Marijuana for Medicinal Purposes:

An Evidence-Based Assessment

Prepared for Alberta's Workers' Compensation Board

Marijuana for Medicinal Purposes:

An Evidence-Based Assessment

A Research Project Sponsored by Medical Services

Workers' Compensation Board Alberta

June, 2002

Research Team:
Bruce Fisher, MD, MSc, FRCP[C]
Don Johnston, MD, MSc, FRCP[C], Specialist, Occupational Medicine
Patricia Leake, MPP

The content, judgments and conclusions of this document are those of the members of the research team
and are not necessarily endorsed by WCB-Alberta.

Contents
Summary
I.

Context

II.

Assessing the scientific evidence

Research method
Studies meeting the inclusion criteria
Findings: potential therapeutic applications of herbal marijuana
Findings: potential harmful effects of herbal marijuana
Smoking marijuana
Marijuana research: challenges and limitations
III. Prescribing marijuana: challenges and limitations

19

IV. Marijuana for injured workers: potential therapeutic applications

20

V. Conclusion

20

Appendices

22
Appendix A
Appendix B
Appendix C
Appendix D
Appendix E
Appendix F
Appendix G
Appendix H

Organizational statements
Study designs
Comprehensive reviews
Levels of evidence summary
Worksheet for using an article about causation of harm
Worksheet for using an article about therapy or prevention
Psychoactive effect/therapeutic effect
Examples of ongoing marijuana research

Annotated Bibliography

37

References

62

SUMMARY
Systematic review of the literature reveals that scientific knowledge about herbal marijuana is
incomplete, with insufficient evidence to determine its therapeutic potential or harmful effects.
There were few studies that met the review's quality inclusion criteria and that suggested
medical utility of smoked herbal marijuana for some conditions. These studies yielded low level
evidence of questionable clinical importance and with dubious applicability to medical issues
related to the workplace. Furthermore, there have been significant advances in approved
therapies since the 1970s and 1980s and herbal marijuana does not appear to provide
treatment options not currently available with approved pharmaceutical drugs. Although the
evidence for health risks associated with inhaled marijuana smoke had similar methodological
limitations, the benefit to harm relationship of such long term use in chronic, non-life threatening
conditions is uncertain and concerning.
Smoking marijuana is reported to reduce intraocular pressure in glaucoma and to ameliorate
pain, nausea, multiple sclerosis, spasticity and asthma. The evidence, however, comes from
small randomized control trials, or case control studies characterized by surrogate or short term
outcome assessments, comparisons to out-dated standards of care, and lack of consideration
or measurement of benefit to harm relationships associated with long term inhaled marijuana
use. The paucity and poor quality of the evidence make it difficult to compare herbal marijuana
with current pharmaceutical drugs that have received regulatory approval under much more
rigorous experimental conditions.
Identified risks associated with herbal marijuana use include impairment of motor skills and
driving ability with an increased risk of motor vehicle accident culpability (particularly if
marijuana and alcohol are used together), respiratory tract irritation (apparently reversible if
cannabis use is not prolonged), possible increased risk of aerodigestive cancers (especially if
there is associated tobacco use) and the possibility of subtle cognitive impairment (of unknown
reversibility) if marijuana use is long-term.
The concept of a predictable, quantifiable "dose" is a fundamental principle of medical therapy.
Few (if any) of the prescribing criteria of medical pharmacology can be met in the case of
smoked or ingested herbal marijuana: marijuana contains a variable mixture of poorly defined
biologically active compounds and the level of its active ingredient (9-tetrahydrocannabinol or
THC) fluctuates significantly between samples and is impossible to quantify by inspection.
Scientific knowledge about herbal marijuana is incomplete and appropriate rigorous randomized
controlled studies are needed to answer questions about marijuana's therapeutic potential.
Clinical trials of herbal marijuana are currently underway. As the results of each new trial
become available, the study's "level of evidence" should be determined and the validity of its
results, including clinical importance and applicability to Alberta's injured workers, should be
critically appraised.
There is presently insufficient scientific evidence to treat marijuana as a "prescribable" drug.

I. Context
In July 2001, Canada became the first country in the world to adopt a federal system regulating
the use of herbal marijuana for "medicinal purposes," codified in the Marihuana Medical Access
Regulations (the Regulations). The Regulations are controversial and many questions about
"prescribing" marijuana remain unanswered (Appendix A).
Should herbal marijuana be treated as a prescribable drug"? This document evaluates the
scope and quality of scientific evidence available for medical decision-makers. It is the result of
the work of a collaborative, interdisciplinary research team that included Bruce Fisher, MD,
Master of Science, Fellow of the Royal College of Physicians and Surgeons of Canada; Don
Johnston, MD, Master of Science, Fellow of the Royal College of Physicians and Surgeons of
Canada and Specialist, Occupational Medicine; and Patricia Leake, Master of Pubic Policy.
The information in this report was collected between September and December 2001.
Marijuana, the term for the dried flowering tops (buds) and leaves of the plant cannabis sativa,
is a variable and complex mixture of more than 400 biologically active chemical compounds.
Approximately 60 of these compounds are called cannabinoids. Cannabinoids appear in no
other plant. Throughout this report, marijuana refers to unpurified plant material, including
leaves and flower tops, regardless of whether it is consumed by ingestion or by smoking.
The primary psychoactive ingredient in cannabis is the complex chemical 9tetrahydrocannabinol (9-THC). Throughout this report, use of the acronym THC indicates 9THC. The concentration of THC and other cannabinoids in marijuana varies significantly
depending on growing conditions, plant genetics and processing after harvest.
The psychological effects of cannabinoids include euphoria, anxiety reduction and sedation;
these complicate both the study and the interpretation of other aspects of marijuanas effect.
Historically, plants and other natural products were the source of most medicinal substances.
The effectiveness of these products was hampered, however, by variable and poorly defined
concentrations of active ingredients and by all manner of contaminants. As the science of
medicinal chemistry evolved, it became possible to isolate the pure drug molecules so that
drug dosage could be precise and side effects minimized.
Marijuana has been used as an herbal remedy for thousands of years by some estimates.
There are questions about whether such traditional uses of marijuana are clinically justifiable
today. Most scientific experts assert that marijuanas future as a drug lies primarily in its
pharmacologically active and unique components, the cannabinoids, which can be isolated,
subjected to scientific scrutiny and potentially developed as pharmaceutical drug products.
Within the full set of approved pharmaceutical drug products available to patients there are two
commercially available pure drug molecules inspired by and related to herbal marijuana:
dronabinol (brand name MARINOL), which contains chemically synthesized THC, and nabilone
(brand name CESAMET), a synthetic cannabinoid. Both drugs are taken orally and must be
prescribed by a physician (HC-RIAS 2001).
Herbal marijuana has not been reviewed by Health Canada for safety or effectiveness and has
not been approved for sale as a therapeutic product in Canada.
Please note that both marijuana and marihuana are accepted spellings. We use marijuana in this document, except when
quoting directly from documents that use the spelling with the h.

II. ASSESSING THE SCIENTIFIC EVIDENCE

Evidence-based medicine is the conscientious, explicit and judicious use of current best
evidence in medical decision-making. External clinical evidence both invalidates previously
accepted treatments and replaces them with new ones that are more powerful, more efficacious
and safer (Sackett 1996). In view of the limitations of anecdote, uncontrolled experience and
unsystematic clinical observations, it is expected that clinical decision-making today will be
guided by high quality scientific evidence.
The concept of a "hierarchy of evidence" is fundamental to evidence-based medicine. This is a
schema for grading the evidence based on the tenet that different grades of evidence (study
designs) vary in their predictive ability. Appendix B includes a brief discussion of study designs.
Not all studies using the same design are equally valid. Potentially useful evidence must be
critically appraised: its scientific validity, clinical importance and applicability to the person or
population under consideration must be determined.
Research method
Stage 1: research context
Five recent comprehensive reviews on the subject of marijuana as a medicinal agent provided a
context for the task of assessing the primary research. The reviews are arranged in descending
chronological order in Table 1.
TABLE 1: Comprehensive Reviews
REVIEWING AGENCY

TITLE

DATE

American Medical Association Council on Scientific

Affairs

Report to the AMA House of Delegates. Subject:

Medical Marijuana

1997
Updated:
2001

Institute of Medicine (US)

Marijuana and Medicine: Assessing the Science

Base

1999

House of Lords (UK Parliament), Science and

th
Technology Committee 9 Report

Cannabis: The Medical and Scientific

Evidence

1998

National Institutes of Health (US)

Workshop on the Medical Utility of Marijuana

1997

British Medical Association

Therapeutic Uses of Cannabis

1997

Each of these reports was prepared by a deliberative group of medical and scientific experts.
While each report was written for a different purpose, all reached the same general conclusions
regarding herbal marijuana: while in certain forms it may be moderately effective in treating a

variety of symptoms, more research on the use of marijuana for "medicinal purposes" is needed
and the use of whole and/or smoked marijuana as a medicine is not recommended. More
detailed information on these reviews is found in Appendix C.
Stage 2: literature search
We searched the published, peer-reviewed literature using MEDLINE (1966-May 2001),
EMBASE (1988-June 2001), the Cochrane Database of Systematic Reviews (2nd Quarter 2001),
EBM Reviews-ACP Journal Club (1991 to March/April 2001) and the Database of Abstracts of
Reviews of Effectiveness (1st Quarter 2001) through the OVID online system. The most recent
search was completed in September 2001. The research team designed the search strategy
with the assistance of a medical reference librarian at the J. W. Scott Health Sciences Library,
University of Alberta, Edmonton, Alberta.
The search terms marijuana, cannabis and delta9-tetrahydrocannabinol were cross-searched
with the terms therapeutic use, adverse effects, toxicity, clinical trials, fibromyalgia, multiple
chemical sensitivity, mesothelioma, pain, chronic pain, glaucoma, chemotherapy, drug therapy,
weight loss, spasticity, upper-aero-digestive cancer, immune system, bronchial neoplasms, lung
neoplasms, prostate cancer, bladder cancer, digestive cancer and reproductive hormonal
abnormalities. Terms were consistently exploded. Hedges or standardized search
strategies based on research design were used to select the most valid studies from the search
results. The search was not limited to the English language or to human studies or by age. This
process resulted in a total of 546 titles.
Stage 3: review of abstracts and selection of articles for retrieval
Abstracts were screened and assessed independently by members of the research team.
Reports that were obviously not relevant to the research question were excluded at this stage.
Full text articles of abstracts identified as potentially relevant to the research question were
retrieved for appraisal. Reference lists from these articles were reviewed and full text articles of
relevant citations were also retrieved for appraisal, for a total of 202 articles.
Stage 4: critical appraisal, including the selection and assessment of studies
The articles were divided into four groups: possible therapeutic potential, adverse effects, policy
and review articles. Policy articles were set aside for separate evaluation. Members of the
research team assessed the remaining articles independently. A study was recommended for
inclusion at this stage if it was relevant to the research question, asked and answered a
question in a systematic way, applied the scientific method (posited and evaluated hypotheses
using rational unbiased objective experimentation) and adhered to its study protocol. To be
included, papers had to report on findings about crude herbal marijuana rather than a subset of
its molecular components: research on purified drug molecules such as THC, CESAMET and
MARINOL was excluded. Sixteen harm studies and eight therapy studies met the inclusion
criteria. High quality review articles were identified and set aside for separate evaluation.
Stage 5: data extraction, levels of evidence
Structured abstracts (appended in the Annotated Bibliography) were produced for the sixteen
harm and eight therapy studies using the Annals of Internal Medicine guidelines (Haynes 1990).
Each studys level of evidence, validity of results, clinical importance and applicability were

evaluated independently by research team members, based on study type and study
characteristics. Discrepancies were resolved by consensus.
Critical appraisal of the evidence was made with reference to documents produced by the
Evidence-Based Medicine Working Group: Levels of Evidence Summary for Therapy, Harm or
Causation (Appendix D), Worksheet for Using an Article about Causation of Harm (Appendix
E) and Worksheet for Using an Article about Therapy or Prevention (Appendix F).
Studies meeting the inclusion criteria
Tables 2 and 3 present summaries and critical appraisal of the eight therapy studies and sixteen
harm studies that met the inclusion criteria. Author, title and date, study type, authors
conclusions, critical appraisal by members of the research team and level of evidence are
included for each study. Level of evidence is rated on a 1 (high level or strong evidence) to 5
(low level or weak evidence) scale. Appendix D outlines the evidence rating system.
Findings: potential therapeutic applications of herbal marijuana
Chemotherapy-induced nausea and vomiting
Three studies related to marijuanas potential as an antiemetic met the inclusion criteria.
Despite their methodological difficulties, they provide some evidence that smoked marijuana is a
moderately effective antiemetic agent for patients undergoing cancer chemotherapy, especially
those patients whose nausea has proved resistant to the antiemetic drugs used in the late
1970s and early 1980s, when the research was conducted.
There are potential advantages to the use of antiemetics that can be delivered by inhalation.
Patients with severe vomiting are sometimes unable to swallow or keep pills down long enough
for the pills to take effect. The onset of drug effect is much faster with an antiemetic delivered
by inhalation (Joy 1999). On the other hand, a serious problem encountered in the New York
State open trial with marijuana was the inability of nearly one-fourth of the patients to tolerate
smoking marijuana (Vinciguerra 1988).
In the last decade, substantial progress has been made in controlling chemotherapy-induced
nausea and vomiting, and none of the studies compared smoked herbal marijuana to the
standard care antiemetic therapies of today. It is therefore uncertain whether smoked marijuana
is as effective as serotonin antagonists, currently considered the most effective antiemetics.
Other unresolved issues include the types of nausea against which smoked marijuana is most
effective and the degree of patient tolerance of the psychotropic side effects.
Glaucoma
The one study that met the inclusion criteria was published in 1975. At that time conventional
medications for glaucoma caused a variety of adverse side effects, so there was much interest
in the possible use of smoked marijuana in the treatment of glaucoma. Contemporary
conventional therapies for intraocular pressure outperform cannabinoids, however, and the next
generation of glaucoma drugs is expected to treat the disease even more effectively (Joy 2001).
In addition, smoked marijuanas clinical utility in reducing intraocular pressure is compromised
by its short duration of action and accompanying side effects. The 1975 study did not address
the issue of long-term effects of smoked marijuana.

TABLE 2. STUDIES MEETING THE INCLUSION CRITERIA: THERAPY

STUDY

STUDY TYPE

AUTHORS CONCLUSIONS

CRITICAL APPRAISAL

LEVEL OF
EVIDENCE

Experimental
randomized
placebo-self controlled clinical
trial with five paid
subjects who
regularly smoked
marijuana.

While statistically significant, at the highest doses

(producing substantial biological exposure), the
antinociceptive effects of marijuana were rather
weak. The antinociceptive efficacy of marijuana in
a human laboratory setting is probably marginal in
relation to its other biological, abuse-related,
subject rejection and performance-impairing
effects.

Underpowered RCT. Eight potential

subjects left the study after the first
session because they found the
higher doses of marijuana intolerable.
Although there is evidence that pain
sensation diminished at these levels,
the side effects suggest that
marijuana is a very questionable
treatment modality for this indication.
Study used surrogate marker for
naturally occurring pain.

2b

Tashkin DP. Bronchial effects of

aerosolized delta 9tetrahydrocannabinol in healthy and
asthmatic subjects. Am Rev Respir
Dis 1977

Experimental randomized
controlled clinical
trial.

The findings indicate that aerosolized -THC,

although capable of causing significant
bronchodilatation with minimal systemic side
effects, has a local irritating effect on the airways
which may make it unsuitable for prolonged
therapeutic use.

Study looked at immediate

pharmacologic reaction and was
silent on long term effects of
marijuana smoke.

2b

Tashkin DP. Effects of smoked

marijuana in experimentally induced
asthma. Am Rev Respir Dis 1975

Experimental
randomly
ordered, single
blind placebo
controlled clinical
trial.

Findings demonstrated acute airway dilation after

marijuana smoking. Smoking does not appear to
be an appropriate long-term method for
administration of bronchodilator cannabinoid
compounds for potential therapeutic purposes.
THC does not appear to be a suitable
bronchodilator for therapeutic use because of its
systemic psychotropic and possible undesirable
endocrine, immunologic and cytogenetic effects.

Study looked at immediate

pharmacologic reaction and was
silent on long term effects of
marijuana smoke.

