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Cannabinoids for control of chemotherapy induced
nausea and vomiting: quantitative systematic review
Martin R Tramèr, Dawn Carroll, Fiona A Campbell, D John M Reynolds, R Andrew Moore,
Henry J McQuay
Abstract
Objective To quantify the antiemetic efficacy and
adverse effects of cannabis used for sickness induced
by chemotherapy.
Design Systematic review.
Data sources Systematic search (Medline, Embase,
Cochrane library, bibliographies), any language, to
August 2000.
Studies 30 randomised comparisons of cannabis with
placebo or antiemetics from which dichotomous data
on efficacy and harm were available (1366 patients).
Oral nabilone, oral dronabinol
(tetrahydrocannabinol), and intramuscular
levonantradol were tested. No cannabis was smoked.
Follow up lasted 24 hours.
Results Cannabinoids were more effective antiemetics
than prochlorperazine, metoclopramide,
chlorpromazine, thiethylperazine, haloperidol,
domperidone, or alizapride: relative risk 1.38 (95%
confidence interval 1.18 to 1.62), number needed to
treat 6 for complete control of nausea; 1.28 (1.08 to
1.51), NNT 8 for complete control of vomiting.
Cannabinoids were not more effective in patients
receiving very low or very high emetogenic
chemotherapy. In crossover trials, patients preferred
cannabinoids for future chemotherapy cycles: 2.39
(2.05 to 2.78), NNT 3. Some potentially beneficial side
effects occurred more often with cannabinoids: “high”
10.6 (6.86 to 16.5), NNT 3; sedation or drowsiness
1.66 (1.46 to 1.89), NNT 5; euphoria 12.5 (3.00 to
52.1), NNT 7. Harmful side effects also occurred more
often with cannabinoids: dizziness 2.97 (2.31 to 3.83),
NNT 3; dysphoria or depression 8.06 (3.38 to 19.2),
NNT 8; hallucinations 6.10 (2.41 to 15.4), NNT 17;
paranoia 8.58 (6.38 to 11.5), NNT 20; and arterial
hypotension 2.23 (1.75 to 2.83), NNT 7. Patients given
cannabinoids were more likely to withdraw due to
side effects 4.67 (3.07 to 7.09), NNT 11.
Conclusions In selected patients, the cannabinoids
tested in these trials may be useful as mood
enhancing adjuvants for controlling chemotherapy
related sickness. Potentially serious adverse effects,
even when taken short term orally or intramuscularly,
are likely to limit their widespread use.
Introduction
Sections of the medical establishment have pleaded for
legalisation of cannabis (marijuana) for medical use.
12
Interest in cannabis and its active constituents,
cannabinoids, as therapeutic agents has increased
recently.
3
Dronabinol (Ä
9
-tetrahydrocannabinol, one of
the main ingredients in cannabis) and the synthetic
cannabinoid compound nabilone are available by pre-
scription in some countries.
A Medline search using the terms cannabis,
cannabinoids, marijuana, and marijuana smoking
found 6059 articles from 1975 to 1996; most were on
the antiemetic properties of cannabis.
4
Surveys of
oncologists’ choices of treatment for emesis caused by
chemotherapy came to divergent results.
4
In one, 63%
of responding oncologists agreed with the statement
affirming the efficacy of cannabis for treatment of
emesis.
5
In another, oncologists ranked dronabinol or
smoked cannabis only ninth out of nine choices for
mild nausea, and sixth out of nine for severe nausea.
6
An early literature review on cannabinoids and emesis
concluded that orally administered dronabinol repre-
sented a major advance in antiemetic therapy.
7
We searched systematically for the strongest
evidence of efficacy and harm of cannabis in patients
having chemotherapy. We examined whether there is
any evidence that cannabis is antiemetic when given
concomitantly with emetogenic chemotherapy, how
well cannabis works in this setting compared with pla-
cebo or conventional antiemetics, the evidence for a
dose-response relation, and the profile of adverse
effects.
Methods
Search strategy
We searched systematically for randomised controlled
comparisons of the antiemetic efficacy of cannabis
(experimental intervention) with any antiemetic or
placebo (control) in chemotherapy. Two authors (DC
and MRT) searched independently, using different
search strategies, in Medline and Embase (last search,
10 August 2000). Free text key words used were
cannabinoids, cannabis, nabilone, tetrahydrocannabi-
nol, THC, marihuana, marijuana, levonantradol,
dronabinol, randomised, randomized, and human. We
also searched the Cochrane Library (issue 3, 2000). Ref-
Division
d’Anesthésiologie,
Département
Anesthésiologie,
Pharmacologie
Clinique et Soins
Intensif de
Chirurgie, Hôpitaux
Universitaires,
CH-1211 Genève
14, Switzerland
Martin R Tramèr
staff anaesthetist
Pain Research,
Nuffield
Department of
Anaesthetics,
Churchill, Oxford
Radcliffe Hospital,
Oxford OX3 7LJ
Dawn Carroll
senior research nurse
R Andrew Moore
consultant biochemist
Henry J McQuay
professor of pain relief
Pain Management
Centre, Undercroft,
South Block,
Queen’s Medical
Centre, Nottingham
NG7 2UH
Fiona A Campbell
consultant in
anaesthetics and pain
management
Department of
Clinical
Pharmacology,
Radcliffe Infirmary,
Oxford OX2 6HE
D John M Reynolds
consultant clinical
pharmacologist
Correspondence to:
M R Tramèr,
martin.tramer@
hcuge.ch
BMJ 2001;323:1–8
1BMJ VOLUME 323 7 JULY 2001 bmj.com
erence lists of retrieved reports and review articles
were checked. The search included data in any
language. Only full publications in peer reviewed jour-
nals were considered. Data from abstracts, letters, and
reports from other clinical settings (radiotherapy and
postoperative nausea and vomiting) were not consid-
ered. We did not contact authors or manufacturers.
Critical appraisal
All retrieved reports were checked for inclusion
criteria by one author (MRT). Those definitely not rel-
evant were excluded at this stage. All potentially
relevant reports were then read by all authors
independently to assess adequacy of randomisation
and blinding and description of withdrawals according
to the validated three item, five point Oxford score.
8
The maximum score of an included randomised
controlled trial was five and the minimum was one.
Authors met to reach a consensus.
Data extraction
From relevant reports we obtained information on
patients, dose of cannabis and control treatments,
chemotherapy regimens, and relevant end points. The
end point of primary interest was antiemetic efficacy.
