Chapter 3 - Continued
One of the more controversial of the effects claimed for marijuana is
the production of an "amotivational syndrome." This syndrome
is not a medical diagnosis, but it has been used to describe young people
who drop out of social activities and show little interest in school,
work, or other goal-directed activity. When heavy marijuana use accompanies
these symptoms, the drug is often cited as the cause, but there are no
convincing data to demonstrate a causal relationship between marijuana
smoking and these behavioral characteristics.23 It is not enough
to observe that a chronic marijuana user lacks motivation. Instead, relevant
personality traits and behavior of subjects must be assessed before, as
well as, after the subject becomes a heavy marijuana user. Because such
research can only be done on subjects who become heavy marijuana users
on their own, a large population study such as the Epidemiological Catchment
Area study described earlier in this chapter - would be needed to shed
light on the relationship between motivation and marijuana use. Even then,
while a causal relationship between the two could, in theory, be dismissed
by an epidemiological study, causality not be proven.
Summary on Psychological Effects
Measures of mood, cognition, and psychomotor performance should be incorporated
into clinical trials evaluating the efficacy of marijuana or cannabinoid
drugs for a given medical condition. Ideally, participants would complete
mood assessment questionnaires at various intervals throughout the day
for a period prior to and at weekly intervals during treatment, and, where
appropriate, after the cessation of marijuana therapy. A full psychological
screening of research participants should be conducted to determine whether
there is an interaction between the mood altering effects of chronic marijuana
use and the psychological characteristics of the individual. Similarly,
the cognitive and psychomotor functioning of individuals should be assessed
prior to and at regular intervals during the course of a chronic regimen
of marijuana or cannabinoid treatment to determine to what extent tolerance
develops to the impairing effects of marijuana and to monitor whether
new problems develop.
When compared to changes produced by either placebo or an active control
medication, the magnitude of desirable therapeutic effects produced by
marijuana could be determined, as well as the frequency and magnitude
of adverse psychological side effects. This would allow a more thorough
assessment of the risk:benefit ratio associated with the use of marijuana
for a given indication.
CONCLUSION: The psychological effects of cannabinoids, such
as anxiety reduction, sedation, and euphoria can influence their potential
therapeutic value. Those effects are potentially undesirable for certain
patients and situations, and beneficial for others. In addition, psychological
effects can complicate the interpretation of other aspects of the
RECOMMENDATION: Psychological effects of cannabinoids such as
anxiety reduction and sedation, which can influence medical benefits,
should be evaluated in clinical trials.
Physiological Harms: Tissue and Organ Damage
Many people who spoke to the IOM study team in favor of the medical
use of marijuana cited the absence of marijuana overdoses as evidence
that it is safe. Indeed, epidemiological data indicate that - for the
general population - marijuana use is not associated with increased
mortality.(Sidney 1997a ) However, there are other serious health outcomes
to consider, and they are discussed below.
It is important to keep in mind that most of the studies that report
physiological harms resulting from marijuana use are based on the effects
of marijuana smoking. Thus we emphasize that the effects reported cannot
be presumed to be caused by THC alone or even in combination with other
cannabinoids found in marijuana. It is likely that smoke is a major
cause of the reported effects. In most studies, the methods used make
it impossible to weigh the relative contributions of smoke versus cannabinoids.
The relationship between marijuana and the immune system presents many
facets, including potential benefits and suspected harms. This section
reviews the evidence on suspected harms to the immune system caused by
Despite the many claims that marijuana suppresses the human immune system,
the health impact of marijuana-induced immunomodulation is still unclear.
Few studies have been done with animals or humans to assess the effects
of marijuana exposure on host resistance to bacteria, viruses or tumors.
Several approaches have been used to determine the effects of marijuana
on the human immune system, but each of these has serious limitations
which will be discussed below.
Leukocyte assays from marijuana smokers
One of the more common approaches has been to isolate peripheral blood
leukocytes from individuals who have smoked marijuana in order to evaluate
the immune response of those cells in vitro - most often by measuring
mitogen-induced cell proliferation, a normal immune response. Almost without
exception, this approach has failed to demonstrate any reduction in leukocyte
function. The major problem with this approach is that after drawing blood
samples from the study subjects, the leukocytes need to be isolated from
whole blood before they are tested. This is done by high-speed centrifugation
followed by extensive washing of the cells, thus resulting in removal
of the cannabinoid; perhaps for that reason no adverse effects have been
demonstrated in peripheral blood leukocytes from marijuana Smokers. 74,
90, 122, 159
Leukocyte responses to THC
Another approach is to isolate peripheral blood leukocytes from healthy
control individuals who do not smoke marijuana and then to measure the
effect of THC on the ability of these cells to proliferate in response
to mitogenic stimulation in vitro. However, it is notable that
one significant difference between leukocytes isolated from a marijuana
smoker, as described above, and the in vitro studies in which THC
has been added directly to leukocyte cell cultures is in the cannabinoid
composition. Marijuana smoke contains many distinct cannabinoid compounds
of which THC is just one. Moreover, since the immunomodulatory activity
of many of the other cannabinoid compounds present in marijuana smoke
has never been tested, and because it is now known that at least one of
those - cannabinol (CBN) - has greater activity on the immune system than
the central nervous system, 63
it is unclear whether the profile of activity observed with THC accurately
represents the effects of marijuana smoke on immune competence. Likewise,
it is unclear to what extent different cannabinoids in combination exhibit
additive, synergistic or antagonistic effects with respect to their
immunomodulatory activity. This issue is further complicated by the
fact that leukocytes express both types of cannabinoid receptors, CB1
One additional factor which may affect the immunomodulatory activity
of cannabinoids in leukocytes is metabolism. Since leukocytes have very
low levels of
the cytochrome P-450 drug metabolizing enzymes 20, the
metabolism of cannabinoids is probably different between in vivo
and in vitro exposure. This last point is primarily pertinent
to investigations of chronic and not acute cannabinoid exposure.