2b

Analgesia
Greenwald MK. Antinociceptive,
subjective and behavioral effects of
smoked marijuana in humans.
Drug Alcohol Depend 2000

Asthma
9

TABLE 2. STUDIES MEETING THE INCLUSION CRITERIA: THERAPY (Continued)

STUDY

STUDY TYPE

AUTHORS CONCLUSIONS

CRITICAL APPRAISAL

LEVEL OF
EVIDENCE

Vinciguerra V. Inhalation marijuana

as an antiemetic for cancer
chemotherapy. N Y State J Med
1988

Prospective case
series.

This preliminary trial suggests the usefulness of

inhalation marijuana as an antiemetic agent.
Because of the lack of a randomized placebo
control group, the precise role of this agent is
unclear. Further studies should include derivatives
of this substance in combination with standard
effective drugs to control chemotherapy-induced
nausea and vomiting.

25% of the patients who initially

consented to the study refused
treatment for a variety of reasons,
most commonly because they did not
want to smoke marijuana.

Chang AE. A prospective evaluation

9
of -tetrahydrocannabinol as an
antiemetic in patients receiving
adriamycin and cytoxan
chemotherapy. Cancer 1981

Experimental randomized,
double blind, self
control and
placebo
controlled trial of
9
oral -THC and
smoked
marijuana.

The findings suggest that the antiemetic properties

of THC are effective only against specific
chemotherapeutic drugs.

The study was published in 1981 and

does not compare herbal marijuana
to current standard of care antiemetic
therapies.

1b

Chang AE. Delta 9tetrahydrocannabinol as an

antiemetic in cancer patients
receiving high-dose methotrexate. A
prospective, randomized evaluation.
Ann Intern Med 1979

Experimental randomized,
double-blind,
self-control and
placebocontrolled clinical
trial.

-THC appears to have significant antiemetic

properties when compared with placebo in patients
receiving high-dose methotrexate.

The study was published in 1979 and

does not compare herbal marijuana
to current standard of care antiemetic
therapies.

1b

Chemotherapy Induced Nausea

and Vomiting

TABLE 2. STUDIES MEETING THE INCLUSION CRITERIA: THERAPY (Continued)

STUDY

STUDY TYPE

AUTHORS CONCLUSIONS

CRITICAL APPRAISAL

LEVEL OF
EVIDENCE

Experimental double blind

placebo selfcontrol clinical
trial.

Analysis suggests an indirect effect of the drug

associated with relaxation - a psychophysiologic
state that can be produced by drug and non-drug
means.

Effects of long-term use of marijuana

are not addressed by the study. This
study was published in 1975 and
does not compare herbal marijuana
to current standard of care glaucoma
therapies. Therapeutic use of
marijuana for treatment of glaucoma
seems premature considering the
state of knowledge of the drugs
action.

3b

Experimental - 2
in 1 case series.

Marijuana smoking further impairs posture and

balance in patients with spastic MS.

Patients had the subjective feeling

that they were clinically improved,
despite the fact that their posture and
balance were actually impaired by
smoking marijuana.

Glaucoma
Flom MC. Marijuana smoking and
reduced pressure in human eyes:
drug action or epiphenomenon?
Invest Ophthalmol 1975

Multiple Sclerosis and Spasticity

Greenberg HS. Short-term effects of
smoking marijuana on balance in
patients with multiple sclerosis and
normal volunteers. Clin Pharmacol
Ther 1994

TABLE 3. STUDIES MEETING INCLUSIONS CRITERIA: HARM

STUDY

STUDY TYPE

AUTHORS CONCLUSIONS

CRITICAL APPRAISAL

LEVEL OF
EVIDENCE

Taylor DR. The respiratory effects of

cannabis dependence in young
adults. Addiction 2000

Outcomes study
at single time
interval with
exposure and
outcome
determined
simultaneously.

Significant respiratory symptoms and changes in

spirometry occur in cannabis-dependent individuals
at age 21 years, although the cannabis smoking
history is of relatively short duration.

This study lacked a control group.

The cannabis user group comprised
less than 10% of the total and twothirds of this group also smoked
tobacco. Generalizing from the
relatively small sample size is difficult.

2c

Tashkin DP. Effects of smoked

substance abuse on nonspecific
airway hyperresponsiveness. Am Rev
Respir Dis 1993

Case-control
study of the
pulmonary effects
of habitual
smoking of illicit
substances.

No significant differences (as measured by

methacholine positive responses of 10%
decreases from baseline FEV) to any concentration
of methacholine were found between marijuana
nonsmokers and smokers.

Tashkin DP. Subacute effects of

heavy marihuana smoking on
pulmonary function in healthy men. N
Engl J Med 1976

Experimental
self-control nonrandomized
study.

These findings suggest that customary social use

of marijuana may not result in detectable functional
respiratory impairment in healthy young men,
whereas very heavy marijuana smoking for six to
eight weeks causes mild but statistically significant
airway obstruction.

Bronchial and Pulmonary Damage

3b

This study had a small sample size

and all subjects were also heavy
tobacco smokers. Airway obstruction
was statistically but not clinically
significant.

10

TABLE 3. STUDIES MEETING INCLUSIONS CRITERIA: HARM (Continued)

STUDY

STUDY TYPE

AUTHORS CONCLUSIONS

CRITICAL APPRAISAL

LEVEL OF
EVIDENCE

Lyketsos CG. Cannabis use and

cognitive decline in persons under 65
years of age. Am J Epidemiol 1999

Observational cohort study.

This was a followup study of a
probability
sample of the
adult household
residents of East
Baltimore.

Over long time periods, in persons under age 65

years, cognitive decline occurs in all age groups.
This decline is closely associated with aging and
educational level but does not appear to be
associated with cannabis use. The Mini-Mental
Status Examination (MMSE) is not a very sensitive
measure of cognitive decline, however, and so
small or subtle effects of cannabis use on cognition
or psychomotor speed may have been missed.

Although random sampling was

undertaken, no demographic tables
were provided to determine whether it
was successful. The degree of
exposure was not clear or likely
consistent over time between groups.
The MMSE is an insensitive measure
of cognitive function.

2b

Fletcher JM. Cognitive correlates of

long-term cannabis use in Costa
Rican men. Arch Gen Psychiatry
1996

Observational cohort study.

Long-term cannabis use was associated with

disruption of short-term memory, working memory
and attentional skills in older long-term cannabis
users.

This small cohort study detected

subtle disruption in memory and
cognitive skills, but was unable to
determine the degree of confounding
based on age-related changes alone,
and studied a population not likely
comparable to that of the WCB.

2b

Block RI. Effects of chronic

marijuana use on human cognition.
Psychopharmacology 1993

Observational
cohort study.

More work is needed to evaluate alternative

interpretations of the cognitive impairments
associated with heavy marijuana use.

This study of a mostly male lowincome group had multiple

confounders, did not report a doseresponse relationship and reported
outcomes of unclear clinical
importance.

2b

Cognitive Impairment

11

TABLE 3. STUDIES MEETING INCLUSIONS CRITERIA: HARM (Continued)

STUDY

STUDY TYPE

AUTHORS CONCLUSIONS

CRITICAL APPRAISAL

LEVEL OF
EVIDENCE

Robbe H. Marijuanas impairing

effects on driving are moderate when
taken alone but severe when
combined with alcohol. Hum
Psychopharmacol Clin Exp 1998

Experimental four single-blind,

randomized,
crossover
studies.

Marijuana alone impairs driving performance, with

the degree of impairment increasing from small to
moderate as the THC dose increases from 100 to
300 g/kg. However, when low to moderate doses
of THC (100 and 200 g/kg) are taken in
combination with a Blood Alcohol Concentration
(BAC) of about 0.04%, driving is severely impaired.

This small study reported on

surrogate markers of poor driving
performance.

2b

Longo MC. The prevalence of

alcohol, cannabinoids,
benzodiazepines and stimulants
amongst injured drivers and their role
in driver culpability. Part ii: The
relationship between drug prevalence
and drug concentration and driver
culpability. Accid Anal Prev 2000

Case-control
study.

The study found a clear, concentration-dependent

relationship between alcohol and culpability. It also
found a significant relationship between
benzodiazepines and culpability. In contrast, it
found no significant relationship between THC and
culpability, although the data here and in other
culpability studies do not exclude the possibility of
an adverse effect of cannabinoids if the
concentration is sufficiently high.

Yesavage JA. Carry-over effects of

marijuana intoxication on aircraft pilot
performance: a preliminary report.
Am J Psychiatry 1985

Experimental
self-control
clinical trial.

Psychomotor Impairment

The results may have implications for performance

of complex tasks the day after smoking marijuana.

3b

This study was not randomized and

lacked a control group.

12

TABLE 3. STUDIES MEETING INCLUSIONS CRITERIA: HARM (Continued)

STUDY

STUDY TYPE

AUTHORS CONCLUSIONS

CRITICAL APPRAISAL

LEVEL OF
EVIDENCE

Scragg RK. Maternal cannabis use in

the sudden death syndrome. Acta
Paediatr 2001

Observational a
nationwide case
control study.

Frequent maternal cannabis use may be a weak

risk factor for SIDS, but this finding requires further
research.

The confidence intervals for the odds

ratios for reported outcomes were
wide and were not statistically
significant.

3b

Goldschmidt L. Effects of prenatal

marijuana exposure on child behavior
problems at age 10. Neurotoxicol
Teratol 2000

Case-control
study.

Prenatal marijuana exposure has an effect on child

behavior problems at age 10.

Prenatal marijuana may have an

effect on child behavior problems at
age 10. This large case-series was
seriously confounded by the lack of
non-ethanol and non-cannabis control
groups.

3b

Shiono PH. The impact of cocaine

and marijuana use on low birth weight
and preterm birth: a multicenter
study. Am J Obstet Gynecol 1995

Observational prospective
multicenter cohort
study.

In this population of women receiving prenatal

care, cocaine use was uncommon and was not
related to most adverse birth outcomes. Marijuana
use was relatively common and was not related to
adverse pregnancy outcomes. Tobacco is still the
most commonly abused drug during pregnancy,
and 15% of all cases of low birth weight in this
study could have been prevented if women had not
smoked cigarettes during pregnancy.

This large study was unable to

demonstrate a harmful effect from
cannabis use.

2b

Gibson GT. Maternal alcohol,

tobacco and cannabis consumption
and the outcome of pregnancy. Aust
N Z J Obstet Gynaecol 1983

Observational
prospective
cohort study.

Cannabis used regularly, frequently and in its more

potent forms is significantly associated with
preterm labor and its sequelae (e.g. perinatal
death). Cannabis used in pregnancy is probably
associated with intrauterine growth retardation.

This study was seriously confounded

by simultaneous tobacco and ethanol
use in cannabis smokers. When this
was factored in there was not
apparent association between
cannabis use and IUGR.

2b

Adverse Reproductive Effects

13

TABLE 3. STUDIES MEETING INCLUSIONS CRITERIA: HARM (Continued)

STUDY

STUDY TYPE

AUTHORS CONCLUSIONS

CRITICAL APPRAISAL

LEVEL OF
EVIDENCE

Observational
study without
control group.

These data are consistent with other studies that

report that cannabis consumption is associated
with a poorer outcome of schizophrenia. The
nature of the association is unclear. Cannabis use
might be a result of the severity of the
schizophrenia, so that patients with a poorer
outcome would consume more cannabis
secondarily. On the other hand, cannabis could be
a factor in relapse.

Increased use of cannabis may be a

marker for schizophrenia, but it could
not be determined from this study
whether the relationship was
correlational or causal.

Zhang ZF. Marijuana use and

increased risk of squamous cell
carcinoma of the head and neck.
Cancer Epidemiol Biomarkers Prev
1999

Observational case-control
study.

The results suggest that marijuana may increase

the risk of head and neck cancer with a strong
dose-response pattern. Analysis indicated that
marijuana use may interact with mutagen
sensitivity and other risk factors to increase the risk
of head and neck cancer. The results need to be
interpreted with some caution in drawing causal
inferences because of certain methodological
limitations, especially with regard to interactions.

Although authors suggest that

marijuana use may increase the risk
of head and neck cancer with a trend
toward a dose-response pattern (wide
confidence intervals associated with
point estimate), tobacco smoking may
have been a confounder: 93% of
users with cancer smoked tobacco,
compared to 79% of non-users with
cancer and 63% of the non-cancer
group.

3b

Sridhar KS. Possible role of

marijuana smoking as a carcinogen in
the development of lung cancer at a
young age. J Psychoactive Drugs
1994

Exploratory
case series
study.

Exposure to marijuana smoke is associated with

presentation of cancer of the lung, particularly in
younger patients.

The population studied was from one

practice and 90% of the patients also
had a tobacco smoking history.

Marijuana and schizophrenia

Martinez-Arevalo MJ. Cannabis
consumption as a prognostic factor in
schizophrenia. Br J Psychiatry 1994

Upper Aero-Digestive Cancer

14

Multiple sclerosis and spasticity

Marijuana is anecdotally reported to reduce the muscle spasticity associated with multiple
sclerosis. However, clinical data reported in the single study meeting the inclusion criteria did
not confirm a therapeutic effect.
The double blind placebo-controlled study of postural responses in ten multiple sclerosis
patients and ten healthy volunteers indicated that marijuana smoking impaired posture and
balance in both multiple sclerosis patients and volunteers. The patients subjective evaluations
of their improvement contrasted with objective measure of their physical performance. Although
patients had the subjective feeling that they were clinically improved, clinical measures
showed that in fact marijuana smoking further impaired their posture and balance.
There is insufficient evidence to determine whether marijuana could yield useful medicines for
spasticity. The paucity of universally effective medicine for muscle spasticity and anecdotal
accounts from marijuana users with multiple sclerosis and spinal cord injuries suggest the need
for carefully designed clinical trials to determine the role of cannabinoid drugs.
The regular use of smoked herbal marijuana would be contraindicated in a chronic condition like
multiple sclerosis.
Analgesia
There is a dearth of clinical pain research on herbal marijuana. There is no published evidence
that marijuana is superior to or equivalent to available therapies (NIH 1997).
Only one study in this area met the inclusion criteria. The study looked at experimentally
induced pain. If information could be extrapolated, it would be to acute rather than to chronic
pain. According to this study, in the laboratory setting, marijuana smoke showed antinociceptive
effects only at the highest dose. The study raises the issue of intolerance to the dose eight
potential study subjects, all experienced marijuana users, left after the first session because
they found the higher doses intolerable.
The small margin between clinical benefit and unacceptable adverse effects make this a
questionable therapeutic modality.
Marijuana as an anti-asthmatic agent
Two studies addressing the use of smoked marijuana as an anti-asthmatic agent met the
inclusion criteria. Their results suggest that smoked marijuana has an acute bronchodilatory
effect in both asthmatic and non-asthmatic individuals, and that asthma itself is apparently not a
contraindication to the short term use of smoked marijuana.
Since these studies were conducted in the 1970s, more effective asthma therapies have been
developed. Neither of these studies provide evidence that long-term marijuana therapy would
lead to long-term clinical improvement, as they focussed on immediate pharmacologic reaction,
not long term effects of the many ingredients in marijuana smoke.
Despite this early suggestion of a therapeutic effect in asthma, marijuana has not been used
therapeutically, nor has it been investigated as an anti-asthmatic agent by other than Tashkin
and his colleagues. There is an understandable concern among clinical researchers that