Different end points for antiemetic efficacy were
reported. A “major response,” for instance, could be “no
more than two vomiting episodes” in one trial. A “partial
response” could be defined as “a reduction of 50% or
more in the duration or severity of nausea, and in the
number of vomiting episodes, compared with previous
courses of identical chemotherapy” in another trial.
Because of this inconsistency in definitions we extracted
only dichotomous data that came closest to complete
control (that is, absence) of nausea or vomiting in the
first 24 hours of chemotherapy. Some studies reported
incidence of nausea or vomiting per “treatment episode”
or per “treatment cycle” rather than per patient. These
data were not further analysed. The end point of
secondary interest was the number of patients who, after
completion of the trial, expressed preference for canna-
bis or control for future chemotherapy cycles. Data on
adverse effects were extracted when reported in
dichotomous form.
Quantitative analysis
As an estimate of the significance of a difference
between cannabis and control treatments we calculated
relative risks with 95% confidence intervals.
9
For com-
bined data, a fixed effect model was used because
heterogeneity tests lack sensitivity and because we
pooled data only when they were clinically homogene-
ous.
10
Clinical relevance of treatment effect was
expressed as numbers needed to treat and 95% confi-
dence intervals.
11
When the 95% confidence interval of
the relative risk excluded 1, the 95% confidence
interval for the number needed to treat ranged from a
positive limit to a negative limit, indicating that the
confidence interval includes infinity.
12
We looked for a dose-response relation in data from
clinically homogeneous subgroups. Such subgroups had
to report comparisons of different doses of one
cannabinoid (for instance, nabilone) with one compara-
tor (for instance, placebo), have a similar underlying
emetogenic risk (for instance, highly emetogenic
chemotherapy with cisplatin), and have a well defined
end point (for instance, complete control of vomiting).
Results
Included and excluded trials
We screened 198 reports; 51 were potentially relevant
randomised controlled trials. Twenty one were
subsequently excluded. Seven were not primarily stud-
ies of cannabinoids or had no relevant information.
13–19
Four were in other clinical settings (radiotherapy,
20 21
surgery,
22
or AIDS
23
). Five randomised trials (four
reports) were excluded because they reported emesis
data per chemotherapy cycle only and no other
relevant data could be extracted,
24
the data could not be
analysed,
25
the study design was unclear,
26
or the study
used only physiological measurements.
27
Finally, five
reports (or parts of them
28
) were duplicates
—
that is,
they contained data that had previously been
published as full reports.
29–32
We analysed data from 30 randomised controlled
trials published between 1975 and 1997 (table 1). In
the 30 trials, 1760 patients were randomised, but
subsequently 394 (22%) were excluded by the original
trialists. Thus, efficacy data from 1366 patients could be
analysed. The average trial size was 46 patients (range
8 to 139). The median quality score was 4 (range 1 to
4); 17 scored 4, eight 3, two 2, and three 1. The method
of blinding was adequate in 21 (70%) trials
—
for exam-
ple, identical tablets. Twenty five trials (83%) used a
crossover design. Since the results from crossover trials
were usually reported as if they had come from a par-
allel group trial we used the data accordingly. The
median number of chemotherapy cycles was two
(range one to six). Two trials were in children,
34 39
and
one in both children and adults.
58
All other trials were
in adults only. Various tumours were treated.
Chemotherapy was with a variety of cytotoxic
regimens with different emetogenic potencies (table 1).
Five trials reported on the number of patients with a
history of cannabis use.
35 36 58–60
In nine trials, all
patients were reported not to have used cannabis
previously.
33 34 39 41–43 46 49 51
In the other 16 trials, it was
unclear whether patients had used cannabis previously.
Three different cannabinoids were tested. Oral
nabilone was tested in 16 trials, oral dronabinol in 13,
and intramuscular levonantradol in one. Nabilone
doses ranged from 1 mg per 24 hours in children
34
to 8
mg per 24 hours in adults
40
; the commonest dose was 4
mg per 24 hours. Dronabinol regimens were most
often given according to body surface area in m
2
. Doses
ranged from 10 mg/m
2
twice daily
48
to 15 mg/m
2
six
times a day.
51
Inhaled cannabis was not tested in these
trials; however, in one trial comparing dronabinol with
placebo, cannabis cigarettes were used as a rescue
treatment in the event of a vomiting episode.
35
Commonest controls were prochlorperazine (12
trials), and placebo (10 trials). Other comparators were
metoclopramide (four), chlorpromazine (two), thiethyl-
perazine (one), haloperidol (one), domperidone (two),
and alizapride (one).
Antiemetic efficacy
In 14 trials, the observation period was clearly defined
as 24 hours. In the other trials, chemotherapy cycles
may have lasted longer, but it was unclear how long
observations continued for antiemetic efficacy. We had
to assume for all these trials that they reported
antiemetic efficacy per patient within 24 hours
—
that
is, acute antiemetic efficacy. In one trial, additional effi-
Papers
2 BMJ VOLUME 323 7 JULY 2001 bmj.com
cacy data were clearly defined for days 2 to 4
—
that is,
delayed antiemetic efficacy. This was not considered
for combined analyses. Twelve trials reported
antiemetic efficacy with various scoring systems, but
we could not extract dichotomous data on the number
of patients who were completely free of nausea or
vomiting.
28 37-40 42 43 47 48 50 56 57
The 10 trials that reported dichotomous data on
nausea or vomiting showed a wide variability in event
rates with both cannabinoids and controls (fig 1); the
event rate scatter suggested increased efficacy with
cannabinoids and relative homogeneity of the
data.
33-36 41 46 53-55
Complete control of nausea or vomiting
Across all trials, cannabinoids were more effective than
active comparators and placebo (table 2). Six to eight
patients needed to be treated with cannabinoids for
one to benefit who would have vomited or had nausea
had they all received a conventional antiemetic.
