhäuser Verlag, P.O. Box 133, CH-4010 Basel, Switzerland
Part of Springer Science+Business Media
Printed on acid-free paper produced from chlorine-free pulp. TFC
Cover illustration: With the friendly permission of Lumír Hanusˇ
Printed in Germany
ISBN-10: 3-7643-7055-6
ISBN-13: 978-3-7643-7055-8
9 8 7 6 5 4 3 2 1 www. birkhauser.ch
Contents
List of contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . VII
Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . IX
Ethan Russo
Cannabis in India: ancient lore and modern medicine . . . . . . . . . . . . 1
Lumír O. Hanusˇ and Raphael Mechoulam
Cannabinoid chemistry: an overview . . . . . . . . . . . . . . . . . . . . . . . . . 23
Roger G. Pertwee
Cannabidiol as a potential medicine . . . . . . . . . . . . . . . . . . . . . . . . . 47
Mauro Maccarrone
Endocannabinoids and regulation of fertility . . . . . . . . . . . . . . . . . . . 67
Javier Fernández-Ruiz, Sara González, Julián Romero and
José Antonio Ramos
Cannabinoids in neurodegeneration and neuroprotection . . . . . . . . . . 79
Stephen A. Varvel and Aron H. Lichtman
Role of the endocannabinoid system in learning and memory . . . . . . 111
Richard E. Musty
Cannabinoids and anxiety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141
Susan M. Huang and J. Michael Walker
Cannabinoid targets for pain therapeutics . . . . . . . . . . . . . . . . . . . . . 149
Luciano De Petrocellis, Maurizio Bifulco, Alessia Ligresti and
Vincenzo Di Marzo
Potential use of cannabimimetics in the treatment of cancer . . . . . . . 165
Linda A. Parker, Cheryl L. Limebeer and Magdalena Kwiatkowska
Cannabinoids: effects on vomiting and nausea in animal models . . . . 183
Itai A. Bab
The skeleton: stone bones and stoned heads? . . . . . . . . . . . . . . . . . . . 201
V
Daniela Parolaro and Tiziana Rubino
Cannabinoids and drugs of abuse . . . . . . . . . . . . . . . . . . . . . . . . . . . . 207
Francis Barth and Murielle Rinaldi-Carmona
Cannabinoids in appetite and obesity . . . . . . . . . . . . . . . . . . . . . . . . . 219
Geoffrey W. Guy and Colin G. Stott
The development of Sativex®– a natural cannabis-based medicine . . 231
Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 265
VI
VII
List of contributors
Itai A. Bab, Bone Laboratory, The Hebrew University of Jerusalem, P.O.B.
12272, Jerusalem 91120, Israel; babi@cc.huji.ac.il
Francis Barth, Sanofi-aventis, 371, rue du Professeur Joseph Blayac, 34184
Montpellier Cedex 04, France, e-mail: francis.barth@sanofi-aventis.com
Maurizio Bifulco, Istituto di Endocrinologia ed Oncologia Sperimentale,
Consiglio Nazionale delle Ricerche, and Dipartimento di Scienze
Farmaceutiche, Università degli Studi di Salerno, via Ponte Don Melillo,
84084 Fisciano (SA), Italy
Luciano de Petrocellis, Istituto di Cibernetica “Eduardo Caianiello”, Consiglio
Nazionale delle Ricerche, Via Campi Flegrei 34, Comprensorio Olivetti,
Fabbricato 70, 80078 Pozzuoli (Napoli), Italy
Vincenzo Di Marzo, Istituto di Chimica Biomolecolare, Consiglio Nazionale
delle Ricerche, Via Campi Flegrei 34, Comprensorio Olivetti, Fabbricato
70, 80078 Pozzuoli (Napoli), Italy; e-mail: vdimarzo@icmib.na.cnr.it
Javier Fernández-Ruiz, Departamento de Bioquímica y Biología Molecular,
Facultad de Medicina, Universidad Complutense, 28040 Madrid, Spain;
e-mail: jjfr@med.ucm.es
Sara González, Departamento de Bioquímica y Biología Molecular, Facultad
de Medicina, Universidad Complutense, 28040 Madrid, Spain; e-mail:
sgrc@med.ucm.es
Geoffrey W. Guy, GW Pharmaceuticals plc, Porton Down Science Park,
Salisbury, Wiltshire, SP4 OjQ, UK
Lumír O. Hanusˇ, Department of Medicinal Chemistry and Natural Products,
Pharmacy School, Medical Faculty, Hebrew University, Ein Kerem
Campus, 91120 Jerusalem, Israel; e-mail: lumir@cc.huji.ac.il
Susan M. Huang, Department of Neuroscience Brown University, Providence,
RI 02912, USA
Magdalena Kwiatkowska, Department of Psychology, Wilfrid Laurier
University, Waterloo, Ontario N2L 3C5, Canada
Aron H. Lichtman, Department of Pharmacology and Toxicology, Virginia
Commonwealth University, PO Box 980613, Richmond, VA 23298, USA;
e-mail: alichtma@hsc.vcu.edu
Alessia Ligresti, Istituto di Chimica Biomolecolare, Consiglio Nazionale delle
Ricerche, Via Campi Flegrei 34, Comprensorio Olivetti, Fabbricato 70,
80078 Pozzuoli (Napoli), Italy
Cheryl L. Limebeer, Department of Psychology, Wilfrid Laurier University,
Waterloo, Ontario N2L 3C5, Canada
Mauro Maccarrone, Department of Biomedical Sciences, University of Teramo,
Piazza A. Moro 45, 64100 Teramo, Italy; e-mail: mmaccarrone@unite.it
Raphael Mechoulam, Medical Faculty, Hebrew University, Ein Kerem
Campus, 91120 Jerusalem, Israel; e-mail: mechou@cc.huji.ac.il
Richard E. Musty, Department of Psychology, University of Vermont,
Burlington, VT 05405, USA; e-mail: musty@uvm.edu
Linda A. Parker, Department of Psychology, Wilfrid Laurier University,
Waterloo, Ontario N2L 3C5, Canada; e-mail: lparker@wlu.ca
Daniela Parolaro, Center of Neuroscience, University of Insubria, Via A. da
Giussano 10, 20152 Busto Arsizio (VA), Italy; e-mail: daniela.parolaro
@uninsubria.it
Roger G. Pertwee, School of Medical Sciences, Institute of Medical Sciences,
University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, Scotland;
e-mail: rgp@abdn.ac.uk
José Antonio Ramos, Departamento de Bioquímica y Biología Molecular,
Facultad de Medicina, Universidad Complutense, 28040 Madrid, Spain;
e-mail: jara@med.ucm.es
Julián Romero, Laboratorio de Apoyo a la Investigación, Fundación Hospital
Alcorcón, 28922 Alcorcón, Madrid, Spain; e-mail: jromero@fhalcorcon.es
Murielle Rinaldi-Carmona, Sanofi-aventis, 371, rue du Professeur Joseph
Blayac, 34184 Montpellier Cedex 04, France, e-mail: murielle.rinaldi-
carmona@sanofi-aventis.com
Tiziana Rubino, Center of Neuroscience, University of Insubria, Via A. da
Giussano 10, 20152 Busto Arsizio (VA), Italy
Ethan Russo, GW Pharmaceuticals, 2235 Wylie Avenue, Missoula, MT 59809,
USA; e-mail: erusso@montanadsl.net
Colin G. Stott, GW Pharmaceuticals plc, Porton Down Science Park,
Salisbury, Wiltshire, SP4 OjQ, UK; e-mail: cgs@gwpharm.com
Stephen A. Varvel, Department of Pharmacology and Toxicology, Virginia
Commonwealth University, PO Box 980613, Richmond, VA 23298, USA
J. Michael Walker, Department of Psychology, Indiana University, 1101 E 10th
Street, Bloomington IN 47405-7007, USA; e-mail: walkerjm@indiana.edu
VIII List of contributors
IX
Preface
Twenty years ago the endocannabinoid system was unknown. We knew much
about the use over millennia of Cannabis plant preparations both as a medi-
cine and as “a drug that takes away the mind” (as so-well stated in ancient
Assyrian clay tablets). During the early part of the last century considerable
progress was made on the chemistry and pharmacology of Cannabis, but it
was only after the identification in 1964 of 9-tetrahydrocannabinol (9-THC)
as the active constituent of the plant that this field caught the interest of many
research groups and hundreds of papers on the chemistry, biochemistry,
metabolism and clinical effects of this compound were published. However, its
mechanism of action remained unknown for nearly two decades. In the mid-
1980s the presence of a cannabinoid receptor in the brain was identified and
shortly thereafter it was cloned. This was followed by the isolation of the
major endogenous cannabinoids, anandamide and 2-arachidonoyl glycerol,
and the clarification of their biosyntheses and degradations. These advances
led to an avalanche of publications in a wide variety of fields. We are now in
the midst of major advances in biochemistry/physiology associated with the
actions of the endocannabinoids.
This short volume tries to present an up-to-date picture in some of the major
fields of endocannabinoid research. The first chapter in this book, on the use
of Cannabis in India, can be viewed as an expression of thanks to the herbal
practitioners, who for centuries passed on the medical traditions associated
with the drug. The chemistry chapter is a short summary of active plant, syn-
thetic and endogenous cannabinoids being investigated today, many of which
are mentioned later in the book. Cannabidiol is an unusual cannabinoid – it
does not bind to the known receptors and yet exerts a variety of effects. Hence
a chapter is devoted to it. Most of the remaining chapters deal with the endo-
cannabinoid system and the endocannabinoids in a variety of conditions and
physiological systems. A chapter describes the research done on Sativex®,a
standardized plant extract, shortly to be introduced in Canada as a drug for
multiple sclerosis symptoms.
Numerous fields known to be affected by cannabinoids were not reviewed.
The vast expanse of emotions is one of them. Most marijuana users smoke the
drug in order to ‘get high’. But we know very little about the mechanisms
through which cannabis affects emotions. Under certain circumstances
9-THC causes aggression, although usually it leads to sedation. Anxiety is
another emotional aspect affected by cannabinoids. Although a short chapter is
devoted to the calming of anxiety by cannabinoids it does not attempt to pres-
ent a mechanistic picture. And we know next to nothing on the chemistry link-
X Preface
ing endocannabinoids with stress, fear, love, satisfaction or despair. Are the
endocannabinoids one of nature’s tools to shape emotions? This is probably
one of the fields which will be explored in the future. But books review the
past. Possibly the next edition of this book, in 5 or 10 years time, will report
on the progress made in associating endocannabinoids with emotions. Until
then we shall have to remain content with more mundane topics such as neu-
roprotection, reproduction, appetite and effects on cancer.
The multitude of endocannabinoid effects seems like a fertile field for
exploration by pharmaceutical firms. We soon expect to see the introduction of
a synthetic cannabinoid antagonist in the treatment of obesity and, possibly
later, drugs for neuroprotection, pain, multiple sclerosis, rheumatoid arthritis
and cancer. Will post-traumatic stress disorder, schizophrenia and Tourette’s
syndrome come next?
Raphael Mechoulam Jerusalem, January 2005
Cannabis in India: ancient lore and modern
medicine
Ethan Russo
GW Pharmaceuticals, 2235 Wylie Avenue, Missoula, MT 59809, USA
Introduction: Ayurvedic medicine
India is a land steeped in faith and mysticism. Ayurveda, combining the
Sanskrit words for life and knowledge, is a system of medicine intertwined
inextricably with these traits. That a core of belief combined with empirical
experimentation could produce a viable medical regimen still widely practiced
after well over 3000 years is astounding to Western physicians. Cannabis was
similarly bound to faith and mysticism in India in the past, in the Hindu and
Islamic traditions, as well as in numerous other minority religions [1]. Merlin
recently explained it well [2], “with the powerful tools of modern science and
human imagination, our understanding of our deep-rooted desire to experience
ecstasy in the original sense of the word (to break the mind free from the body
and communicate with the ‘gods’ or the ancestors) will become clear with
time”. This chapter will seek to examine the medical claims for cannabis of the
past, and place them in a contemporary light given current pharmacological
knowledge.