15

smoking is an unsuitable mode of administering any drug, and an especially inappropriate way
to administer a drug to patients with asthma, because it would inevitably involve the delivery of
other noxious chemicals that could nullify its therapeutic value in the short term and carry an
increased risk of respiratory disease and possibly cancer in the long term (Hall 1994).
Findings: potential harmful effects of herbal marijuana
Harmful effects of herbal marijuana depend, among other things, on the route of delivery, the
duration of exposure and the "dose." They may be acute or chronic.
Effects on the respiratory system
The major concerns about the respiratory effects of cannabis use have been the possible
adverse effects of chronic, heavy marijuana smoking, including the production of chronic
bronchitis as a precursor of irreversible obstructive lung disease and the possible causation of
cancers of the aerodigestive tract (including the lungs, mouth, pharynx, larynx and trachea) after
20 to 30 years of regular marijuana smoking (Hall 1994).
Upper aerodigestive cancer
The evidence in the two articles that met the inclusion criteria is inconclusive. The studies
lacked the necessary comparison groups to calculate the isolated effects of marijuana use on
cancer risk. The numbers were very small and there was serious confounding with tobacco
smoking and alcohol use.
Despite the absence of such evidence, similarities between constituents of marijuana and
tobacco smoke and the known latency periods between exposure and development of
aerodigestive tract cancers may be caveats to consideration of long term marijuana smoking for
medical indications.
Bronchial and pulmonary damage
The four studies meeting the inclusion criteria were limited by design and none addressed the
long-term effects of marijuana smoking. Tobacco smoking was a confounder in most of these
studies. Evidence of airway obstruction was not conclusive and demonstrated acute effects of
marijuana smoking seem to be largely reversible.
Cognitive impairment
Two cognitive effects of cannabis must be distinguished: acute effects associated with
intoxication and residual effects (both short and long term) persisting after the drug has left the
central nervous system. The studies meeting the inclusion criteria examined marijuanas
residual effects.
Three studies on cognitive impairment met the inclusion criteria. Marijuana does not appear to
grossly affect cognitive functions, although depending on the instrument used, it is possible to
detect subtle impairments in intellectual and executive function with chronic marijuana use. It is
not clear whether there is a dose-response relationship.
The clinical and work-related implications of these findings are unclear, due to the many
confounding variables, to the fact that acute cognitive effects of marijuana were not addressed

16

by the studies meeting the inclusion criteria, and to difficulty in applying results derived from the
cognitive testing instruments to tasks performed in the workplace.
Reproductive effects of marijuana
Four epidemiological studies of the effects of marijuana smoking on reproduction met the
inclusion criteria. Their results were mixed and conflicting.
Both the adverse reproductive outcomes and the prevalence of heavy marijuana use are
relatively rare events, so unless marijuana produces a large effect, very large sample sizes
would be required to detect adverse effects of cannabis. There may also be difficulties in
identifying marijuana smokers among pregnant women: the stigma associated with illicit drug
use may discourage honest reporting (Hall 1994).
Studies were confounded by concomitant use of tobacco, alcohol and other illicit drugs and
there was a lack of control for income status, education and nutrition. These are all factors
known to be associated with poorer obstetrical outcomes. Sources of confounding make it
difficult to unequivocally attribute any relationship between reproductive outcomes and
marijuana use to marijuana per se. The clinical significance of the singular effects of marijuana
use remains unclear since these effects were small when compared with the effects of maternal
tobacco use.
Marijuana and schizophrenia
The association between marijuana and schizophrenia is not well understood. One study about
marijuana and schizophrenia met the inclusion criteria. Increased use of cannabis may be a
marker for schizophrenia, but it could not be determined from this study whether the relationship
was correlational or causal.
Psychomotor impairment
The major potential health risk from the acute use of herbal marijuana (both for the user and for
the public) appears to arise from its effects on psychomotor performance.
Marijuana produces dose-related impairments in cognitive and behavioral functions that may
potentially impair driving a motor vehicle or operating machinery but the extent to which
cannabis contributes to traffic accidents is unknown. There are serious problems of causal
attribution. Results of the three studies meeting the inclusion criteria were equivocal because
most drivers who had cannabinoids in their blood also had high blood alcohol levels. The main
effect of marijuana use on driving may be to amplify the impairments caused by alcohol, which
is often used with the marijuana. Marijuana use may also impair users appraisal of their motor
skills. Decreased performance on a complex task (simulated landing of an airplane) was not
noticed by participants, and patients with multiple sclerosis reported improvements in
coordination despite any objective clinical improvement.
Smoking marijuana
Given the well-known consequences of smoking tobacco, it seems logical to suspect that
chronic marijuana smoking could also be detrimental to the respiratory system.

17

Marijuana contains some 400 chemical compounds that convert into more than 2000
substances when the plant material is burned, including carcinogens like benzene and
benzopyrene (Voelker 1994, PSFC 2002). Marijuana joints have been shown to deliver at
least four times as much tar to the lungs as tobacco cigarettes of equivalent weight. This
difference is due to the lack of filters on joints and because marijuana smokers typically inhale
a larger volume of smoke and take it more deeply into the lungs than do tobacco smokers.
Marijuana smokers also tend to hold smoke in for a time before exhaling, further increasing
exposure to smoke and volatile toxins (Joy 2001).
On the other hand, because they are more tightly packed, commercial tobacco cigarettes
produce more smoke than hand rolled marijuana cigarettes. Most tobacco users typically
smoke more cigarettes per day than their marijuana-using counterparts. Therefore, most
tobacco users take far more smoke into their lungs than people who smoke marijuana
exclusively (Joy 2001).
Since an estimated 70% of marijuana users also smoke tobacco, it is difficult to conduct
epidemiological studies that isolate the effects of marijuana on the respiratory system (Joy
2001).
In principle, the respiratory risks of cannabis smoking could be eliminated if cannabis users
adopted the oral route. This seems unlikely to happen, however. Most long term users have
experimented with ingested marijuana but continue to smoke it because it is a more efficient
way to use cannabis and an easier way to titrate their dose of THC (Hall 1998). Onset of
psychoactive and other pharmacologic effects of marijuana is rapid after smoking: THC in the
form of an aerosol in the inhaled smoke is absorbed within seconds. In contrast, maximum THC
and other cannabinoid levels are only reached one to three hours after ingesting marijuana.
Marijuana research: challenges and limitations
Marijuana research poses many challenges: one researcher has commented that designing a
trial of herbal marijuana that will yield meaningful data is a trial in itself (Voelker 1994).
Assessment of potential harm: challenges and limitations
Evaluation of the health hazards of herbal marijuana is difficult for a number of reasons. Causal
inferences about the effects of drugs on human health are difficult to make, especially when
there is a long interval between use and alleged ill effects. Doses of illicit drugs consumed over
periods of years are difficult to quantify because of the varied strength of black market drugs,
the dependence on subjective retrospective estimation of use and the stigma attached to
admitting to illicit drug use. Interpretation is further complicated by correlations between
marijuana, alcohol, tobacco and use of other illicit drugs.
Assessment of potential benefit: challenges and limitations
General research problems
Most human studies administered marijuana to relatively young, medically screened, healthy
male volunteers well experienced in the effects of marijuana. Females rarely participated in
marijuana research completed to date (NIH 1997).

18

In many instances research protocols to study marijuanas effects were required to use
participants who already had experience with marijuana. In other cases, those who might have
had adverse reactions to marijuana chose not to participate in this type of study or were
screened out by the investigator. The incidence of adverse reactions to marijuana that might
occur in people with no marijuana experience therefore cannot be estimated from these studies.
The "dose regimen" used for laboratory studies is another complicating factor. In most
instances, laboratory research studies have looked at the effects of one or two "doses" of
marijuana. These effects may well be different from those observed when the drug is taken
repeatedly for a chronic medical condition (Joy 1999).
Research problems that arise because marijuana is dried plant material
THC given orally alone in its pure form is the most thoroughly researched cannabinoid. Much of
what is written about the clinical pharmacology of crude herbal marijuana is actually inferred
from the results of experiments using only the pure drug molecule THC. The result of this
strategy is that a good deal is known about the pharmacology of ingested THC, but
experimental confirmation that the pharmacology of a smoked marijuana cigarette is indeed
entirely or mainly determined by the amount of THC it contains remains to be completed.
Generally, in experiments actually using herbal marijuana, the assumed "dose" of herbal
marijuana is based only on the concentration of THC in the dried plant material. The amounts
of cannabidiol and other cannabinoids in the plant also vary, however, and pharmacologic
interactions modifying the effects of THC may occur when herbal marijuana is used instead of
pure THC (NIH 1997). Furthermore, the compounds in smoked marijuana differ substantially
from the compounds in the unburned plant material.
Dose is defined as the quantity (weight) of a pure drug molecule administered to a subject at a
given time. Standardizing "marijuana dosage" is difficult. The potency of the plant material
used in research studies is variable. Most of what is known about the pharmacology of smoked
herbal marijuana comes from experiments with plant material containing about 2% THC, which
is less than the THC concentrations commonly found in marijuana today. Average
concentrations are significantly higher and some samples have tested at up to 35% THC
(Gieringer 1999). Thus a cigarette containing one gram of marijuana might contain anywhere
from 20 mgs of THC to 350 mgs of THC - an exceptionally wide variation.
Clinical trials carried out on herbal marijuana are unreliable if the sample has not been assayed
for active constituents. Not only would the dose of active component(s) be unknown or
unstandardized, other constituents might have a modifying effect, either directly or by altering
the pharmacokinetic parameters of the principal constituents, and mistakes have been made in
using unstandardized samples for clinical testing (Williamson 2000).
Research problems that arise because smoking is the common means of drug delivery
Besides potency of marijuana, other factors influence the amount of THC received in marijuana
smoke and produce significant changes in post-smoking plasma THC levels. Subjects smoking
behavior during an experiment is difficult for a researcher to control and may vary considerably
based on subjects' prior experience with marijuana. Variables like puff volume, breath-hold
duration, number of puffs, inter-puff interval and inhalation volume (Azorlosa 1995) are not
easily quantified. A marijuana researcher attempting to control or specify the THC dose in a

19

pharmacologic experiment with smoked marijuana has only partial control over drug dose
actually delivered (NIH 1997).
As with any smoked drug (e.g. nicotine or cocaine) characterizing the pharmacokinetics of THC
and other cannabinoids from smoked marijuana is a challenge. Puff and inhalation volumes
change with the phase of smoking, tending to be highest at the beginning and lowest at the end
of smoking a marijuana cigarette. During smoking, as the cigarette length shortens, the
concentration of THC in the remaining marijuana increases; thus each successive puff contains
an increasing concentration of THC. One consequence of this process is that an experienced
marijuana smoker can regulate almost on a puff by puff basis the dose of THC delivered to
lungs and brain to obtain the desired psychological effects and avoid overdose and/or minimize
the undesired effects. A less experienced smoker is more likely to overdose or underdose (NIH
1997).
Research problems that arise because marijuana has pronounced psychoactive effects
Objective measurement of positive therapeutic effect is difficult. A blinded study is problematic
with a psychoactive drug like marijuana, especially if the study involves subjects with previous
marijuana experience. One researcher gave up and simply noted that no placebo was used,
since prior studies using the same cigarette found that 90% of the subjects could identify the
active drug (Yesavage 1985).
At the same time, there is uncertainty and disagreement about whether it is necessary or
possible to distinguish between marijuana's psychoactive and purported therapeutic effects
(Appendix G). It the context of this debate, it may be useful to note that although in the 1970s
academic and pharmaceutical researchers made extensive attempts to develop new chemically
modified cannabinoid molecules that separated the desired therapeutic effects from the
psychoactive properties of these substances, so far no such compound has been discovered
(HLSCST 1998 Sec. 3.11).
III. PRESCRIBING MARIJUANA: CHALLENGES AND LIMITATIONS
Many of the factors that complicate marijuana research are also problematic for the medical
practitioner who must decide whether to "prescribe" marijuana.
The concept of a predictable, quantifiable "dose" is a fundamental principle of medical therapy.
Physicians are required to have knowledge of the amount of the pure drug compound in a
medication, its uptake, distribution, absorption in the target tissue, its metabolism, half-life,
metabolic products and interactions with other compounds, particularly with other medications.
Few (if any) of the prescribing criteria of medical pharmacology can be met in the case of
smoked or ingested herbal marijuana: marijuana contains a variable mixture of poorly defined
biologically active compounds and the level of its active ingredient (9-tetrahydrocannabinol or
THC) fluctuates significantly between samples and is impossible to quantify by inspection.
The medical practitioner considering "prescription" of marijuana faces additional irregularities.
Marijuana has not been reviewed for safety or effectiveness by health Canada and is not an
approved therapeutic product in Canada. Moreover, the evidence necessary to make informed
medical decisions about the relative harm and potential therapeutic value of marijuana is
lacking.

20

IV. MARIJUANA FOR INJURED WORKERS:

POTENTIAL THERAPEUTIC APPLICATIONS
Two conceivable therapeutic applications of marijuana for injured workers are glaucoma that is
unresponsive to conventional therapy and chemotherapy induced nausea and vomiting that is
unresponsive to conventional therapy. A review of WCB-Alberta electronic claims data did not
identify any cases that meet these criteria.
Injured workers who experience chronic pain unresponsive to conventional therapy may raise
questions about "medicinal" use of herbal marijuana. Scientific evidence of the effectiveness of
marijuana as a therapy for chronic pain, however, does not currently exist.
V. CONCLUSION
Systematic review of the literature revealed that scientific knowledge about herbal marijuana is
incomplete, with insufficient evidence to determine its therapeutic potential or harmful effects.
There were few studies that met the reviews quality inclusion criteria and that suggested
medical utility of smoked herbal marijuana for some conditions. These studies yielded low level
evidence of questionable clinical importance and with dubious applicability to medical issues
related to the workplace.
Smoking marijuana is reported to reduce intraocular pressure in glaucoma and to ameliorate
pain, nausea, multiple sclerosis spasticity and asthma. The evidence, however, comes from
small randomized control trials or case-control studies that are characterized by surrogate or
short term outcome assessments, comparisons to out-dated standards of care and lack of
consideration or measurement of benefit to harm relationships associated with long term inhaled
marijuana use.
Furthermore, there have been significant advances in approved therapies since the 1970s and
1980s, and herbal marijuana does not appear to provide treatment options not currently
available with approved pharmaceutical drugs. The paucity and poor quality of the evidence
make it difficult to compare herbal marijuana with current pharmaceutical drugs that have
received regulatory approval under much more rigorous experimental conditions.
Although the evidence for health risks associated with inhaled herbal marijuana smoke had
similar methodological limitations, the benefit to harm relationship of such long term use in
chronic, non-terminal or life or limb threatening conditions remains uncertain and concerning.
Identified risks associated with herbal marijuana use include impairment of motor skills and
driving ability with an increased risk of motor vehicle accident culpability (particularly if
marijuana and alcohol are used together), respiratory tract irritation (apparently reversible if
cannabis use is not prolonged), possible increased risk of aerodigestive cancers (especially if
there is associated tobacco use) and the possibility of subtle cognitive impairment (of unknown
reversibility) if marijuana use is long-term.
Scientific knowledge about herbal marijuana is incomplete and appropriate rigorous randomized
controlled studies are needed to answer questions about marijuana's therapeutic potential.
Clinical trials of herbal marijuana are currently underway (Appendix H). As the results of each
new trial become available, the study's "level of evidence" should be determined, and the

21

validity of its results, including clinical importance and applicability to Alberta's injured workers,
should be critically appraised.
There is presently insufficient evidence to treat marijuana as a "prescribable" drug.

22

APPENDIX A: ORGANIZATIONAL STATEMENTS

In November 1996, California voters enacted an initiative measure entitled the Compassionate Use Act of 1996. To ensure that
seriously ill Californians have the right to obtain and use marijuana for medical purposes, the statute created an exemption to
California laws prohibiting the possession and cultivation of marijuana. Over the next five years, voters in Connecticut, Louisiana,
New Hampshire, Ohio, Vermont, Virginia, Arizona, Alaska, Oregon, Nevada and Washington enacted "medical marijuana" initiatives.
In July 2001, Canada became the first country in the world to adopt a federal system regulating the use of herbal marijuana for
"medicinal purposes," codified in the Marihuana Medical Access Regulations (the Regulations). In order for a patient to qualify, a
physician must complete and sign a medical declaration indicating the nature of the symptom for which he or she is recommending
marijuana. The physician must also specify a marijuana dosage," (defined by Health Canada by weight of dry plant material) and a
route and form of administration to the patient.
Use of marijuana for medicinal purposes is controversial, and many questions about "prescribing" marijuana remain unanswered.
Excerpts from statements made by of a number of North American organizations and agencies follow: organizations representing
physicians, organizations regulating physicians, governmental agencies and patient advocacy groups.

23

GOVERNMENTAL AGENCIES
Agency

Statement (excerpt)

Health Canada

. . . due to the health risks associated with the smoked form in particular, and due to the lack of evidence supporting the
claimed health benefits, access to marihuana will be granted under these Regulations in special medical circumstances only
. . . The requirements will range from minimal, in the case of terminal illness situations, to more substantive for non-terminal
illness cases where little or no conclusive scientific evidence exists . . .
Marihuana has not been reviewed for safety or effectiveness and has therefore not been approved for sale as a drug in
Canada or any other country. Most scientific experts assert that marihuanas future as a drug lies primarily in its
pharmacologically active components, the cannabinoids. These chemicals can be isolated, subjected to scientific scrutiny
and potentially developed as standardized pharmaceutical drug products . . . Much of the evidence of the potential
therapeutic effects of smoked marijuana is heavily anecdotal. Scientific studies supporting the safety and efficacy of
marihuana for therapeutic use are often inconclusive (HC-RIAS 2001).