Table 1 Characteristics of studies included in systematic review of cannabinoids for chemotherapy induced nausea and vomiting
Setting Chemotherapy Active v control (No of patients)*
Oxford score
(random/blinding/
drop outs)
8
Adults, small cell bronchial
carcinoma
33
Doxorubicin, cyclophosphamide, methotrexate, vincristine,
etoposide
Nabilone 2 mg×2 (27) v prochlorperazine 10 mg×3 (30) 1/2/1
Children, age 3.5 to 17.8 years,
various paediatric malignancies
34
Doxorubicin, cyclophosphamide, fluorouracil, methotrexate,
vincristine, etoposide
Nabilone 1-4 mg (30) v prochlorperazine 5-20 mg (30) 1/2/1
Adults, osteogenic sarcoma
35
High dose methotrexate Dronabinol 10 mg/m
2
×4 (15) v placebo (15) 1/2/1
Adults, various tumours
36
Doxorubicin, cytoxane Dronabinol 10 mg/m
2
×4 (8) v placebo (8) 1/2/1
Adults, solid tumours
37
Cyclophosphamide, mustine Dronabinol 12 mg/m
2
×2 (35) v metoclopramide 4.5 mg/m
2
×1
intravenous (35) v thiethylperazine 6.6 mg/m
2
×3 (35)
1/2/0
Adults, adenocarcinoma of the ovary,
germ cell tumours
38
Doxorubicin, cisplatin, cyclophosphamide, methotrexate,
vincristine
Nabilone 1 mg×5 (37) v metoclopramide 1 mg/kg×5 intravenous (39) 1/2/0
Children <17 years, various tumours
39
Cisplatin, cyclophosphamide, vincristine Nabilone 1-3 mg (18) v domperidone 15-45 mg (18) 1/2/1
Adults, 15 to 74 years, various
tumours
40
Bleomycin, cisplatin, cyclophosphamide, vincristine Nabilone 2 mg×4 (80) v prochlorperazine 10 mg×4 (80) 1/2/1
Adults, 17 to 69 years, various
tumours
29
Bleomycin, cyclophosphamide, vincristine Nabilone 2 mg×2 (50) v placebo (50) 1/2/1
Adults, median age 61 years,
gastrointestinal tumours
41
Doxorubicin, fluorouracil, vincristine Dronabinol 15 mg×2 (38) v prochlorperazine 10 mg×2 (41) v placebo
(37)
1/2/1
Women, various gynaecological
tumours
42
Doxorubicin, cisplatin, cyclophosphamide Nabilone 1 mg×3 (18) v chlorpromazine 12.5 mg×1-2 intramuscular
(18)
1/2/1
Adults 39 to 73 years, various
tumours
43
High dose cisplatin Dronabinol 10 mg/m
2
×5 (15) v metoclopramide 10 mg/kg×5
intravenous (15)
1/2/1
Adults, median age 33 (range 15 to
74) years, various tumours
44
Bleomycin, cyclophosphamide, cisplatin, vincristine Nabilone 2 mg×3-4 (113) v prochlorperazine 10 mg×3-4 (113) 1/2/1
Adults, mean age 50 (range 17 to 80)
years, various tumours
45
Cisplatin, cyclophosphamide, fluorouracil, vincristine Levonantradol 0.5 mg×3 intramuscular (27) v levonantradol 0.75
mg×3 intramuscular (28) v levonantradol 1.0 mg×3 intramuscular
(26) v chlorpromazine 25 mg×3 intramuscular (27)
1/0/0
Adults aged 18 to 70 years, various
tumours
46
Doxorubicin, cisplatin, cyclophosphamide, vincristine Nabilone 2 mg×2 (18) v prochlorperazine 10 mg×2 (18) 1/0/1
Adults aged 20 to 58 years, various
tumours
47
Doxorubicin, cisplatin Nabilone 2 mg×2 (24) v placebo (24) 1/1/1
Adults, Hodgkin’s or non-Hodgkin’s
lymphoma
48
Vincristine, chlormethine Dronabinol 10 mg/m
2
×2 (11) v placebo (11) 1/2/0
Adults aged 20 to 68 years, various
tumours
49
Cisplatin (not high dose) Dronabinol 10 mg×4 (17) v prochlorperazine 10 mg×4(20) v
dronabinol 10 mg×4 plus prochlorperazine 10 mg×4(17)
1/1/1
Adults, 50th centile = 57 years,
various tumours
50
Doxorubicin, cisplatin, cyclophosphamide, fluorouracil,
methotrexate, vincristine
Nabilone 2 mg×2 (36) v placebo (36) 1/1/0
Adults aged 18 to 69 years, various
tumours, history of emesis due to
chemotherapy
51
Cyclophosphamide, doxorubicin, fluorouracil, vincristine Dronabinol 15 mg/m
2
×6 (36) v prochlorperazine 10 mg×6 (36) 1/0/0
Adults, mean age 41-45 years, various
tumours
52
Cisplatin, doxorubicin Dronabinol 10 mg×4 (average) (37) v haloperidol 2 mg×5 (average)
(36)
1/2/0
Adults aged 19 to 45 years, testicular
cancer
53
Doxorubicin, cisplatin Nabilone 2 mg×2 (20) v alizapride 150 mg×3 (20) 1/0/0
Adults aged 48 to 78 years, lung
cancer
54
Doxorubicin, cisplatin, cyclophosphamide, vincristine Nabilone 1 mg×2 (24) v prochlorperazine 7.5 mg×2 (24) 1/2/1
Adults aged 22 to 71 years, various
tumours
55
Cyclophosphamide, doxorubicin, fluorouracil Dronabinol 7 mg/m
2
×4 (55) v prochlorperazine 7 mg/m
2
×4 (55) v
placebo (55)
1/2/1
Adults aged 21 to 66 years, various
tumours
56
Doxorubicin, cisplatin Nabilone 1 mg×3 (19) v domperidone 20 mg×3 (19) 1/1/1
Adults aged 18 to 76 years, various
tumours
57
No data Dronabinol 15 mg or 10 mg/m
2
×3 (20) v placebo (20) 1/2/1
Children and adults, aged 9 to 70
years, various tumours
58
Cisplatin, cyclophosphamide, methotrexate Dronabinol 15 mg or 10 mg/m
2
×3 (73) v prochlorperazine 10 mg×3
(73)
1/2/1
Adults aged 19 to 65 years, various
tumours
59
Cisplatin Nabilone 2 mg×2 (37) v prochlorperazine sr 10 mg×2 (37) 1/1/1
Adults aged 18 to 82 years, various
tumours
60
Various Dronabinol 7.5 to 12.5 mg×3 (172) v prochlorperazine 10 mg×3
(181)
2/1/1
Adults aged 18 to 81 years, various
tumours
61
Doxorubicin, cisplatin Nabilone 2 mg×2 (84) v placebo (84) 1/2/1
*Drugs taken orally unless stated otherwise.
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3BMJ VOLUME 323 7 JULY 2001 bmj.com
Sensitivity analyses
One trial reported very low event rates in the control
groups: 16% of patients felt nauseous with placebo and
2% with prochlorperazine.