Ayurveda is based on a conceptual medical system that seeks to balance
three functional elements, called doshas, that the human body is composed of,
and are commonly represented as Vat a or Vayu (ether or air), Pitta (fire and
water) and Kapha (phlegm or water and earth). Nadkarni [3] has rejected these
simple relationships in favor of more abstract assignations [3]:
“…the word Vayu, does not imply ‘Wind’ in Ayurvedic literature, but
comprehends all the phenomena which come under the functions of the
Central and Sympathetic Nervous Systems; that the word Pitta does not
essentially mean ‘Bile’ but signifies the functions of Thermogenesis or
heat production and metabolism, comprehending in its scope the
process of digestion, coloration of blood and formation of various
secretions and excretions and that the word Kapha does not mean
‘Phlegm’ but is used primarily to imply the functions of Thermo-taxis
or heat regulation and secondarily formation of the various preservative
fluids, e.g., Mucus, Synovia, etc., …”
Cannabinoids as Therapeutics
Edited by R. Mechoulam
© 2005 Birkhäuser Verlag/Switzerland
1
Good health in Ayurveda is dependent upon attaining an equilibrium state
of these factors. Disease is due to an imbalance or disharmony of the Tridosha
system as the results of some cause, internal or external. A disease of pro-
longed extent will overflow its site of origin and spread through the body.
Therapy is effected by a combination of religious, magical and prescriptive
regimens, herbal therapy being an important element of the latter.
According to Kapoor [4], the materia medica of India comprises in excess
of 2000 drugs, mostly of vegetal origin, with 700 medicinal plants known even
during Buddhist times, c.250 BCE. Cannabis remains important among them.
Cannabis: its history in the medicine of India
Cannabis sativa seems to have diffused from a geographic point in Central
Asia, according to classical plant explorers [5–8] and more modern authorities
[9–11]. Sharma [12] felt its origin was in the Himalayan foothills, but offered
little documentation. This botanical sleuthing has been supported by physical
evidence of cannabis flowers and seeds associated with haoma-soma religious
rites in ancient Bactrian sites in excavations by Sarianidi [13, 14] in Margiana
(present day Turkmenistan), dating to the second millennium BCE. Philological
support derives from the term bhanga, also seemingly originating among the
Central Asian Arya peoples [15].
The Zend-Avesta, the holy book of Zoroastrianism, which survives in frag-
ments, dating from around 600 BCE in Persia, alludes to the use of Banga in a
medical context, identified as hemp [16]. Of this use, Bouquet stated [10]: “It
is solely to its inebriating properties that hemp owes the signal honour of being
sung in the Vedas, and it was probably the peoples of Northern Iran who dis-
covered those properties, for they were already using the leaves (Cheng) and
the resin (Cers) as inebriants before the Hindus.” Mahdihassan [17] has
attempted to draw a philological link between the Ho-Ma of the Chinese, the
Hao-Ma of the Avesta and the So-Ma of Sanskrit, felt cognate to cannabis.
The earliest written reference to cannabis in India may occur in the
Atharvaveda, dating to about 1500 BCE [18]: “We tell of the five kingdoms of
herbs headed by Soma; may it, and kusa grass, and bhanga and barley, and the
herb saha, release us from anxiety.” Grierson [18] suggested this 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), perhaps dating
from the third to the eighth centuries BCE, cannabis was recommended for
phlegm, catarrh and diarrhea [18]. As noted, an anti-phlegmatic would be
interpreted in Ayurvedic medicine as possessing a wide variety of effects.
Similarly, Dwarakanath [19] has maintained that cannabis was employed in
Indian folk medicine in aphrodisiacs and treatments for pain in the same era
[19], while Sanyal observed [20] that “They also used the fumes of burning
Indian Hemp (Canabis Indica) [sic] as an anaesthetic from ancient times…”.
2E. Russo
Watt [21] felt that by this early date the sexual dimorphism of cannabis was
already evident to its cultivators, as well as the superiority of bhanga (mistak-
enly assigned as female) for cordage, and bhang (mistaken as male) for med-
ical and mystical application. It was also likely about this time that the prepa-
ration of ganja (labeled sinsemilla in contemporary North America) was devel-
oped by isolating female cannabis plants to prevent fertilization, and increase
resin production.
Aldrich [22] documented the development of tantric cannabis usage around
the seventh century as a mingling of Shaivite Hinduism and Tibetan
Buddhism. Apparently, the 11th century text, Mahanirvana Tantra, is current-
ly still consulted with regard to sexual practices, withholding of male ejacula-
tion and promotion of sexual pleasure in both genders.
An anonymous work, Anandakanda, added some 43 Sanskrit cannabis syn-
onyms (Tab. 1) [23], many attesting the remarkable rejuvenating effects of
cannabis. Dash [23] described the lengthy methods of cultivation, processing
and mixing of cannabis with eight other medicinal plants, that when combined
with personal isolation and celibacy for 3 years produce a result in which “it
is claimed that the man lives for 300 years free from any disease and signs of
old age”. He dated this work to the 10th century, while Rao [24] placed it in
the range of the 9th to the 12th centuries, and noted some 10 known manu-
scripts.
There is philological debate among Sanskrit scholars as to whether the iden-
tification of bhanga as cannabis can be authenticated before the year 1000 [25,
26]. Wujastyk [26] and Meulenbeld [25] dated the Anandakanda, or Root of
Bliss, to c.1200, also noting its full accounting of cannabis’ side effects. Their
candidate for the first uncontested source for cannabis is the
Cikitsasarasangraha of the Bengal author Vangasena, in the late 11th century,
who included bhanga as an appetizer and digestive, noting it as “a drug like
opium whose mode of action is to pervade the whole body before being
absorbed and digested” [26]. It was also suggested in two recipes for a long
and happy life. A contemporary work, the Dhanvantariyanighantu, observed a
narcotic effect [26].
In the 12th–13th centuries from Gujarat, Nagarjuna’s Yogaratnamala (The
Garland of Jewels of Yoga), suggested cannabis smoke as a method by which
to produce an impression of spirit possession in one’s enemies [26].
The Rajanighantu of the 13th century added additional synonyms (Tab. 1),
with attributed activities characterized as [18] (1) katutva (acridity), (2)
kashayatva (astringency), (3) ushnatva (heat), (4) tiktatva (pungency), (5)
vatakaphapahatva (removing wind and phlegm), (6) samgrdhitva (astrin-
gency), (7) vakpradatva (speech giving), (8) balyatva (strength-giving), (9)
medhakaritva (inspiring of mental power) and (10) sreshthadipanatva (the
property of a most excellent excitant).
According to interpretation of this source [27], “Its effects on man are
described as excitant, heating, astringent; it destroys phlegm, expels flatulence,
induces costiveness, sharpens the memory, excites appetite, etc.
Cannabis in India: ancient lore and modern medicine 3
4E. Russo
Table 1. Indian names for cannabis in Sanskrit and Hindi
Indian name Meaning
ajaya the unconquered, invincible
ananda the joyful, joyous, laughter moving, bliss
bahuvadini causing excessive garrulousness
bhang,bhanga hemp, mature cannabis leaves
bhangini breaks three kinds of misery
bharita the green one
capala agile, capricious, mischievous, scatter-brained
capta light-hearted
chapala the light-hearted, causer of reeling gait, causer of vacillation
charas cannabis resin (hashish), either hand-rubbed or sifted
cidalhada gives happiness to mind
divyaka gives pleasure, lustre, intoxication, beauty
dnayana vardhani knowledge promoter
ganja unfertilized female cannabis flowers
ganjakini the noisy, vibrator
gatra-bhanga body disintegrator
harshani joy-giver
harshini the exciter of sexual desire, the rejoicer, delight-giver, causer of elation
hursini the exciter of sexual desire
Indrasana Indra’s food
jaya victorious, the conquering
kalaghni helps to overcome death
madhudrava helps excrete nectar
madini the intoxicator, sex intoxicator
manonmana accomplishes the objects of the mind
matulani wife of the datura
matkunari an enemy of bugs
mohini fascinating
pasupasavinaini liberates creatures from earthly bonds
ranjika causer of excitement
sakrasana the worthy food of Indra
samvida manjari flower causes garrulousness
sana cannabis
sarvarogaghni which cures all diseases
sawi green leaved
Shivbooty Shiva’s plant
siddha which has attained spiritual perfection
sidhamuli on whose root is siddha
siddhapatri vessel of highest attainment
siddhi success giver
siddhidi which endows siddhi on others
sidhdi emancipation, beatitude, fruit of worship
suknidhan fountain of pleasures
tandrakrit causer of drowsiness
trailokya vijaya victorious in the three worlds, conqueror of the three regions of the universe
trilok kamaya desired in the three worlds
ununda the laughter mover
urjaya promoter of success
vijaya victorious, promoter of success, all-conquering
vijpatta the strong leaved
virapattra leaf of heroes
vrijapata strong nerved
About the same time, in the Sharangadhara Samhita, fresh extracts of
bhang were employed medicinally [19], and it was linked to opium: “Drugs
which act very quickly in the body first by spreading all over and undergoing
change later are vyavayi; for example, bhanga, ahiphena” [28]. Additionally,
cannabis was cited as an intoxicant and employed as the primary ingredient in
a therapeutic mixture of herbs: “This recipe known as jatiphaladi churna if
taken in doses of one karpa, with honey, relieves quickly grahani (sprue
[chronic diarrhea]), kasa (cough), swasa (dyspnoea), aruchi (anorexia), kshaya
(consumption) and pratishyaya [nasal congestion] due to vata kapha (rhinitis)”
[28]. Inter-relationships of Tantra and Ayurveda in this work were explored by
Sharma [29].
The 15th-century Rajavallabha, written by Sutradhar Mandan for Rana
Kumhha of Mewar, attributed several additional qualities to cannabis [18]:
“Indra’s food (i.e., ganja) is acid, produces infatuation, and destroys
leprosy. It creates vital energy, the mental powers and internal heat, cor-
rects irregularities of the phlegmatic humour, and is an elixir vitae. It
was originally produced, like nectar from the ocean by the churning
with Mount Mandara, and inasmuch as it gives victory in the three
worlds, it, the delight of the king of the gods, is called vijaya, the vic-
torious. This desire-fulfilling drug was obtained by men on the earth,
through desire for the welfare of all people. To those who regularly use
it, it begets joy and destroys every anxiety.
Dymock added [27], “The Rahbulubha alludes to the use of hemp in gonor-
rhoea.”
According to Chopra and Chopra [30], “In Dhurtasamagama (A.D. 1500),
ganja is described as a soporific which ‘corrects derangements of humours and
produces a healthy appetite, sharpens the wit and act as an aphrodisiac’.” In the
Ayurveda Saukhyam of Todarananda [31] it was said of cannabis that “It caus-
es unconsciousness, intoxication and talkativeness”.
During the Renaissance European awareness of the psychoactivity of
cannabis was kindled with the writings of Garcia da Orta, a Spanish Jew, who
in the service of Portugal visited India in 1563. In addition to his descriptions
of the plant as bangue, and a good illustration, he noted important medical
properties [32], “The profit from its use is for the man to be beside himself,
and to be raised above all cares and anxieties, and it makes some break into a
foolish laugh.” In another passage, stimulation of energy and appetite was
noted: “Those of my servants who took it, unknown to me, said that it made
them so as not to feel work, to be very happy, and to have a craving for food.
Soon thereafter, it was observed [30], “In Bhavaprakash (A.D. 1600),
cannabis is mentioned as ‘anti-phlegmatic, pungent, astringent and digestive’.
On account of these marked narcotic properties it was probably also used as an
anaesthetic, sometimes combined with alcohol, by the ancient Indian and
Chinese surgeons.
Cannabis in India: ancient lore and modern medicine 5
The 18th century Persian medical text Makhzan-al-Adwiya, written by M.
Husain Khan, was extremely influential in the Unani Tibbi, or Arabic-tradition
medicine on the subcontinent. In it, cannabis was described in its various prepa-
rations as an intoxicant, stimulant and sedative, but also the following [33]:
“The leaves make a good snuff for deterging the brain; the juice of the
leaves applied to the head as a wash, removes dandriff [sic] and vermin;
drops of the juice thrown into the ear allay pain and destroy worms or
insects. It checks diarrhea, is useful in gonorrhea, restrains seminal
secretions, and is diuretic. The bark has a similar effect.
The powder is recommended as an external application to fresh
wounds and sores, and for causing granulations; a poultice of the boiled
root and leaves for discussing inflammations, and cure of erysipelas,
and for allaying neuralgic pains.”