Human-derived cell lines
A third approach for investigating the effects of cannabinoids on human
leukocytes has been to study human-derived cell lines. b As
described above, the cell lines are treated in vitro with cannabinoids
to test their responses to different stimuli. Although cell lines are
a convenient source of human cells, the same problems described above
apply. Additionally, the cell lines might not be the same as the original
cells. For example, cell lines do not necessarily have the same number
of cannabinoid receptors as the original human cells.
The most widely used approach is to evaluate the effects of cannabinoids
in rodents, using rodent-derived cells in vitro. The rationale for this
approach is based on the fact that the human and rodent immune systems
are remarkably similar, and it is assumed that the effects produced by
cannabinoids on the rodent immune system will be similar to those produced
in humans. Although no significant species differences in immune system
sensitivity to cannabinoids have been reported, it is important to consider
The complete effect of marijuana smoking on immune function remains
unknown. More importantly, it is not known whether smoking leads to increased
rates of infections, tumors, allergies, or autoimmune responses. The problem
is how to duplicate the "normal" marijuana smoking pattern while
at the same time removing other potential immune modulating life-style
factors such as alcohol and tobacco use. Epidemiological studies are needed
to determine whether marijuana users have a higher incidence of diseases
such as infections, tumors, allergies, and autoimmune disease. Studies
on resistance to bacterial and viral infection are clearly needed, and
should involve the collaboration of immunologists, infectious disease
specialists, oncologists, and pharmacologists.
b Cell lines are created by removing cells from an organism
and then treating them so they are "immortalized,' meaning they
will continue to divide indefinitely in culture. Cellular processes
can then be studied in isolation from their original source.
Tobacco is the predominant cause of lung diseases such as cancer and
emphysema, and marijuana smoke contains many of the same components as
tobacco smoke. 7 Thus, it is important to consider the relationship
between habitual marijuana smoking and certain lung diseases.
Given a cigarette of comparable weight as much as four times the amount
of tar can be deposited in the lungs of marijuana smokers compared to
tobacco smokers. 161 This is primarily due to the differences
in filtration and smoking technique between tobacco and marijuana smokers.
Marijuana cigarettes usually do not have filters, and marijuana smokers
typically develop a larger puff volume, inhale more deeply, and hold their
breath several times longer than tobacco smokers. 118 However,
a marijuana cigarette smoked recreationally typically is not packed as
tightly as a tobacco cigarette, and thus the smokable substance is about
half that in a tobacco cigarette. In addition, tobacco smokers generally
smoke considerably more cigarettes per day than do marijuana smokers.
Lymphocytes: T and B Cells
Human studies of the effect of marijuana smoking on immune agents are
not all consistent with cannabinoid cell culture and animal studies. For
example, antibody production was decreased in a group of hospitalized
patients who smoked marijuana for four days (twelve cigarettes/day), but
this decrease was seen in only one subtype of humoral antibody (IgG),
while two other subtypes (IgA and IgM) remained normal and one (IgE) was
elevated. 107 Additionally, T cell proliferation was normal
in the blood of a group of marijuana smokers, although when evaluated
more closely, there was an increase in one subset of T cells 160
and a decrease in a different subset (CD8). 156 From these
studies it appears that marijuana use is associated with intermittent
disturbances in T and B cell function, but the magnitude is small and
other measures are frequently normal. 86
Alveolar macrophages are the principal immune-effector cells in the
lung and are primarily responsible for protecting the lung against infectious
microorganisms, inhaled foreign substances, and tumor cells. They are
increased during tissue inflammation. In a large sample of volunteers,
habitual marijuana smokers had twice as many alveolar macrophages as nonsmokers,
and smokers of both marijuana and
tobacco had twice as many again. 11 Marijuana smoking also
reduced the ability of alveolar macrophages to kill fungus such as Candida
aIbicans, c pathogenic bacteria such as Staphylococcus
aureus, and tumor target cells. This reduction in ability to destroy
fungal organisms was similar to that seen in tobacco smokers. The inability
to kill pathogenic bacteria was not seen in tobacco smokers. 10
Furthermore, marijuana smoking depressed pro-inflammatory cytokine production
(such as TNF-a and IL-6), but not Immunosuppressive cytokines. 10
Since cytokines are important regulators of macrophage function, this
marijuana-related decrease in inflammatory cytokine production might
be a mechanism whereby marijuana smokers are less able to destroy fungal
and bacterial organisms, as well as tumor cells.
The inability of alveolar macrophages from habitual marijuana smokers
without apparent disease to destroy fungus, bacteria, and tumor cells,
and to release pro-inflammatory cytokines, suggests that marijuana might
be an immunosuppressant with clinically significant effects on host defense.
Therefore, the risks of smoking marijuana should be seriously weighed
before recommending ifs use in any patient with pre-existing immune deficits
-- including AIDS patients, cancer patients, and those receiving immunosuppressive
therapies (for example, transplant or cancer patients).
A number of animal studies have revealed certain respiratory tract changes
and diseases associated with marijuana smoking, while others have not.