41
Chemotherapy was
mainly with low emetogenic substances (vincristine,
fluorouracil) (table 1).
Six trials reported event rates above 75% in the
control group (fig 1). In two nausea rates with placebo
were 93% and 100%, respectively, and vomiting rates
were 87% and 100%.
35 36
Chemotherapy was with high
dose methotrexate
35
or with doxorubicin and cytoxan.
36
In one trial rates of nausea and vomiting were 100%
despite prochlorperazine
46
; chemotherapy was with
cisplatin. In two trials, the nausea rate was 85% despite
alizapride
53
and 83% despite prochlorperazine
54
; again,
the chemotherapy regimen contained cisplatin. Finally,
in one trial 90% of controls receiving prochlorperazine
vomited; chemotherapy was with moderately eme-
togenic drugs (cyclophosphamide, methotrexate,
fluorouracil).
34
When data from active controlled trials with
medium control event rates (25% to 75%) were
combined, cannabinoids were superior to conventional
antiemetics, and numbers needed to treat were below 4
to prevent nausea and below 7 to prevent vomiting
(table 2). When data from active controlled trials with
extreme event rates in control groups ( < 25% and
> 75%) were combined, there were no significant
differences between cannabinoids and active compara-
tors (table 2).
It became clear that cannabinoids were antiemetic
only when the components of the chemotherapy regi-
men and the event rates in control patients suggested a
medium emetogenic setting. We therefore tried to test
for dose responsiveness after excluding trials that
reported extreme event rates in control groups. The
largest clinically homogeneous subgroup contained
just two trials, which compared dronabinol 30 mg per
day with prochlorperazine 20 mg
41
and dronabinol 28
mg/m
2
with prochlorperazine 30 mg/m
2
.
55
No sensible
conclusion on dose-response relations with cannabi-
noids could be drawn. For the same reason, no conclu-
sion could be drawn on the relative efficacy of nabilone,
dronabinol, or levonantradol.
Patients’ preference
At the end of 18 crossover trials, patients were asked
which treatment they preferred for further chemo-
therapy cycles. Between 38% and 90% of patients pre-
ferred cannabinoids (fig 2). In four placebo controlled
crossover trials preference for placebo was between 4%
and 22%.
28 47 50 61
The difference in favour of cannabi-
noids was significant (table 2). In 14 active controlled
crossover trials 3% to 46% of patients preferred the
standard antiemetic.
32-34 38-40 42 44 46 51-54 59
The difference in
favour of cannabinoids was significant (table 2). A sub-
group analysis, taking into account history of cannabis
use, was not possible since this was inconsistently
reported.
In the only parallel group trial that reported
preference as an end point,
45
78% of the patients who
had received chlorpromazine and 58% of those who
had received levonantradol wished to receive the same
100
75
50
25
0
Event rate with controls (%)
0 25 50 75 100
Event rate with cannabinoids (%)
Nausea, placebo controlled
Nausea, active controlled
Vomiting, placebo controlled
Vomiting, active controlled
Fig 1 Incidences of nausea and vomiting with cannabinoids and
control treatments. Each symbol represents one trial. Data are from
10 trials that reported separate dichotomous data on nausea or
vomiting. Two trials had two comparators (active and placebo) and
nine trials had data on both nausea and vomiting. Symbol sizes are
proportional to trial sizes. The solid line represents equality
Table 2 Control of nausea and vomiting and patients’ preference for treatment in trials of cannabinoid against active antiemetic or
control treatment
End point
No of
trials
Event rate (No of patients)
Relative risk (95% CI)
No needed to treat
(95% CI)Cannabis (%) Control (%)
Control of nausea and vomiting
Complete control of nausea v placebo 4 70 (81/116) 57 (66/115) 1.21 (1.03 to 1.42) 8.0 (4.0 to 775)
Complete control of vomiting v placebo 4 66 (76/116) 36 (41/115) 1.84 (1.42 to 2.38) 3.3 (2.4 to 5.7)
Complete control of nausea v active 7 59 (122/207) 43 (93/215) 1.38 (1.18 to 1.62) 6.4 (4.0 to 16)
Complete control of vomiting v active 6 57 (111/194) 45 (90/201) 1.28 (1.08 to 1.51) 8.0 (4.5 to 38)
Sensitivity analysis (cannabinoids v active)
Complete control of nausea:
Event rate in controls 25% to 75% 3 70 (75/107) 41 (46/112) 1.70 (1.32 to 2.18) 3.4 (2.4 to 6.1)
Event rate in controls <25% or >75% 4 47 (47/100) 46 (47/103) 1.06 (0.88 to 1.27) 73 (6.6 to −8.1)
Complete control of vomiting
Event rate in controls 25% to 75% 4 72 (105/146) 57 (87/153) 1.26 (1.07 to 1.48) 6.6 (3.9 to 23)
Event rate in controls <25% or >75% 2 13 (6/48) 6 (3/48) 1.86 (0.53 to 6.47) 16 (5.6 to −19)
Patients’ rating
Preference for cannabinoid v placebo 4 76 (153/202) 13 (27/202) 5.67 (3.95 to 8.15) 1.6 (1.4 to 1.8)
Preference for cannabinoid v active 14 61 (371/604) 26 (156/608) 2.39 (2.05 to 2.78) 2.8 (2.4 to 3.3)
Active=prochlorperazine, metoclopramide, chlorpromazine, tiethylperazine, haloperidol, domperidone, alizapride.
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4 BMJ VOLUME 323 7 JULY 2001 bmj.com
drug for future chemotherapy cycles. This difference
that was not significant (relative risk 0.74, 95%
confidence interval 0.50 to 1.09).
Side effects
Side effects happened significantly more often with
cannabinoids (table 3). Some side effects could be clas-
sified as potentially beneficial (for instance, a sensation
of a “high,” euphoria, and drowsiness, sedation, or
somnolence) whereas others were definitely harmful
(for instance, dysphoria and depression, hallucinations,
or paranoia). Hallucinations and paranoia occurred
exclusively with cannabinoids. Arterial hypotension
( > 20% decrease in blood pressure compared with
baseline) was also more common with cannabinoids
(table 3). In 19 trials, the number of patients who with-
drew from the study due to intolerable adverse effects
was significantly increased with cannabinoids (table 3).
Discussion
The evidence we have from randomised trials shows
cannabinoids to be slightly better than conventional
antiemetics for treating chemotherapy induced emesis,
and patients prefer them. They are also more toxic.