Ali Gorji (personal communication, 2004) has recently consulted this work
and added that it was helpful for stomach problems, nausea and uterine inflam-
mation. Campbell [1], translated additional Persian names from this source:
“Bhang is the Joy-giver, the Sky-flier, the Heavenly-guide, the Poor Man’s
Heaven, the Soother of Grief”. Dymock and co-authors added a few more syn-
onyms [34]: “the inebriating leaf”, “fakir’s grass”, “the green tent” and “the
throne giver”. Chopra and Chopra [30] rendered another passage from the
Makhzan as follows: “It is said that bhang is one of the best of God’s gifts, it
is a cordial, a bile absorber, and an appetizer, and its moderate use prolongs
life. It quickens the fancy, deepens thought and sharpens judgment.”
A nexus with Western medicine
The medical use of so-called Indian hemp was reintroduced to the West in the
19th century. In 1813,Ainslie [35] cited the use of ganjah and bangie as intox-
icants, but also to treat diarrhea, and in a local application for hemorrhoids. In
1839, the seminal work of Sir William B. O’Shaughnessy on cannabis was
written [36], then republished in England in 1843 [33]. His contribution was a
model of modern investigation, involving a review of classical Sanskrit and
Unani sources, a description of cannabis preparations including bhang (mature
cannabis leaves), ganja (unfertilized female flowers), and charas (processed
cannabis resin), an examination of contemporary Indian ethnobotanical uses
and experiments of cannabis extracts in dogs, finally culminating with a series
of human clinical trials with appropriate cautious dose titration. His treatise on
the subject demonstrated the apparent clinical utility of cannabis in a wide
range of disorders including cholera, rheumatic diseases, delirium tremens and
infantile convulsions. For the first time miraculous recoveries were evidenced
in a series of tetanus victims due to cannabis. Noting the anti-spasmodic and
muscle-relaxant effects, it was tried in rabies, where [33] “the influence of a
6E. Russo
narcotic, capable either of cheering or of inducing harmless insensibility,
would be fraught with blessing to the wretched patient”. Although no cure was
forthcoming, the patient was visibly relieved of distress, and able to take some
sustenance through his suffering. Its palliative benefit was not lost upon the
physician, “the awful malady was stripped of its horrors; if not less fatal than
before, it was reduced to less than the scale of suffering which precedes death
from most ordinary diseases”. Summing up his experience with cannabis,
O’Shaughnessy concluded that “in hemp the profession has gained an
anti-convulsive remedy of the greatest value”.
A series of other practitioners both in India and in Great Britain soon noted
success in extending the use of cannabis to treatment of migraine, and neuro-
pathic and other pain conditions [37, 38]. Few clinical syndromes seemed
unassailable: another Western physician in India observed the alleviation not
only of an alcohol hangover with accompanying headache, but the patient’s
cholera as well [39]. Churchill employed cannabis to treat excessive uterine
bleeding [40], and Christison applied it to childbirth [41] (reviewed in [42]).
In little more than a decade, a section on cannabis was deemed worthy of
inclusion in Johnston’s The Chemistry of Common Life, wherein the topic was
treated at length [43]: “In India it is spoken of as the increaser of pleasure, the
exciter of desire, the cementer of friendship, the laughter-mover, and the
causer of the reeling gait, – all epithets indicative of its peculiar effects. About
the same time, medical usage became common in North America [44].
In 1870, Dutt provided information on certain bhang preparations [45],
“Numerous confections of bhang such a Kamesvara modaka,Madana moda-
ka,Balyasakrasana modaka…are considered aphrodisiacs and are used in
chronic bowel complaints, and nervous debility.” A recipe for Madana moda-
ka was then supplied, containing numerous herbs, but with “hemp leaves with
flowers and seeds fried in clarified butter, equal in weight to all the other
ingredients”, which was “used in cough, chronic bowels complaints and
impotence”.
In 1877, Kerr submitted an extremely detailed report from Bengal encom-
passing history, religious context, cultivation and employment of cannabis in
all its preparations [46]. This would form one source for the subsequent
Report of the Indian Hemp Drugs Commission [47]. Documentation of ganja
production, necessitating culling of male plants by the “ganja doctor” to pre-
vent fertilization and increase resin production, was emphasized. Despite
some apparent value judgments expressed, the author observed, “I am of
opinion, however, that no moral gain whatever will be effected by the total
suppression of ganja.”
Watt noted that cannabis was [21] “valuable as a remedy for sick headache,
and especially in preventing such attacks. It removes the nervous effects of a
malady.” Watt listed numerous contemporary European physicians on the sub-
continent and their successes in treating a large variety of disorders with
cannabis preparations. Dymock was one such [34]: “I have given the extract in
doses of from 1/2to 1 grain to a large number of European hospital patients suf-
Cannabis in India: ancient lore and modern medicine 7
fering from chronic rheumatism; it entirely relieved the pains and made them
excessively talkative and jolly, complaining that they could not get enough to
eat.” Dymock also appreciated popular Indian descriptions of the time [34]:
“When the ganja pipe begins to smoke all cares at once disappear” and
“Smoke ganja and increase your knowledge”.
Cannabis in its various forms remained the focus of intense scrutiny, and
continued to harbor critics. Because of concerns of its moral dangers, the
British and colonial authorities in India organized a commission to examine all
aspects of the issue [47]. Its findings exceeded 3000 pages after exhaustive
investigation and testimony, and may be summarized as follows [48]. (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 ulti-
mately 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 cer-
tain rare cases cannabis intoxication could result in violence, such cases were
few and far between.
The commission advocated against governmental suppression of cannabis
drugs. Many positive statements accompanied descriptions of their religious
associations, and particularly their legion medical usage, both human and vet-
erinary [1]:
“It is interesting, however, to note that while the drugs appear now to be
frequently used for precisely the same purposes and in the same man-
ner as was recommended centuries ago, many uses of these drugs by
native doctors are in accord with their application in modern European
therapeutics. Cannabis indica must be looked upon as one of the most
important drugs of Indian Materia Medica.”
Particular attention remained focused on possible mental health sequelae of
cannabis despite the lack of such findings from the Commission. In the con-
clusions of Mills [49]:
“Indians used hemp narcotics for a variety of reasons and it is entirely
possible that its use at certain times disagreed with certain individuals
to the extent that they became muddled or even murderous. Yet the few
of those that did become muddled or murderous and that were snared in
the net of the colonial state came to be taken as representative of all
those in India that used cannabis preparations. From this, colonial gov-
ernment developed an image of all Indian users of hemp narcotics as
dangerous, lunatic and potentially violent.”
8E. Russo
Occasionally, colonial officials were enlightened enough to free themselves
from ethnocentric chauvinism. One Captain R. Huddleston, a Deputy
Commissioner in the Akola District, wrote in 1872 [50], “Therefore I should
not condemn these compounds [cannabis preparations] as being directly con-
nected with crime; that is to say, they are no more the cause of offence than is
the bazar liquor with which the Banjara is so often primed when he does high-
way robbery, or the beer and gin guzzled by the British rough before he beats
his wife and assaults a policeman.” Modern epidemiological investigation
refutes the etiological relationship of cannabis to violence and insanity [51],
but the debate continues.
In 1897, cannabis retained a key indication [52], “The treatment of Tetanus
by smoking gunjah…promises to supercede all other in India.” Waring [52]
went on to describe its effective application at the onset of spasms, and titra-
tion to patient requirements so long as was needed. In a previous source [53],
smoking every few hours was recommended for the duration of need, which in
four subjects ranged from 7 days to 11/2months. Lucas [54] introduced the
concept of smoking cannabis for tetanus to the British medical press in 1880.
Meanwhile, cannabis spread to other British colonies with the Indian dias-
pora. Emigrants brought the herb along with them as a work accessory or med-
icine. In South Africa they adopted the local name dagga [55], whereas in
Jamaica the Indian name, ganja, has been pre-eminent since the 19th century
[56, 57], and its tonic effects are part of national medical lore today [57].
Politics and cannabis collide
At the dawn of the 20th century, cannabis suffered further downturns. In
1914 it was dropped from the pharmacopoeia of Ceylon (now Sri Lanka),
over the vociferous objections of its adherents, such as Ratnam [58], whose
points of debate included passionate defenses of its medical benefits and
poignant political arguments comparing its benign nature to the relative dan-
gers of other popular recreational agents, alcohol in particular. The status of
cannabis was compounded by increasingly severe quality-control problems
with material exported from India to the UK [59]. These two factors, politi-
cal and pharmacological, were paramount in the decline of cannabis medi-
cines in the West.
Cannabis use remained common in 20th-century India, however. It was
noted [60]:
“Labourers who have to do hard physical work use hemp drugs in small
quantities to alleviate the sense of fatigue, depression and sometimes
hunger. … This produces a sense of well-being, relieves fatigue, stimu-
lates the appetite, and induces a feeling of mild stimulation which
enables the worker to bear the strain and perhaps the monotony of this
daily routine of life more cheerfully.
Cannabis in India: ancient lore and modern medicine 9
Similarly, by 1954, cannabis remained integral in Indian faith, as one Brahmin
explained to a Western writer [61], “‘It gives good bhakti’, …the sort of devo-
tional act which consists in emptying the mind of all worldly distractions and
thinking only of God.”
As late as 1957, two authorities in India noted [30], “Cannabis undoubted-
ly has remarkable therapeutic properties. …the drug has no constipating
action, it does not depress the respiratory centre; and there is little or no lia-
bility to addiction formation.” They went on to describe the usage in veteri-
nary medicine for diarrhea in livestock, treating parasites, “footsore disease,
increasing milk-flow in cows, and pacifying them, but also it is often admin-
istered to bullocks as a tonic, to relieve fatigue and to impart additional stay-
ing power.” As a human household remedy, “A mild beverage made from
bhang leaves is believed to sharpen the appetite and help the digestion.”
Religious mendicants were said to employ it for gastrointestinal and rheu-
matic afflictions during their peregrinations. Continued attestations were
claimed for dysmenorrhea, gonorrhea, dysuria, asthma and spasmodic condi-
tions. A fresh leaf poultice was said to reduce eye pain and conjunctivitis,
swollen joints and local inflammations, while a piece of charas placed in den-
tal caries was said to alleviate toothache. They noted, “Much of the sanctity
attached to bhang is put down to its supposed properties ‘clearing the head
and stimulating the brain to think’.” Finally, contributions to sexual perform-
ance were still claimed, as cannabis preparations “are frequently used by both
young and middle-aged individuals for stimulating sexual desire and pro-
longing the sexual act”.
Usage in Unani medicine at this time included treatment of insomnia,
migraine, neuralgic pains, asthma, spasmodic conditions and previously noted
gynecological conditions [30]. A continued contribution to Islamic mysticism
was also noted as cannabis use “frees them from worldly bonds, and induces
communion with the divine spirit”.
In another book about medicinal plants of India [62], the author stated:
“Charas…is a valuable narcotic, especially in cases where opium can-
not be administered; it is of great value in malarial and periodical
headaches, migraine, acute mania, whooping cough, cough of phthisis,
asthma, anaemia of brain, nervous vomiting, tetanus, convulsion, insan-
ity, delirium, dysuria, and nervous exhaustion; it is also used as an
anaesthetic in dysmenorrhea, as an appetizer and aphrodisiac, as an
anodyne in itching of eczema, neuralgia, severe pains of various kinds
of corns, etc.”
Indian charas of good quality is said to have a resin content of about 35–45%
[63], which according to the calculations of Clarke [64], might yield a theo-
retical tetrahydrocannabinol (THC) content of up to 30%. Higher concentra-
tions have been achieved with modern techniques.
10 E. Russo
Nadkarni [3] observed of cannabis, “All parts of the plant are intoxicating
(narcotic), stomachic, antispasmodic, analgesic (anodyne), stimulating, aphro-
disiac and sedative.
In 1977, Sharma observed [65] 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.”
In a modern review of Indian uses of cannabis, it was observed [66] that
“Cannabis was used medicinally for almost all the ills flesh is heir to”.
Cannabis remained a key ingredient in two aphrodisiacal preparations,
Madana modaka and Kamesvara modaka [67].
In a treatise entitled Indigenous Drugs of India [68] the authors noted the
requirement of dose titration due to increasingly inconsistent cannabis prepa-
rations. This drawback was addressed in a prior study [69] in which the authors
extracted local ganja to produce a 17% THC yield, which at intraperitoneal
doses of 75 mg/kg in rats resulted in a potentiation of sub-analgesic doses of
morphine.