Canadian Institutes of
Health Research

. . . evidence of potential therapeutic effect of smoked marijuana is heavily anecdotal. While there are reports of the
therapeutic value of smoked marijuana, scientific studies supporting the safety and efficacy of marijuana for therapeutic
claims are inconclusive . . . based on existing data, the use of smoked marijuana for therapeutic indications should not be
considered outside of controlled clinical trials (CIHR 2000-2001).

24

ORGANIZATIONS REGULATING CANADIAN PHYSICIANS: COLLEGES OF PHYSICIANS AND SURGEONS

College

Statement (excerpt)

College of Physicians
and Surgeons of
British Columbia

The alleged medical benefits of smoked marijuana are hitherto unproven and are based on anecdotal information . . . The
lack of availability of credible scientific information on the indications for smoked marijuanas medicinal use, together with the
absence of information on the risks and benefits of the substance, make it questionable, if not dangerous, for physicians to
prescribe this agent for their patients. Little is known about the interaction of this agent with other drugs or medications. Its
analgesic effects alone are reported to be no better than codeine. What is known is that THC potentiates the analgesic
action of narcotics many-fold. That fact alone requires that it be used very cautiously and may indicate a potential for harm.
Marijuana is also known to create dependency or to be addictive for a significant number of its users.
Physicians are advised that they should not prescribe any drug for their patients without knowing the risks, benefits, potential
complications and drug interactions associated with the use of that agent. Currently, that would certainly include marijuana
in its smoked form, where it may cause significant harm. Furthermore, physicians may be the subject of accusations or
suggestions of negligence, including liability, if a prescribed drug, including prescribed marijuana, produces unforeseen
negative effects. . . The regulations for prescribing marijuana recently published by Health Canada do not take into account
the requirement for physicians to follow evidence based protocols and guidelines in providing care for their patients.
Smoked marijuana has not been the subject of the investigative protocols and the pre-public release requirement required
for all new drugs (VanAndel 2001).

College of Physicians
and Surgeons of
Manitoba

The alleged medical benefits of smoking marijuana are not proven and are based mainly on anecdotal information. There
are three categories of symptoms for which marijuana may be prescribed for medicinal purposes, yet the extensive list of
conditions which arise out of these three categories encompasses medical conditions for which there is not good scientific
evidence supporting the use of marijuana. . . Based on the available scientific evidence, the medicinal use of smoked
marijuana is at present generally without valid scientific foundation and physicians should not feel obligated to recommend,
support or prescribe this substance (CPSM 2001).

Collge des
mdecins du Qubec

The federal government seems to have forgotten that the physician is a scientist who treats patients using methods that
have been subjected to tried and tested procedures. Indeed, the new Marijuana Medical Access Regulations are the
outcome of a court decision, and not scientific evidence. Physicians need not respond to politico-legal trickery or involve
themselves in this issue as long as there are no precise data on the posology, safety, and effectiveness of this treatment.
Yet, the Minister of Health seems to have foisted this hot potato on them (Lamontagne 2001).

25

ORGANIZATIONS REPRESENTING CANADIAN PHYSICIANS

Medical Association
or Organization

Statement (excerpt)

Alberta Medical
Association

These regulations announced by Health Canada are unacceptable because there has not been thorough and rigorous
scientific testing. This, in turn, may negatively affect the physician-patient relationship: patients may believe that they could
benefit from use of marijuana for one of a number of conditions, or that they may be able to obtain marijuana for recreational
use through their physician. There are several reasons why the AMA finds these new regulations unacceptable: this method
of treatment is not evidence-based and has not yet had any rigorous testing of long-term implications, there are no clinical
practice guidelines in place for the medicinal use of marijuana including appropriate dosage, physicians have no way of
knowing product potency (or consistency of same), and they place physicians in an untenable position (Steed 2001).

Canadian Medical
Association

The CMA supports access to any therapy proven safe and effective and manufactured with appropriate diligence. I also
want to make clear that we understand the needs of those individuals who may have gained, or hope to gain, benefit from
the use of marijuana to ameliorate medical symptoms or who have exhausted other proven therapies. We recognize that a
regulatory scheme for medicinal use of marijuana must exist. However, these regulations are placing Canadian physicians
and their patients in the precarious position of attempting to access a product that has not gone through the normal
protocols of rigorous pre-market testing (Barrett 2001).

Canadian Medical
Protective
Association

The CMPA believes the medical declarations under the regulations place an unacceptable burden on member physicians to
inform themselves as to the effectiveness of medical marijuana in each patients case, as well as the relative risks and
benefits of the drug and what dosage would be appropriate. This information is simply not available. In medicine,
knowledge is typically derived from clinical trials, of which we understand there are very few for marijuana. Given the fact
that many physicians would not have the necessary knowledge about the effectiveness, risks or benefits of marijuana, we
believe it is unreasonable to make physicians gatekeepers in this process (Gray 2001 Nov).

26

ORGANIZATIONS REPRESENTING CANADIAN PHYSICIANS (continued)

Medical Association
or Society

Statement (excerpt)

Canadian Society of
Addiction Medicine

Although there is anecdotal, pre-clinical and limited controlled evidence that cannabis products may be effective in some
conditions . . . this evidence is weak and existing studies have demonstrated significant side effects. There are alternative
therapies that have less risk of side effects for these conditions. Cannabis products are not first-line treatment for any
known medical condition. Therefore, our Medicinal Use of Cannabis Products Policy Statement is:
Currently, available scientific information and clinical practice experience indicate that overall, there is more risk than benefit,
in the use of cannabis products for medicinal purposes. Ongoing well-designed clinical research into the possible medicinal
uses of cannabis products is essential, using the same rigorous standards that are applied to any therapeutic agent prior to
its introduction into general clinical practice (CSAM 1999).

Physicians for a
Smoke-Free Canada

Based on Health Canada's literature and the independent evidence available linking marijuana smoke to acute and chronic
health problems, the following conclusions can be drawn:
. . . Given the lack of substantial scientific data regarding the benefits of specific chemical compounds contained in
marijuana, marijuana cannot be considered a medicine in the conventional sense.
When considering applications for CDSA exemption, physicians cannot in good faith testify that the benefits of treatment
with marijuana outweigh the risks.
The health risks associated with smoking marijuana are an appropriate reason for physicians to deny patients access to
marijuana for medicinal purposes (PSFC 2002).

Ontario Medical
Association

The Ontario Medical Association strongly objects to the Marijuana Medical Access Regulations . . . as they have the
potential to compromise patient safety and are not grounded in science. The medicinal use of marijuana should not be
expanded without proper scientific evidence of its benefits. These regulations are inconsistent with Health Canadas
process of approving pharmaceuticals, which requires thorough scientific research before making drugs available to
patients. The lack of sound research seriously compromises the physicians ability to appropriately advise patients (OMA
2001).

27

ORGANIZATIONS REPRESENTING AMERICAN PHYSICIANS

Medical Association
or Academy

Statement (excerpt)

American Academy
of Ophthalmology

Based on reviews by the National Eye Institute (NEI) and the Institute of Medicine on available scientific evidence, the Task
Force on Complementary Therapies believes that no scientific evidence has been found that demonstrates increased
benefits and/or diminished risks of marijuana use to treat glaucoma compared with the wide variety of pharmaceutical
agents now available (AAO 1999).

American Medical
Association

The AMAs House of Delegates recently rejected a committee report that would have urged the organization to consider
compassionate use of medical marijuana for cancer and other patients. The AMA declared that the scientific evidence was
lacking to prove marijuanas usefulness in relieving symptoms like nausea in cancer patients and spasticity in MS patients . .
. AMA Trustee Dr. Herman Abromowitz stated: To endorse something on the basis of anecdotal comments is not our
policy" (Stern 2001, Susman 2001).

California Medical
Association

CMA has consistently maintained its position that cannabis should be available for therapeutic use as a Schedule II drug
only if there are properly controlled studies proving it is efficacious. CMA believes that seriously ill patients should not be
offered a treatment whose efficacy may be illusory and which in some cases may actually worsen the patients medical
condition. Therefore, CMA has opposed the medicalization of cannabis unless and until there is objective proof that such
use is scientifically justifiable (CMALC 2001).

28

PATIENT ADVOCACY GROUPS

Patient Advocacy
Group

Statement (excerpt)

American Cancer
Society

Though marijuana smoke delivers THC and other cannabinoids to the body, it also delivers harmful substances, including
most of those found in tobacco smoke. In addition, plants contain a variable mixture of biologically active compounds and
cannot be expected to provide a precisely defined drug effect. For these reasons, chemically-defined drugs that act on the
cannabinoid receptors of the brain are likely to provide the safe and most effective cannabinoid . . . The American Cancer
Society does not advocate the use of inhaled marijuana or the legalization of marijuana (ACS 1999).
In an article entitled Experts: Pot Smoking is not Best Choice to Treat Chemo Side-Effects, Dawn Willis, director of research
and communication for the American Cancer Society noted that considering that many cancer patients undergoing
chemotherapy today will survive their disease, patients would be unwise to increase risk of another cancer by smoking
marijuana" (ACS 2001).

Canadian Cancer
Society

The Canadian Cancer Society supports the government in its efforts to provide clear criteria so that patients who qualify to
use marijuana to alleviate symptoms of cancer or side effects of treatment will be permitted to do so. Whether or not a
person chooses to use marijuana to help them with their experience with cancer is an individuals choice and the Society
encourages people to discuss this with their doctor (CCS 2001).

National Multiple
Sclerosis Society
(US)

In a 1997 statement, the National Multiple Sclerosis Societys Medical Advisory Board indicated that neither marijuana nor
its active ingredient can be recommended as a treatment for symptoms of MS. Studies done to date have not provided
convincing clinical evidence of benefit. Side effects, including memory impairment and personality change have been noted.
Individuals concerned about the medicinal use of marijuana for MS should consult their personal physicians (NMSS 1999
Mar).
In the summer of 1999, Dr. Nancy Holland, vice president of Clinical Programs at the Society noted that since multiple
sclerosis is a lifelong chronic illness, not a terminal disease like AIDS, or a short-term crisis like severe nausea from cancer
chemotherapy, the health dangers of smoked marijuana are significant for people with MS. We urge people to explore other
options for managing spasticity while research pushes forward for answers about the potential of the cannabinoids. We
hope this question will be settled by medical science, not by court cases or politics she said (King 1999).

29

APPENDIX B: STUDY DESIGNS

Studies may be classified into three broad groups by study design: experimental studies,
observational studies and exploratory studies.
Experimental studies are also known as intervention studies or clinical trials. These are
prospective studies involving human subjects designed to answer specific questions about the
effects or impact of a particular biomedical intervention. Randomized Controlled Trials (RCTs)
are part of this group.
The outcome of a well designed clinical trial involves objective measurements whenever
possible, using predetermined outcome measures or endpoints. The success or failure of
the trial is measured by criteria established in a written protocol before the start of the trial.
The trial should include a sufficiently large number of subjects to provide statistically
significant differences in outcome measures between placebo and drug-treated groups.
Observational studies explore a topic in order to generate basic statistics and hypotheses.
Cross sectional studies, cohort studies and case control studies are part of this category.
Exploratory studies generate hypotheses for further and scientifically rigorous investigation.
Case series and case reports, which look at individuals who manifest a particular health
problem, are part of this category.
Higher grades of evidence are more likely to reliably predict outcomes. Inferences about
therapy, for example, may be very strong if the results come from a systematic review of well
designed, methodologically strong RCTs with consistent results. They are somewhat weaker if
they are made based on a single RCT, unless it is very large and has enrolled a diverse patient
population. Because observational studies may under (or more typically over) estimate
treatment effects in an unpredictable fashion, their results are far less trustworthy than those of
RCTs. Unsystematic clinical observations (case series and case reports) provide the weakest
inferences about treatment effects. Much of the evidence regarding the harmful effects of a
therapy come from observational studies (Guyatt 2000).

30

APPENDIX C. Comprehensive Reviews

Based on exhaustive reviews of the scientific evidence, six panels of scientific and medical experts have released major reports on the subject of medicinal use of
herbal marijuana and purified cannabinoids in the last five years. In January 1997, the White House Office of National Drug Policy asked the Institute of Medicine
(IOM) to conduct a review of the scientific evidence to assess the potential health benefits and risks of marijuana and its constituent cannabinoids. That review
began in August 1997 and culminated with a report issued in 1999, Marijuana and Medicine, Assessing the Science Base (Joy 1999). Widely regarded as the
landmark study on the issue, it is being used to guide medical research around the world. The most recently updated report is the AMAs document, based on a
review of the literature current to April 2001.
Reports are summarized below in tabular form, including their findings on marijuana's potential harms and possible therapeutic effects. Each of these reports was
written for a different purpose, but all reached the same general conclusions regarding herbal marijuana: while in certain dosage forms it may be moderately
effective in treating a variety of symptoms, more research on the medical use of marijuana is needed, and the use of whole and/or smoked marijuana as a
medicine is not recommended. The table below is adapted from Marijuana as Medicine? The Science Behind the Controversy (Joy 2001).

CANNABINOIDS AND MARIJUANA: RECENT CONCLUSIONS OF PANELS OF SCIENTIFIC AND MEDICAL EXPERTS

Reviewing Agency
American Medical
Association
2001 update
1997 report

Institute of Medicine
(US) 1999

UK Parliament
House of Lords Select
Committee on Science
and Technology
1998

Conditions
recommended for
treatment in clinical trials
of smoked marijuana

Promising targets for

cannabinoid drugs

Recommended research
on potential harms of
marijuana and
cannabinoids?

Use of whole and/or

smoked marijuana as a
medicine

Primary goals of
cannabinoid drug
development

Smoke-free inhaled
delivery system for
marijuana and
cannabinoids

Various, including AIDS,

wasting, chemotherapyinduced nausea and
vomiting, MS, spinal
cord injury, neuropathy,
or chronic pain

Various, including
nausea and vomiting,
wasting, pain

Multiple sclerosis,
chronic pain

Not discussed

None recommended

Not recommended

Various, including
nausea and vomiting,
wasting, pain, and
spasticity

Yes, especially on
smoking-related harms

Whole marijuana is not

a modern medicine

Not discussed

None recommended

Hazards of marijuana
smoke noted

Safe, reliable, rapidonset delivery method

for cannabinoids

Rapid-onset, smoke-free
delivery systems (e.g.,
inhalation, under the
tongue, and rectal
suppositories)

31

Reviewing Agency

World Health
Organization
1997

National Institutes of
Health (US)
1997

British Medical
Association
1997

Conditions
recommended for
treatment in clinical trials
of smoked marijuana

Not discussed
Wasting, chemotherapyinduced nausea and
vomiting, neurological
and movement
disorders, glaucoma

Not discussed

Promising targets for

cannabinoid drugs

Nausea and vomiting;

spasticity

Nausea and vomiting,

neuropathy, possibly
muscle spasticity,
certain dystonias and
epilepsy

Muscle spasticity,
neurodegenerative
disorders, epilepsy

Recommended research
on potential harms of
marijuana and
cannabinoids?

Use of whole and/or

smoked marijuana as a
medicine

Primary goals of
cannabinoid drug
development

Various, including
infertility, respiratory
damage, immune
dysfunction,
schizophrenia, and
antimotivational
syndrome

Hazards of marijuana
smoke noted

Not discussed

None recommended

Should be held to same

standards of safety and
efficacy as FDAapproved drugs

Smoke-free inhaled
delivery systems for
marijuana and
cannabinoids

Cigarettes and crude

marijuana preparations
should not be used
None recommended

Novel cannabinoid
analogs for new uses

Report of the Council on Scientific Affairs. 1997. Report to the AMA House of Delegates. Subject: Medical Marijuana. Updated with a review of articles published between 1997 and
April 2001 in Report 6 of the Council on Scientific Affairs (A-01).
Institute of Medicine. 1999. Marijuana and Medicine: Assessing the Science Base.
th

House of Lords (UK Parliament). 1998. Science and Technology Committee 9 Report. Cannabis: The Scientific and Medical Evidence. London: Her Majestys Stationary Office.
National Institutes of Health. 1997. Workshop on the medical utility of marijuana. Bethesda, Maryland: National Institutes of Health.
British Medical Association. 1997. Therapeutic uses of cannabis. Harwood Academic Publishers, United Kingdom.