Two extreme positions could be taken, perhaps using
the following arguments.
Arguments for and against
The optimistic position favours cannabinoids. Over-
whelmingly, patients preferred cannabinoids for future
chemotherapy, even though cannabinoids were only
slightly more effective than other antiemetics and only
for moderately emetogenic chemotherapy. Patients’
subjective view on preference is more important than
the scientifically evaluated efficacy of that intervention.
Although side effects occur more often with cannabi-
noids, these may be concentrated in a fairly small
number of patients so that most patients find cannabi-
noids effective without undue adverse effects. There are
even some potentially beneficial side effects. Of 100
cancer patients undergoing chemotherapy who
received a cannabinoid 30 more would be sedated, 20
would feel a sensation of a “high,” and 15 would feel
euphoric compared with 100 who received a
conventional antiemetic. Some patients may perceive a
degree of sedation or somnolence as useful during
chemotherapy. Thus, further clinical trials with
cannabinoids in chemotherapy are justified.
The pessimistic position favours conventional
antiemetics, as cannabinoids are not much better, and
their toxicity is unacceptably high (dizziness, dysphoria,
hallucinations, paranoia). The toxic effects may lead to
study withdrawal. There were no comparisons of
cannabinoids with a serotonin (5-HT
3
) receptor
antagonist, the best comparator for prevention of acute
emesis in highly emetogenic chemotherapy. It is, how-
ever, unlikely that cannabinoids would be more
effective and less toxic than a 5-HT
3
receptor
antagonist.
The correct position is probably somewhere in the
middle. Undoubtedly, most patients preferred cannabi-
noids for future chemotherapy cycles. One in two
compared with placebo, and one in three compared
with conventional antiemetics would have preferred to
receive cannabinoids again. We do not know whether
the incidence of cannabinoid related “beneficial” side
effects was related to this overwhelming preference for
cannabinoids for future chemotherapy.
Efficacy and safety
Before a chemical compound can be recommended
for medical use, both its efficacy and safety must be
proved. Cannabinoids were more effective than
conventional antiemetics (prochlorperazine, metoclo-
100
75
50
25
0
% preferring control
Placebo controlled
Active controlled
0 25 50 75 100
% preferring cannabinoids
Fig 2 Percentages of patients preferring cannabinoids or control for
future chemotherapy. Each symbol represents one trial. Symbol sizes
are proportional to trial sizes. The solid line represents equality
Table 3 Rates of side effects among patients receiving cannabinoid antiemetic treatment compared with placebo or active control
End point
No of
trials
Event rate (No of patients)
Relative risk (95% CI)
No needed to treat
(95% CI)Cannabis (%) Control (%)
“Beneficial” central side effects:
“High” sensation 8 35 (162/470) 3 (17/562) 10.6 (6.86 to 16.5) 3.2 (2.8 to 3.7)
Drowsiness, sedation, somnolence 15 50 (320/636) 30 (224/737) 1.66 (1.46 to 1.89) 5.0 (4.0 to 6.8)
Euphoria* 3 14 (24/168) 1 (1/168) 12.5 (3.00 to 52.1) 7.3 (5.2 to 12)
Harmful central side effects:
Dizziness* 9 49 (173/357) 17 (57/344) 2.97 (2.31 to 3.83) 3.1 (2.6 to 3.9)
Dysphoria or depression 10 13 (39/312) 0.3 (1/378) 8.06 (3.38 to 19.2) 8.2 (6.3 to 12)
Hallucination 10 6 (26/435) 0 (0/424) 6.10 (2.41 to 15.4) 17 (12 to 27)
Paranoia 6 5 (14/285) 0 (0/286) 8.58 (6.38 to 11.5) 20 (13 to 42)
Hypotension 13 25 (124/497) 11 (53/485) 2.23 (1.75 to 2.83) 7.1 (5.3 to 11)
Withdrawal due to side effects 19 11 (108/1003) 2 (18/1108) 4.67 (3.07 to 7.09) 11 (8.9 to 14)
*No studies used a placebo control.
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5BMJ VOLUME 323 7 JULY 2001 bmj.com
pramide). Of 100 cancer patients treated with oral can-
nabinoids during chemotherapy, 16 will not be
nauseated (number needed to treat 6.4) and 13 will not
vomit (8) who would have done so had they all received
a conventional antiemetic. Compared with placebo,
cannabinoids were obviously better, although a
placebo may not be an adequate comparator in
patients having chemotherapy. We could not establish
a dose-response relation, mainly because there were
insufficient quality data from the original trials. In some
trials, dose was adjusted during the trial.
34
The relation
between plasma concentration of a cannabinoid and its
antiemetic efficacy is unclear. In one trial, antiemetic
efficacy was related to the plasma concentration of
dronabinol.
35
Another trial found no correlation
between dronabinol serum levels and efficacy or
adverse reactions.
41
Defining an intervention’s usefulness includes esti-
mates of the likelihood for harm. The physical and
neuropsychiatric adverse effects of long term use of
cannabis are well established, based mainly on
observations from long term marijuana smokers.
62
Our
systematic review shows clearly that cannabinoids are
toxic for many patients even when taken orally and
acutely (for 24 hours). Some adverse effects occurred
almost exclusively with cannabinoid exposure. For
instance, 5% of patients had paranoia, 6% had halluci-
nations, and almost 13% had dysphoria or depression
(table 3). The number of patients withdrawing from the
studies due to intolerable side effects is the most
reliable parameter of the severity of cannabinoid
related toxicity. One in eleven patients treated with
cannabinoids will stop treatment who would not have
stopped treatment had they taken a placebo or another
antiemetic. This is an important new message for doc-
tors, policy makers, and patients.
These results should make us think hard about the
ethics of clinical trials of cannabinoids when safe and
effective alternatives are known to exist and when effi-
cacy of cannabinoids is known to be marginal. The
trials analysed here are likely to be the largest
subgroup on the medical use of cannabinoids and
therefore the single most important source of
information on their potential for harm.
Effect of bias
This meta-analysis is open to some biases, and they all
have the potential to overestimate the efficacy and to
underestimate the harm of cannabinoids. The trials we
included were of acceptable quality according to the
Oxford quality scale, with 25 of 30 trials scoring 3 or 4.