Extensive damage to the smaller airways, which are the major site of chronic
obstructive pulmonary disease (COPD), d as well as acute and
chronic pneumonia have been observed in various species exposed to different
doses of marijuana smoke. 41, 42, 127 In contrast, rats exposed
to increasing doses of marijuana smoke for one year did not show any signs
of COPD, whereas rats exposed to tobacco smoke did. 66
Chronic Bronchitis and Respiratory Illness
Human studies suggest that there is a greater chance of respiratory
illness in individuals who smoke marijuana. In a survey of outpatient
medical visits in a large HMO, marijuana users were more likely to seek
help for respiratory illnesses than people who smoked neither marijuana
nor tobacco. 119 However, the incidence of
c A yeast infection that is particularly prevalent among
people whose immune systems are suppressed, such as in AIDS patients.
d A slow progressive obstruction of the airways, loss of
their elasticity, and loss of lung volume. Characterized by chronic
shortness of breath, chronic bronchitis and reduced oxygenation of blood.
seeking help for respiratory illnesses was not elevated for those who
smoked marijuana for 10 years or more when compared to those who smoked
for less than 10 years. One explanation for this is that people who
experience respiratory symptoms are more likely to quit smoking, and
the people who continue to smoke represent a set of survivors who do
not develop or are indifferent to such symptoms. A limitation of this
study is that no data were available on the use of cocaine, which when
used with marijuana could contribute to the observed differences. Another
limitation is that the survey relied on self-reporting, and tobacco,
alcohol and marijuana use might have been underreported (S. Sidney,
When marijuana smokers were compared to non-smokers and tobacco smokers
in a group of 446 volunteers, 15-20 % reported symptoms of chronic bronchitis,
including chronic cough and phlegm production. 145 Twenty to
25 % of the tobacco smokers also reported symptoms of chronic bronchitis.
Despite a marked disparity in the amount of each substance smoked per
day (3-4 joints of marijuana versus more than 20 cigarettes of tobacco),
the difference in the percent of tobacco-smokers and marijuana-smokers
experiencing symptoms of chronic bronchitis was insignificant. 145
Similar findings were reported by Bloom and coworkers, 15
and these investigators noted an additive effect of smoking both marijuana
Bronchial Tissue Changes
Habitual marijuana smoking is associated with changes in the lining
of the human respiratory tract. Many marijuana or tobacco smokers have
increased redness (erythema) and swelling (edema) of the airway tissues
and increased mucus secretions. 43, 55 In marijuana smokers,
the number and size of small blood vessels in the bronchial wall are increased,
tissue edema is present, and the normal ciliated cells e lining
the inner surface of the bronchial wall are largely replaced by mucus
secreting goblet cells.. Moreover, the damage is even greater in people
who smoke both marijuana and tobacco. 129 Overproduction of
mucus by the increased numbers of mucus-secreting cells in the face of
diminished numbers of ciliated cells tends to leave cough as the only
major mechanism to remove mucus from the airways. This might explain the
relatively high proportion of marijuana smokers who complain of chronic
cough and phlegm production. 147
A 1998 study has shown that, compared to nonsmokers, both marijuana
and tobacco smokers have significantly more cellular and molecular abnormalities
in bronchial epithelium cells; those changes are associated with increased
risk of cancer. 12 The tobacco-only smokers in that study smoked
an average of 25 cigarettes per day, whereas the marijuana-only smokers
smoked an average of 21 marijuana cigarettes per week. Despite the fact
that the marijuana smokers smoked many fewer
e Ciliated cells have hair-like projections that function
to transport mucus toward the mouth by rapid wave-like motion.
cigarettes, their cellular abnormalities were equivalent, or greater
than, those seen in tobacco smokers. This and earlier studies have shown
than such abnormalities are greatest in people who smoke both marijuana
and tobacco, suggesting an additive effect of marijuana and tobacco
smoke on airway tissue. 12 43 55 Tenant and coworkers 149
found similar results in U.S. servicemen who suffered from respiratory
symptoms and were heavy hashish smokers. (Hashish is the resin from
the marijuana plant).
Chronic Obstructive Pulmonary Disease
In the absence of epidemiological data, indirect evidence, such as nonspecific
airway hyperresponsiveness and measures of lung function, offers an indicator
of the vulnerability of marijuana smokers to COPD. 153 For
example, the methacholine provocative challenge test, used to evaluate
airway hyperresponsiveness, showed that tobacco smokers develop more airway
hyperresponsiveness. But no such correlation has been shown between marijuana
smoking and airway hyperresponsiveness.
There are conflicting results as to whether regular marijuana use harms
the small airways of the lungs. Bloom found that an average of one joint
smoked per day significantly impaired the function of small airways. 15
On the other hand, Tashkin and coworkers 145 did not observe
such damage among heavier marijuana users (3-4 joints per day for at least
10 years), but did note a narrowing of large, central airways. Tashkin
s long-term study, which adjusted for age-related decline in lung function
(associated with an increased risk for developing COPD), showed an accelerated
rate of decline in tobacco smokers, but not in marijuana smokers. 146
Thus the question as to whether usual marijuana smoking habits are enough
to cause COPD remains open.
Chronic marijuana smoking might lead to acute and chronic bronchitis
and extensive microscopic abnormalities in the cells lining the bronchial
passageways, some of which may be pre-malignant. These respiratory symptoms
are similar to that of tobacco smokers, and the combination of marijuana
and tobacco smoking augments these effects. At the time of this writing,
it has not been established whether chronic smoking marijuana causes COPD,
but there is probably an association.
The relationship between marijuana smoking and the natural course of
AIDS is of particular concern because HIV patients are the largest group
who report using
marijuana for medical purposes. Marijuana use has been linked to both
increased risk of progression to AIDS in HIV-seropositive patients,
and to increased mortality in AIDS patients.