32

APPENDIX D
Levels of evidence summary for therapy harm or causation
Grade of Recommendation

Level of
Evidence

Type of Study

Study characteristics

1a

Systematic review (with

homogeneity) of RCT

A systematic summary of the medical literature that

uses quantitative methods to summarize the results

1b

Single RCT with narrow

Confidence Interval

Randomized controlled trial. A group of patients is

randomized to either experimental or control groups,
which are followed for the variables or outcomes of
interest

1c

All-or-none case series

Where all patients die or fail without intervention and

some survive or succeed with it

2a

Systematic review (with

homogeneity) of cohort studies

2b

Cohort study or poor quality or

under-powered RCT (e.g. <80%
follow-up)

Identification of two groups of patients, one of which

did receive exposure of interest and one of which did
not and following these cohorts forward in time for the
outcome of interest

2c

Outcomes research

Observation of a defined population at a single point in

time or time interval. Exposure and outcome are
determined simultaneously

3a

Systematic review (with

homogeneity) of case-control
studies

3b

Case control study

Study that identifies patients who have the outcome of

interest (cases) and a control group of patients who
have not had the outcome of interest, and looks
retrospectively to see if they had the exposure of
interest.

Case-series

A report on a series of patients with an outcome of

interest. No control group involved.

Expert opinion without explicit

critical appraisal or based on
physiology or bench research

Homogeneity means that a systematic review is free of heterogeneity in the directions and degrees of results between individual
studies.

33

APPENDIX E
Worksheet for Using an Article About Causation of Harm
Citation: ________________________________________________________________
Grade/level of evidence: ____________________________________________
1. Are the results of the study valid? (yes/no/cannot tell)
A. Were there clearly identified comparison groups that were similar with respect to
important determinants of outcome, other than the one of interest? (RCT, cohort,
case-control? Other known prognosis factors similar or adjusted for?)
B. Were the outcomes and exposures measured in the same way in the groups being
compared? (Recall bias? Interviewer bias? Exposure to opportunity similar?)
C. Was follow-up sufficiently long and complete? (Reasons for incomplete follow-up?
Risk factors similar in those lost and not lost to follow-up?)
D. Is the temporal relationship correct? (Exposure preceded outcome?)
E. Is there a dose-response gradient? (Risk of outcome increases with quantity or
duration of exposure?)
F. Overall, are the results of the study valid?
2. What are the results?
A. How strong is the association between exposure and outcome? Relative Risk?
Odds Ratios?
B. How precise is the estimate of risk? (Confidence intervals?)
3. Will the results help in patient care?
A. Are the results applicable to injured workers in Alberta? Patients similar for
demographics, morbidity and other prognostic factors? Are treatments and exposures
similar?
B. What is the magnitude of the risk? Absolute risk increase (and its reciprocal)?
C. On this basis should one attempt to stop the exposure? Strength of evidence?
Magnitude of risk? Adverse effects of reducing exposure?
Based on a worksheet developed by the Evidence Based Medicine (EBM) Working Group. A complete list of members (with
affiliations) of the EBM Working Group appears in the first article in the "Users' Guides to the Medical Literature" series, JAMA 1993;
270:2093-2095).

34

APPENDIX F
Worksheet for Using an Article About Therapy or Prevention
Citation: ________________________________________________________________
Grade/level of evidence: ____________________________________________

1. Are the results valid? (yes/no/cannot tell)

A. Was the assignment of patients to treatment randomized?
B. Where all patients who entered the trial properly accounted for and attributed at
its conclusion? Was follow-up complete? Were patients analyzed in the groups to
which they were randomized? Intention to treat analysis used?
C. Were patients, their clinicians and study personnel blind to treatment?
D. Were the groups similar at the start of the trial? Baseline prognostic factors
(demographics, co-morbidity, disease severity, other known confounders) balanced? If
different, were these adjusted for?
E. Aside from the experimental intervention, were the groups treated equally? Cointervention? Contamination? Compliance?
2. What are the results?
A. How large is the treatment effect? Absolute risk reduction? Relative risk reduction?
B. How precise is the estimate of the treatment effect? Confidence intervals?
3. Will the results help in patient care?
A. Can the results be applied to injured workers in Alberta? Patients similar for
demographics, severity, co-morbidity and other prognostic factors? Compelling reason
why they should not be applied?
B. Were all clinically relevant outcomes considered? Are substitute endpoints valid?
C. Are the benefits worth the harms and costs? Number needed to treat for different
outcomes?
Based on a worksheet developed by the Evidence Based Medicine (EBM) Working Group. A complete list of members (with
affiliations) of the EBM Working Group appears in the first article in the "Users' Guides to the Medical Literature" series, JAMA 1993;
270:2093-2095).

35

APPENDIX G: PSYCHOACTIVE EFFECT / THERAPEUTIC EFFECT

There is uncertainty and disagreement about whether it is necessary or possible to distinguish between
marijuana's psychoactive and purported therapeutic effects.
The psychoactive effects of cannabis including euphoria, anxiety reduction and sedation reportedly do
make some patients feel better. Marijuana diminishes to a large extent the subjective feeling of being ill
(Neelman 1996) and some contend that the marijuana high should be considered an integral part of
marijuana's therapeutic value:
My mom and I both have MS, and both live in Canada. Neither of us is applying for an exemption
because neither of use is sufficiently ill or sufficiently harmed by conventional pharms to make a
workable case for our MDs to back us . . . so we both smoke in fear . . . I think anyone with MS
should automatically qualify. It just adds so immensely to my overall sense of well being (NYT-DPF
2001).
Dr. Mark Ware, a researcher heading an ongoing McGill University Pain Centre study of the benefits of
cannabis as a pain reliever, stated:
I dont think theres any reason why we should consider getting high as a negative side effect in
patients who are feeling dreadful, depressed and in a lot of pain and really suffering. Something
which may reduce pain and make them feel better is not a bad thing (Nestruck 2001).
An editorial in the New England Journal of Medicine argues:
what really counts for therapy with this kind of safety margin is whether a seriously ill patient feels
relief as a result of the intervention, not whether a controlled trial proves its efficacy (Kassirer 1997).
Marijuanas known psychoactive effects could be at least partially responsible for the disjunction between
anecdotes about feeling better and the sparse clinical evidence of marijuanas therapeutic value:
while formal clinical research has not conclusively shown that marijuana is effective . . . it appears
that a number of patients who have tried the drug have found relief (Grey 1996).
Skeptics argue that:
it is likely that the self-administration of marijuana smoke produces some or all of its purported
therapeutic benefits through its non-specific reward mechanism (DuPont 1999).
The UK Parliament's House of Lords Select Committee on Science and Technology observed:
it is natural to wonder whether the beneficial effects of cannabis reported by patients might simply be
related to the feeling of well-being caused by the intoxicant properties of the drug (HLSCST 1998
Sec. 5.22).
The British Medical Association notes:
it is somewhat paradoxical that cannabinoids are reported to be of therapeutic value in neurological
disorders . . . since very similar symptoms can be caused by cannabis itself . . . it is not clear how
much of the reputed effects of cannabis in motor disorders are due to psychoactive or analgesic
effects (HLSCST 1998 Sec. 5.23).
In 1997, after an extensive review of the literature, the Health Council of the Netherlands' Standing
Committee on Medicine (HCNSCM) concluded:
the evidence is insufficient to justify the medicinal use of marijuana . . . patients themselves must bear
the full responsibility if they wish to consume marihuana (in whatever form) because it makes them
feel better (HCNSCM 1996).
It the context of this debate, it may be useful to note that although in the 1970s academic and
pharmaceutical researchers made extensive attempts to develop new chemically modified cannabinoid
molecules that separated the desired therapeutic effects from the psychoactive properties of these
substances, so far no such compound has been discovered (HLSCST 1998 Sec. 3.11).

36

APPENDIX H: EXAMPLES OF ONGOING MARIJUANA RESEARCH

Recently there has been renewed interest in research on herbal marijuana. With funding from
Health Canada, for example, in July 2001 the McGill Pain Centre launched a study directed by
Dr. Mark Ware to examine the effects of cannabis on neuropathic pain. The main hypothesis of
the study is that herbal cannabis containing 8% THC is superior to cannabis containing lower
concentrations of THC in reducing chronic neuropathic pain. According to Health Minister Allan
Rock, the clinical trial furthers our compassionate effort to ascertain the potential of marijuana
to provide therapeutic benefit to Canadians" (Desjardins 2001).
In November, 2001, Ronald Ellis, MD and Jody Corey-Bloom, MD, of the University of California
at San Diego Medical Center received final approval from the US federal government to study
the effects of marijuana on patients with multiple sclerosis and those who suffer neuropathy, or
nerve pain, associated with AIDS. The Drug Enforcement Administration (DEA), which granted
the final approval, said it hoped to introduce some science into an emotionally charged debate.
The question of whether marijuana has any legitimate medical purpose should be determined
by sound science and medicine, said DEA administrator Asa Hutchinson (Hettena 2001).

37

ANNOTATED BIBLIOGRAPHY

HERBAL MARIJUANAS THERAPEUTIC POTENTIAL AND HARMFUL EFFECTS

Structured Abstracts of Studies Meeting the Inclusion Criteria
September, 2001

Please note that throughout this bibliography, use of the acronym THC indicates delta -THC.

38

Psychopharmacology 1993;110(1-2):219-28
Effects of chronic marijuana use on human cognition.
Block RI, Ghoneim MM.
Department of Anesthesia, University of Iowa, Iowa City 52242.
BACKGROUND: Impairments of human cognition and learning following chronic marijuana use are of
serious concern, but have not been clearly demonstrated.
OBJECTIVE: To determine whether such impairments occur by comparing the performance of adult
marijuana users and non-users on scores from standardized tests.
DESIGN: Observational cohort study. N: 144 users and 72 non-users.
SETTING: Iowa.
PARTICIPANTS: 144 adult marijuana users and 72 adult marijuana non-users matched on intellectual
functioning before the onset of drug use, i.e., on scores from standardized tests administered during the
fourth grade of grammar school (Iowa Tests of Basic Skills).
MEASUREMENTS: Subjects were given the twelfth grade versions of these tests (Iowa Tests of
Educational Development) and other computerized cognitive tests in successive test sessions.
RESULTS: "Heavy" marijuana use (defined by use seven or more times weekly) was associated with
deficits in mathematical skills and verbal expression in the Iowa Tests of Educational Development and
selective impairments in memory retrieval processes in Buschke's Test. The retrieval impairments were
restricted to words that were easy to visualize. Impairments depended on the frequency of chronic
marijuana use, i.e., "light" and "intermediate" marijuana use (defined by use one to four and five to six
times weekly, respectively) were not associated with deficits. Intermediate use was associated with
superior performance in one condition ("fuzzy" concepts) of a Concept Formation test.
AUTHORS' CONCLUSION: More work is needed to evaluate alternative interpretations of the cognitive
impairments associated with heavy marijuana use.

39

Cancer 1981 Apr 1;47(7):1746-51

A prospective evaluation of delta-9-tetrahydrocannabinol as an antiemetic in patients receiving
Adriamycin and Cytoxan chemotherapy.
Chang AE, Shiling DJ, Stillman RC, Goldberg NH, Seipp CA, Barofsky I, Rosenberg SA.
BACKGROUND: The nausea and vomiting induced by cancer chemotherapeutic agents contributes to
the decreased ability of patients to undergo long-term treatment schedules and impairs quality of life.
OBJECTIVE: To examine the possible significant antiemetic properties of THC in patients receiving a
combination of doxorubicin (Adriamycin) and cyclophosphamide (Cytoxan) chemotherapy.
DESIGN: Experimental - randomized double blind, self-control and placebo-controlled trial of oral THC
and smoked marijuana.
SETTING: Surgery Branch of the National Cancer Institute, Bethesda, Maryland.
PATIENTS: Eight patients ranging in age from 17 58 years (median 41) with soft-tissue carcinomas.
All patients had undergone surgical removal of their primary tumor, were clinically disease free and
receiving adjuvant Adriamycin and Cytoxan chemotherapy.
INTERVENTION: The National Institute on Drug Abuse supplied THC capsules and marijuana cigarettes.
The THC was suspended in sesame oil and placed in gelatin capsules. Identical appearing placebo
capsules contained only sesame oil. The marijuana cigarettes each weighed 900 mg and contained
1.93% THC (approximately 17.4 mg). Identical appearing placebo cigarettes were produced by multiple
2
extractions of natural marijuana with ethanol. THC was administered at a dose of 10 mg/M given orally
every three hours for a total of five doses. In the event of a vomiting episode, the patient was given a
marijuana cigarette for the remaining doses of the trial. Employing a standard inhalation technique
minimized variation of the amount of smoke inhaled by each patient. Placebo drug administration was
handled in a similar fashion. Each patient served as his own control.
MEASUREMENTS: A member of the nursing staff rated the patient every hour by completing an
objective questionnaire, which measured the number of vomiting episodes, number or retching episodes,
volume of emesis, degree of nausea, duration of nausea, and volume of oral intake. Once during each
wakeful hour the patient completed a subjective questionnaire rating the psychological high, degree of
nausea, degree of comfort, and other drug effects.
RESULTS: THC, in comparison with a placebo, did not significantly reduce the number of vomiting and
retching episodes, volume of emesis, degree of nausea, or duration of nausea. In contrast to a previous
report where significant antiemetic effects of THC were observed in patients receiving high-dose
methotrexate, THC did not effectively reduce emesis induced by Adriamycin and Cytoxan.
AUTHORS' CONCLUSION: The findings suggest that the antiemetic properties of THC are effective only
against specific chemotherapeutic drugs.

40

Ann Intern Med 1979 Dec;91(6):819-24

Delta-9-tetrahydrocannabinol as an antiemetic in cancer patients receiving high-dose
methotrexate. A prospective, randomized evaluation.
Chang AE, Shiling DJ, Stillman RC, Goldberg NH, Seipp CA, Barofsky I, Simon RM, Rosenberg SA.
BACKGROUND: Nausea and vomiting are frequent and distressing side effects of cancer chemotherapy.
The severity of these symptoms contributes to the decreased ability of patients to undergo long-term
chemotherapy schedules and impairs their quality of life.
OBJECTIVE: To examine the antiemetic efficacy of oral THC and smoked marijuana.
DESIGN: Experimental - randomized double blind, "self-control" and placebo-controlled clinical trial of
oral THC and smoked marijuana.
SETTING: Surgery Branch of the National Cancer Institute, Bethesda, Maryland.
PATIENTS: Fifteen patients ranging in age from 15 to 49 years (median 24 years) with osteogenic
sarcoma receiving high-dose methotrexate chemotherapy. All patients had undergone surgical removal
of their primary tumor and were disease free upon entry into the study.
INTERVENTION: Patients received THC three times and placebo three times during six subsequent
hospital visits for chemotherapy infusion. The THC was suspended in sesame oil and placed in gelatin
capsules. Identical appearing placebo capsules contained only sesame oil. The marijuana cigarettes
each weighed 900 mg and contained 1.93% THC (17.4 mg). Identical appearing placebo cigarettes were
produced by multiple extractions of natural marijuana with ethanol. The odor and taste of a lit placebo
2
cigarette were identical to those of a marijuana cigarette. THC was administered at a dose of 10 mg/M
given orally every three hours for a total of five doses. In the event of a vomiting episode, the patient was
given a marijuana cigarette for the remaining doses of the trial. Employing a standard inhalation
technique minimized variation of the amount of smoke inhaled by each patient. Placebo drug
administration was handled in a similar fashion. Each patient served as his or her own control.
MEASUREMENTS: A member of the nursing staff rated the patient every hour by completing an
objective questionnaire, which measured the number of vomiting episodes, number or retching episodes,
volume of emesis, degree of nausea, duration of nausea, and volume of oral intake. Once during each
wakeful hour the patient completed a subjective questionnaire rating the psychological high, degree of
nausea, degree of comfort, and other drug effects.
RESULTS: Fourteen of fifteen patients had a reduction in nausea and vomiting on THC as compared to
placebo. THC was significantly more effective than placebo in reducing the number of vomiting and
retching episodes, degree of nausea, duration of nausea, and volume of emesis (P < 0.001). There was a
72% incidence of nausea and vomiting on placebo. When plasma THC concentrations measured < 5.0
ng/mL, 5.0 to 10.0 ng/mL, and > 10.0 ng/mL, the incidences of nausea and vomiting were 44%, 21%, and
6%, respectively.
AUTHORS' CONCLUSION: THC appears to have significant antiemetic properties when compared with
placebo in patients receiving high-dose methotrexate.