In 70% of trials an adequate method of blinding was
described. Most crossover trials used a double dummy
design. Cannabinoids were given as tablets or
intramuscular injection, so any psychological effect of
smoking a joint was not a factor. However, cannabi-
noids showed specific adverse effects that control treat-
ments did not, and their incidence was high. In one
trial of oral nabilone, many patients identified which
drug they received because of the adverse effects expe-
rienced.
59
In a series of 100 blinded dronabinol and
placebo treatments, nurses correctly identified the
active treatment in 85% and patients in 95%; seven of
the 10 errors were made by patients on the first drug
trial of the study.
63
We must therefore assume that most
of these trials had some degree of observer bias.
Some trials studied selected groups of patients who
either had not responded to conventional antiemetic
prophylaxis during previous chemotherapy cycles
(“high risk” patients) or regularly used cannabis. Both
subgroups introduce a bias in favour of cannabinoids.
The selection of refractory patients introduces bias
against the regimens that do not include cannabi-
noids.
4
Younger age and previous marijuana exposure
have been identified as factors that predicted response
to antiemetic treatment.
64
Regular cannabis users may
be more likely to believe in its antiemetic efficacy. They
may also experience adverse effects of cannabis more
positively than patients who have not previously taken
cannabis (for instance, a “high” or somnolence). In one
trial, where more than 50% of patients were regular
cannabis users, only 6% did not believe that cannabis
would reduce their nausea and vomiting symptoms.
60
In view of the numerous biases in these trials, “prefer-
ence” and “satisfaction” are likely to be surrogate end
points. These endpoints alone do not allow to judge
with confidence on the usefulness of cannabinoids in
the control of chemotherapy related emesis.
Finally, we have the problem of size. Small trials can
be greatly affected by the random play of chance.
65
Of
the 30 studies available for analysis, only nine had over
50 analysable patients and only four more than 100.
Small size has been shown to overestimate treatment
effects in other circumstances,
66
and it is not possible to
rule out similar effects here.
Implications
The research agenda needs to be clear. Priority should
go to trials of cannabinoids for indications where there
are few competing drugs, such as spasticity in multiple
sclerosis. In chemotherapy, the combination of weak
antiemetic efficacy with potentially beneficial side
effects (sedation, euphoria) raises the question whether
further trials should be designed to establish the
usefulness of cannabinoids as adjuncts to modern
antiemetics (for instance, 5-HT
3
receptor antagonists).
Minimal effective doses would then be needed. Identifi-
What is already known on this topic
Requests have been made for legalisation of
cannabis (marijuana) for medical use
Long term smoking of cannabis can have physical
and neuropsychiatric adverse effects
Cannabis may be useful in the control of
chemotherapy related sickness
What this study adds
Oral nabilone and dronabinol and intramuscular
levonantradol are superior to conventional
antiemetics (such as prochlorperazine or
metoclopramide) in chemotherapy
Side effects are common with cannabinoids, and
although some may be potentially beneficial
(euphoria, “high,” sedation), others are harmful
(dysphoria, depression, hallucinations)
Many patients have a strong preference for
cannabinoids
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6 BMJ VOLUME 323 7 JULY 2001 bmj.com
cation of patients who are most likely to profit from the
antiemetic effect of cannabinoids and least likely to
suffer from neuropsychiatric adverse effects is needed.
In conclusion, the cannabinoids reviewed here
were slightly superior to conventional antiemetics after
chemotherapy, and patients preferred them. However,
potentially serious adverse effects, even when the drugs
are taken short term orally or intramuscularly, are
likely to limit their widespread use. In selected patients,
cannabinoids may be useful as mood enhancing adju-
vants for the control of chemotherapy related sickness.
We thank Daniel Haake from the Documentation Service of the
Swiss Academy of Medical Sciences for his help in searching
electronic databases.
Contributors: MRT initiated the project, searched, extracted,
and analysed the data and is the study guarantor. DC initiated
the project, searched and cross checked extracted data. DJMR,
FAC, RAM, and HJM cross checked extracted data. RAM and
HJM provided the Excel template for data analyses. All authors
participated in discussing the results and in writing the paper.
Funding: MRT received a PROSPER grant (No
32-51939.97) from the Swiss National Science Foundation. DC
was supported by the Royal College of Nursing Institute RAE
Grant.
Competing interests: None declared.
1 Kassirer JP. Federal foolishness and marijuana (editorial). N Engl J Med
1997;336:366.
2 Grinspoon L, Bakalar JB. Marihuana as medicine: a plea for reconsidera-
tion. JAMA 1995;273:1875-6.
3 Morris K. The cannabis remedy
—
wonder worker or evil weed? Lancet
1997;350:1828.
4 Voth EA, Schwartz RH. Medicinal applications of delta-9-
tetrahydrocannabinol and marijuana. Ann Intern Med 1997;126:791-8.
5 Doblin RE, Kleiman MA. Marijuana as antiemetic medicine: a survey of
oncologists’ experiences and attitudes. J Clin Oncol 1991;9:1314-9.
6 Schwartz RH, Beveridge RA. Marijuana as an antiemetic drug: How use-
ful is it today? Opinions from clinical oncologists. J Addict Dis
1994;13:53-65.
7 Poster DS, Penta JS, Bruno S, Macdonald JS. Ä
9
-tetrahydrocannabinol in
clinical oncology. JAMA 1981;245:2047-51.
8 Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJM, Gavaghan
DJ, et al. Assessing the quality of reports of randomized clinical trials: is
blinding necessary? Control Clin Trials 1996;17:1-12.
9 Morris JA, Gardner MJ. Calculating confidence intervals for relative risk,
odds ratios, and standardised ratios and rates. In: Gardner MJ, Altman
DG, eds. Statistics with confidence:confidence intervals and statistical guidelines.
London: BMJ Books, 1995:50-63.
10 Gavaghan DJ, Moore RA, McQuay HJ. An evaluation of homogeneity
tests in meta-analysis in pain using simulations of individual patient data.
Pain 2000;85:415-24.
11 Cook RJ, Sackett DL. The number needed to treat: a clinically useful
measure of treatment effect. BMJ 1995;310:452-4.
12 Altman D. Confidence intervals for the number needed to treat. BMJ
1998;317:1309-12.
13 Higi M, Niederle N, Bremer K, Schmitt G, Schmidt CG, Seeber S.
Levonantradol bei der Behandlung von zytostatika-bedingter Übelkeit
und Erbrechen. Dtsch med Wschr 1982;107:1232-4.