For reasons as yet unknown, marijuana use is associated with increased
mortality among men with AIDS, but not among the general population. 137
(The relative risk of AIDS mortality for current marijuana users in this
12-year study was 1.90, indicating that, compared to non-current marijuana
users, almost twice as many marijuana users died of AIDS.) Never married
men used twice as much marijuana as married men and accounted for 83%
of the AIDS deaths in the study. The authors of the study note that, while
marital status is insufficient to adjust for lifestyle factors -particularly,
homosexual behavior - a substantial proportion of the never married men
with AIDS were likely homosexuals or bisexuals. This raises the possibility
that the association of marijuana use with AIDS deaths might be related
to indirect factors, such as use of other drugs or high risk sexual behavior,
both of which increase risks of infection to which AIDS patients are more
susceptible. The higher mortality of AIDS patients who were current marijuana
users also raises the question as to whether this was because patients
increased their use marijuana at the end-stages of the disease to treat
their symptoms. However, the association between marijuana use and AIDS
deaths was similar even when the subjects who died earliest in the first
5 years of this 12 year study, and who were presumably the most sick,
were excluded from the analysis. In sum, it is premature to conclude what
the underlying causes of this association might be.
For the general population, the risk of mortality associated with marijuana
use was lower than that associated with cigarette smoking, and tobacco
smoking was not an independent risk factor in AIDS mortality in this study.
Interestingly, the authors of this study concluded that therapeutic use
of marijuana did not contribute to the increased mortality among men with
Marijuana use has been associated with a higher prevalence of HIV seropositivity
in cross-sectional studies,(Ostrow 1994) 83 but the relationship
of marijuana to the progression to AIDS in HIV-seropositive patients is
a reasonable question. It remains unclear whether marijuana smoking is
an independent risk factor in the progression of AIDS in HIV-seropositive
men. Marijuana use did not increase the risk of AIDS in HIV-seropositive
men in the Multicenter AIDS Cohort Study, in which 1,795 HIV-seropositive
men were studied for 18 months, 83 or in the San Francisco
Men's Health Study, in which 451 HIV-seropositive men were studied for
6 years. 34 In contrast, the Sydney AIDS Project in Australia
(386 HIV seropositive men were studied for 12 months) 151
reported that marijuana use was associated with increased risk of progression
to AIDS. But the results of the 1988 Sydney study are less reliable than
the other two studies described. For one, this was the shortest of the
studies; and, second, according to the 1993 definition of
AIDS, many of the subjects probably already had AIDS at the beginning
of the study. f
The most compelling concerns regarding marijuana smoking in HIV/AIDS
patients are the possible effects of marijuana on human immunity. 110
Reports of Opportunistic fungal and bacterial pneumonia in patients with
AIDS who used marijuana suggest that marijuana smoking either suppresses
the immune system, 33 or that it exposes patients to an added
burden of pathogens. 21 In sum, patients with preexisting
immune deficits due to AIDS should be expected to be vulnerable to serious
harms caused by smoking marijuana. The relative contribution of marijuana
smoke versus THC or other cannabinoids is not known.
The gas and tar phases of marijuana and tobacco smoke contain many of
the same compounds. Furthermore, the tar phase of marijuana smoke contains
higher concentrations of polycyclic aromatic hydrocarbons (PAHs), such
as the carcinogen benzopyrene. The higher content of carcinogenic PAHs
in marijuana tar and the greater deposition of this tar in the lung might
act in conjunction to amplify the exposure of the marijuana smoker to
carcinogens. For these reasons the carcinogenicity of marijuana smoke
is an important concern.
Compared to studies on tobacco smoke, it is more difficult to collect
the epidemiological data necessary to establish or refute the link between
marijuana smoke and cancer. Far fewer people smoke only marijuana than
who smoke only tobacco, and marijuana smokers are more likely to underreport
Several case-series suggest that marijuana might play a role in the
development of human respiratory cancer. Those reports indicate an unexpectedly
large proportion of marijuana users among cases of lung cancer 140,
148 and cancers of the upper aerodigestive tract - that is, the
oral cavity, pharynx, larynx, and esophagus - that occur before age 45
years. 36, 39, 148 Respiratory tract cancers associated with
heavy tobacco and alcohol consumption are not usually seen before the
age of 60 years, 153 and the occurrence of such cancers in
marijuana users younger than 60 years suggests that long-term marijuana
smoking potentiates the effects of other risk factors, such as tobacco
smoking, and is a more potent risk factor than tobacco and alcohol use
in the early development of respiratory cancers. Unfortunately, most studies
lack the necessary comparison groups to calculate the isolated effect
of marijuana use on cancer risk. Many marijuana smokers also smoke tobacco,
so when studies lack information regarding cigarette smoking status, there
is no way to separate the effects of marijuana smoke from tobacco smoke.
f In 1993, the diagnosis of AIDS was expanded to include
anyone with a CD4 count less than 200. Prior to 1993, this alone would
have been insufficient for a diagnosis of AIDS.
As of this writing, Sidney and coworkers 138 have conducted
the only epidemiological study to evaluate the association between marijuana
use and cancer. The study included a cohort of approximately 65,000 men
and women between the ages of 15 and 49 years. Marijuana users were defined
as those who had used marijuana on six or more occasions. Among the 1,421
cases of cancer in this cohort, marijuana use was associated only with
an increased risk of prostate cancer in men who did not smoke tobacco.
In these relatively young HMO clients, no association was found between
marijuana use and other cancers, including all tobacco-related cancers,
colorectal or melanoma. The major limitation associated with interpreting
this study is that the development of lung cancer requires a long exposure
to smoking, and most marijuana users quit before this level of exposure
is achieved. Additionally, marijuana use has only been widespread in the
U.S. since the late 1960s; therefore, despite the large cohort size there
might not have been a sufficient number of heavy and/or long-term marijuana
smokers to observe an effect.