In 1988 [70] cannabis was still mentioned as a remedy for malaria and
blood poisoning, among many other indications. In neighboring Nepal,
cannabis retains ethnobotanical applications among some 15 ethnic groups
[71], for diarrhea, dysentery, local wound treatment and in veterinary medi-
cine. In discussing the native use of cannabis and opium products by village
doctors in India, who provided 80% of the population with their medical care
in a report to the United Nations, the author felt that a legitimate role for them
persisted [19]:
“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.
Cannabis in contemporary Ayurvedic medicine
According to Chopra and Chopra [30], the modern Ayurvedic properties of
cannabis are: paphahari, promoting loosening, separation and the elimination
of phlegm; grahini, promoting retention and binding the bowels; pachani, pro-
moting digestion; ushna, promoting heat; pitala, exciting the flow of bile;
mada-vardhani, promoting talkativeness or releasing the volitional restraint of
speech; moda-vardhani, promoting happiness; vag-vardhani, stimulating the
digestive fire; dipani, stimulating appetite; ruchya, promoting taste; nidrapra-
da, hypnotic. Kapoor [4] described its Ayurvedic attributes as follows [4]: its
rasa (taste) is tikta (bitter); its guna (physical properties) are laghu (light, easy
to digest), teeshan (acute, pungent) and rooksha (ununctuous); its veerya
Cannabis in India: ancient lore and modern medicine 11
(energy modality or potency) is ushana (heating, digestive); and its vipaka
(transformation reactions after digestion) are katu (constipative, semen
increasing). Among its properties and uses, it is conceived of as: madakari
(causing intoxication), nidrajanan (sleep-inducing), dipan (affecting appetite),
grahi (absorbable) and pachan (affecting digestion). Dwarakanath’s [19]
assignations were quite similar to these, but added Muslim descriptions such
as constipative, stomachic, appetizer, causing elation, aphrodisiac, retentive,
devitalizing, anodyne, hypnotic, anti-convulsant, causing delirium and intoxi-
cating. The same author listed the names of 48 modern Ayurvedic and eight
Unani Tibbi formulas containing cannabis for a wide range of indications.
A recent survey of bhang use in the holy city of Varanasi (formerly Benares)
found it quite prevalent across socioeconomic strata, especially the working
class, businessmen and among the more educated [72]. Most users in the third
or fourth decades of life employed it for anxiety or mood disorders for the
resulting pleasure, while older people cited benefits on gastrointestinal disorders
with improvement in appetite and bowel habits, or for alleviating insomnia.
Among the 100 subjects, 90% reported improvement in sleep without daytime
fatigue. Improvement in “marital adjustment” was also claimed. All employed
bhang orally, generally 1.5 g/day, for gastrointestinal indications, but 56%
employed 4–10 g/day, without evidence of associated toxic adverse events.
In 1996, native cannabis was again extracted to a yield of 17% THC, which
was then used to treat cancer pain in 42 human subjects [73]. In 11.9% there was
no analgesia with doses of 25 mg, but 64.3% had up to 50% pain reduction, and
9.5% had greater than 75% pain relief with no use of adjunctive medicine.
Dash [23] identified cannabis as one of the primary herbs of rejuvenation
and a synergist with other agents, promoting health, preventing disease and
offering “side benefits”. In order of therapeutic priority, its uses were listed as:
sprue syndrome, sterility, impotency, diarrhea, indigestion, epilepsy, insanity
and colic pain. In addition to the many indications above, the following were
also noted: gastritis, anorexia, anal fistula, throat obstruction, jaundice, bron-
chitis, tuberculosis, torticollis, splenic disorder, delirium, obstinate urinary dis-
orders, sinus problems, anemia, rhinitis, elephantiasis, edema, puerperal sep-
sis, gout and constipation.
The scientific basis of Indian cannabis claims
This chapter has enumerated the lore of Indian medicine with respect to ther-
apeutic benefits of clinical cannabis, but what is its scientific rationale? The
issues will be addressed systemically (Tab. 2).
The oldest cannabis claims are psychiatric from the Atharvaveda, citing its
usage for anxiety. Current research is supportive, particularly for cannabidiol
(CBD) as an anti-anxiety agent as well as an anti-psychotic (reviewed in
[74]). Similar benefit may accrue in calming dementia, as THC proved bene-
ficial in Alzheimer’s disease patients [75]. Recently, cannabichromene (CBC)
12 E. Russo
Cannabis in India: ancient lore and modern medicine 13
Table 2. Indications for cannabis in India
Cannabis indication Physiological basis Reference
Psychiatric
Anxiety CBD reduces anxiety in humans [74]
Extinction of aversive memories EC control in hippocampus [77]
Insomnia Increased sleep in pain/multiple [79, 80]
sclerosis patients
Addiction treatment Decreased usage of cocaine/alcohol [84, 86]
Neurological
Neuropathic pain EC modulation of CNS pathways [87, 88]
Clinical pain reduction [79, 80]
Muscle relaxation Spinal interneuron effects? [79, 89]
Neuroprotection THC/CBD antioxidant/NMDA [91]
antagonism
Migraine Effects on periaqueductal grey, 5-HT, [88, 92, 93]
inflammation, etc.
Seizures CBD anticonvulsant [95]
THC anticonvulsant, EC modulation [96, 97]
of seizure threshold
Dermatological
Anti-psoriatic? TNF-αantagonism [99]
Anti-pruritic Peripheral anti-nociception [100]
Rheumatic
Benefit in rheumatoid arthritis TNF-αantagonism [99]
Endocrinological
Appetite stimulation Hypothalamic effect? [101]
Oncological
Anti-nausea 5-HT3antagonism or other? [102, 103]
Tumor reduction Promotes apoptosis [104, 105]
Reduces angiogenesis [104]
Anti-prolactin effect [106]
Blocks pulmonary carcinogenesis [107]
Pulmonary
Asthma Bronchodilation [108, 110]
Gastroenterological
Intestinal spasm Smooth muscle relaxation [88, 112]
Secretory diarrhea EC modulation of secretion [112]
Gastritis Anti-inflammatory/gastric [114, 115]
cytoprotection
Jaundice ? immunomodulatory [116]
(Continued on next page)
has also demonstrated anti-depressant effects in an animal model [76].
Additional support for benefits of cannabis on mood is evident from work
demonstrating the regulation of extinction of aversive memories by the endo-
cannabinoid system [77].
Insomnia treatment is another ancient claim that finds documentation in
modern phase II–III clinical-trial results in multiple sclerosis patients and
those with chronic neuropathic pain [78–81]. The 19th-century observation of
benefit on addiction is echoed in modern studies of alcoholics [82] and cocaine
users [83], with experimental support for decreased use rates in clinical exper-
iments for each [84–86].
In the neurological realm, the ability of cannabis to treat pain, particularly
of neuropathic origin, is the subject of a great deal of current research. Results
to date are very encouraging, in terms of both basic science support (reviewed
in [87, 88]) and the benefits in clinical trials [78–80].
Although tetanus is rarely observed in the modern age of immunization, the
observed benefits on muscle relaxation underlie current application to treat-
ment of spasms and spasticity in multiple sclerosis and spinal cord trauma [79,
89], where cannabis extracts have proven as effective as any currently avail-
able agent [90]. Although rabies remains invariably fatal, the neuroprotective
effects of cannabis [91] may warrant new trials of cannabis extracts in its treat-
ment, and that of slow virus (prion) diseases. Indian medical literature on
migraine treatment is also supportive, as is a tremendous amount of patho-
physiological data [88, 92, 93]. As for clinical trials, however, the words of Dr
Mechoulam still ring true [94]: “no modern work exists”.
14 E. Russo
Table 2. (Continued)
Cannabis indication Physiological basis Reference
Gynecological
Dysmenorrhea Smooth muscle relaxation Reviewed in [42]
Uterine bleeding EC modulation in uterus Reviewed in [42]
Lower-urinary-tract symptoms Increased bladder capacity, [118]
decreased incontinence
Sexual
Impotence Pain reduction/spinal effects? [119]
Premature ejaculation EC modulation [120]
Infectious
Antibiotic Effects of cannabinoids/terpenoids [111, 121]
Anti-malarial Caryophyllene, α-terpineol [121, 123]
Insecticidal/pediculicidal Octopamine/GABA [126–128]
CBD, cannabidiol; CNS, central nervous system; EC, endocannabinoid; GABA, γ-aminobutyric acid;
5-HT, 5-hydroxytryptamine; 5-HT3, serotonin type-3 receptor; NMDA, N-methyl-D-aspartate; TNF-α,
tumor necrosis factor-α.
Another long-held claim pertains to cannabis in epilepsy. Previous experi-
mental work showed some support for CBD [95], but this has been greatly bol-
stered by current experiments by Wallace et al. [96, 97], demonstrating the
anti-convulsant properties of THC, and the modulation of seizure thresholds
by anandamide.
Examining additional ectodermal tissue, both eczema and itch were cited in
Indian literature as benefiting from cannabis treatment. Recent work demon-
strating the value of tumor necrosis factor-α(TNF-α) antagonists in psoriasis
[98] may justify the use of cannabis, particularly CBD-rich extracts, in the
treatment of related diseases, as CBD shares this mechanism of action [99].
Similarly, the benefits of THC on peripheral pain and itch are becoming
increasingly evident [88, 100].
Rheumatic diseases cited by O’Shaughnessy [36] and other authors remain
an issue, but experiments underline the benefits of CBD in experimental
rodent models of rheumatoid arthritis [99]. Phase II clinical trials are pend-
ing. Modern investigation demonstrates that cannabinoid treatments definite-
ly have a clinical role to play in issues of appetite, with benefit seen in
HIV/AIDS subjects [101], and in multiple sclerosis/neuropathic pain patients
[79].
The role of cannabis in oncology may now extend far beyond its demon-
strated ability to allay nausea in chemotherapy [102, 103], but include promo-
tion of apoptosis, and suppression of angiogenesis in a wide variety of tissue
types (reviewed in [104, 105]). Additionally, THC has anti-prolactin activity in
breast carcinomas [106], and introduces a metabolic block in pulmonary car-
cinogenesis [107].
The role of cannabis in asthma has been much debated, but it is clear that
THC is a bronchodilator [108], as is its terpenoid component, α-pinene [109],
and that smooth muscle contraction in the lungs is mediated by endocannabi-
noids [110]. Given these facts, plus the prominent anti-inflammatory benefits
of THC, CBD and terpenoids [111], it is apparent that additional investigation
with vaporizer or other non-smoked inhalant technology with cannabis
extracts is warranted.
The treatment of digestive issues with cannabis has figured prominently in
India to the current day. Whether it be through reduction of intestinal spasms,
constipation or inhibition of secretory diarrhea processes in cholera, cannabis
components offer neuromodulatory amelioration (reviewed in [88, 112]).
Given the combination of these factors mediated by THC, the TNF-αantago-
nism of CBD and the observed up-regulation of endogenous cannabinoids in
human inflammatory bowel disease [113], there is every reason to believe that
benefits will be forthcoming in clinical trials of cannabis extracts in Crohn’s
disease and ulcerative colitis. The gastritis claim finds support in studies doc-
umenting the benefit of cannabis in ulcer treatment [114], and the gastric cyto-
protective effect of the cannabis essential-oil component, caryophyllene [115].
Even claims for treatment of jaundice may find support in recent claimed ben-
efits seen in hepatitis C patients who use cannabis [116].
Cannabis in India: ancient lore and modern medicine 15
Hemorrhoids continue to plague mankind, and anecdotal evidence for the
benefits of cannabis from rural Kentucky echo the Indian claims [117]. Myriad
anti-inflammatory and anti-pruritic mechanisms may underlie the basis of such
treatment. The benefits of cannabis in dysmenorrhea and excessive uterine
bleeding are plausible given the expression of endocannabinoids in the uterus
(reviewed in [42]). The benefits of cannabis in symptoms of the lower urinary
tract have been strongly supported by increases in mean maximum cystomet-
ric capacity, decreased mean daytime frequency of urination, decreased fre-
quency of nocturia and mean daily episodes of incontinence in multiple scle-
rosis patients treated with cannabis-based medicine extracts [118].
The persistence of claims of cannabis increasing sexual pleasure and per-
formance is compelling, but not particularly amenable to simple experimental
verification. Does cannabis treat impotence? There are frequent claims of
such, including a successful pregnancy induced by one man who was previ-
ously impotent due to spinal damage, treated successfully with oromucosal
cannabis-based medicine [119]. Additionally, recent data demonstrate that a
cannabinoid agonist delayed ejaculatory responses in rats [120]. Thus, a con-
vincing case may be made for human clinical trials [88].
