Compositions comprising cannabinoids for treatment of nausea, vomiting,
emesis, motion sickness or like conditions
United States Patent: 8,034,843
Issued: October 11, 2011
Inventors: Whittle; Brian (Hornsea,
GB), Javid; Farideh Afshin (Yorkshire, GB)
Assignee: GW Pharma Limited
(Salisbury, Wiltshire, GB)
Appl. No.: 10/502,822
Filed: February 3, 2003
PCT Filed: February 03,
PCT No.: PCT/GB03/00451
371(c)(1),(2),(4) Date: March
PCT Pub. No.:
PCT Pub. Date: August 07,
Pharm Bus Intell
& Healthcare Studies
Cannabinoids, in particular CBD and CBDA
and their acid derivatives are provided for use as an active
pharmaceutical substance in the treatment of nausea, vomiting, emesis,
motion sickness. In particular extracts of cannabis plants are presented
which are rich in these substances and suitable for pharmaceutical use.
Description of the
This application is a national stage filing under 35 U.S.C. .sctn.371 of
PCT International application PCT/GB2003/000451, filed Feb. 3, 2003, which
was published under PCT Article 21(2) in English.
Functional vomiting is the forceful expulsion of gastric contents produced
by involuntary contraction of the abdominal musculature. This occurs when
the gastric fundus and lower oesophageal sphincter are relaxed. Functional
vomiting may be accompanied by nausea (an unpleasant feeling that vomiting
is about to occur). Nausea is associated with altered physiological
activity, including gastric hypomotility, and increased parasympathetic
tone. Nausea may precede and accompany vomiting. They represent the
patient's awareness of afferent stimuli to the medullary vomiting centre.
Physiological vomiting is a functional condition that occurs in response
to a number of factors affecting the vomiting centre. It may also be
triggered by peripheral factors such as ingestion of toxins, disturbance
of the vestibular system, peritoneal inflammation and bowel obstruction.
It may also occur in disorders of delayed gastric emptying as, for
example, in diabetes and idiopathic gastroparesis.
Psychogenic vomiting may be self-induced or may occur involuntarily in
situations that are anxiety inducing, threatening or in some way regarded
as distasteful by the subject. It is also possible that psychological
factors leading to vomiting are culturally determined (for example, eating
exotic food may be considered repulsive in the subject's own cultural
group). Vomiting may also express hostility as when children vomit during
a temper tantrum or in certain conversion disorders.
Nausea and vomiting may also be induced by cytotoxic chemotherapy and
radiotherapy. Post-operatively, patients may also vomit and experience
nausea, which may be attributable to the anaesthetic and analgesic agents
frequently administered concurrently.
There are therefore peripheral and central mechanisms which are involved
in the expression of nausea and frank vomiting. Existing therapies are
available for the treatment of these conditions but they have limitations,
and there is a need for alternative treatments, particularly where these
can exert their effect through a central nervous mechanism.
Investigation of a number of agents in a conscious animal model in which
motion sickness is induced has confirmed that extracts of cannabis have an
anti-emetic effect. Conventionally, the anti-emetic effect of cannabis has
been ascribed to delta.sup.9-tetrahydrocannabinol (.DELTA..sup.9-THC). The
use of a whole animal, conscious model to explore this effect, and the
availability of cannabis extracts containing predominantly one cannabinoid
or another have allowed for more detailed analysis of the contribution of
Surprisingly, it has been found that the anti-emetic effect, in a model of
motion sickness in Suncus murinus (the Asian musk (house) shrew), is
greatest in high cannabidiol (CBD)(and/or its acid form CBDA) containing
extracts rather than in high tetrahydrocannabinol (THC) (and/or its acid
form THCA) containing extracts (greater than 50% CBD more preferably
greater than 80% most preferably greater than 90% relative to other
It is hypothesised that the results will extend to the propyl variant of
CBD, namely CBDV and its acid form CBDVA.
More particularly, the results were noted in extracts in which the
cannabinoids were predominantly in their acid form since the extracts were
prepared by a methanolic extraction and had not been subjected to a
decarboxylation step by, for example, heating. It is possible therefore
that the therapeutic effects noted are due to the acid form of the
cannabinoids. If it is the acid form of the cannabinoid that is
responsible for the observed therapeutic effect this is particularly
surprising since the acid forms of cannabinoids have not hitherto been
known to exhibit therapeutic effects.
According to a first aspect of the present invention there is provided a
cannabis extract, rich in CBD and/or CBDA and/or the propyl variants CBDV
and/or CBDVA, for use in the manufacture of a medicament for the treatment
of nausea, vomiting, emesis, motion sickness or like conditions.
By rich is meant greater than 2% w/w of CBD and/or CBDA and/or the propyl
variants CBDV and/or CBDVA, more particularly greater than 5%, more
preferably still greater than 7%.
According to another aspect of the present invention there is provided the
use of CBD and/or CBDV in the manufacture of a medicament for the
treatment of nausea, vomiting, emesis, motion sickness or like conditions.