14 Niiranen A, Mattson K. Antiemetic efficacy of nabilone and dexametha-
sone: a randomized study of patients with lung cancer receiving chemo-
therapy. Am J Clin Oncol 1987;10:325-9.
15 Roffman RA. The controlled substances therapeutic research act in the
state of Washington. J Clin Pharmacol 1981;8-9(suppl):133-40S.
16 Citron ML, Herman TS, Vreeland F, Kransow SH, Fossieck Jr BE,
Harwood S, et al. Antiemetic efficacy of levonantradol compared to delta-
9-tetrahydrocannabinol for chemotherapy-induced nausea and vomit-
ing. Cancer Treat Rep 1985;69:109-12.
17 Cunningham D, Forrest GJ, Soukop M, Gilchrist NL, Calder IT. Nabilone
and prochlorperazine: a useful combination for emesis induced by cyto-
toxic drugs. BMJ 1985;291:864-5.
18 Cunningham D, Bradley CJ, Forrest GJ, Hutcheon AW, Adams L,
Sneddon M, et al. A randomized trial of oral nabilone and prochlorpera-
zine compared to intravenous metoclopramide and dexamethasone in
the treatment of nausea and vomiting induced by chemotherapy
regimens containing cisplatin or cisplatin analogues. Eur J Cancer Clin
Oncol 1988;24:685-9.
19 Gilbert CJ, Ohly KV, Rosner G, Peters WP. Randomized, double-blind
comparison of a prochlorperazine-based versus a metoclopramide-based
antiemetic regimen in patients undergoing autologous bone marrow
transplantation. Cancer 1995;76:2330-7.
20 Priestman SG, Priestman TJ, Canney PA. A double-blind randomised
cross-over comparison of nabilone and metoclopramide in the control of
radiation-induced nausea. Clin Radiol 1987;38:543-4.
21 Lucraft HH, Palmer MK. Randomised clinical trial of levonantradol and
chlorpromazine in the prevention of radiotherapy-induced vomiting.
Clin Radiol 1982;33:621-2.
22 Lewis IH, Campbell DN, Barrowcliffe MP. Effect of nabilone on nausea
and vomiting after total abdominal hysterectomy. Br J Anaesth
1994;73:244-6.
23 Beal JE, Olson R, Laubenstein L, Morales JO, Bellman P, Yangco B, et al.
Dronabinol as a treatment for anorexia associated with weight loss in
patients with AIDS. J Pain Symptom Manag 1995;10:89-97.
24 Ekert K, Waters KD, Jurk IH, Mobilia J, Loughnan P. Amelioration of can-
cer chemotherapy induced nausea and vomiting by delta-9-
tetrahydrocannabinol. Med J Aus 1979;2:657-9.
25 Garb S, Beers AL, Bograd M, McMahon RT, Magalik A, Ashmann A, et al.
Two-pronged study of tetrahydrocannabinol (THC) prevention of vomit-
ing from cancer chemotherapy. IRCS Med Sci 1980;8:203-4.
26 Stambaugh JE Jr, McAdams J, Vreeland F. Dose ranging evaluation of the
antiemetic efficacy and toxicity of intramuscular levonantradol in cancer
subjects with chemotherapy-induced emesis. J Clin Pharmacol
1984;24:480-5.
27 Levitt M, Wilson A, Bowman D, Kemel S, Krepart G, Marks V, et al. Physi-
ologic observations in a controlled clinical trial of the antiemetic
effectiveness of 5, 10, and 15 mg of delta 9-tetrahydrocannabinol in can-
cer chemotherapy. Ophthalmologic implications. J Clin Pharmacol
1981;21:103-9S.
28 Einhorn LH. Nabilone: an effective antiemetic agent in patients receiving
cancer chemotherapy. Cancer Treat Rev 1982;9(suppl B):55-61.
29 Colls BM. Cannabis and cancer chemotherapy. Lancet 1980;i:1187-8.
30 Lane M, Smith FE, Sullivan RA, Plasse TF. Dronabinol and prochlorpera-
zine alone and in combination as antiemetic agents for cancer
chemotherapy. Am J Clin Oncol 1990;13:480-4.
31 Orr LE, McKernan JF. Antiemetic effect of delta 9-tetrahydrocannabinol
in chemotherapy-associated nausea and emesis as compared to placebo
and compazine. J Clin Pharmacol 1981;21:76-80S.
32 Ungerleider JT, Sarna G, Fairbanks LA, Goodnight J, Andrysiak T,
Jamison K. THC or compazine for the cancer chemotherapy patient
—
the
UCLA study. Part II: patient drug preference. Am J Clin Oncol
1985;8:142-7.
33 Ahmedzai S, Carlyle DL, Calder IT, Moran F. Anti-emetic efficacy and
toxicity of nabilone, a synthetic cannabinoid, in lung cancer
chemotherapy. BrJCancer1983;48:657-63.
34 Chan HS, Correia JA, MacLeod SM. Nabilone versus prochlorperazine
for control of cancer chemotherapy-induced emesis in children: a
double-blind, crossover trial. Pediatrics 1987;79:946-52.
35 Chang AE, Shiling DJ, Stillman RC, Goldberg NH, Seipp CA, Barofsky I,
et al. Delta-9-tetrahydrocannabinol as an antiemetic in cancer patients
receiving high-dose methotrexate. A prospective, randomized evaluation.
Ann Intern Med 1979;91:819-24.
36 Chang AE, Shiling DJ, Stillman RC, Goldberg NH, Seipp CA, Barofsky I,
et al. A prospective evaluation of delta-9-tetrahydrocannabinol as an
antiemetic in patients receiving adriamycin and cytoxan chemotherapy.
Cancer 1981;47:1746-51.
37 Colls BM, Ferry DG, Gray AJ, Harvey VJ, McQueen EG. The antiemetic
activity of tetrahydrocannabinol versus metoclopramide and thiethylp-
erazine in patients undergoing cancer chemotherapy. N Z Med J
1980;91:449-51.
38 Crawford SM, Buckman R. Nabilone and metoclopramide in the
treatment of nausea and vomiting due to cisplatinum: a double blind
study. Med Oncol Tumor Pharmacother 1986;3:39-42.
39 Dalzell AM, Bartlett H, Lilleyman JS. Nabilone: an alternative antiemetic
for cancer chemotherapy. Arch Dis Child 1986;61:502-5.
40 Einhorn LH, Nagy C, Furnas B, Williams SD. Nabilone: an effective
antiemetic in patients receiving cancer chemotherapy. J Clin Pharmacol
1981;21:64-9S.