Claims of the benefits of cannabis in infectious diseases have received little
investigation since studies on bacteria in 1960 [121], wherein the authors
demonstrated that an isolated resin from cannabis inhibited growth of
Mycobacterium tuberculosis down to a dilution of 1:150000. Studies on
human herpes simplex virus in 1980 revealed the inhibition of viral growth by
THC even at low dosages [122]. A variety of cannabis components are
anti-infective (reviewed in [111]), supporting such applications, as well as the
use of cannabis in the treatment of malaria, where the essential oil components
caryophyllene and α-terpineol demonstrate anti-protozoal activity [123].
Cannabis may yet prove useful in the treatment of dandruff, as suggested in
Indian sources. Cannabichromene demonstrated anti-fungal activity [124], and
ρ-cymene showed anti-candidal effects [125]. Cannabis effects on the
causative yeast in dandruff, Malassezia ovalis, could be easily tested.
Clear benefits also seem likely in the treatment of lice, as this ancient indi-
cation has been supported by pediculicidal efficacy of cannabis terpenoid com-
ponents [126], the activity of terpenoids on insect octopaminergic receptors
[127], and their allosteric modulation of insect homo-oligomeric γ-aminobu-
tyric acid (GABA) receptors [128]. A whole range of new applications of
cannabis as an insecticide are possible [129]. Mechoulam decried the lack of
investigation of cannabis effects on intestinal parasites [94], and this remains
an area of deficiency in our cannabis knowledge.
Cannabis in India in context
As we have seen, the vast majority of claims for cannabis from India are fully
corroborated by modern scientific and clinical investigation. In closing, a pas-
16 E. Russo
sage from Campbell [1] written for the Report of the Indian Hemp Drugs
Commission more than a century ago offers a plaintive plea for this venerable
herb:
“By the help of bhang ascetics pass days without food or drink. The
supporting power of bhang has brought many a Hindu family safe
through the miseries of famine. To forbid or even seriously to restrict
the use of so holy and gracious a herb as the hemp would cause wide-
spread suffering and annoyance and to the large bands of worshipped
ascetics deep-seated anger. It would rob the people of a solace in dis-
comfort, of a cure in sickness, of a guardian whose gracious protection
saves them from the attacks of evil influences, and whose mighty power
makes the devotee of the Victorious, overcoming the demons of hunger
and thirst, of panic fear, of the glamour of Maya or matter, and of mad-
ness, able in rest to brood on the Eternal, till the Eternal, possessing him
body and soul, frees him from the having of self and receives him into
the ocean of Being. These beliefs the Musalman devotee shares to the
full. Like his Hindu brother the Musalman fakir reveres bhang as the
lengthener of life, the freer from the bonds of self. Bhang brings union
with the Divine Spirit. ‘We drank bhang and the mystery I am He grew
plain. So grand a result, so tiny a sin.’”
It is appropriate that modern-day cannabinoid researchers have acknowledged
the integral role that Indian culture has played in our understanding of the bio-
chemistry of cannabis. Thus, the first endocannabinoid, arachi-
donylethanolamide, was dubbed anandamide (ananda is Sanskrit for bliss;
Tab. 1) [130]. In like manner, the most recently identified endocannabinoid,
the cannabinoid antagonist O-arachidonylethanolamine, which is arachidonic
acid and ethanolamine joined by an ester linkage, has been nicknamed virod-
hamine (virodha is Sanskrit for opposition) [131].
It is fascinating to note that our own endogenous cannabinoid physiology
encompasses these positive and negative influences, in a manner analogous to
THC and CBD effects from cannabis, the Indian phytopharmaceutical that
leads us to this knowledge: nature and neurophysiology in symmetry and bal-
ance.
Acknowledgments
The author would like to thank Dominik Wujastyk, Jan Meulenbeld, Robert A. Nelson, Knut Movik,
Ali Gorji and the dedicated staff of Interlibrary Loan at Mansfield Library, University of Montana, for
their kind provision of resource materials for this chapter.
References
1 Kaplan J (1969) Marijuana.Report of the Indian Hemp Drugs Commission,1893–1894. Thomas
Jefferson Publishing Co., Silver Spring, MD
Cannabis in India: ancient lore and modern medicine 17
2 Merlin MD (2003) Archaeological evidence for the tradition of psychoactive plant use in the Old
World. Econ Bot 57: 295–323
3 Nadkarni KM (1976) Indian materia medica. Popular Prakashan, Bombay
4 Kapoor LD (1990) CRC handbook of Ayurvedic Medicinal Plants. CRC Press, Boca Raton, FL
5 Candolle Ad (1883) Origine des plantes cultivées. G. Baillière et Cie., Paris
6 Candolle Ad (1886) Origin of cultivated plants. Paul Trench, London
7 de Bunge A (1860) Lettre de M. Alex. de Bunge à M. Decaisne. Botanique de France 7: 29– 31
8 Ames O (1939) Economic annuals and human cultures. Botanical Museum of Harvard University,
Cambridge, MA
9 Fleming MP, Clarke RC (1998) Physical evidence for the antiquity of Cannabis sativa L. J Int
Hemp Assoc 5: 280–293
10 Bouquet RJ (1950) Cannabis. Bull Narc 2: 14–30
11 Merlin MD (1972) Man and marijuana; some aspects of their ancient relationship. Fairleigh
Dickinson University Press, Rutherford, NJ
12 Sharma GK (1979) Significance of eco-chemical studies of cannabis. Science and Culture 45:
303–307
13 Sarianidi V (1994) Temples of Bronze Age Margiana: traditions of ritual architecture. Antiquity
68: 388–397
14 Sarianidi V (1998) Margiana and protozoroastrism. Kapon Editions, Athens
15 Witzel M (1999) Early sources for South Asian substrate languages. Mother Tongue October:
1–70
16 Darmesteter J (1895) Zend-Avesta, Part I, The Vendidad. Oxford University, London
17 Mahdihassan S (1982) Etymology of names – ephedra and cannabis. Studies in the History of
Medicine 6: 63–66
18 Grierson GA (1894) The hemp plant in Sanskrit and Hindi literature. Indian Antiquary September:
260–262
19 Dwarakanath C (1965) Use of opium and cannabis in the traditional systems of medicine in India.
Bull Narc 17: 15–19
20 Sanyal PK (1964) A story of medicine and pharmacy in India: Pharmacy 2000 years ago and
after. Shri Amitava Sanyal, Calcutta
21 Watt G (1889) A dictionary of the economic products of India. Superintendent of Government
Printing, Calcutta
22 Aldrich MR (1977) Tantric cannabis use in India. J Psychedelic Drugs 9: 227–233
23 Dash VB (1999) Fundamentals of Ayurvedic medicine. Sri Satguru Publications, Delhi
24 Rao BR (1971) Anandakandam (root of bliss). A medieval medical treatise of South India. Bulletin
of the Intistute of History of Medicine (Hyderabad) 1: 7–9
25 Meulenbeld GJ (1989) The search for clues to the chronology of Sanskrit medical texts as illus-
trated by the history of bhanga. Studien zur Indologie und Iranistik 15: 59–70
26 Wujastyk D (2002) Cannabis in traditionnal Indian herbal medicine. In:A Salema (ed.): Ayudveda
at the crossroad of care and cure. Universidade Nova, Lisbon, 45– 73
27 Dymock W (1884) The vegetable materia medica of Western India. Education Society’s Press,
Bombay
28 Sarngadhara, Srikanthamurthy KR (1984) Sarngadhara-samhita: a treatise of Ayurveda.
Chaukhambha Orientalia, Varanasi
29 Sharma PV (1984) Tantrik influence on Sarngadhara. Ancient Science of Life 3: 129–131
30 Chopra IC, Chopra RW (1957) The use of cannabis drugs in India. Bull Narc 9: 4–29
31 Dash B, Kashyap L, Todaramalla (1980) Materia medica of ayurveda: based on Ayurveda
saukhyam of Todarananda. Concept, New Delhi
32 da Orta G (1913) Colloquies on the simples and drugs of India. Henry Sotheran, London
33 O’Shaughnessy WB (1843) On the preparations of the Indian hemp, or gunjah (Cannabis indica).
Their effects on the animal system in health, and their utility in the treatment of tetanus and other
convulsive diseases. Provincial Medical Journal and Retrospect of the Medical Sciences 5:
343–347, 363–369: 397 –398
34 Dymock W, Warden CJH, Hooper D (1890) Pharmacographia indica. A history of the principal
drugs of vegetable origin, met with in British India. K. Paul Trench Trübner and Co., London
35 Ainslie W (1813) Materia medica of Hindoostan, and artisan’s and agriculturist’s nomenclature.
Government Press, Madras
36 O’Shaughnessy WB (1838–1840) On the preparations of the Indian hemp, or gunjah (Cannabis
18 E. Russo
indica); Their effects on the animal system in health, and their utility in the treatment of tetanus
and other convulsive diseases. Transactions of the Medical and Physical Society of Bengal
71–102, 421–461
37 Ley W (1843) Observations on the Cannabis indica, or Indian hemp. Provincial Medical Journal
and Retrospect of the Medical Sciences 5: 487–489
38 Clendinning J (1843) Observation on the medicinal properties of Cannabis sativa of India.
Medico-Chirurgical Transactions 26: 188–210
39 Shaw J (1843) On the use of the Cannabis indica (or Indian hemp)-1st-in tetanus-2nd-in
hydrophobia-3rd-in cholera-with remarks on its effects. Madras Quarterly Medical Journal 5:
74–80
40 Churchill F (1849) Essays on the puerperal fever and other diseases peculiar to women. Selected
from the writings of British authors previous to the close of the eighteenth century. Sydenham