Cellular and Molecular Studies
In contrast to clinical studies, the evidence from cellular and molecular
studies provides strong evidence that marijuana smoke is carcinogenic.
Cell culture studies implicate marijuana smoke in the development of cancer.
Prolonged exposure of hamster lung cell cultures to marijuana smoke led
to malignant transformations, 93 and human lung explants exposed
to marijuana smoke resulted in chromosomal and DNA alterations. 153
Additionally, the tar from marijuana smoke induced mutations similar to
those produced by tar from the same quantity of tobacco in a common bacterial
assay for mutagenicity. 157
Molecular studies also implicate marijuana smoke as a carcinogen. Protooncogenes
and tumor suppressor genes are a group of genes that affect cell growth
and differentiation. Normally, those genes code for proteins that control
cellular proliferation. Once mutated or activated, these genes produce
proteins which cause cells to multiply rapidly and out of control, resulting
in tumors or cancer. g When the production of these proteins
was evaluated in tissue biopsies taken from marijuana, tobacco, marijuana
plus tobacco smokers, and non-smokers, respectively, two of them (EGFR
and Ki-67) were markedly increased in the marijuana smokers compared to
non-smokers and tobacco smokers. Moreover, the effects of marijuana and
tobacco were additive. 130 Thus, in relatively young smokers
of marijuana, and
g Some of the genes involved in the development of lung
cancer include those that encode for Ki-67 (a nuclear proliferation
protein responsible for cell division), the p53 tumor suppressor (a
protein that normally suppresses cell growth), and epidermal growth
factor receptor (EGFR) (a receptor found on a variety of cell types,
especially epithelia, and which promotes cellular growth and proliferation
when bound to epidermal growth factor).
particularly in those who smoke both marijuana and tobacco, marijuana
is implicated as a risk factor for lung cancer.
DNA alterations are known to be early events in the development of cancer,
and have been observed in the lymphocytes of pregnant marijuana smokers,
as well as in those of their newborns. 4 This is an important
study because the investigators were careful to exclude tobacco smokers
- a problem in previous studies that cited mutagenic effects of marijuana
smoke. 26, 53, 62, 141 These same investigators found similar
effects in previous studies among tobacco smokers, 5, 6 so
the effects cannot be attributed solely to THC or other cannabinoids.
Although it can only be determined by experiment, it is likely that the
smoke contents - other than cannabinoids - are responsible for a large
part of the mutagenic effect.
Preliminary findings suggest that marijuana smoke activates cytochrome
P4501A1 (CYPlA1), the enzyme that converts PAHs, such as benz[a]pyrene,
into active carcinogens 98 Bronchial epithelial cells in tissue
biopsies taken from marijuana smokers show more binding to CYP1A1 antibodies
than do comparable cells in biopsies from nonsmokers (D.Tashkin, IOM workshop).
This suggests that there is more of the carcinogen-producing enzyme, CYP1A1,
itself in bronchial cells of marijuana smokers, but different experimental
methods will be needed to definitely establish that possibility.
At this time, there is no conclusive evidence that marijuana causes
cancer in humans, including cancers usually related to tobacco use. However,
cellular, genetic and human studies all suggest that marijuana smoke maybe
an important risk factor for the development of respiratory cancer. More
definitive evidence that habitual marijuana smoking does or does not lead
to respiratory cancer awaits the results of well-designed case-controlled
epidemiological studies. It has been 30 years since the initiation of
widespread marijuana use among young individuals in our society, and such
studies should now be feasible.
The following studies or activities would be useful in providing data
that could more precisely define the health risks of smoking marijuana.
1. Case-control studies to determine whether marijuana use is associated
with an increased risk of respiratory cancer: Despite the lack of
compelling epidemiological evidence to date, findings from the biochemical,
cellular, immunologic, genetic, tissue and animal studies cited above
strongly suggest that marijuana is a risk factor for human cancer. What
is required to address this hypothesis more convincingly is a population-based
case-controlled study of sufficiently large numbers of lung cancer cases
and cases of upper aerodigestive tumors (cancers of the oral cavity and
pharynx, larynx and esophagus), as well as non-cancer controls, to demonstrate
a statistically significant association, if one exists. Because of the
long time period required for induction of human carcinomas and the infrequent
use of marijuana in the general U.S. population prior to 1966, no
epidemiological studies so far have been extensive enough to adequately
measure the association between marijuana and cancer. However, epidemiological
investigation of this association is probably possible now, since approximately
30 years have elapsed since the start of widespread marijuana use in
the U.S. among teenagers and young adults.
2. Molecular markers of respiratory cancer progression in marijuana
smokers. If an epidemiological association between marijuana use and
risk of respiratory cancer is demonstrated, then studies are warranted
to explore the presence of molecular markers that may be predictive of
genetically increased risk of carcinogenesis in marijuana users, such
as TP53, p16, NATZ and GSTML.
3. Prospective epidemiological studies of populations with HIV-seropositivity
or at high risk for HIV infection. Because HIV/AIDS patients are largest
group that reports smoking marijuana for medical purposes and they are
particularly vulnerable to immunosuppressive effects, there is a pressing
need for a better understanding of the relative risk and rewards of smoking
marijuana. Such studies should include history of marijuana use in the
analysis of potential risk factors for seroconversion and acquisition
of opportunistic infections/progression to AIDS. h These studies
could be carried out in the context of any federally approved clinical
trials of medicinal marijuana in immunocompromised patients and should
provide a sufficiently long period of follow-up to capture any potential
4. Regularized recording of marijuana use by patients. Although
marijuana is the most commonly used illicit drug, medical providers often
do not question patients about marijuana use and rarely document its use.
