Marijuana for Medicinal Purposes: An Evidence-Based Assessment
←
→
Page content transcription
If your browser does not render page correctly, please read the page content below
Marijuana for Medicinal Purposes:
An Evidence-Based Assessment
Prepared for Alberta's Workers' Compensation BoardMarijuana 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 2
II. Assessing the scientific evidence 3
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 Organizational statements
Appendix B Study designs
Appendix C Comprehensive reviews
Appendix D Levels of evidence summary
Appendix E Worksheet for using an article about causation of harm
Appendix F Worksheet for using an article about therapy or prevention
Appendix G Psychoactive effect/therapeutic effect
Appendix H Examples of ongoing marijuana research
Annotated Bibliography 37
References 62SUMMARY 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.
2
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 ∆9-
tetrahydrocannabinol (∆9-THC). Throughout this report, use of the acronym THC indicates ∆9-
THC. 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 marijuana’s 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 marijuana’s 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.”3
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 Report to the AMA House of Delegates. Subject: 1997
Affairs Medical Marijuana Updated:
2001
Institute of Medicine (US) Marijuana and Medicine: Assessing the Science 1999
Base
House of Lords (UK Parliament), Science and Cannabis: The Medical and Scientific 1998
th
Technology Committee 9 Report Evidence
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 a4 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 study’s level of evidence, validity of results, clinical importance and applicability were
5 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 marijuana’s 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 marijuana’s 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.
6
TABLE 2. STUDIES MEETING THE INCLUSION CRITERIA: THERAPY
STUDY STUDY TYPE AUTHORS’ CONCLUSIONS CRITICAL APPRAISAL LEVEL OF
EVIDENCE
Analgesia
Greenwald MK. Antinociceptive, Experimental – While statistically significant, at the highest doses Underpowered RCT. Eight potential 2b
subjective and behavioral effects of randomized (producing substantial biological exposure), the subjects left the study after the first
smoked marijuana in humans. placebo-self - antinociceptive effects of marijuana were rather session because they found the
Drug Alcohol Depend 2000 controlled clinical weak. The antinociceptive efficacy of marijuana in higher doses of marijuana intolerable.
trial with five paid a human laboratory setting is probably marginal in Although there is evidence that pain
subjects who relation to its other biological, abuse-related, sensation diminished at these levels,
regularly smoked subject rejection and performance-impairing the side effects suggest that
marijuana. effects. marijuana is a very questionable
treatment modality for this indication.
Study used surrogate marker for
naturally occurring pain.
Asthma
9
Tashkin DP. Bronchial effects of Experimental - The findings indicate that aerosolized ∆ -THC, Study looked at immediate 2b
aerosolized delta 9- randomized although capable of causing significant pharmacologic reaction and was
tetrahydrocannabinol in healthy and controlled clinical bronchodilatation with minimal systemic side silent on long term effects of
asthmatic subjects. Am Rev Respir trial. effects, has a local irritating effect on the airways marijuana smoke.
Dis 1977 which may make it unsuitable for prolonged
therapeutic use.
Tashkin DP. Effects of smoked Experimental – Findings demonstrated acute airway dilation after Study looked at immediate 2b
marijuana in experimentally induced randomly marijuana smoking. Smoking does not appear to pharmacologic reaction and was
asthma. Am Rev Respir Dis 1975 ordered, single be an appropriate long-term method for silent on long term effects of
blind placebo administration of bronchodilator cannabinoid marijuana smoke.
controlled clinical compounds for potential therapeutic purposes.
trial. 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.7
TABLE 2. STUDIES MEETING THE INCLUSION CRITERIA: THERAPY (Continued)
STUDY STUDY TYPE AUTHORS’ CONCLUSIONS CRITICAL APPRAISAL LEVEL OF
EVIDENCE
Chemotherapy Induced Nausea
and Vomiting
Vinciguerra V. Inhalation marijuana Prospective case This preliminary trial suggests the usefulness of 25% of the patients who initially 4
as an antiemetic for cancer series. inhalation marijuana as an antiemetic agent. consented to the study refused
chemotherapy. N Y State J Med Because of the lack of a randomized placebo treatment for a variety of reasons,
1988 control group, the precise role of this agent is most commonly because they did not
unclear. Further studies should include derivatives want to smoke marijuana.
of this substance in combination with standard
effective drugs to control chemotherapy-induced
nausea and vomiting.