According to another aspect of the present invention there is provided a
cannabinoid acid for use as an active pharmaceutical substance.
According to yet another aspect of the present invention there is provided
CBDA or CBDVA for use as an active pharmaceutical substance.
Preferably the active pharmaceutical substance is present as a medicament
for the treatment of nausea, vomiting, emesis, motion sickness or like
In one embodiment the CBD and/or CBDA and/or CBDV and/or CBDVA are present
with other cannabinoids as a mixture derived from a plant extract (CMBE,
cannabis based medicinal extract).
Plant extracts are preferred as, in addition to one or more cannabinoids,
they will contain other chemical entities that may provide a beneficial
effect either in their own right or in combination with the one or more
cannabinoids. Such other chemicals include, for example, volatile oils
e.g. terpene or carotene rich volatiles. Known terpenes present in the
CMBE include C.sub.10 terpenes, e.g. mycerene, and pinenes and C.sub.15
terpenes e.g. caryophyllene.
Preferably the CBD or CBDV and/or the acids thereof are present with THC
or THCV and/or the acids thereof.
Alternatively the CBD or CBDV and/or the acids thereof are substantially
free (less than 10%, more prferably less than 5% and most preferably less
than 2% relative to other cannabinoids present) from other cannabinoids.
In another embodiment the CBD or CBDV and/or the acids thereof are
The invention also extends to methods of treating nausea, vomiting,
emesis, motion sickness or like conditions with CBD or CBDV and/or the
acids thereof, either as the sole active ingredient or in mixtures as
Whilst the observation has been made on an extract administered
intraperitoneally, the skilled man will appreciate that a medicament can
be prepared for administration by any suitable means. These include, but
are not limited to, solids, semi solids, e.g. gels, liquids, sprays,
aerosols, inhalers, vapourisers, enemas, rectal suppositories and the
like. The route of administration need not be intraperitoneally but could
be oral, buccal, sublingual, or by any other suitable route e.g. the
respiratory tract, nasal tract and distal rectum.
A "plant extract" is an extract from a plant material as defined in the
Guidance for Industry Botanical Drug Products Draft Guidance, August 2000,
US Department of Health and Human Services, Food and Drug Administration
Centre for Drug Evaluation and Research.
"Plant material" is defined as a plant or plant part (e.g. bark, wood,
leaves, stems, roots, flowers, fruits, seeds, berries or parts thereof) as
well as exudates.
The term "Cannabis plant(s)" encompasses wild type Cannabis sativa and
also variants thereof, including cannabis chemovars which naturally
contain different amounts of the individual cannabinoids, Cannabis sativa
subspecies indica including the variants var. indica and var.
kafiristanica, Cannabis indica and also plants which are the result of
genetic crosses, self-crosses or hybrids thereof. The term "Cannabis plant
material" is to be interpreted accordingly as encompassing plant material
derived from one or more cannabis plants. For the avoidance of doubt it is
hereby stated that "cannabis plant material" includes dried cannabis
In the context of this application the terms "cannabis extract" or
"extract from a cannabis plant", which are used interchangeably encompass
"Botanical Drug Substances (BDS)" derived from cannabis plant material. A
Botanical Drug Substance is defined in the Guidance for Industry Botanical
Drug Products Draft Guidance, August 2000, US Department of Health and
Human Services, Food and Drug Administration Centre for Drug Evaluation
and Research as: "A drug substance derived from one or more plants, algae,
or macroscopic fungi. It is prepared from botanical raw materials by one
or more of the following processes: pulverisation, decoction, expression,
aqueous extraction, ethanolic extraction, or other similar processes." A
botanical drug substance does not include a highly purified or chemically
modified substance derived from natural sources. Thus, in the case of
cannabis, "botanical drug substances" derived from cannabis plants do not
include highly purified, Pharmacopoeial grade cannabinoids.
"Botanical drug substances" derived from cannabis plants include primary
extracts prepared by such processes as, for example, maceration,
percolation, extraction with solvents such as C1 to C5 alcohols (e.g.
ethanol), Norflurane (HFA134a), HFA227 and liquid carbon dioxide under
pressure. The primary extract may be further purified for example by
supercritical or subcritical extraction, vaporisation and chromatography.
When solvents such as those listed above are used, the resultant extract
contains non-specific lipid-soluble material. This can be removed by a
variety of processes including "winterisation", which involves chilling to
-20.degree. C. followed by filtration to remove waxy ballast, extraction
with liquid carbon dioxide and by distillation.
Preferred "cannabis extracts" include those which are obtainable by using
any of the methods or processes specifically disclosed herein for
preparing extracts from cannabis plant material. The extracts are
preferably substantially free of waxes and other non-specific lipid
soluble material but preferably contain substantially all of the
cannabinoids naturally present in the plant, most preferably in
substantially the same ratios in which they occur in the intact cannabis
Botanical drug substances are formulated into "Botanical Drug Products"
which are defined in the Guidance for Industry Botanical Drug Products
Draft Guidance, August 2000, US Department of Health and Human Services,
Food and Drug Administration Centre for Drug Evaluation and Research as:
"A botanical product that is intended for use as a drug; a drug product
that is prepared from a botanical drug substance."