101 Among 452 Kaiser Permanente patients who reported daily
or almost daily marijuana use, physicians recorded marijuana use in only
3 % of their medical records (S. Sidney, IOM workshop).
5. Additional cellular, animal and human studies to investigate further
the impact of THC and marijuana on immune function, including their
effects on proinflammatory versus immunosuppressive cytokines, and on
the function of leukocytes that present antigen to T cells.
The question that needs to be addressed is whether THC or marijuana
is a risk factor for HIV infection, for progression to more severe stages
of AIDS, or for opportunistic infection among HIV-positive patients. Studies
are needed to determine the effects of marijuana use on the function of
alveolar macrophages. It would be important to compare the HIV infectivity
and replication of alveolar macrophages harvested from habitual marijuana
users with those harvested from non- or infrequent marijuana users. Cell
culture studies could be used to compare the
h A prospective study is one in which a group of
subjects is identified and then studied over the course of time. Such
a study allows an experimenter to balance different factors that may
contribute to the study outcome. For example, age, family history, and
smoking are risk factors for lung cancer. In a prospective study these
factors can be balanced to measure how much smoking increases the risk
of lung cancer. A retrospective study is one in which people
with a particular disease are identified and their histories are studied.
Such studies are easier and less expensive to conduct, but they generally
lack the explanatory power of prospective studies.
susceptibility of HIV-infected alveolar macrophages to additional infection
with Opportunistic pathogens. Similarly, further studies on cell cultures
of peripheral blood mononuclear cells could be used to assess the impact
of exposure to THC on HIV infectivity and replication.
Marijuana smoke and oral THC can cause tachycardia (elevated heart rate)
in humans, usually 20 - 100 % above baseline. 56, 84 The increase
in heart rate is greatest in the first 10-20 minutes after smoking, and
decreases sharply and steadily; depending on whether smoked marijuana
or oral THC are used, these side effects can last 3 or 5 hours, respectively.
67, 94 In some cases, blood pressure can be increased while
a person is in a reclining position, but can decrease inordinately on
standing, resulting in postural hypotension. i In contrast
to acute administration of THC, chronic oral ingestion of THC reduces
heart rate in humans. 13
In animals, THC decreases heart rate and blood pressure. 56, 155
However, most such animals studies are conducted in anaesthetized animals,
and anesthesia causes hypertension. Thus, those studies should be interpreted
as reports on the effects of cannabinoids in hypertensive subjects. The
results of the animal and human studies are consistent with the conclusion
that cannabinoids are hypotensive at high doses in animals, as well as
humans (see 1998 review by Wagner and coworkers). 155
Tolerance can appear after a few days of frequent daily dosing (2 -
3 times per day) of oral THC or marijuana extract with heart rate slowing,
reclining blood pressure falling, and postural hypotension disappearing.
72 Thus, the intensity of these effects depends on the frequency
of use, dose, and even body position.
The cardiovascular changes have not been a health problem for healthy,
young users of marijuana or THC. However, such changes in heart rate and
blood pressure could present a serious problem for older patients, especially
those with coronary artery or cerebrovascular disease. Since cardiovascular
diseases are the leading causes of death in the United States (coronary
heart disease is first, stroke is third), any impact of marijuana use
on cardiovascular disease could have a substantial impact on public health
(S. Sidney, IOM workshop). The magnitude of this impact remains to be
determined as chronic marijuana users from the late 1960s enter the age
where coronary artery and cerebrovascular diseases become common. Additionally,
smoking marijuana is known to decrease maximal exercise performance. This,
along with the increased heart rate, could theoretically induce angina
(S. Sidney, IOM workshop). Therefore, this raises the possibility that
patients with symptomatic coronary artery disease should be advised not
to smoke marijuana, and THC might be contraindicated in patients with
restricted cardiovascular function.
i Decreased blood pressure due to changing posture from
a lying or sitting position to a standing position, which can cause
dizziness and faintness.
Marijuana and THC can inhibit many reproductive functions on a short-term
basis. In both male and female animals, THC injections suppress reproductive
hormones and behavior.106, 158 Studies have consistently
shown that injections of THC result in rapid, dose-dependent suppression
of serum luteinizing hormone (LH) levels. 69 (LH is the pituitary
hormone that stimulates release of the gonadal hormones, testosterone
and estrogen.) Embryo implantation also appears to be inhibited by THC.
But it does not necessarily follow from this that marijuana use will
interfere with human reproduction. With few exceptions, the animal studies
are based on acute (i.e., single injections) or short-term treatments
(i.e., THC injections given over a series of days). The results are
generally observed for only several hours, or sometimes in females for
only one ovulatory cycle.
Acute treatments of cannabinoids, including THC, CBD, and cannabinol,
and anandamide can decrease the fertilizing capacity of sea urchin sperm.
134, 135, 136 While the sea urchin is only a distant relative
of humans, the cellular processes that regulate fertilization are similar
enough that one can expect a similar effect in humans. However, the
effect of cannabinoids on the capacity of sperm to fertilize eggs is
reversible, and is observed at 6-100 µM concentrations, 135,
136 which are higher than those likely to be experienced by marijuana
smokers. At the same time, the presence of cannabinoid receptors in
sperm suggests the possibility of a natural role for anandamide in modulating
sperm function during fertilization. However, it remains to be determined
whether smoked marijuana or oral THC taken in prescribed doses has a
clinically significant effect on the fertilizing capacity of human sperm.