Society, London
41 Christison A (1851) On the natural history, action, and uses of Indian hemp. Monthly J Medical
Science of Edinburgh, Scotland 13: 26–45: 117– 121
42 Russo E (2002) Cannabis treatments in obstetrics and gynecology: A historical review. J Cannabis
Therapeutics 2: 5–35
43 Johnston JFW (1855) The chemistry of common life. D. Appleton, New York
44 McMeens RR (1860) Report of the Ohio State Medical Committee on Cannabis indica. In: Ohio
State Medical Society, White Sulphur Springs, OH, 75 –100
45 Dutt UC, Sen BL, Sen A, Sen PK (1980) The materia medica of the Hindus. Chowkhamba
Saraswatibhawan, Varanasi
46 Kerr HC (1893–1894) Report of the cultivation of, and trade in, ganja in Bengal. Birtish
Parliamentary Papers 66: 94–154
47 Commission IHD (1894) Report of the Indian Hemp Drugs Commission, 1893–94. Government
Central Printing Office, Simla
48 Abel EL (1980) Marihuana, the first twelve thousand years. Plenum Press, New York
49 Mills JH (2000) Madness, cannabis and colonialism: the ‘native only’ lunatic asylums of British
India, 1857–1900. St. Martin’s Press, New York
50 Godley A (1893–1894) Papers relating to the consumption of ganja and other drugs in India.
British Parliamentary Papers 66: 1–93
51 Macleod J, Oakes R, Copello A, Crome I, Egger M, Hickman M, Oppenkowski T,
Stokes-Lampard H, Davey Smith G (2004) Psychological and social sequelae of cannabis and
other illicit drug use by young people: a systematic review of longitudinal, general population
studies. Lancet 363: 1579–1588
52 Waring EJ (1897) Remarks on the uses of some of the bazaar medicines and common medical
plants of India; with a full index of diseases, indicating their treatment by these and other agents
procurable throughout India. To which are added directions for treatment in cases of drowning,
snake-bite, &c. J. and A. Churchill, London
53 Khastagir AC (1878) Hemp (ganja) smoking in tetanus on a new principle. Indian Medical Gazette
210–211
54 Lucas JC (1880) Notes on tetanus; with remarks on the efficacy of Cannabis indica when admin-
istered through the lungs. Medical Times and Gazette 202–204
55 Du Toit BM (1977) Historical and cultural factors influencing cannabis use among Indians in
South Africa. J Psychedelic Drugs 9: 235– 246
56 Rubin VD, Comitas L (1975) Ganja in Jamaica: A medical anthropological study of chronic mar-
ihuana use. Mouton, The Hague
57 Dreher MC (1982) Working men and ganja: marihuana use in rural Jamaica. Institute for the
Study of Human Issues, Philadelphia
58 Ratnam EV (1920) Cannabis indica.J Ceylon Branch of the British Medical Association 17:
36–42
59 Dixon WE (1923) Smoking of Indian hemp and opium. Brit Med J 2: 1179–1180
60 Chopra RN (1940) Use of hemp drugs in India. Indian Medical Gazette 75: 356–367
61 Carstairs GM (1954) Daru and bhang; cultural factors in the choice of intoxicant. Q J Stud Alcohol
15: 220–237
62 Dastur JF (1962) Medicinal plants of India and Pakistan; A concise work describing plants used
for drugs and remedies according to Ayurvedic, Unani and Tibbi systems and mentioned in British
and American pharmacopoeias. D.B. Taraporevala Sons, Bombay
Cannabis in India: ancient lore and modern medicine 19
63 Karnick CR (1996) Ayurvedic narcotic medicinal plants. Sri Satguru Publications, Delhi
64 Clarke RC (1998) Hashish! Red Eye Press, Los Angeles
65 Sharma GK (1977) Ethnobotany and its significance for Cannabis studies in the Himalayas. J
Psychedelic Drugs 9: 337–339
66 Touw M (1981) The religious and medicinal uses of Cannabis in China, India and Tibet. J
Psychoactive Drugs 13: 23–34
67 Chaturvedi GN, Tiwari SK, Rai NP (1981) Medicinal use of opium and cannabis in medieval
India. Indian JHistory of Science 16: 31–25
68 Chopra RN (1982) Chopra’s indigenous drugs of India. Academic Publishers, Calcutta
69 Ghosh P, Bhattacharya SK (1979) Cannabis-induced potentiation of morphine analgesia in rat –
role of brain monoamines. Indian J Med Res 70: 275–280
70 Majupuria TC, Joshi DP (1988) Religious and useful plants of Nepal and India. M. Gupta,
Lashkar, India
71 Manandhar NP, Manandhar S (2002) Plants and people of Nepal. Timber Press, Portland, OR
72 Chaturvedi GN, Rai NP, Pandey US, Sing KP, Tiwari SK (1991) Clinical survey of cannabis users
in Varanasi. Ancient Science of Life 10: 194 –198
73 Gehlot S, Rastogi V, Dubby GP (1996) Role of cannabis extract (tetrahydrocannabinol) for relief
of cancer pain. Sachitra Ayurveda 49: 138–140
74 Zuardi AW, Guimaraes FS (1997) Cannabidiol as an anxiolytic and antipsychotic. In: ML Mathre
(ed.): Cannabis in medical practice: a legal, historical and pharmacological overview of the ther-
apeutic use of marijuana. McFarland, Jefferson, NC, 133–141
75 Volicer L, Stelly M, Morris J, McLaughlin J, Volicer BJ (1997) Effects of dronabinol on anorexia
and disturbed behavior in patients with Alzheimer’s disease. Int J Geriat Psychiat 12: 913–919
76 Deyo RA, Musty RE (2003) A cannabichromene (CBC) extract alters behavioral despair on the
mouse tail suspension test of depression. In: 2003 Symposium on the Cannabinoids. International
Cannabinoid Research Society, Cornwall, ON, Canada, 146
77 Marsicano G, Wotjak CT, Azad SC, Bisogno T, Rammes G, Cascio MG, Hermann H, Tang J,
Hofmann C, Zieglgansberger W et al. (2002) The endogenous cannabinoid system controls extinc-
tion of aversive memories. Nature 418: 530– 534
78 Russo EB (2003) Cannabis and cannabis-based medicine extracts: Additional results. J Cannabis
Therapeutics 3: 153–162
79 Wade DT, Robson P, House H, Makela P, Aram J (2003) A preliminary controlled study to deter-
mine whether whole-plant cannabis extracts can improve intractable neurogenic symptoms. Clin
Rehabil 17: 18–26
80 Notcutt W, Price M, Miller R, Newport S, Phillips C, Simmonds S, Sansom C (2004) Initial expe-
riences with medicinal extracts of cannabis for chronic pain: results from 34 “N of 1” studies.
Anaesthesia 59: 440–452
81 Nicholson AN, Turner C, Stone BM, Robson PJ (2004) Effect of delta-9-tetrahydrocannabinol and
cannabidiol on nocturnal sleep and early-morning behavior in young adults. J Clin
Psychopharmacol 24: 305–313
82 Mikuriya TH (2004) Cannabis as a substitute for alcohol: a harm-reduction approach. J Cannabis
Therapeutics 4: 79–93
83 Dreher M (2002) Crack heads and roots daughters: The therapeutic use of cannabis in Jamaica. J
Cannabis Therapeutics 2: 121–133
84 Labigalini E Jr, Rodrigues LR, Da Silveira DX (1999) Therapeutic use of cannabis by crack
addicts in Brazil. J Psychoactive Drugs 31: 451–455
85 Mello NK, Mendelson JH (1978) Marihuana, alcohol, and polydrug use: human self-administra-
tion studies. NIDA Res Monogr 93–127
86 Mello NK, Mendelson JH, Kuehnle JC, Sellers ML (1978) Human polydrug use: marihuana and
alcohol. J Pharmacol Exp Ther 207: 922–935
87 Richardson JD, Aanonsen L, Hargreaves KM (1998) Antihyperalgesic effects of spinal cannabi-
noids. Eur J Pharmacol 345: 145–153
88 Russo EB (2004) Clinical endocannabinoid deficiency (CECD): Can this concept explain thera-
peutic benefits of cannabis in migraine, fibromyalgia, irritable bowel syndrome and other treat-
ment-resistant conditions? Neuroendocrinol Lett 25: 31–39
89 Zajicek J, Fox P, Sanders H, Wright D, Vickery J, Nunn A, Thompson A (2003) Cannabinoids for
treatment of spasticity and other symptoms related to multiple sclerosis (CAMS study): multicen-
tre randomised placebo-controlled trial. Lancet 362: 1517–1526
20 E. Russo
90 Metz L, Page S (2003) Oral cannabinoids for spasticity in multiple sclerosis: will attitude con-
tinue to limit use? Lancet 362: 1513
91 Hampson AJ, Grimaldi M, Axelrod J, Wink D (1998) Cannabidiol and (–)Delta9-tetrahydro-
cannabinol are neuroprotective antioxidants. Proc Natl Acad Sci USA 95: 8268– 8273
92 Russo E (1998) Cannabis for migraine treatment: The once and future prescription? An histori-
cal and scientific review. Pain 76: 3–8
93 Russo EB (2001) Hemp for headache: An in-depth historical and scientific review of cannabis in
migraine treatment. J Cannabis Therapeutics 1: 21–92
94 Mechoulam R (1986) The pharmacohistory of Cannabis sativa. In: R Mechoulam (ed.):
Cannabinoids as therapeutic agents. CRC Press, Boca Raton, FL, 1–19
95 Carlini EA, Cunha JM (1981) Hypnotic and antiepileptic effects of cannabidiol. J Clin
Pharmacol 21: 417S–427S
96 Wallace MJ, Blair RE, Falenski KW, Martin BR, DeLorenzo RJ (2003) The endogenous cannabi-
noid system regulates seizure frequency and duration in a model of temporal lobe epilepsy. J
Pharmacol Exp Ther 307: 129–137
97 Wallace MJ, Martin BR, DeLorenzo RJ (2002) Evidence for a physiological role of endo-
cannabinoids in the modulation of seizure threshold and severity. Eur J Pharmacol 452: 295– 301
98 Leonardi CL, Powers JL, Matheson RT, Goffe BS, Zitnik R, Wang A, Gottlieb AB (2003)
Etanercept as monotherapy in patients with psoriasis. N Engl J Med 349: 2014–2022
99 Malfait AM, Gallily R, Sumariwalla PF, Malik AS, Andreakos E, Mechoulam R, Feldmann M
(2000) The nonpsychoactive cannabis constituent cannabidiol is an oral anti-arthritic therapeutic
in murine collagen-induced arthritis. Proc Natl Acad Sci USA 97: 9561–9566
100 Richardson JD, Kilo S, Hargreaves KM (1998) Cannabinoids reduce hyperalgesia and inflam-
mation via interaction with peripheral CB1 receptors. Pain 75: 111–119
101 Abrams DI, Hilton JF, Leiser RJ, Shade SB, Elbeik TA, Aweeka FT, Benewitz NL, Bredt BM,
Kosel B, Aberg JA et al. (2003) Short-term effects of cannabinoids in patients with HIV-1 infec-
tion. A randomized, placbo-controlled clinical trial. Ann Intern Med 139: 258–266
102 Abrahamov A, Mechoulam R (1995) An efficient new cannabinoid antiemetic in pediatric oncol-
ogy. Life Sci 56: 2097–2102
103 Musty RE, Rossi R (2001) Effects of smoked cannabis and oral delta-9-tetrahydrocannabinol on
nausea and emesis after cancer chemotherapy: A review of state clinical trials. J Cannabis
Therapeutics 1: 29–42
104 Guzman M (2003) Cannabinoids: potential anticancer agents. Nat Rev Cancer 3: 745–755
105 Maccarrone M, Finazzi-Agro A (2003) The endocannabinoid system, anandamide and the regu-
lation of mammalian cell apoptosis. Cell Death Differ 10: 946–955
106 De Petrocellis L, Melck D, Palmisano A, Bisogno T, Laezza C, Bifulco M, Di Marzo V (1998)
The endogenous cannabinoid anandamide inhibits human breast cancer cell proliferation. Proc
Natl Acad Sci USA 95: 8375–8380
107 Roth MD, Marques-Magallanes JA, Yuan M, Sun W, Tashkin DP, Hankinson O (2001) Induction
and regulation of the carcinogen-metabolizing enzyme CYP1A1 by marijuana smoke and delta
(9)-tetrahydrocannabinol. Am J Respir Cell Mol Biol 24: 339–344
108 Williams SJ, Hartley JP, Graham JD (1976) Bronchodilator effect of delta1-tetrahydrocannabinol
administered by aerosol of asthmatic patients. Thorax 31: 720–723
109 Falk AA, Hagberg MT, Lof AE, Wigaeus-Hjelm EM, Wang ZP (1990) Uptake, distribution and
elimination of alpha-pinene in man after exposure by inhalation. Scand J Work Environ Health
16: 372–378
110 Pertwee RG, Ross RA (2002) Cannabinoid receptors and their ligands. Prostaglandins Leukot
Essent Fatty Acids 66: 101 –121
111 McPartland JM, Russo EB (2001) Cannabis and cannabis extracts: Greater than the sum of their
parts? J Cannabis Therapeutics 1: 103–132
112 Pertwee RG (2001) Cannabinoids and the gastrointestinal tract. Gut 48: 859–867
113 Wright K, Rooney N, Tate J, Feeney M, Robertson D, Welham M, Ward S (2003) Functional
cannabinoid receptor expression in human colonic epithelium. In: 2003 Symposium on the
Cannabinoids. International Cannabinoid Research Society, Cornwall, ON, Canada, 25
114 Douthwaite AH (1947) Choice of drugs in the treatment of duodenal ulcer. Brit Med J 2: 43–47
115 Tambe Y, Tsujiuchi H, Honda G, Ikeshiro Y, Tanaka S (1996) Gastric cytoprotection of the
non-steroidal anti-inflammatory sesquiterpene, beta-caryophyllene. Planta Med 62: 469–470
116 Schnelle M, Grotenhermen F, Reif M, Gorter RW (1999) [Results of a standardized survey on the
Cannabis in India: ancient lore and modern medicine 21
medical use of cannabis products in the German-speaking area]. Forsch Komplementarmed 6
(suppl 3): 28–36
117 Thompson LS (1972) Cannabis sativa and traditions associated with it. Kentucky Folklore Record
18: 1–4
118 Brady CM, DasGupta R, Dalton C, Wiseman OJ, Berkley KJ, Fowler CJ (2004) An open-label
pilot study of cannabis based extracts for bladder dysfunction in advanced multiple sclerosis.