Chang AE. A prospective evaluation Experimental - The findings suggest that the antiemetic properties The study was published in 1981 and 1b
9
of ∆ -tetrahydrocannabinol as an randomized, of THC are effective only against specific does not compare herbal marijuana
antiemetic in patients receiving double blind, “self chemotherapeutic drugs. to current standard of care antiemetic
adriamycin and cytoxan control” and therapies.
chemotherapy. Cancer 1981 placebo
controlled trial of
9
oral ∆ -THC and
smoked
marijuana.
9
Chang AE. Delta 9- Experimental - ∆ -THC appears to have significant antiemetic The study was published in 1979 and 1b
tetrahydrocannabinol as an randomized, properties when compared with placebo in patients does not compare herbal marijuana
antiemetic in cancer patients double-blind, receiving high-dose methotrexate. to current standard of care antiemetic
receiving high-dose methotrexate. A “self-control” and therapies.
prospective, randomized evaluation. placebo-
Ann Intern Med 1979 controlled clinical
trial.8
TABLE 2. STUDIES MEETING THE INCLUSION CRITERIA: THERAPY (Continued)
STUDY STUDY TYPE AUTHORS’ CONCLUSIONS CRITICAL APPRAISAL LEVEL OF
EVIDENCE
Glaucoma
Flom MC. Marijuana smoking and Experimental - Analysis suggests an indirect effect of the drug Effects of long-term use of marijuana 3b
reduced pressure in human eyes: double blind associated with relaxation - a psychophysiologic are not addressed by the study. This
drug action or epiphenomenon? placebo self- state that can be produced by drug and non-drug study was published in 1975 and
Invest Ophthalmol 1975 control clinical means. does not compare herbal marijuana
trial. to current standard of care glaucoma
therapies. Therapeutic use of
marijuana for treatment of glaucoma
seems premature considering the
state of knowledge of the drug’s
action.
Multiple Sclerosis and Spasticity
Greenberg HS. Short-term effects of Experimental - 2 Marijuana smoking further impairs posture and Patients had the subjective feeling 4
smoking marijuana on balance in in 1 case series. balance in patients with spastic MS. that they were clinically improved,
patients with multiple sclerosis and despite the fact that their posture and
normal volunteers. Clin Pharmacol balance were actually impaired by
Ther 1994 smoking marijuana.9
TABLE 3. STUDIES MEETING INCLUSIONS CRITERIA: HARM
STUDY STUDY TYPE AUTHORS’ CONCLUSIONS CRITICAL APPRAISAL LEVEL OF
EVIDENCE
Bronchial and Pulmonary Damage
Taylor DR. The respiratory effects of Outcomes study Significant respiratory symptoms and changes in This study lacked a control group. 2c
cannabis dependence in young at single time spirometry occur in cannabis-dependent individuals The cannabis user group comprised
adults. Addiction 2000 interval with at age 21 years, although the cannabis smoking less than 10% of the total and two-
exposure and history is of relatively short duration. thirds of this group also smoked
outcome tobacco. Generalizing from the
determined relatively small sample size is difficult.
simultaneously.
Tashkin DP. Effects of smoked Case-control No significant differences (as measured by 3b
substance abuse on nonspecific study of the methacholine positive responses of ≥ 10%
airway hyperresponsiveness. Am Rev pulmonary effects decreases from baseline FEV) to any concentration
Respir Dis 1993 of habitual of methacholine were found between marijuana
smoking of illicit nonsmokers and smokers.
substances.