Exposure to THC in utero can result in long-term changes. Many
in utero effects interfere with embryo implantation (see review
by Wenger and coworkers 158). Exposure to THC: close to the
time of, or shortly after, their birth can also result in impaired reproductive
behavior in adult mice: females are slower to show sexual receptivity
and males are slower to mount. 106
Although THC can act directly on endocrine tissues, such as the testes
or ovaries, it appears to affect reproductive physiology through its actions
on the brain, but somewhere other than the pituitary. Some, but not all,
of the effects of THC are through its effect on stress hormones such as
The few human studies are consistent with the acute animal studies:
THC inhibits reproductive functions. However, studies of men and women
who use marijuana regularly have yielded conflicting results, and show
either depression of
reproductive hormones, effect, or only a short-term effect. Overall,
the results from human studies are consistent with the hypothesis that
THC inhibits LH on a short-term basis, but not in long-term marijuana
users. In other words, long-term users develop tolerance to the inhibitory
effect of THC on LH. The results in women are similar, with the added
consideration of the menstrual cycle; the acute effects of THC appear
to vary with cycle stage. THC appears to have little effect during the
follicular phase (the phase after menses and before ovulation), and
to inhibit the LH pulse during the luteal phase (the phase after ovulation
and before menses).102 In brief, although there are no data
on fertility per se, marijuana or THC would likely decrease human fertility
- at least in the short-term-for both men and women. And it is reasonable
to predict that THC can interfere with early pregnancy, particularly
implantation of the embryo. Like tobacco, marijuana smoke is highly
likely to be harmful to fetal development and should be avoided by pregnant
women as well as those who might become pregnant in the near future.
Nevertheless, although fertility and fetal development are important
concerns for many, they are unlikely to be of much concern to people
with seriously debilitating or life-threatening diseases. The well-documented
inhibition of reproductive functions by THC is thus not a serious concern
for evaluating the short-term medical use of marijuana or specific cannabinoids.
Developmental impact of use during pregnancy
Among the studies that have investigated the relationship between prenatal
marijuana exposure and birth outcome, the results have been inconsistent
(reviewed by Cornelius and coworkers 30 in 1995). Except for
adolescent mothers, there is little evidence that gestation is shorter
in mothers who smoke marijuana. 30 Several studies of women
who smoked marijuana regularly during pregnancy show that they tend to
give birth to lower weight babies.46, 64 Mothers who smoke
tobacco also give birth to lower weight babies, and the relative contributions
of smoking versus THC are not known from these studies.
Babies born to mothers who smoked marijuana during pregnancy weighed,
on average, 3.4 ounces less than babies born to the study's control group
of mothers who did not smoke marijuana; there was no significant difference
in either gestational age or frequency of congenital abnormalities.163
These results were based on women whose urine tests indicated recent marijuana.
However, when the analysis was based only on self-reports of marijuana
use (without verification by urine tests), there was no difference between
the weight of babies born to women who reported themselves as marijuana
smokers and those born to women who reported they did not smoke marijuana.
This raises an important concern about the methods used to measure the
effects of marijuana smoking in any study, and perhaps even more so in
studies on the effects of marijuana during pregnancy when subjects might
be even less likely to admit to smoking marijuana. (The study was conducted
in the last trimester of pregnancy, and there was no information about
the extent of marijuana use earlier in the pregnancy).
For most of these studies, much of the harms associated with marijuana
use are consistent with those associated with tobacco use, and smoking
is a significant
factor so the contribution of cannabinoids cannot be confirmed. However,
Jamaican women who use marijuana rarely smoke it, but instead prepare
it as tea. 37 In a study of neonates born to Jamaican women
who either did or did not ingest marijuana during pregnancy, there was
no difference in neurobehavioral assessments made at 3 days after birth
and at one month. 38 A limitation of this study is that there
was no direct measure of marijuana use. Estimates of marijuana use were
based on self reports, which might be more accurate in Jamaica than
in the U.S. since there is less social stigma associated with marijuana
use in Jamaica, but are nonetheless less reliable than direct measures
Newborns of mothers who smoke either marijuana or tobacco have significantly
higher mutation rates than those of non-smokers. 4, 5 Since
1978, the Ottawa Prenatal Prospective Study has been measuring the cognitive
functions of children born to mothers who smoked marijuana during pregnancy.
47 Children of mothers who smoked either moderately (1-6 marijuana
cigarettes per week) or heavily (more than 6 marijuana cigarettes per
week) have been studied from age four days to 9-12 years. It is important
to keep in mind that studies like this provide important data about the
risks associated with marijuana use during pregnancy, but they do not
establish the causes of any such association.
The children in the different marijuana exposure groups showed no lasting
differences in global measures of intelligence such as language development,
reading scores, and visual or perceptual tests. Moderate cognitive deficits
were detectable among these children when they were four days old and
again at four years, but these deficits were no longer apparent at five
Prenatal marijuana exposure was not, however, without lasting impact.
By comparison, at both ages 5-6 and 9-12, children in the same study who
were prenatally exposed to tobacco smoke scored significantly lower on
tests of language skills and cognitive functioning.48 In another
study, 49, 50 nine-to-twelve years olds who were exposed to
marijuana prenatally scored lower than control subjects on tasks associated
with "executive function," a term used by psychologists to describe
an individual's ability to plan ahead, anticipate, and suppress behaviors
that are incompatible with a current goal. 50 This was reflected
in how the mothers described their children. The mothers of the marijuana-exposed
children were more likely to describe their offspring as hyperactive or
impulsive than did mothers of control children. This alteration in executive
function was not seen in children born to tobacco smokers. The underlying
causes might be the marijuana exposure, or might be more closely related
to the reasons underlying their mothers' use of marijuana during pregnancy.