41

Arch Gen Psychiatry 1996 Nov;53(11):1051-7

Cognitive correlates of long-term cannabis use in Costa Rican men.
Fletcher JM, Page JB, Francis DJ, Copeland K, Naus MJ, Davis CM, Morris R, Krauskopf D, Satz P.
Department of Pediatrics, University of Texas-Houston Medical School, USA.
BACKGROUND: Cognitive correlates of long-term cannabis use have been elusive.
OBJECTIVE: To test the hypothesis that long-term cannabis use is associated with deficits in short-term
memory, working memory, and attention in a westernized, literate culture (Costa Rica) in which the effects
of cannabis can be isolated.
DESIGN: Observational - cohort study. N: older = 60, younger = 86.
SETTING: San Jos, Costa Rica.
PARTICIPANTS: Two cohorts of long-term cannabis users and non-users were studied. Within each
cohort, users and non-users were comparable in age and socioeconomic status. Polydrug users and
users who tested positive for the use of cannabis at the time of cognitive assessment after a 72-hour
abstention period were excluded. The older cohort (whose age was approximately 45 years) had
consumed cannabis for an average of 34 years, and comprised 17 users and 30 non-users, who had
been recruited in San Jose, Costa Rica, and had been observed since 1973. The younger cohort (whose
age was approximately 28 years) had consumed cannabis for an average of 8 years, and comprised 37
users and 49 non-users.
MEASUREMENTS: Each subject provided a urine sample to be assayed for use of cannabis and other
drugs 72 hours prior to and at the time of cognitive assessment. Subjects were instructed to abstain from
the use of cannabis and other drugs for the interval between the two samples. Short-term memory,
working memory, and attentional skills were measured in each subject.
RESULTS: Older long-term users performed worse than older non-users on two short-term memory tests
involving learning lists of words. In addition, older long-term users performed worse than older non-users
on selective and divided attention tasks associated with working memory. No notable differences were
apparent between younger users and non-users.
AUTHORS' CONCLUSION: Long-term cannabis use was associated with disruption of short-term
memory, working memory, and attentional skills in older long-term cannabis users.

42

Invest Ophthalmol 1975 Jan;14(1):52-5

Marijuana smoking and reduced pressure in human eyes: drug action or epiphenomenon?
Flom MC, Adams AJ, Jones RT.
BACKGROUND: Marijuana has been reported to reduce the pressure within the human eye. There is
interest in using marijuana for the treatment of glaucoma.
DESIGN: Experimental - double blind placebo self-control clinical trial.
PARTICIPANTS: 15 young male adults experienced in marijuana smoking.
INTERVENTION: After several trials to establish the presmoke IOP baseline, the subject smoked a 0.8
gm cigarette that contained either marijuana placebo material or natural marijuana plant material with 12
mg THC, a socially relevant dose. The cigarette was smoked in the subjects usual style in about 10
minutes. Marijuana and marijuana placebo were given on alternate experimental days.
MEASUREMENTS: IOP measurements were obtained following instillation of one drop of 0.5 per cent
ophthalmic solution of proparacaine hydrochloride onto the cornea. A Mackay-Marg tonometer was used
for all IOP measurements.
RESULTS: Normal pressure within the human eye was reduced in 7 out of 15 subjects after smoking a
socially relevant dose of marijuana (12 mg THC), but only for light to moderate users who experienced a
substantial "high" and a state of peaceful relaxation from the experimental dose.
AUTHORS' CONCLUSION: Analysis suggests an indirect effect of the drug associated with relaxation - a
psychophysiologic state that can be produced by drug and non-drug means.

43

Aust N Z J Obstet Gynaecol 1983 Feb;23(1):15-9

Maternal alcohol, tobacco and cannabis consumption and the outcome of pregnancy.
Gibson GT, Baghurst PA, Colley DP.
BACKGROUND: There is meager literature on the effects of cannabis in pregnancy.
OBJECTIVE: To study the influence of maternal cannabis use upon various outcomes of pregnancy
while controlling for the influence of alcohol and tobacco use.
DESIGN: Observational prospective cohort study.
SETTING: Queen Victoria Hospital, South Australia.
STUDY POPULATION: Prospective mothers attending the Queen Victoria Hospital during 1975-1981
were invited to participate by responding to questions; a second interview was conducted postnatally.
The final study population included 7,301 births.
MEASUREMENTS: Low birth weight, prematurity, intrauterine growth retardation, presence of congenital
abnormalities, perinatal death, low Apgar score and delayed time to commencement of respiration were
the outcomes measured.
RESULTS: Apparent effects of alcohol use on prematurity, intrauterine growth retardation, congenital
abnormalities and low Apgar score were consistent with previously reported work, but were not
statistically significant. Infants born to smokers had lower birthweights and were more prone to
intrauterine growth retardation, but they did not appear to have an increased risk of prematurity or
perinatal death. Only 36 women reported using cannabis two or more times a week, not merely as
smokers of marijuana but also as users of the more potent resin forms of cannabis. Subsequently 25% of
these women gave birth to premature infants. Most cannabis users (92%) used either alcohol or tobacco
or both (compared to cohort mean of 40% smokers and 69.5% ethanol), but only 33 (8%) did not use
ethanol and did not smoke.
AUTHORS' CONCLUSION: Cannabis used regularly, frequently and in its more potent forms is
significantly associated with preterm labor and its sequelae (e.g. perinatal death). Cannabis in pregnancy
is probably associated with intrauterine growth retardation.

44

Neurotoxicol Teratol 2000 May-Jun;22(3):325-36

Effects of prenatal marijuana exposure on child behavior problems at age 10.
Goldschmidt L, Day NL, Richardson GA.
Western Psychiatric Institute and Clinic, University of Pittsburgh Medical Center, 15213, Pittsburgh, PA,
USA.
BACKGROUND: Marijuana is the illicit drug most commonly used by pregnant women. However, little is
known about the long-term effects of prenatal marijuana exposure on behavior problems of the offspring.
OBJECTIVE: To investigate the relationship between prenatal marijuana exposure and child behavior at
age ten.
DESIGN: Case-control study.
SETTING: Prenatal clinic at the Magee-Womens Hospital, Pittsburgh, PA.
PARTICIPANTS: The sample consisted of low-income women attending a prenatal clinic. Half of the
women were African-American and half were Caucasian. The majority of the women decreased their use
of marijuana during pregnancy. The 636 subjects interviewed at the ten-year follow-up represented 91%
of the eligible subjects and 83% of the birth cohort.
MEASUREMENTS: Marijuana use was assessed using the methods developed by the Maternal Health
Practices and Child Development (MHPCD) study. The women were asked about their maximum,
minimum, usual amount and frequency of marijuana, hashish and sinsemilla use. Hashish and sinsemilla
were translated into joints of marijuana based on the relative amounts of THC in each substance. A bowl
or a joint of hashish was counted as three joints of marijuana, and sinsemilla was transformed into two
joints of marijuana. The assessments of child behavior problems included the Child Behavior Checklist
(CBCL), Teacher's Report Form (TRF), and the Swanson, Noland, and Pelham (SNAP) checklist. Multiple
and logistic regressions were employed to analyze the relations between marijuana use and behavior
problems of the children, while controlling for the effects of other extraneous variables.
RESULTS: Prenatal marijuana use was significantly related to increased hyperactivity, impulsivity, and
inattention symptoms as measured by the SNAP, increased delinquency as measured by the CBCL, and
increased delinquency and externalizing problems as measured by the TRF. The pathway between
prenatal marijuana exposure and delinquency was mediated by the effects of marijuana exposure on
inattention symptoms.
AUTHORS' CONCLUSION: Prenatal marijuana exposure has an effect on child behavior problems at age
ten.

45

Clin Pharmacol Ther 1994 Mar;55(3):324-8

Short-term effects of smoking marijuana on balance in patients with multiple sclerosis and normal
volunteers.
Greenberg HS, Werness SA, Pugh JE, Andrus RO, Anderson DJ, Domino EF.
Department of Neurology, University of Michigan, Ann Arbor 48109-0316.
BACKGROUND: Anecdotal reports frequently suggest that smoking marijuana has beneficial effects in
spasticity.
OBJECTIVE: The hypothesis of this study was that marijuana smoking would relieve the spasticity of
patients with multiple sclerosis (MS) sufficiently to allow better postural control and thus produce a
therapeutic benefit.
DESIGN: Two case series in one study.
SETTING: University of Michigan Medical Center, Ann Arbor, Michigan.
PARTICIPANTS: Ten adult patients with spastic multiple sclerosis (MS) and ten normal volunteers
matched as closely as possible for age, sex and height.
INTERVENTION: Each subject was tested in a double-blind trial on three consecutive days. On two of
those days, the subject received active marijuana on one day and placebo on the other. A single
marijuana cigarette (1.54% THC) or alcohol-extracted marijuana placebo cigarette was smoked and
inhaled by each subject taking deep breaths over ten minutes.
MEASUREMENTS: A computer-controlled dynamic posturographic platform with a video line scan
camera measured shoulder displacement in response to pseudorandom platform movements.
RESULTS: Pre-marijuana smoking patient tracking was inferior to that of the normal volunteers as
indicated by the higher noise variance of the former. Smoking one marijuana cigarette containing 1.54%
THC increased postural tracking error in both the patients and normal control subjects with eyes open
and closed; this untoward effect was greatest for the patients. The tracking error was also accompanied
by a decrease in response speed for the patients with their eyes closed. Patients had the subjective
feeling that they were clinically improved.
AUTHORS' CONCLUSION: Marijuana smoking further impairs posture and balance in patients with
spastic multiple sclerosis.

46

Drug Alcohol Depend 2000 Jun 1;59(3):261-75

Antinociceptive, subjective and behavioral effects of smoked marijuana in humans.
Greenwald MK, Stitzer ML.
Behavioral Pharmacology Research Unit, Department of Psychiatry and Behavioral Sciences, Johns
Hopkins University School of Medicine, Baltimore, MD, USA.
BACKGROUND: Effects of THC on clinical pain have been infrequently studied in humans, with mixed
results. Analgesic effects of THC are usually overshadowed by side effects, e.g., sedation. Cannabinoid
effects on human pain sensitivity have been studied in double blind, placebo controlled laboratory
situations, again with conflicting findings. Contributing to this uncertain body of literature is the fact that
procedures for measuring human pain sensitivity are often unreliable.
OBJECTIVE: The purpose of this study was to determine whether marijuana produced dose-dependent
antinociception in humans and, if so, whether endogenous opiates modulate this effect.
DESIGN: Experimental randomized placebo self-controlled clinical trial with paid subjects who regularly
smoked marijuana.
SETTING: Undisclosed.
PARTICIPANTS: A total of five male regular marijuana users completed the study out of thirteen who
enrolled. Five subjects (four women and one man) withdrew after the first session because they disliked
the strength of the marijuana effect.
INTERVENTION: Subjects participated in three test sessions during which they smoked marijuana
cigarettes containing 0% (placebo) and 3. 55% THC (active). Each of four controlled smoking bouts per
session, spaced at 40-min intervals, consisted of nine puffs from active and placebo cigarettes (three
cigarettes, three puffs per cigarette, one puff per minute). During successive bouts, participants smoked
0, 3, 6 and 9 (0, 3, 9 and 18 cumulative) puffs from active marijuana cigarettes, with the remainder of
puffs from placebo cigarettes. Tests were identical, except for naltrexone 0, 50 or 200 mg p.o.
(randomized, double blind) administration one hour before the first smoking bout on the different days.
MEASUREMENTS: Before smoking, between smoking bouts and post-smoking, participants completed
an assessment battery that included antinociceptive (finger withdrawal from radiant heat stimulation),
biological, subjective, observer-rated signs and performance measures, including the digit symbol
substitution test (DSST).
RESULTS: Marijuana produced significant dose-dependent antinociception (increased finger withdrawal
latency) and bio-behavioral effects. Naltrexone did not significantly influence marijuana dose-effect
curves, suggesting no role of endogenous opiates in marijuana-induced antinociception under these
conditions.
AUTHORS' CONCLUSION: While statistically significant, at the highest doses (producing substantial
biological exposure), the antinociceptive effects of marijuana were rather weak. The antinociceptive
efficacy of marijuana in a human laboratory setting is probably marginal in relation to its other biological,
abuse-related, subject rejection and performance-impairing effects.

47

Accid Anal Prev 2000 Sep;32(5):623-32

The prevalence of alcohol, cannabinoids, benzodiazepines and stimulants amongst injured
drivers and their role in driver culpability
Part ii: The relationship between drug prevalence and drug concentration, and driver culpability.
Longo MC, Hunter CE, Lokan RJ, White JM, White MA.
Department of Clinical and Experimental Pharmacology, University of Adelaide, SA, Australia.
BACKGROUND: A variety of methods have been used to assess the role of drugs in car crashes.
OBJECTIVE: To conduct culpability analyses using an objective scoring criterion and method for analysis
of blood samples that permitted determination of the presence and concentration of each drug in blood
samples from non-fatally injured drivers.
DESIGN: Case-control study.
SETTING: South Australia
SUBJECT OF ANALYSIS: Blood samples from 2500 drivers injured in the periods April 1995 to August
1995, and December 1995 to August 1996.
MEASUREMENTS: Blood samples from 2,500 injured drivers were analyzed for alcohol, cannabinoids
(measured by the presence of THC), benzodiazepines and stimulants. The relationship between the
prevalence and concentration of drugs and the culpability of the driver was examined using an objective
method for assessing culpability.
RESULTS: There were no significant differences between males and females with respect to culpability.
However, there was a relationship between age and culpability: drivers under 26 years and over 60 years
were more likely to be culpable. Drivers who tested positive for alcohol only, benzodiazepines only and
the combinations of alcohol and THC and alcohol and benzodiazepines were significantly more likely to
be culpable for the crash compared with the drug-free group. Conversely, a lower percentage of drivers
who only tested positive for THC were culpable for the crash compared with drug-free drivers. This
difference was not statistically significant. For car drivers in single-vehicle crashes, the majority of drivers
were judged culpable irrespective of drug use. In multiple-vehicle crashes, car drivers testing positive for
alcohol only or benzodiazepines only were more likely to be culpable for the crash compared with drugfree drivers. For motorcycle riders in both single- and multiple-vehicle crashes, there were no significant
differences between the drug-positive and drug-free groups. A higher percentage of drug-free riders in
multiple-vehicle crashes were culpable compared with riders who only tested positive for THC, but this
difference was not statistically significant. There was a significant concentration-dependent relationship
between alcohol and culpability: as blood alcohol concentration increased, so did the percentage of
culpable drivers. When THC was used alone, there was no significant increase in culpability. For those
drivers with benzodiazepines at therapeutic concentrations and above, there was a significant increase in
culpability. The relationship between stimulants and culpability was not significant, although a higher
proportion of stimulant-positive drivers were culpable compared with drug-free drivers. The combinations
of alcohol and THC, and alcohol and benzodiazepines also produced a significant increase in culpability,
but this increase was not significantly greater than that produced by alcohol alone.
AUTHORS' CONCLUSION: The study found a clear, concentration-dependent relationship between
alcohol and culpability. It also found a significant relationship between benzodiazepines and culpability.
In contrast, it found no significant relationship between THC and culpability, although the data here and in
other culpability studies do not exclude the possibility of an adverse effect of cannabinoids if the
concentration is sufficiently high.