Multiple Sclerosis 10: 425–433
119 Notcutt W, Price M, Miller R, Newport S, Sansom C, Simmonds S (2002) Medicinal cannabis
extract in chronic pain: (7) Results from long term safety extension study (CBME-SAFEX). J
Cannabis Therapeutics 2: 99–100
120 Ferrari F, Ottani A, Giuliani D (2000) Inhibitory effects of the cannabinoid agonist HU 210 on
rat sexual behaviour. Physiol Behav 69: 547–554
121 Kabelik J, Krejcˇí Z, Santavy´ F (1960) Cannabis as a medicament. Bull Narc 12: 5– 23
122 Blevins RD, Dumic MP (1980) The effect of delta-9-tetrahydrocannabinol on herpes simplex
virus replication. J Gen Virol 49: 427–431
123 Campbell WE, Gammon DW, Smith P, Abrahams M, Purves TD (1997) Composition and anti-
malarial activity in vitro of the essential oil of Tetradenia riparia. Planta Med 63: 270–272
124 ElSohly HN, Turner CE, Clark AM, Eisohly MA (1982) Synthesis and antimicrobial activities of
certain cannabichromene and cannabigerol related compounds. J Pharm Sci 71: 1319–1323
125 Carson CF, Riley TV (1995) Antimicrobial activity of the major components of the essential oil
of Melaleuca alternifolia. J Appl Bacteriol 78: 264– 269
126 Downs AM, Stafford KA, Coles GC (2000) Monoterpenoids and tetralin as pediculocides. Acta
Derm. Venereology 80: 69–70
127 Enan E (2001) Insecticidal activity of essential oils: octopaminergic sites of action. Comp
Biochem Physiol C Toxicol Pharmacol 130: 325–337
128 Priestley CM, Williamson EM, Wafford KA, Sattelle DB (2003) Thymol, a constituent of thyme
essential oil, is a positive allosteric modulator of human GABA-A receptors and a
homo-oligomeric GABA receptor form Drosophila melanogaster.Brit J Pharmacol 140:
1363–1372
129 McPartland JM, Clarke RC, Watson DP (2000) Hemp diseases and pests: Management and bio-
logical control. CABI, Wallingford, UK
130 Devane WA, Hanusˇ L, Breuer A, Pertwee RG, Stevenson LA, Griffin G, Gibson D, Mandelbaum
A, Etinger A, Mechoulam R (1992) Isolation and structure of a brain constituent that binds to the
cannabinoid receptor. Science 258: 1946–1949
131 Porter AC, Sauer JM, Knierman MD, Becker GW, Berna MJ, Bao J, Nomikos GG, Carter P,
Bymaster FP, Leese AB, Felder CC (2002) Characterization of a novel endocannabinoid, virod-
hamine, with antagonist activity at the CB1 receptor. J Pharmacol Exp Ther 301: 1020– 1024
22 E. Russo
Cannabinoid chemistry: an overview
Lumír O. Hanusˇ and Raphael Mechoulam
Department of Medicinal Chemistry and Natural Products, Medical Faculty, The Hebrew University
of Jerusalem, Ein Kerem Campus, 91120 Jerusalem, Israel
Introduction
Cannabis sativa probably originates from neolithic China [1]. However the
exact period of its domestication is unknown. The first known record of the use
of cannabis as a medicine was published in China 5000 years ago in the reign
of the Emperor Chen Nung. It was recommended for malaria, constipation,
rheumatic pains, absent-mindedness and female disorders. Later its use spread
into India and other Asian countries, the Middle East, Asia, South Africa and
South America. It was highly valued in medieval Europe. In Western Europe,
particularly in England, cannabis was extensively used as a medicine during the
19th century, while in France it was mostly known as a “recreational” drug [2].
Natural cannabinoids
The first successful attempt to identify a typical cannabis constituent was
achieved by Wood et al. [3], who isolated cannabinol from the exuded resin of
Indian hemp (charas), which was analysed as C21H26O2. Another big step was
made by Cahn, who advanced the elucidation of the structure of cannabinol
[4], leaving as uncertain only the positions of a hydroxyl and a pentyl group.
Several years later Todd’s group in the UK [5, 6] and independently Adam’s
group in the USA [7] synthesized several cannabinol isomers and compared
them with the natural one. One of the synthetic isomers was identical to the
natural product. The correct structure of the first natural cannabinoid, cannabi-
nol, was thus finally elucidated. These two groups assumed that the psy-
chotropically active constituents were tetrahydrocannabinols (THCs), which
however they could not isolate in pure form and therefore they could not elu-
cidate their structures.
A second cannabis constituent, the psychotropically inactive cannabidiol,
was also isolated, but its structure was only partially clarified [8]. Synthetic
THC derivatives, which showed cannabis-like activity in animal tests, were
prepared, but they obviously differed from the active natural product, on the
basis of their UV spectrum [9–12].
Cannabinoids as Therapeutics
Edited by R. Mechoulam
© 2005 Birkhäuser Verlag/Switzerland
23
In a systematic study of the antibacterial substances in hemp Krejcˇ í and
S
ˇantavy´ found that an extract containing carboxylic acids was effective against
Staphylococcus aureus and other Gram-positive micro-organisms. They isolat-
ed cannabidiolic acid and reported a nearly correct structure [13, 14] (Fig. 1).
24 L.O. Hanusˇ and R. Mechoulam
Figure 1. A tentative biogenesis of the plant cannabinoids
Advances in isolation methods made possible a clarification of the chem-
istry of cannabis. In 1963 our group reisolated cannabidiol and reported its
correct structure and stereochemistry [15]. A year later we finally succeeded in
isolating pure THC (9-THC); we elucidated its structure, obtained a crys-
talline derivative and achieved a partial synthesis from cannabidiol [16]. The
absolute configuration of cannabidiol and of THC was established by correla-
tion with known terpenoids [17]. Several years later a minor psychotomimeti-
cally active constituent, 8-THC, was isolated from marijuana [18]. Whether
this THC isomer is a natural compound, or an artifact formed during the dry-
ing of the plant, remains an open problem.
Several additional, non-psychotropic cannabinoids were also identified at
that time. The best known are cannabigerol [19], cannabichromene [20, 21]
and cannabicyclol [22]. For a better understanding of the biogenesis of a
cannabinoids in the plant the isolation and identification of cannabinoid acids
turned out to be essential. Alongside cannabidiolic acid, the cannabinolic and
cannabigerolic acids were identified [23], followed by two 9-THC acids, A
and B [24, 25], as well as 8-THC acid [26, 27] and cannabielsoic acid [28].
The decarboxylated product of cannabielsoic acid, cannabielsoin, is found in
mammals as a metabolite of cannabidiol [29]. The syntheses of some of the
cannabinoid acids have been reported [30].
A tentative pathway for the biogenesis of cannabinoids in the plant has been
published [3134]. However the only experimental support for 9-THC acid
formation from cannabigerolic acid (by direct oxidocyclization and not
through cannabidiolic acid as was assumed before) has been reported by
Shoyama’s group [35]. They showed that the presence of a carboxyl group in
the substrate is essential for enzymatic cyclization of the terpene moiety. This
finding may explain the presence of THC and THC acids in certain cannabis
strains (e.g. South African) that do not contain cannabidiol or its acid [36–38].
In a series of elegant publications Shoyama’s group identified an enzyme
forming cannabichromenic acid and showed that this acid is formed directly
from cannabigerolic acid [39, 40].
It is possible that some of the natural neutral cannabinoids are artifacts
formed through decarboxylation, photochemical cyclization (cannabicyclol),
oxidation (cannabielsoic acid) or isomerization (8-THC and 8-THC acid) of
other constituents.
Endogenous cannabinoids
The discovery of a high-affinity, stereoselective and pharmacologically dis-
tinct cannabinoid receptor in a rat brain tissue [41] led to a search for natural
endogenous ligands in the brain, which bind to this cannabinoid receptor. We
assumed that the cannabinoid receptor in the brain is not present just to bind a
plant constituent, but to be activated by specific endogenous ligands. Our
approach involved first the synthesis of a potent labeled agonist (HU-243),
Cannabinoid chemistry: an overview 25
which made possible a sensitive bioassay. This compound is the most active
cannabinoid known so far [65]. In a standard bioassay we expected that
endogenous compounds with cannabinoid activity would displace tritiated
HU-243 bound to the central cannabinoid receptor (CB1).
Rat brains are too small and hence we started our isolations with porcine
brains. After nearly 2 years of tedious work, which involved numerous chro-
matographic separations, we isolated from brain an endogenous compound that
binds to the cannabinoid receptor with about the same potency as 9-THC. This
endogenous ligand was named anandamide [42], a name derived from the
Sanskrit word for bliss, ananda. When administered intraperitoneally to mice it
caused reduced activity in an immobility test and in open field tests, and pro-
duced hypothermia and analgesia, a tetrad of assays typical of the psychotropic
cannabinoids [43]. Later we isolated two additional, apparently minor, endo-
genous cannabinoids, homo-γ-linoleoylethanolamide and 7,10,13,16-docosa-
tetraenoylethanolamide [44].
The existence of a peripheral cannabinoid receptor (CB2) led to the search
for a ligand to this receptor. We isolated from canine gut another arachidonic
acid derivative, 2-arachidonoyl glycerol (2-AG) [45]. At around the same time
this compound was detected in brain [46] (see Fig. 2).
Hanusˇ et al. reported a third, ether-type endocannabinoid, 2-arachidonyl
glyceryl ether (noladin ether), isolated from porcine brain [47]. It binds to the
CB1cannabinoid receptor (Ki= 21.2 ± 0.5 nM) and causes sedation, hypother-
mia, intestinal immobility and mild antinociception in mice. It binds very
weakly to the CB2receptor. The presence of this endocannabinoid in brain has
been questioned [48]. However as this type of natural glycerol derivative (an
ether group on the 2-position) is unusual, we have repeated its isolation with
an identical result (unpublished observations).
In the course of the development of a bioanalytical method to assay anan-
damide in brain and peripheral tissues, a compound with the same molecular
weight as anandamide, but with a shorter retention time, was identified as
O-arachidonoyl ethanolamine (arachidonic acid and ethanolamine joined by
an ester linkage). This compound was named virodhamine [49].
On the basis of previous structure–activity relationship studies and on the
existence in body tissues of biosynthetic precursors, Huang et al. assumed that
N-arachidonoyl-dopamine (NADA) may exist as an endogenous
“capsaicin-like” cannabinoid in mammalian nervous tissues and may possibly
bind to the vanilloid receptor VR1 [50]. They found that NADA is indeed a
natural endocannabinoid in nervous tissues, with high concentrations found in
the striatum, hippocampus and cerebellum and lower concentrations in the
dorsal root ganglion. NADA binds to the cannabinoid receptors with a 40-fold
greater selectivity for the CB1(Ki= 250 ± 130 nM) than the CB2receptor
[50–52].
One of the typical endocannabinoid effects is pain suppression. Some
endogenous fatty acid derivatives (palmitoylethanolamide, oleamide), which
do not bind to CB1or CB2, either enhance this effect (the so-called entourage
26 L.O. Hanusˇ and R. Mechoulam
effect) or actually show activity by themselves, presumably by binding to
as-yet unidentified cannabinoid receptors [53].
Shortly after the isolation of anandamide, its biosynthesis, metabolism and
degradation in the body were studied [54, 55].
Synthetic cannabinoid receptors agonists/antagonists
In the late 1970s Pfizer initiated a cannabinoid project aimed at novel anal-
gesic compounds. Numerous active bicyclic compounds were synthesized.
The compound chosen for clinical evaluation was CP-55,940 [56, 57]. This
compound is more potent than morphine and is at least 200-fold more potent
than its enantiomer [55]. Structural and stereochemical evaluations led to high-
ly active analogs [58]. The cannabinoid-type side effects observed with this
group of “non-classical” cannabinoids led to the termination of the project
[58]. However, these compounds helped advance the cannabinoid field as they
Cannabinoid chemistry: an overview 27
Figure 2. The main endocannabinoids
were the first cannabinoids that were widely used as labeled ligands. Indeed,
in 1988 Allyn Howlett’s group used tritium-labeled CP-55,940 for the identi-
fication of the first cannabinoid receptor [59]. [3H]CP-55,940 is now an impor-
tant tool in the study of cannabinoid receptors [60].
The need for stereospecific cannabinoid ligands led to further syntheses of
enantiomers with essentially absolute stereochemical purity. This endevour
culminated by the preparation of very potent cannabimimetic compounds [61].
Replacement of the n-pentyl side chain with a 1,1-dimethyl heptyl side chain in
one of the major active primary metabolites of 8-THC, 11-hydroxy-8-THC,
led to the highly active ligand 11-hydroxy-8-THC-dimethylheptyl, or HU-210.