Tashkin DP. Subacute effects of Experimental – These findings suggest that customary social use This study had a small sample size 4
heavy marihuana smoking on “self-control” non- of marijuana may not result in detectable functional and all subjects were also heavy
pulmonary function in healthy men. N randomized respiratory impairment in healthy young men, tobacco smokers. Airway obstruction
Engl J Med 1976 study. whereas very heavy marijuana smoking for six to was statistically but not clinically
eight weeks causes mild but statistically significant significant.
airway obstruction.10
TABLE 3. STUDIES MEETING INCLUSIONS CRITERIA: HARM (Continued)
STUDY STUDY TYPE AUTHORS’ CONCLUSIONS CRITICAL APPRAISAL LEVEL OF
EVIDENCE
Cognitive Impairment
Lyketsos CG. Cannabis use and Observational - Over long time periods, in persons under age 65 Although random sampling was 2b
cognitive decline in persons under 65 cohort study. years, cognitive decline occurs in all age groups. undertaken, no demographic tables
years of age. Am J Epidemiol 1999 This was a follow- This decline is closely associated with aging and were provided to determine whether it
up study of a educational level but does not appear to be was successful. The degree of
probability associated with cannabis use. The Mini-Mental exposure was not clear or likely
sample of the Status Examination (MMSE) is not a very sensitive consistent over time between groups.
adult household measure of cognitive decline, however, and so The MMSE is an insensitive measure
residents of East small or subtle effects of cannabis use on cognition of cognitive function.
Baltimore. or psychomotor speed may have been missed.
Fletcher JM. Cognitive correlates of Observational - Long-term cannabis use was associated with This small cohort study detected 2b
long-term cannabis use in Costa cohort study. disruption of short-term memory, working memory subtle disruption in memory and
Rican men. Arch Gen Psychiatry and attentional skills in older long-term cannabis cognitive skills, but was unable to
1996 users. determine the degree of confounding
based on age-related changes alone,
and studied a population not likely
comparable to that of the WCB.
Block RI. Effects of chronic Observational – More work is needed to evaluate alternative This study of a mostly male low- 2b
marijuana use on human cognition. cohort study. interpretations of the cognitive impairments income group had multiple
Psychopharmacology 1993 associated with heavy marijuana use. confounders, did not report a dose-
response relationship and reported
outcomes of unclear clinical
importance.11
TABLE 3. STUDIES MEETING INCLUSIONS CRITERIA: HARM (Continued)
STUDY STUDY TYPE AUTHORS’ CONCLUSIONS CRITICAL APPRAISAL LEVEL OF
EVIDENCE
Psychomotor Impairment
Robbe H. Marijuana’s impairing Experimental - Marijuana alone impairs driving performance, with This small study reported on 2b
effects on driving are moderate when four single-blind, the degree of impairment increasing from small to surrogate markers of poor driving
taken alone but severe when randomized, moderate as the THC dose increases from 100 to performance.
combined with alcohol. Hum crossover 300 µg/kg. However, when low to moderate doses
Psychopharmacol Clin Exp 1998 studies. of THC (100 and 200 µg/kg) are taken in
combination with a Blood Alcohol Concentration
(BAC) of about 0.04%, driving is severely impaired.
Longo MC. The prevalence of Case-control The study found a clear, concentration-dependent 3b
alcohol, cannabinoids, study. relationship between alcohol and culpability. It also
benzodiazepines and stimulants found a significant relationship between
amongst injured drivers and their role benzodiazepines and culpability. In contrast, it
in driver culpability. Part ii: The found no significant relationship between THC and
relationship between drug prevalence culpability, although the data here and in other
and drug concentration and driver culpability studies do not exclude the possibility of
culpability. Accid Anal Prev 2000 an adverse effect of cannabinoids if the
concentration is sufficiently high.
Yesavage JA. Carry-over effects of Experimental – The results may have implications for performance This study was not randomized and 4
marijuana intoxication on aircraft pilot “self-control” of complex tasks the day after smoking marijuana. lacked a control group.
performance: a preliminary report. clinical trial.