48

Am J Epidemiol 1999 May 1;149(9):794-800

Cannabis use and cognitive decline in persons under 65 years of age.
Lyketsos CG, Garrett E, Liang KY, Anthony JC.
Department of Psychiatry and Behavioral Sciences, School of Medicine, The Johns Hopkins
University, Baltimore, MD, USA.
BACKGROUND: The relation between cognitive functioning or cognitive decline and use of cannabis has
received limited attention in epidemiologic studies. Two cognitive effects of cannabis must be
distinguished: acute effects, those associated with intoxication, and residual effects (both short and long
term), which persist after the drug has left the central nervous system.
OBJECTIVE: The purpose of this study was to use an epidemiologic sample to investigate possible
adverse effects of cannabis use on cognitive decline after twelve years in persons under age 65 years.
DESIGN: Observational - cohort study. This was a follow-up study of a probability sample of the adult
household residents of East Baltimore (only including those who completed all three MMSEs).
SETTING: The Baltimore, Maryland, portion of the Epidemiologic Catchment Area.
PARTICIPANTS: Patients: N = 1,318. The study cohort included 1,318 participants who completed the
Mini-Mental State Examination (MMSE) during three study waves in 1981, 1982, and 1993-1996.
MEASUREMENTS: Participants were separated into five groups based on their self-reported drug use
during three waves of the study. Individual MMSE score differences between waves two and three were
calculated for each study participant.
RESULTS: After twelve years, study participants' scores declined a mean of 1.20 points on the MMSE
(standard deviation 1.90), with 66% having scores that declined by at least one point. Significant numbers
of scores declined by three points or more (15% of participants in the 18-29 age group). There were no
significant differences in cognitive decline between heavy users, light users, and nonusers of cannabis.
There were also no male-female differences in cognitive decline in relation to cannabis use.
AUTHORS' CONCLUSION: Over long time periods, in persons under age 65 years, cognitive decline
occurs in all age groups. This decline is closely associated with aging and educational level but does not
appear to be associated with cannabis use. The MMSE is not a very sensitive measure of cognitive
decline, however. Small or subtle effects of cannabis use on cognition or psychomotor speed may have
been missed.

49

Br J Psychiatry 1994 May;164(5):679-81

Cannabis consumption as a prognostic factor in schizophrenia.
Martinez-Arevalo MJ, Calcedo-Ordonez A, Varo-Prieto JR.
Alcobendas Mental Health Centre, Madrid, Spain.
BACKGROUND: Many authors have described higher drug consumption by psychiatric patients
compared with the overall population. Excluding alcohol and tobacco, cannabis is the drug most
frequently used by patients with psychiatric disorders. Moreover, a greater consumption of cannabis has
been observed in schizophrenic patients compared with other psychiatric patients.
OBJECTIVE: To assess the importance of cannabis consumption as a short-term prognostic factor in
schizophrenia.
DESIGN: Observational study without control group.
SETTING: The community mental health centers in Navarra, Spain.
PATIENTS: 62 schizophrenic patients between 18 and 30 years of age who had relapsed and then
completed a one-year follow-up study.
MEASUREMENTS: Axis IV of DSM III was used to define the acute/chronic stress factors. Treatment
compliance was defined as adequate intake of prescribed medication as assessed by physicians, as well
as by attending follow-up at medical centers. For evaluating follow-up, patients were divided into groups:
active cannabis consumers during follow-up (THC+), former cannabis consumers, abstinent during followup (THC+-, and non-consumers (THC-).
RESULTS: Of a number of candidate variables for logistic regression analysis, only chronic stress factors,
acute stress factors and treatment compliance yielded significant Spearman correlations over the
dependent variable (relapse). Findings indicate that stress is less predictive of relapse than a history of
cannabis consumption or non-compliance with treatment. The most predictive factor of relapse was the
continuing consumption of cannabis. Factors influencing the course of illness during follow-up were:
continuing cannabis consumption; previous cannabis intake; non-compliance with treatment; and stress.
During the year of follow-up, continuing cannabis consumers presented a much higher frequency of
relapse, non-compliance with treatment and acute stress factors than non consumers; former consumers
showed an intermediate position between the first group and non-consumers with respect to relapse and
acute stresses.
AUTHORS' CONCLUSION: These data are consistent with other studies that report that cannabis
consumption is associated with a poorer outcome of schizophrenia. The nature of the association is
unclear. Cannabis use might be a result of the severity of the schizophrenia, so that patients with a
poorer outcome would consume more cannabis secondarily. On the other hand, cannabis could be a
factor in relapse.

50

Hum Psychopharmacol Clin Exp 13, S70-S78 (1998)

Marijuanas impairing effects on driving are moderate when taken alone but severe when
combined with alcohol
Robbe H.
Maastricht University, Maastricht, The Netherlands
Presently at: Bakken Research Center, P.O. Box 1220, 6201 MP Maastricht, The Netherlands
BACKGROUND: Previous experimental and epidemiological studies fail to provide unequivocal evidence
that marijuana, either alone or in combination with alcohol, impairs a drivers performance to the extent
that it will compromise traffic safety.
OBJECTIVE: To investigate the effects of marijuana, alone and in combination with alcohol, on actual
driving.
DESIGN: Experimental - four single blind, randomized, crossover studies.
SETTING: Maastricht, The Netherlands.
PARTICIPANTS: Subjects in all studies were so-called recreational users of marijuana or hashish, were
all healthy, between 21 and 40 years of age, had normal weight and binocular acuity and were licensed to
drive an automobile. Study 1 N=24. Study 2 N=16. Study 3 N=32. Study 4 N=18.
INTERVENTION AND MEASUREMENTS: In Study 1, 24 subjects performed a road-tracking test on a
closed segment of a primary highway after smoking marijuana that contained 0, 100, 200 and 300 g/kg
THC. In Study 2, 16 new subjects smoked the same THC doses before they performed a road-tracking
and car-following test; however, this time in the presence of other traffic. In Study 3, two groups of 16
subjects performed a city driving test. One group smoked marijuana delivering 0 and 100 g/kg THC
prior to driving; the other group drank orange juice mixed with or without a low dose of alcohol. In Study
4, 18 subjects performed a road-tracking and car-following test in each of six conditions where they
smoked marijuana with 0, 100, or 200 g/kg THC after they had consumed orange juice with or without
alcohol.
RESULTS: In these studies, marijuana alone significantly increased lateral position variability in the roadtracking test and distance variability during deceleration manoeuvers in the car-following test. Reaction
times during car-following were not significantly affected, and a THC dose of 100 g/kg did not impair city
driving performance. Blood plasma concentrations of THC and THC-COOH were not related to the
degree of impairment. A low dose of alcohol (i.e. blood alcohol concentrations around 0.04%) impaired
performance in all driving tests. Whereas marijuanas effects on driving performance were small (100
g/kg) or moderate (200 and 300 g/kg) when taken alone, they were severe when combined with a low
dose of alcohol.
AUTHOR'S CONCLUSION: Marijuana alone impairs driving performance, with the degree of impairment
increasing from small to moderate as the THC dose increases from 100 to 300 g/kg. However, when
low to moderate doses of THC (100 and 200 g/kg) are taken in combination with a low dose of alcohol
sufficient for attaining a BAC of about 0.04% actual driving is severely impaired.

51

Acta Paediatr 2001 Jan;90(1):57-60

Maternal cannabis use in the sudden death syndrome.
Scragg RK, Mitchell EA, Ford RP, Thompson JM, Taylor BJ, Stewart AW.
Department of Community Health, University of Auckland, New Zealand.
BACKGROUND: The smoking of cannabis and tobacco is common in many countries. In contrast to
tobacco, which is an established risk factor for the sudden infant death syndrome (SIDS), nothing is
known about cannabis and its effects on SIDS risk.
OBJECTIVE: To determine whether there is any association between reported maternal use of marijuana
and the risk of SIDS.
DESIGN: Observational a nationwide case control study, the New Zealand Cot Death Study, carried
out from October 1, 1987 through September 30, 1990.
SETTING: New Zealand.
STUDY POPULATION: 393 cases, 1592 controls.
MEASUREMENTS: Interviews were conducted. Mothers were asked: did you ever smoke
pot/marijuana during pregnancy? and have you had pot/marijuana since the birth of the baby? If yes,
they were also asked how often. In addition, they were asked have you taken any of these drugs since
the birth of the baby? Possible responses included buprenorphine, cocaine, LSD, opiates, blue or
solvents. Information was also collected on a variety of other variables.
RESULTS: Adjusting for ethnicity and maternal tobacco use, the SIDS odds ratio for greater than weekly
maternal cannabis use since the infant's birth was 2.23 (95% CI = 1.39, 3.57) compared to non-users;
and the multivariate odds ratio (controlling for the confounders, plus others, including socioeconomic
status, marital status, infant age, etc.) was 1.55 (95% CI = 0.87, 2.75).
AUTHORS' CONCLUSION: Frequent maternal cannabis use may be a weak risk factor for SIDS, but this
finding requires further research.

52

Am J Obstet Gynecol 1995 Jan;172(1 Pt 1):19-27

The impact of cocaine and marijuana use on low birth weight and preterm birth: a multicenter
study.
Shiono PH, Klebanoff MA, Nugent RP, Cotch MF, Wilkins DG, Rollins DE, Carey JC, Behrman RE.
Center for the Future of Children, David and Lucille Pakcard Foundation, Los Altos, CA 94022.
BACKGROUND: The number of reports linking illicit drug use with adverse pregnancy outcomes has
increased dramatically. These reports have fueled important public policy debates and concerns.
OBJECTIVE: To evaluate prospectively the effects of cocaine and marijuana use on pregnancy
outcomes.
DESIGN: Observational - prospective multicenter cohort study.
SETTING: Seven university-based prenatal clinics in the United States from 1984 to 1989.
STUDY POPULATION: The cohort consisted of a multiethnic population of 7470 pregnant women.
DATA COLLECTION: Information on the use of drugs was obtained from personal interviews at entry to
the study and assays of serum obtained during pregnancy. Pregnancy outcome data (low birth weight [<
2500 gm], preterm birth [< 37 weeks' gestation], and abruptio placentae) were obtained with a
standardized study protocol.
RESULTS: A total of 2.3% of the women used cocaine and 11.0% used marijuana during pregnancy.
Cocaine use was not associated with having a low-birth-weight infant (adjusted odds ratio 0.7, 95%
confidence interval 0.4 to 1.3) or a preterm birth (1.3, 0.9 to 2.0). There was no association between
short-term exposure to cocaine and preterm delivery (1.1, 0.3 to 4.0). However, cocaine use was strongly
associated with abruptio placentae (adjusted odds ratio 4.2, 1.9 to 9.5). Marijuana use was not associated
with low birth weight (1.1, 0.9 to 1.5), preterm delivery (1.1, 0.8 to 1.3) or abruptio placentae (1.3, 0.6 to
2.8). By comparison, 35% of the women smoked cigarettes during pregnancy, and cigarette smoking was
positively associated with low birth weight (1.5, 1.2 to 1.8).
AUTHORS' CONCLUSION: In this population of women receiving prenatal care, cocaine use was
uncommon and was not related to most adverse birth outcomes. Marijuana use was relatively common
and was not related to adverse pregnancy outcomes. Tobacco is still the most commonly abused drug
during pregnancy. Fifteen percent of all cases of low birth weight in this study could have been prevented
if women had not smoked cigarettes during pregnancy.

53

J Psychoactive Drugs 1994 Jul-Sep;26(3):285-8

Possible role of marijuana smoking as a carcinogen in the development of lung cancer at a young
age.
Sridhar KS, Raub WA Jr, Weatherby NL, Metsch LR, Surratt HL, Inciardi JA, Duncan RC, Anwyl RS,
McCoy CB.
University of Miami School of Medicine, Sylvester Comprehensive Cancer Center, Florida.
BACKGROUND: Numerous studies of cigarette smoking have shown that continued exposure to tobacco
smoke increases the risk of developing chronic bronchitis and/or carcinoma of the lung, however, there is
a paucity of data about the effects of marijuana smoking on the lung with respect to carcinogenic and
cocarcinogenic potential.
OBJECTIVE: To evaluate the effects of marijuana smoking on the development of lung cancer, including
the possible additive effects of tobacco smoking, tobacco smoking status (current, former, never),
exposure to other carcinogens, and family history of cancer.
DESIGN: Case series study.
SETTING: The Medical Oncology clinic of the Sylvester Comprehensive Cancer Center at the University
of Miami Medical Center.
PATIENTS: 110 private patients with lung cancer seen by one of the authors between 1989 and 1992,
90% with smoking history.
MEASUREMENTS: A self-report questionnaire was designed to obtain information on the use of
marijuana and tobacco, as well as other substances, by lung cancer patients.
RESULTS: All of the patients under 45 years of age were marijuana smokers. All but one were tobacco
smokers as well.
AUTHORS' CONCLUSION: Exposure to marijuana smoke is correlated with presentation of cancer of the
lung, particularly in younger patients who actively smoke tobacco.

54

Am Rev Respir Dis 1993 Jan;147(1):97-103

Effects of smoked substance abuse on nonspecific airway hyperresponsiveness.
Tashkin DP, Simmons MS, Chang P, Liu H, Coulson AH.
Department of Medicine, UCLA School of Medicine and Public Health 90024-1690.
BACKGROUND: Previous data suggest that regular tobacco smoking may lead to nonspecific airway
hyperresponsiveness (AHR) independent of airway obstruction, possibly because of effects on bronchial
inflammation or mucosal permeability. Little is known concerning the effects on AHR of other widely
smoked substances besides tobacco such as marijuana or cocaine. The smoke of both marijuana and
cocaine contains respiratory irritants that elicit cough and produce abnormalities in airway dynamics and
bronchial mucosal histopathology in habitual smokers. Therefore, regular smoking of one or both of
these illicit substances could cause AHR or augment the AHR associated with tobacco smoking.
OBJECTIVE: To examine the influence of habitual smoking of marijuana, cocaine, and/or tobacco on
nonspecific AHR in healthy participants.
DESIGN: Case-control study of the pulmonary effects of habitual smoking of illicit substances.
SETTING: UCLA School of Medicine and Public Health, Los Angeles, California.
SUBJECTS: 542 (456 male) healthy participants (mean age, 34.8 +/- 6.8 SD yr). Marijuana only = 103,
non-smoking only = 102.
MEASUREMENTS: Inhalation challenge studies were performed using solutions of diluent and
methacholine chloride (1.25 to 25 mg/ml) aerosolized by a DeVilbiss no. 646 nebulizer attached to a
breath-activated dosimeter inhaled by three to five inspiratory capacity breaths. Positive responses to
methacholine were defined by 20% or 10% declines in FEV1 from the postdiluent control value after
inhalation of each concentration of methacholine. Participants were categorized by smoking status
(nonsmoking and smoking of marijuana, cocaine, and/or tobacco alone and in combination; most
analyses were performed in men and women separately.
RESULTS: No significant differences in prevalence of positive responses (declines in FEV1 of 20% or
10%) to any concentration of methalcholine were found between nonsmokers and smokers of marijuana
and/or cocaine without tobacco in either sex. However, logistical regression revealed significant
associations between marijuana smoking and positive responses to some concentrations of methacholine
( 10 mg/ml) in both men and women. A relationship between heavier and/or longer exposure to tobacco
and AHR was suggested by a significant positive correlation between the slope of the methacholine doseresponse curve and cumulative lifetime amount of tobacco in men, as well as by a significant association
(logistic regression) between current daily amount of tobacco and positive responses to methacholine in
both men and women, independent of baseline lung function. In contrast, no dose-response relationship
was found between AHR and either the current weekly or cumulative lifetime amount of either marijuana
or cocaine smoking. In addition, no evidence of an additive or potentiating influence of marijuana and/or
cocaine on the association between tobacco and airway responsiveness could be demonstrated in either
sex.
AUTHORS' CONCLUSION: No significant differences (as measured by methacholine positive responses
of 10% decreases from baseline FEV1) to any concentration of methacholine were found between
marijuana nonsmokers and smokers.