The psychotropically inactive enantiomer, HU-211, is however analgesic,
antiemetic and is at present being evaluated as an anti-trauma agent. Both com-
pounds were synthesized with very high enantiomeric purity (99.8%) [62]. The
high degree of enantioselectivity and potency of HU-210 was demonstrated in
mice, dogs and pigeons [63, 64].
The synthetic HU-210 was used to prepare a novel probe for the cannabi-
noid receptor. Hydrogenation of this compound yielded two epimers of
5'-(1,1-dimethylheptyl)-7-hydroxyhexahydrocannabinol [65]. The equatorial
epimer (designated HU-243) binds to the cannabinoid receptor with a KDvalue
of 45 pM, and is the most potent CB1agonist described so far. Tritiated
HU-243 was used as a novel probe for the cannabinoid receptor.
An effort to find new synthetic cannabinoids with increased therapeutic
activity and few adverse side effects led to the preparation of ajulemic acid
(HU-239), an analgetic and anti-inflammatory cannabinoid [66, 67]. This com-
pound has anti-tumor effects in mice [68], binds to the peroxisome prolifera-
tor-activated receptor γ(PPARγ), a pharmacologically important member of
the nuclear receptor superfamily [69], and induces apoptosis in human T lym-
phocytes [70]. However, it binds to CB1and has activity at the level of THC in
the tetrad assay in mice [71].
A group at the Sterling pharmaceutical company prepared analogs of the
anti-inflammatory drug pravadoline, an aminoalkylindole. To their surprise
28 L.O. Hanusˇ and R. Mechoulam
Structure 1
they discovered that these compounds acted not only as cyclooxygenase
inhibitors, but also as cannabinoid agonists [72]. In vitro structure–activity
relationship studies of these compounds led to numerous new compounds with
cannabinoid receptor agonist activity [73, 74]. The best-known compound in
this series is the conformationally restricted derivative WIN-55212-2 [75]. A
binding assay in rat cerebellum membranes has been developed. It makes use
of the stereospecific radioligand [3H](R)-(+)-WIN-55212-2.
The first potent and selective antagonist of the central cannabinoid receptor
(CB1), SR-141716A, was reported in 1994 by a group at Sanofi [76]. This
compound is not active on the peripheral cannabinoid receptor (CB2) and has
rapidly become a new tool in the study of cannabinoid receptor mechanisms
and in research on new therapeutic agents. Another novel CB1antagonist,
LY320135, which is not as selective as the previous one, was reported soon
Cannabinoid chemistry: an overview 29
Structure 2
Structure 3
thereafter. This substituted benzofuran reverses anandamide-mediated adeny-
late cyclase inhibition and also blocks WIN-55212-2-mediated inhibition of
N-type calcium channels [77].
The Sanofi group also described the first potent and selective antagonist of
the peripheral cannabinoid receptor (CB2), SR-144528 [78], and like the
above-mentioned CB1antagonist, it soon became a major tool in cannabinoid
research [79].
Our group reported the preparation of a CB2-selective ligand, HU-308 [80],
which is now being investigated as an anti-inflammatory drug by Pharmos, a
pharmaceutical firm. It shows no central nervous system effects due to its
essential lack of affinity for the CB1receptor. In HU-308 both phenolic groups
are blocked as methyl ethers. This is in contrast to cannabinoid CB1agonists
in which at least one of the phenolic groups has to be free.
Traumatic brain injury is a major cause of mortality and morbidity. There is
no effective drug to treat brain-injured patients. We found that on closed head
injury the amounts of 2-AG produced by the brain are increased 10-fold, and
that this endocannabinoid apparently has a neuroprotective role, as adminis-
tration of 2-AG to mice with head trauma reduces both the neurological dam-
age and the edema [81]. Numerous other groups have recorded work on vari-
30 L.O. Hanusˇ and R. Mechoulam
Structure 4
Structure 5
ous aspects of cannabinoids as neuroprotective agents (see Chapter by
Fernández-Ruiz et al. in this volume). On this basis a structurally novel, high-
ly potent CB1/CB2cannabinoid receptor agonist, BAY 38-7271, was prepared
and shown to have pronounced neuroprotective efficacy in a rat model of trau-
matic brain injury [82–85].
Pharmos have developed a cannabinoid, PRS 211,096, that binds to the
peripheral cannabinoid receptor and which is being assayed for treatment of
multiple sclerosis [86].
Cannabinoid chemistry: an overview 31
Structure 7
Structure 6
Structure 8
(R)-Methanandamide (AM-356) is a chiral analog of the endocannabinoid
ligand anandamide, It is more stable than anandamide to hydrolysis by fatty
acid amide hydrolase (FAAH), as the methyl group adjacent to the amide moi-
ety apparently interferes with the enzyme. It has a Kivalue of 20 ± 1.6 nM for
the CB1receptor [87]. The Kivalue for binding to the CB2receptor from
mouse spleen is 815 nM [88]. Thus (R)-methanandamide has a high selectivi-
ty for the CB1receptor.
6-Iodo-pravadofine (AM-630), an aminoalkylindole, attenuates the ability
of a number of cannabinoids to inhibit electrically evoked twitches of vas def-
erens isolated from mouse [89]. AM-630 behaves as a competitive antagonist
of cannabinoid receptor agonists in the guinea-pig brain [90]. AM-630 also
antagonizes the ability of the cannabinoid agonist WIN-55212-2 to stimulate
guanosine-5'-O-(3-[35S]thio)triphosphate ([35S]GTPγS) binding in mouse
brain membrane preparations [91].
Gatley et al. [92] have developed a novel radioligand, [123I]AM-281, struc-
turally related to the CB1-selective antagonist SR-141716A, that is suitable for
in vivo studies of the central cannabinoid receptor and for imaging this recep-
tor in the living human brain [92].
32 L.O. Hanusˇ and R. Mechoulam
Structure 9
Scientists at the University of Connecticut have synthesized and studied a
series of aminoalkylindoles as selective CB2agonists. The compounds are stat-
ed to be useful for the treatment of pain, glaucoma, multiple sclerosis and other
diseases and disorders. Compound AM-1241 has a high affinity for the CB2
receptor in a mouse spleen preparation (Ki= 3.4 ± 0.5 nM), with good selectiv-
ity versus the CB1receptor in a rat brain preparation (Ki= 280 ± 41 nM). This
compound has recently been found to inhibit neuropathic pain in rodents [93].
AM-2233, a novel aminoalkylindole CB1agonist, was found to have a
greater potency than WIN-55212-2 in assays in vitro, but has a similar poten-
cy to it in a mouse locomotor assay. It was suggested that its behavioral effects
could have been mediated, in part, via an action on another receptor type in
addition to the CB1receptor. AM-2233 represents the first agonist CB1 recep-
tor ligand (Ki= 0.4 nM) with potential as an in vivo imaging agent for this
receptor [94, 95]. Stoit et al. [96] have reported the syntheses and biological
activities of potent pyrazole-based tricyclic CB1receptor antagonists. One can
find additional information on cannabinoid receptor agonists and antagonists
in Barth’s review [97].
Gallant et al. [98] have described two indole-derived compounds (see struc-
tures below), with binding potency for the human peripheral cannabinoid
receptor (CB2) in the nanomolar region, They are highly selective.
A new series of rigid 1-aryl-1,4-dihydroindeno[1, 2-c]pyrazole-3-carbox-
amides was recently designed [99]. Seven of the new compounds displayed
very high in vitro CB2-binding affinities. Four compounds showed very high
selectivity for the CB2receptor.
Cannabinoid structure–activity relationship data have indicated that the
cannabinoid side chain and the phenolic hydroxyl are key elements in CB1
receptor recognition. To test this hypothesis, the 1-deoxy analog, JWH-051, of
the very potent cannabinoid 11-hydroxy-8-THC-dimethylheptyl (HU-210)
was prepared and the affinity of this compound for the CB1receptor was deter-
mined [100]. Contrary to expectations, this 1-deoxy analog still had high affin-
ity for the CB1receptor (Ki= 1.2 ± 0.1 nM) and even greater affinity for the
Cannabinoid chemistry: an overview 33
Structure 10
CB2receptor (Ki= 0.032 ± 0.19 nM). On the basis of these data, it is apparent
that a phenolic hydroxyl group is not essential for cannabinoid activity.
To obtain selective ligands for the CB2and to explore the structure–activi-
ty relationship of the 1-deoxy-cannabinoids, the same research group
described the synthesis and pharmacology of 15 1-deoxy-8-THC analogues
[101]. Five of these analogues had high affinity (Ki20 nM) for the CB2
receptor. Four of them also had low affinity for the CB1receptor (Ki295 nM).
3-(1',1'-Dimethylbutyl)-1-deoxy-8-THC (JWH-133) had very high affinity
for the CB2receptor (Ki= 3.4 ± 1.0 nM) and low affinity for the CB1receptor
(Ki= 677 ± 132 nM).
In view of the importance of the CB2receptor, three series of CB2-selective
cannabinoid receptor ligands, 1-methoxy-, 1-deoxy-11-hydroxy- and
11-hydroxy-1-methoxy-8-THCs, were designed [102]. All of these com-
pounds have greater affinity for the CB2receptor than for the CB1receptor;
however, only 1-methoxy-3-(1',1'-dimethylhexyl)-8-THC (JWH-229) had
essentially no affinity for the CB1receptor (Ki= 3134 ± 110 nM) with high
affinity for CB2(Ki= 18 ± 2 nM).
34 L.O. Hanusˇ and R. Mechoulam
Structure 12
Structure 11
Recently the discovery of a further class of diarylpyrazolines with high
potency and selectivity for the CB1receptor was described [103]. These com-
pounds were found to be CB1antagonists. SLV319 was found to be a potent
CB1antagonist (Ki= 7.8 nM) close to that of the Sanofi compound
SR-141716A, with more than 1000-fold selectivity against CB2.
Additional synthetic compounds that bind to the CB1and/or CB2receptors
have been mentioned in patents. These were recently reviewed by Hertzog
[104].
Cannabinoid chemistry: an overview 35
Structure 13
Structure 14
Novartis AG has recently filed a patent application on a series of quinazo-
lines as cannabinoid agonists useful for the treatment of pain, osteoarthritis,
rheumatoid arthritis and glaucoma, among other indications [105]. Compound
1binds to both CB1(Ki= 34 nM) and CB2(Ki= 11 nM). The patent applica-
tion refers to the compound as having CB2agonist activity. Additionally, this
compound has been shown to be active in a rodent neuropathic pain model
when administered at an oral dose of 0.5 mg/kg.
The University of Connecticut has disclosed a series of indazole derivatives
that have been found to act as agonists of cannabinoid receptors [106]. The
compounds exhibit a range of selectivities for CB2over CB1. Compound 2,for
instance, exhibited Kivalues of 2.28 and 0.309 nM for the CB1and CB2recep-
tors, respectively. This compound produced dose-dependent anti-nociception
to thermal stimulus in rats. The compound reduced locomotor activity in rats
after intravenous administration, an effect attributed to activation of the CB1
receptor.
A series of aromatic CB2agonists has been disclosed by the Schering-Plough
Research Institute [107, 108]. The compounds are reported to have anti-inflam-
36 L.O. Hanusˇ and R. Mechoulam
Structure 15
Structure 16
matory and immunomodulatory activities, and to be active in cutaneous T cell
lymphoma, diabetes mellitus and other indications. Compound 3is stated to
bind to CB2with a Kivalue in the range 0.1–10 nM.
Researchers at AstraZeneca have disclosed a series of benzimidazoles and
azabenzimidazoles to be CB2agonists [109]. The compounds are described as
useful in the treatment of pain, cancer, multiple sclerosis, Parkinson’s disease,
Huntington’s chorea, transplant rejection and Alzheimer’s disease. Cannabinoid
receptor selectivity data are provided for some of the new compounds. For
instance, compound 4binds to CB2(Ki= 3.1 nM) with much greater affinity
than to CB1(Ki= 2.8 µM). No in vivo data are provided for the compounds.
The University of Connecticut has disclosed a series of biphenyls as
cannabinoid modulators [110]. These non-classical cannabinoids are described
as useful for the treatment of peripheral pain, neuropathy, neurodegenerative
diseases and other indications. Several of the compounds were found to bind
selectively to the CB2receptor. For instance, compound 5binds to CB2with a
Kivalue of 0.8 nM and to CB1with a Kivalue of 241 nM.
Cannabinoid chemistry: an overview 37
Structure 17
Structure 18
The Virginia Commonwealth University has filed a