41 Frytak S, Moertel CG, O Fallon JR, Rubin J, Creagan ET.
Delta-9-tetrahydrocannabinol as an antiemetic for patients receiving
cancer chemotherapy. A comparison with prochlorperazine and a
placebo. Ann Intern Med 1979;91:825-30.
42 George M, Pejovic MH, Thuaire M, Kramar A, Wolff JP. Randomized
comparative trial of a new anti-emetic: nabilone, in cancer patients
treated with cisplatin. Biomed Pharmacother 1983;37:24-7.
43 Gralla RJ, Tyson LB, Bordin LA, Clark RA, Kelsen DP, Kris MG, et al.
Antiemetic therapy: a review of recent studies and a report of a random
assignment trial comparing metoclopramide with delta-9-
tetrahydrocannabinol. Cancer Treat Rep 1984;68:163-72.
44 Herman TS, Einhorn LH, Jones SE, Nagy C, Chester AB, Dean JC, et al.
Superiority of nabilone over prochlorperazine as an antiemetic in
patients receiving cancer chemotherapy. N Engl J Med 1979;300:1295-7.
45 Hutcheon AW, Palmer JB, Soukop M, Cunningham D, McArdle C, Welsh
J, et al. A randomised multicentre single blind comparison of a cannabi-
noid anti-emetic (levonantradol) with chlorpromazine in patients receiv-
ing their first cytotoxic chemotherapy. Eur J Cancer Clin Oncol
1983;19:1087-90.
46 Johansson R, Kilkku P, Groenroos M. A double-blind, controlled trial of
nabilone vs prochlorperazine for refractory emesis induced by cancer
chemotherapy. Cancer Treat Rev 1982;9:25-33.
47 Jones SE, Durant JR, Greco FA, Robertone A. A multi-institutional phase
III study of nabilone vs placebo in chemotherapy-induced nausea and
vomiting. Cancer Treat Rev 1982;9:45-8.
48 Kluin-Neleman JC, Neleman FA, Meuwissen OJAT, Maes RAA.
Delta
9
-tetrahydrocannabinol (THC) as an antiemetic for patients receiv-
ing cancer chemotherapy; a double blind cross-over trial against placebo.
Vet Hum Toxicol 1979;21:228-40.
49 Lane M, Vogel CL, Ferguson J, Krasnow S, Saiers JL, Hamm J, et al. Dro-
nabinol and prochlorperazine in combination for treatment of cancer
chemotherapy-induced nausea and vomiting. J Pain Symptom Manag
1991;6:352-9.
50 Levitt M. Nabilone vs placebo in the treatment of chemotherapy-induced
nausea and vomiting in cancer patients. Cancer Treat Rev 1982;9(suppl
B):49-53.
Papers
7BMJ VOLUME 323 7 JULY 2001 bmj.com
51 McCabe M, Smith FP, Macdonald JS, Woolley PV, Goldberg D. Efficacy of
tetrahydrocannabinol in patients refractory to standard antiemetic
therapy. Invest New Drugs 1988;6:243-6.
52 Neidhart JA, Gagen MM, Wilson HE, Young DC. Comparative trial of the
antiemetic effects of THC and haloperidol. J Clin Pharmacol 1981;21:38-
42S.
53 Niederle N, Schutte J, Schmidt CG. Crossover comparison of the
antiemetic efficacy of nabilone and alizapride in patients with
nonseminomatous testicular cancer receiving cisplatin therapy. Klin
Wochenschr 1986;64:362-5.
54 Niiranen A, Mattson K. A cross-over comparison of nabilone and
prochlorperazine for emesis induced by cancer chemotherapy. Am J Clin
Oncol 1985;8:336-40.
55 Orr LE, McKernan JF, Bloome B. Antiemetic effect of tetrahydrocannabi-
nol. Compared with placebo and prochlorperazine in chemotherapy-
associated nausea and emesis. Arch Intern Med 1980;140:1431-3.
56 Pomeroy M, Fennelly JJ, Towers M. Prospective randomized double-blind
trial of nabilone versus domperidone in the treatment of cytotoxic-
induced emesis. Cancer Chemother Pharmacol 1986;17:285-8.
57 Sallan SE, Zinberg NE, Frei E 3rd. Antiemetic effect of delta-9-
tetrahydrocannabinol in patients receiving cancer chemotherapy. N Engl
J Med 1975;293:795-7.
58 Sallan SE, Cronin C, Zelen M, Zinberg NE. Antiemetics in patients receiv-
ing chemotherapy for cancer: a randomized comparison of delta-9-
tetrahydrocannabinol and prochlorperazine. N Engl J Med
1980;302:135-8.
59 Steele N, Gralla RJ, Braun DWJr, Young CW. Double-blind comparison of
the antiemetic effects of nabilone and prochlorperazine on
chemotherapy-induced emesis. Cancer Treat Rep 1980;64:219-24.
60 Ungerleider JT, Andrysiak T, Fairbanks L, Goodnight J, Sarna G, Jamison
K. Cannabis and cancer therapy: a comparison of Delta-9-THC and
prochlorperazine. Cancer 1982;50:636-45.
61 Wada JK, Bogdon DL, Gunnell JC, Hum GJ, Gota CH, Rieth TE. Double-
blind, randomized, crossover trial of nabilone vs. placebo in cancer
chemotherapy. Cancer Treat Rev 1982;9(Suppl B):39-44.
62 Hubbard JR, Franco SE, Onaivi ES. Marijuana: medical implications. Am
Fam Physician 1999;60:2583-93.
63 Seipp CA, Chang AE, Shiling DJ, Rosenberg SA. In search of an effective
antiemetic: a nursing staff participates in marijuana research. Cancer
Nursing 1980 Aug:271-6.
64 Vinciguerra V, Moore T, Brennan E. Inhalation marijuana as an
antiemetic for cancer chemotherapy. New York State J Med 1988;88:525-7.
65 Moore RA, Gavaghan D, Tramèr MR, Collins S, McQuay HJ. Size is
everything
—
the impact of event rate variation on clinical trials and meta-
analysis. Pain 1998;78:208-16.
66 Moore RA, Tramèr MR, Carroll D, Wiffen PJ, McQuay HJ. Quantitative
systematic review of topically-applied non-steroidal anti-inflammatory
drugs. BMJ 1998;316:333-8.
(Accepted 12 October 2000)
Papers
8 BMJ VOLUME 323 7 JULY 2001 bmj.com