"Cannabinoids" may be highly purified, Pharmacopoeial Grade substances and
may be obtained by purification from a natural source or via synthetic
means. The cannabinoids will include, but are not limited to,
tetrahydrocannabinoids, their precursors, alkyl (particularly propyl)
analogues, cannabidiols, their precursors, alkyl (particularly propyl)
analogues, and cannabinol.
In preferred embodiments of the invention the formulations comprise
extracts of one or more varieties of whole Cannabis plants, particularly
Cannabis sativa, Cannabis indica or plants which are the result of genetic
crosses, self-crosses or hybrids thereof. The precise cannabinoid content
of any particular cannabis variety may be qualitatively and quantitatively
determined using methods well known to those skilled in the art, such as
TLC or HPLC. Thus, one may chose a Cannabis variety from which to prepare
an extract which will produce the desired ratio of CBD or CBDV to THC or
THCV. Alternatively, extracts from two of more different varieties may be
mixed or blended to produce a material with the preferred cannabinoid
ratio for formulating into a pharmaceutical formulation.
The preparation of convenient ratios of CBD, CBDV, CBDA and CBDVA-containing
medicines is made possible by the cultivation of specific chemovars of
cannabis. These chemovars (plants distinguished by the cannabinoids
produced, rather than the morphological characteristics of the plant) can
be bred by a variety of plant breeding techniques which will be familiar
to a person skilled in the art. Suitable methods are given in Example 3.
Propagation of the plants by cuttings for production material ensures that
the genotype is fixed and that each crop of plants contains the
cannabinoids in substantially the same ratio.
Horticulturally, it is convenient to grow chemovars producing e.g. CBD and
CBDV as the predominant cannabinoid from cuttings. This ensures that the
genotype in each crop is identical and the qualitative formulation (the
proportion of each cannabinoid in the biomass) is the same. From these
chemovars, extracts can be prepared by the similar method of extraction.
Convenient methods of preparing primary extracts include maceration,
percolation, extraction with solvents such as C1 to C5 alcohols (ethanol),
Norflurane (HFA134a), HFA227 and liquid carbon dioxide under pressure. The
primary extract may be further purified for example by supercritical or
subcritical extraction, vaporisation and chromatography. When solvents
such as those listed above are used, the resultant extract contains
non-specific lipid-soluble material. This can be removed by a variety of
processes including chilling to -20.degree. C. followed by filtration to
remove waxy ballast, extraction with liquid carbon dioxide and by
distillation. Preferred plant cultivation and extract preparation methods
are shown in the Examples. The resulting extract is suitable for
incorporation into pharmaceutical preparations.
A detailed examination of the pharmacological differences between CBD and
THC has revealed significant differences in these compounds and
consequently the finding that CBD and/or its acid CBDA appear to be
responsible for the therapeutic effects noted was surprising. THC is bound
with high avidity to CB1 and CB2 receptors in cerebral cortex and other
sites; CBD is relatively inactive against CB1 receptors and appears to
have non-cannabinoid receptor pharmacological actions in the central
nervous system. Without prejudice to the teaching of the invention, it is
possible that the anti-emetic effect of CBD and/or its acid CBDA is
mediated via a non-cannabinergic mechanism.
Table 1 (see Original Patent) illustrates some of the differences between
Whilst it is known that THC can be used to control nausea and vomiting
pre-operatively the effect of other cannabinoids or combinations or the
effect of the acid forms present in, for example, plant extracts was not
The applicants studied the effect of other cannabinoids as cannabis
extracts, and particularly extracts containing predominantly CBD or its
acid form CBDA in Suncus murinus and in which an emetic response can be
induced by a motion stimulus. Compounds which are effective in this test
have therapeutic benefit in the treatment of motion-induced nausea and
vomiting, and also these conditions when induced by other pathways in the
peripheral and central nervous systems.
The applicant has determined that, for example, extracts in which the
content of CBD and/or CBDA is 2-20% w/w, and the content of THC and or
THCA is 0.1-2% w/w are particularly beneficial.
Claim 1 of 16 Claims
1. A method of treating motion sickness
in a mammal comprising administering a pharmaceutically acceptable amount
of, or an extract consisting essentially of a pharmaceutically acceptable
amount of, CBD and/or CBDA and/or the propyl variants CBDV and/or CBDVA,
wherein the amount of CBD and/or CBDA and/or the propyl variants CBDV
and/or CBDVA is greater than 50% of the total cannabinoid content, wherein
the CBDA, and/or CBDVA and/or CBD and/or CBDV is/are present as a cannabis
extract, and wherein the cannabis extract contains less than 10% (w/w) of
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