Am J Psychiatry 198512
TABLE 3. STUDIES MEETING INCLUSIONS CRITERIA: HARM (Continued)
STUDY STUDY TYPE AUTHORS’ CONCLUSIONS CRITICAL APPRAISAL LEVEL OF
EVIDENCE
Adverse Reproductive Effects
Scragg RK. Maternal cannabis use in Observational – a Frequent maternal cannabis use may be a weak The confidence intervals for the odds 3b
the sudden death syndrome. Acta nationwide case risk factor for SIDS, but this finding requires further ratios for reported outcomes were
Paediatr 2001 control study. research. wide and were not statistically
significant.
Goldschmidt L. Effects of prenatal Case-control Prenatal marijuana exposure has an effect on child Prenatal marijuana may have an 3b
marijuana exposure on child behavior study. behavior problems at age 10. effect on child behavior problems at
problems at age 10. Neurotoxicol age 10. This large case-series was
Teratol 2000 seriously confounded by the lack of
non-ethanol and non-cannabis control
groups.
Shiono PH. The impact of cocaine Observational - In this population of women receiving prenatal This large study was unable to 2b
and marijuana use on low birth weight prospective care, cocaine use was uncommon and was not demonstrate a harmful effect from
and preterm birth: a multicenter multicenter cohort related to most adverse birth outcomes. Marijuana cannabis use.
study. Am J Obstet Gynecol 1995 study. 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.
Gibson GT. Maternal alcohol, Observational – Cannabis used regularly, frequently and in its more This study was seriously confounded 2b
tobacco and cannabis consumption prospective potent forms is significantly associated with by simultaneous tobacco and ethanol
and the outcome of pregnancy. Aust cohort study. preterm labor and its sequelae (e.g. perinatal use in cannabis smokers. When this
N Z J Obstet Gynaecol 1983 death). Cannabis used in pregnancy is probably was factored in there was not
associated with intrauterine growth retardation. apparent association between
cannabis use and IUGR.13
TABLE 3. STUDIES MEETING INCLUSIONS CRITERIA: HARM (Continued)
STUDY STUDY TYPE AUTHORS’ CONCLUSIONS CRITICAL APPRAISAL LEVEL OF
EVIDENCE
Marijuana and schizophrenia
Martinez-Arevalo MJ. Cannabis Observational – These data are consistent with other studies that Increased use of cannabis may be a 4
consumption as a prognostic factor in study without report that cannabis consumption is associated marker for schizophrenia, but it could
schizophrenia. Br J Psychiatry 1994 control group. with a poorer outcome of schizophrenia. The not be determined from this study
nature of the association is unclear. Cannabis use whether the relationship was
might be a result of the severity of the correlational or causal.
schizophrenia, so that patients with a poorer
outcome would consume more cannabis
secondarily. On the other hand, cannabis could be
a factor in relapse.
Upper Aero-Digestive Cancer
Zhang ZF. Marijuana use and Observational - The results suggest that marijuana may increase Although authors suggest that 3b
increased risk of squamous cell case-control the risk of head and neck cancer with a strong marijuana use may increase the risk
carcinoma of the head and neck. study. dose-response pattern. Analysis indicated that of head and neck cancer with a trend
Cancer Epidemiol Biomarkers Prev marijuana use may interact with mutagen toward a dose-response pattern (wide
1999 sensitivity and other risk factors to increase the risk confidence intervals associated with
of head and neck cancer. The results need to be point estimate), tobacco smoking may
interpreted with some caution in drawing causal have been a confounder: 93% of
inferences because of certain methodological users with cancer smoked tobacco,
limitations, especially with regard to interactions. compared to 79% of non-users with
cancer and 63% of the non-cancer
group.
Sridhar KS. Possible role of Exploratory – Exposure to marijuana smoke is associated with The population studied was from one 4
marijuana smoking as a carcinogen in case series presentation of cancer of the lung, particularly in practice and 90% of the patients also
the development of lung cancer at a study. younger patients. had a tobacco smoking history.
young age. J Psychoactive Drugs
199414 • 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 marijuana’s 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 marijuana’s 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 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.
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 the21 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.You can also read