Mice born to dams injected with the endogenous cannabinoid, anandamide,
during the last trimester of pregnancy also showed delayed effects. No
effect of anandamide treatment during pregnancy was detected until the
mice were adults (40 days of age), at which time they showed behavioral
changes that are common to the effects of other psychotropic drugs or
prenatal stress. 45 As with the children born to mothers who
smoked marijuana, it is not known what aspect of the treatment caused
the effect. The dams might have found the dose (20 mg/kg of body weight)
anandamide aversive, in which case, the effect could have resulted
from generalized stress, as opposed to a cannabinoid-specific effect.
Either case is possible.
Despite the uncertainty as to the underlying causes of impact of prenatal
exposure to cannabinoid drugs, it is, nonetheless, prudent to advise against
smoking marijuana during pregnancy.
Summary and Conclusions
This chapter summarizes the harmful effects of marijuana to the individual
user and, to a lesser extent, to society. The harmful effects to individuals
were considered from the perspective of possible medical use of marijuana,
and can be divided into acute and chronic effects. The vast majority of
data on harmful effects of marijuana is based on smoked marijuana, and
except for the psychoactive effects that can be reasonably attributable
to THC, it is not possible to distinguish the drug effects from the effects
of inhaling smoke of burning plant material.
For most people, the primary adverse effect of acute marijuana use is
diminished psychomotor performance, it is inadvisable to operate any equipment
that might put the user or others in danger (such as driving and operating
or monitoring complex equipment under the influence of marijuana). While
most people can be expected to show impaired performance of complex tasks,
a minority experience dysphoria. Individuals with or at risk of psychiatric
disorders (including substance dependence) are particularly vulnerable
to developing marijuana dependence and marijuana use would be generally
contraindicated in those individuals. The short term immunosuppressive
effects are not well-established and, if they exist at all, are not likely
great enough to preclude a legitimate medical use. The acute side effects
of marijuana use are within the risks tolerated for many medications.
The chronic effects of marijuana are of greater concern for medical
use and fall into two categories: the effects of chronic smoking, and
the effects of THC. Marijuana smoke is like tobacco smoke in that it is
associated with increased risk of cancer, lung damage, and poor pregnancy
outcomes. Smoked marijuana is unlikely to be a safe medication for any
chronic medical condition. The second category is that associated with
dependence on the psychoactive effects of THC. Despite past skepticism,
it has been established that, although it is not common, a vulnerable
subpopulation of marijuana users can develop dependence. Adolescents,
particularly those with conduct disorders, individuals with psychiatric
disorders, or problems with substance abuse appear to be at greater risk
for marijuana dependence than the general population.
As a cannabinoid drug delivery system, marijuana cigarettes are not
ideal since they deliver a variable mixture of cannabinoids, as well as
a variety of other biologically-active substances, not all of which are
desirable or even known. Unknown substances include possible contaminants
such as fungus or bacteria
Finally, there is the broad social concern that sanctioning the medical
use of marijuana might lead to an increase in its use among the general
population. At this point there are no convincing data to support this
concern. The existing data are
consistent with the idea that this would not be a problem if the medical
use of marijuana were as closely regulated as other medications with
abuse potential, but we acknowledge that there are no data that directly
address this question. Even if there were evidence that the medical
use of marijuana would decrease the perception that it can be a harmful
substance, this is beyond the scope of laws regulating the approval
of therapeutic drugs. Those laws concern scientific data concerning
safety and efficacy drugs for individual use, and do not address perceptions
or beliefs of the general population.
Marijuana is not a completely benign substance. It is a powerful drug
with a variety of effects. However, except for the harms associated with
smoking, the adverse effects of marijuana use are within the range tolerated
for other medications. Thus the safety issues associated with marijuana
do not preclude certain medical uses. But the question remains: is it
effective? This topic is covered here in two chapters: chapter 2 summarizes
what has been learned about the biological activity of cannabinoids in
the past fifteen years from research in the basic sciences, chapter 4
reviews the clinical data on the effectiveness of marijuana and cannabinoids
for the treatment of a variety of medical conditions.
Three factors influence the safely of marijuana or cannabinoid drugs
for medical uses: the delivery system, the use of plant material, and
the side effects of cannabinoid drugs. (l) Smoking marijuana is clearly
harmful, and especially for chronic conditions, and is not an ideal drug
delivery system. (2) Plants are of uncertain composition which render
their effects equally uncertain, hence an undesirable medication. (3)
The side effects of cannabinoid drugs fall within the acceptable risks
for approved medications. Indeed, some of the 'side effects', such as
anxiety reduction and sedation, might be desirable for certain patients.
As with many medications, there are people for whom they would likely
CONCLUSION: Present data on drug use progression neither support
nor refute the suggestion that medical availability would increase
drug abuse. However, this question is beyond the issues normally considered
for medical uses of drugs, and should not be a factor in evaluating
the therapeutic potential of marijuana or cannabinoids.
CONCLUSION: A distinctive marijuana withdrawal syndrome has
been identified, but it is mild and short-lived. The syndrome includes
restlessness, irritability, mild agitation, insomnia, sleep EEG disturbance,
nausea, and cramping.
CONCLUSION: Numerous studies suggest that marijuana smoke
is an important risk factor in the development of respiratory disease.
RECOMMENDATION: Studies to define the individual health risks
of smoking marijuana should be conducted, particularly among populations
in which marijuana use is prevalent.
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