55

Am Rev Respir Dis 1977 Jan;115(1):57-65

Bronchial effects of aerosolized delta 9-tetrahydrocannabinol in healthy and asthmatic subjects.
Tashkin DP, Reiss S, Shapiro BJ, Calvarese B, Olsen JL, Lodge JW.
BACKGROUND: Previous studies have demonstrated that the smoking of marijuana or the ingestion of
its principle psychoactive ingredient, THC, causes acute bronchodilatation both in healthy young men and
in patients with either chronic, stable bronchial asthma, or experimentally induced bronchospasm.
OBJECTIVE: To evaluate the cardiopulmonary effects, intoxicating influence, and side effects of various
doses of aerosolized THC both in healthy men and in asthmatic subjects, and to compare the effects of
aerosolized THC with those of a comparable quantity of smoked or ingested THC.
DESIGN: Experimental - randomized controlled clinical trial.
SETTING: Department of Medicine, UCLA School of Medicine, Los Angeles, California.
PARTICIPANTS: Eleven healthy men (experienced marijuana smokers) and five asthmatic subjects.
INTERVENTION: Subjects inhaled 0, 5, 10, or 20 mg of synthetic THC as an aerosol, smoked a cigarette
containing 900 mg of marijuana assayed at 2.2% THC, or ingested 20 mg of synthetic THC dissolved in
sesame oil within a gelatin capsule. The order in which the various test preparations were administered
was randomized in a crossover fashion, and administration of the various doses of aerosolized THC was
double blind.
MEASUREMENTS: Effects on airway dynamics, heart rate, and the central nervous system of various
doses of THC were evaluated. Effects of aerosolized THC were compared with aerosolized placebo and
isoproterenol and with 20 mg of oral and smoked THC.
RESULTS: In the normal subjects, after 5 to 20 mg of aerosolized THC, specific airway conductance
increased immediately, reached a maximum (33% to 41% increase) after one to two hours, and remained
significantly greater than placebo values for two to three hours. The bronchodilator effect of aerosolized
THC was less than that of isoproterenol after five minutes, but significantly greater than that of
isoproterenol after one to three hours. The magnitude of bronchodilatation after all doses of aerosolized
THC was comparable, but 5 mg of THC caused a significantly smaller increase in heart rate and level of
intoxication than the 20-mg dose. Smoked THC produced greater cardiac and intoxicating effects than
either aerosolized or oral THC. Side effects of aerosolized THC included slight cough and/or chest
discomfort in three of the eleven normal subjects. Aerosolized THC caused significant bronchodilatation
in three of five asthmatic subjects, but caused moderate to severe bronchoconstriction associated with
cough and chest discomfort in the other two.
AUTHORS' CONCLUSION: These findings indicate that aerosolized THC, although capable of causing
significant bronchodilatation with minimal systemic side effects, has a local irritating effect on the airways
which may make it unsuitable for prolonged therapeutic use.

56

N Engl J Med 1976 Jan 15;294(3):125-9

Subacute effects of heavy marihuana smoking on pulmonary function in healthy men.
Tashkin DP, Shapiro BJ, Lee YE, Harper CE.
BACKGROUND: Since the principal route of marijuana administration in the United States is by deep
inhalation into the lungs, there is obvious concern regarding possible adverse effects on the respiratory
tract.
OBJECTIVE: The study was designed to determine prospectively whether or not and to what extent
heavy marijuana smoking over a period of approximately seven to nine weeks might cause functional
respiratory impairment in healthy young experienced cannabis users and whether the quantity of
marijuana smoked over this period might be related to the degree of impairment of lung function.
DESIGN: Experimental self-control non-randomized study.
SETTING: A carefully supervised research ward of the Neuropsychiatric Institute at University of
California, Los Angeles.
SUBJECTS: 28 healthy young male experienced cannabis users.
INTERVENTION: The first eleven days served as a deintoxification period during which cannabis use
was interdicted. Subjects then smoked as many marijuana cigarettes as desired for a period of 80 days,
th
nd
except for one week between the 76 and 82 days in the hospital. Each cigarette contained 900 mg of
marijuana assayed by gas-liquid chromatography at 2.2% THC. The mean number of marijuana
cigarettes smoked per day was 5.2.
MEASUREMENTS: Pulmonary function was tested before and after 47 to 59 days of daily ad-libitum
marijuana smoking.
RESULTS: Base-line pulmonary-function studies were nearly all within normal limits, but after 47 to 59
days of heavy smoking, statistically significant decreases in forced expired volume in one second (3 +/- 1
per cent, S.E.), maximal mid-expiratory flow rate (11 +/- 2 per cent), plethysmographic specific airway
conductance (16 +/- 2 per cent) and diffusing capacity (8 +/- 2 per cent) were noted as compared with the
base-line studies. The decreases in maximal mid-expiratory flow rate and specific airway conductance
were correlated with the quantity of marijuana smoked.
AUTHORS' CONCLUSION: These findings suggest that customary social use of marijuana may not result
in detectable functional respiratory impairment in healthy young men, whereas very heavy marijuana
smoking for six to eight weeks causes mild but statistically significant airway obstruction.

57

Am Rev Respir Dis 1975 Sep;112(3):377-86

Effects of smoked marijuana in experimentally induced asthma.
Tashkin DP, Shapiro BJ, Lee YE, Harper CE.
BACKGROUND: Studies have demonstrated significant acute bronchodilatation in health young men
after both smoked marijuana and oral THC.
OBJECTIVE: To evaluate the effects of smoked marijuana on bronchomotor tone in asthmatic subjects
after bronchospasm was induced either by inhalation of methacholine or by exercise.
DESIGN: Experimental randomly ordered single blind placebo controlled clinical trial.
SETTING: Department of Medicine, UCLA School of Medicine, Los Angeles.
PATIENTS: Eight patients with clinically stable bronchial asthma and without other significant medical
illnesses.
INTERVENTION: Bronchospasm was induced on four separate occasions by inhalation of methacholine
and, on four other occasions, by exercise on a bicycle ergometer or treadmill. Immediately after
experimental induction of acute bronchospasm, subjects smoked a joint containing 500 mg of marijuana
assayed at either 2.0% THC or 0.0% THC (placebo), according to a randomly ordered, single blind
protocol.
MEASUREMENTS: Serial plethysmographic measurements were taken immediately after smoking was
completed. Effects of smoked marijuana on specific airway conductance and thoracic gas volume were
compared with those of smoked placebo marijuana, 0.25 ml of aerosolized saline, and 0.25 ml of
aerosolized isoproterenol (1,250 g).
RESULTS: Methacholine and exercise caused average decreases in specific airway conductance of
40% to 55% and 30% to 39%, respectively, and average increases in thoracic gas volume of 35% to 43%
and 25% to 35%, respectively. After methacholine-induced bronchospasm, placebo marijuana and saline
inhalation produced minimal changes in specific airway conductance and thoracic gas volume, whereas
2.0% marijuana and isoproterenol each caused a prompt correction of the bronchospasm and associated
hyperinflation. After exercise-induced bronchospasm, placebo marijuana and saline were followed by
gradual recovery during 30 to 60 minutes, whereas 2.0% marijuana and isoproterenol caused an
immediate reversal of exercise-induced asthma and hyperinflation.
AUTHORS' CONCLUSION: Findings demonstrated acute airway dilation after smoking marijuana.
Smoking does not appear to be an appropriate long-term method for administration of bronchodilator
cannabinoid compounds for potential therapeutic purposes. THC does not appear to be a suitable
bronchodilator for therapeutic use because of its systemic psychotropic and possible undesirable
endocrine, immunologic, and cytogenetic effects.

58

Addiction 2000 Nov;95(11):1669-77

The respiratory effects of cannabis dependence in young adults.
Taylor DR, Poulton R, Moffitt TE, Ramankutty P, Sears MR.
Department of Medicine, Dunedin School of Medicine, University of Otago Medical School, Dunedin, New
Zealand.
BACKGROUND: Given the increasing public debate in many countries about the merits of
decriminalizing and/or legalizing cannabis, more information is urgently required about its health effects.
OBJECTIVE: To evaluate the relationship between cannabis dependence and respiratory symptoms and
lung function in young adults, while controlling for the effects of tobacco smoking.
DESIGN: Outcomes study at single time interval with exposure and outcome determined simultaneously.
SETTING: New Zealand.
PARTICIPANTS: Nine hundred and forty-three young adults from a birth cohort of 1037 subjects born in
Dunedin, New Zealand in 1972/1973 were studied at age 21.
MEASUREMENTS: Standardized respiratory symptom questionnaires were administered. Spirometry and
methacholine challenge tests were undertaken. Cannabis dependence was determined using DSM-III-R
criteria. Descriptive analyses and comparisons between cannabis-dependent, tobacco-smoking and nonsmoking groups were undertaken. Adjusted odds ratios for respiratory symptoms, lung function and
airway hyper-responsiveness (PC20) were measured.
RESULTS: Ninety-one subjects (9.7%) were cannabis-dependent (only 3% of these took cannabis only)
and 264 (28.1%) were current tobacco smokers. After controlling for tobacco use, respiratory symptoms
associated with cannabis dependence included: wheezing apart from colds, exercise-induced shortness
of breath, nocturnal wakening with chest tightness and early morning sputum production. These were
increased by 61%, 65%, 72% (all p < 0.05) and 144% (p < 0.01) respectively, compared to non-tobacco
smokers. The frequency of respiratory symptoms in cannabis-dependent subjects was similar to tobacco
smokers of 1-10 cigarettes/day. The proportion of cannabis-dependent study members with an FEV1/FVC
ratio of < 80% was 36% compared to 20% for non-smokers (p = 0.04). These outcomes occurred
independently of co-existing bronchial asthma.
AUTHORS' CONCLUSION: Significant respiratory symptoms and changes in spirometry occur in
cannabis-dependent individuals at age 21 years, even though the cannabis smoking history is of relatively
short duration.

59

N Y State J Med 1988 Oct;88(10):525-7

Inhalation marijuana as an antiemetic for cancer chemotherapy.
Vinciguerra V, Moore T, Brennan E.
BACKGROUND: Natural and synthetic cannabinoids are known to be effective antiemetic agents. THC
has been found to be superior to prochlorperazine. Also, patients who are refractory to standard
antiemetic agents have significant reduction in nausea and vomiting with oral THC. There is little
information on the efficacy of inhalation marijuana aside from anecdotal reports from patients who
obtained the drug privately.
OBJECTIVE: To evaluate the efficacy of inhalation marijuana as an antiemetic for patients refractory to
standard agents, to identify patient characteristics to predict response, and to evaluate toxicity and patient
acceptance of this form of treatment.
DESIGN: Case series study.
SETTING: North Shore University Hospital, Manhasset, New York.
PATIENTS: Completed the study: 56 patients with histologically confirmed malignancies who were
actively receiving chemotherapy, were eighteen years of age or older, were refractory to conventional
anti-emetic agents, and absent of severe cardiac or psychiatric disease. It should be noted that 25% of
the patients who initially consented to the study refused treatment for a variety of reasons, most
commonly because they did not want to smoke marijuana.
INTERVENTION: The patients smoked marijuana cigarettes. All patients were instructed on standard
smoking procedures. The dose schedule, which was calculated to the nearest one-fourth cigarette, was 5
2
mg THC/m , starting 6-8 hours prior to chemotherapy and every 4-6 hours thereafter, for a total dose of
four doses per day on each day of chemotherapy (one cigarette = 10.8 mg THC).
MEASUREMENTS: Patients were asked to self-rate their status by completing a patient evaluation form
after each therapeutic episode. Nausea was graded on a scale from 1 (none) to 4 (severe), vomiting was
graded from 1 (none) to 5 (10+ times), appetite was graded from 1 (none) to 4 (above normal), physical
state was graded from 1 (very weak) to 4 (above normal), and mood was graded from 1 (depressed) to 5
(very happy). Based on the degree of nausea, vomiting, food intake, physical state, and overall mood,
patients rated the overall effectiveness of marijuana as none, moderately effective, and very effective.
RESULTS: Eighteen patients rated the marijuana very effective (34%) and twenty-six patients rated it
moderately effective (44%), for an overall response rate of 78%. Twelve patients (22%) noted no benefit.
Patients who responded to marijuana cigarettes were more likely to be younger with prior marijuana
exposure. Toxicity was mild and consisted primarily of sedation and xerostomia.
AUTHORS' CONCLUSION: This preliminary trial suggests the usefulness of inhalation marijuana as an
antiemetic agent. Because of the lack of a randomized placebo control group, the precise role of this
agent is unclear. Further studies should include derivatives of this substance in combination with
standard effective drugs to control chemotherapy-induced nausea and vomiting.

60

Am J Psychiatry 1985 Nov;142(11):1325-9

Carry-over effects of marijuana intoxication on aircraft pilot performance: a preliminary report.
Yesavage JA, Leirer VO, Denari M, Hollister LE.
BACKGROUND: The widespread recreational use of marijuana in both the private and military sectors
suggests the need for more detailed research concerning its effects on pilot performance. Cases of its
use by flight trainees, active pilots, and pilots in fatal accidents have been documented. While plasma
concentrations are usually negligible 3-4 hours after smoking marijuana, urine screens for THC
metabolites remain positive at least 48-72 hours after oral administration.
OBJECTIVE: To examine THC carry-over effects on a simple piloting task 24 hours after smoking of the
drug.
DESIGN: Experimental - self-control clinical trial.
SETTING: A computerized laboratory specifically designed for pilot performance research in
Northhampton, Massachusetts.
PARTICIPANTS: Ten currently licensed experienced private pilots with a (Class III) medical certification,
a mean age of 29 years and a mean of 303 hours of flying experience. All subjects were experienced in
marijuana smoking. Subjects served as their own controls.
INTERVENTION: A marijuana cigarette containing 19 mg of THC was smoked. The entire cigarette was
smoked at a rate comfortable to the subject. No placebo was used, since prior studies using the same
cigarette found that 90% of the subjects could identify the active drug.
MEASUREMENTS: Participants were trained for eight hours on a flight simulator landing task. On the
day of testing, baseline performance was measured between 8:00 and 9:00 a.m. and consisted of one
recorded flight, which was preceded by two practice flights. At 9:00 a.m. a marijuana cigarette was
smoked. At 9:30 a.m. and 12:30 p.m., performance on the task was tested again (hour 1 and hour 4).
The subject returned at 8:00 a.m. the following day and took two practice flights, and then a flight was
recorded. Subjective ratings on a 10 point scale of high, anxiety, happiness, and alertness were
obtained at each testing session.
RESULTS: Twenty-four hours after smoking a marijuana cigarette, the pilots mean performance on the
flight task showed trends toward impairment on all variables, with significant impairment in number and
size of aileron changes, size of elevator changes, distance off center on landing, and vertical and lateral
deviation on approach to landing. Despite these deficits, the pilots reported no awareness of impaired
performance.
AUTHORS' CONCLUSION: These results may have implications for performance of complex tasks the
day after smoking marijuana.

61

Cancer Epidemiol Biomarkers Prev 1999 Dec;8(12):1071-8

Marijuana use and increased risk of squamous cell carcinoma of the head and neck.
Zhang ZF, Morgenstern H, Spitz MR, Tashkin DP, Yu GP, Marshall JR, Hsu TC, Schantz SP.
Department of Epidemiology, University of California at Los Angeles School of Public Health, and
Jonsson Comprehensive Cancer Center, 90095-1772, USA.
BACKGROUND: Marijuana is the most commonly used illegal drug in the United States. In some
subcultures, it is widely perceived to be harmless. Although the carcinogenic properties of marijuana
smoke are similar to those of tobacco, no epidemiological studies of the relationship between marijuana
use and head and neck cancer have been published.
OBJECTIVE: To investigate the relationship between marijuana use and head and neck cancer.
DESIGN: Observational - case-control study.
SETTING: Memorial Sloan-Kettering Cancer Center (New York) between 1992 and 1994.
PATIENTS: 173 previously untreated cases with pathologically confirmed diagnoses of squamous cell
carcinoma of the head and neck and 176 cancer-free controls. Controls without history of cancer were
selected from the Blood Bank Center of Memorial Sloan Kettering Cancer Center during the same period.
DATA COLLECTION: Epidemiological data were collected using a structured questionnaire that included
history of tobacco smoking, alcohol use, and marijuana use. The associations between marijuana use
and head and neck cancer were analyzed by Mantel-Haenszel methods and logistic regression models.
RESULTS: Controlling for age, sex, race, education, alcohol consumption, pack-years of cigarette
smoking, and passive smoking, the risk of squamous cell carcinoma of the head and neck was increased
with marijuana use [odds ratio (OR) comparing ever with never users, 2.6; 95% confidence interval (CI),
1.1-6.6]. Dose-response relationships were observed for frequency of marijuana use/day (P for trend
<0.05) and years of marijuana use (P for trend <0.05). These associations were stronger for subjects who
were 55 years of age and younger (OR, 3.1; 95% CI, 1.0-9.7). Possible interaction effects of marijuana
use were observed with cigarette smoking, mutagen sensitivity, and to a lesser extent, alcohol use.
AUTHORS' CONCLUSION: These results suggest that marijuana use may increase the risk of head and
neck cancer with a strong dose-response pattern. Analysis indicated that marijuana use may interact with
mutagen sensitivity and other risk factors to increase the risk of head and neck cancer. The results need
to be interpreted with some caution in drawing causal inferences because of certain methodological
limitations, especially with regard to interactions.

62

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