FIRST, DO NO HARM:
CONSEQUENCES OF MARIJUANA USE AND ABUSE
CHAPTER 3: First, Do No Harm:
Consequences of Marijuana Use and Abuse
Primum non nocere. This is the physician's first rule: whatever
treatment a physician prescribes to a patient - first, that treatment
must not harm the patient.
The most contentious aspect of the medical marijuana debate is not
whether marijuana can alleviate particular symptoms, but rather the
degree of harm associated with its use. This chapter thus explores the
negative health consequences of marijuana use, first with respect to
drug abuse, then from psychological perspective, and finally from a
The Marijuana "High"
The most commonly reported effects of smoked marijuana are a sense
of well-being or euphoria and increased talkativeness and laughter alternating
with periods of introspective dreaminess followed by lethargy and sleepiness
(see reviews by Adams and Martin I 996, and Hall 1994 and 1998 1,
58, 59). A characteristic feature of a marijuana "high"
is a distortion in the sense of time associated with deficits in short-term
memory and learning. A marijuana smoker typically has a sense of enhanced
physical and emotional sensitivity' including a feeling of greater interpersonal
closeness. The most obvious behavioral abnormality displayed by someone
under the influence of marijuana is difficulty in carrying on an intelligible
conversation, perhaps because of an inability to remember what was just
said even a few words earlier.
The high associated with marijuana is not generally claimed to be
integral to its therapeutic value. But mood enhancement, anxiety reduction,
and mild sedation can be desirable qualities in medications particularly
for patients suffering pain and anxiety. Thus, although the psychological
effects of marijuana are merely side effects in the treatment of some
symptoms, they might contribute directly to relief of other symptoms.
They also must be monitored in controlled clinical trials to discern
which effect of cannabinoids is beneficial. These possibilities are
discussed later under the discussions of specific symptoms in chapter
The effects of various doses and routes of delivery of THC are shown
in table 3.1.
Table 3.1 Psychoactive Doses of THC in Humans
| THC Delivery System
|| THC Dose Administered
|| Resulting Level of THC in Plasma
|| Subjects' Reactions
|One 2.75% THC cigarette smoked
||At higher level subjects felt 100% "high" and
psychomotor performance is decreased. At 50 ng/ml subjects felt
about 50% "high"
||Heishman and coworkers 1990
|1 gm marijuana cigarette smoked (2% or 3.5% THC)
||Enough to feel psychological effects of THC
||Kelly and coworkers 1993
|19 mg THC cigarette smoked (approx 1.9% THC)
||Approx. 0.22 mg/kg**
||Subjects felt "high"
||Ohlsson and coworkers 1980
| 5 mg THC injected i.v.
|| Approx. 0.06 mg/kg**
|| 100 ng/ml
|| Subjects felt "high"
| Chocolate chip cookie containing 20 mg THC
|| Approx. 0.24 mg/kg
|| 8 ng/ml
|| Subjects rated "high" as only about 40%
| 19 mg THC cigarette smoked to "desired high"
|| 12 mg was smoked (7 mg remained in cigarette butt)
|| 85 ng/ml (after 3 min.) 35 ng/ml (after 15 min.)
|| Subjects felt "high" after 3 minutes, and maximally
high after 10-20 minutes (average self ratings of 5.5 on a 10-point
|| Lindgren and coworkers 1981
| 5 mg THC injected i.v.
|| 0.06 mg/kg***
|| 300 ng/ml (after 3 min.) 65 ng/ml (after 15 min.)
|| Subjects felt maximally "high" after 10 minutes (average
self ratings of 7.5 on a 10-point scale)
* Subjects' weights and cigarette weights were not given. Calculation
based on 85 kg body weight, and 1g cigarette weight. Note that some
THC would have remained in the cigarette butt and some would have
been lost in side-stream smoke, so these represent maximal possible
doses administered. Actual doses would have been slightly less.
** Based on estimated average weight of 85 kg for 11 men aged 18-35
*** Based on approximately weight of 80 kg (subjects included men
Adverse mood reactions
Although euphoria is the more common reaction to smoking marijuana,
adverse mood reactions can occur. Such reactions occur most frequently
in inexperienced users after large doses of smoked or oral marijuana.
They usually disappear within hours and respond well to reassurance
and a supportive environment. Anxiety and paranoia are the most common
acute adverse reactions, 58 others include panic, depression,
dysphoria, depersonalization, delusions, illusions, and hallucinations.)
1, 40, 65, 68 Of regular marijuana smokers, 17% report that
they have experienced least one of the symptoms, usually early in their
use of marijuana. 144 Those observations are particularly
relevant for the use of medical marijuana in people who have not previously
There are many misunderstandings about drug abuse and dependence (see
reviews by O'Brien 113 and Goldstein 54). The
terms and concepts used in this report are as defined in the most recent
Diagnostic and Statistical Manual of Mental Disorders (DSM-IV3
), the most influential system in the United States for diagnoses of
mental disorders, including substance abuse (see box on definitions).
Tolerance, dependence, and withdrawal are often presumed to imply abuse
or addiction, but this is not the case. Tolerance and dependence are
normal physiological adaptations to repeated use of any drug. The correct
use of prescribed medications for pain, anxiety, and even hypertension
commonly produces tolerance and some measure of physical dependence.
Even a patient who takes a medicine for appropriate medical indications
and at the correct dosage can develop tolerance, physical dependence,
and withdrawal symptoms if the drug is stopped abruptly rather than
gradually. For example, a hypertensive patient receiving a beta-adrenergic
receptor blocker, such as propranolol, might have a good therapeutic
response; but if the drug is stopped abruptly, there can be a withdrawal
syndrome that consists of tachycardia and a rebound increase in blood
pressure to a point, temporarily higher than before administration of
the medication began.
Because it is an illegal substance, some people consider any use of
marijuana as substance abuse. However, this report uses the medical
definition; that is, substance abuse is a maladaptive pattern of repeated
substance use manifested by recurrent and significant adverse consequences.3
Substance abuse and dependence are both diagnoses of pathological substance
use. Dependence is the more serious diagnosis and implies compulsive
drug use that is difficult to stop despite significant substance-related
problems (see box on criteria for substance dependence).
Addiction. Substance dependence.
Craving refers to the intense desire for a drug and is the
most difficult aspect of addiction to overcome.
Physiological dependence is diagnosed when there is evidence
of either tolerance or withdrawal; it is sometimes, but not always,
manifested in substance dependence
Reinforcement. A drug - or any other stimulus -- is referred
to as a reinforcer if exposure to it is followed by an increase
in frequency of drug-seeking behavior. The taste of chocolate is
a reinforcer for biting into a chocolate bar. Likewise, for many
people, the sensation experienced after drinking alcohol or smoking
marijuana is a reinforcer.
Substance dependence is a cluster of cognitive, behavioral,
and physiological symptoms indicating that a person continues use
of the substance despite significant substance-related problems.
Tolerance is the most common response to repetitive use
of a drug and can be defined as the reduction in responses to the
drug after repeated administrations.
Withdrawal. The collective symptoms that occur when the
drug is abruptly withdrawn are known as withdrawal syndrome and
are often the only evidence of physical dependence.
DSM-IV Criteria for Substance Dependence
A maladaptive pattern of substance use. leading to clinically significant
impairment or distress as manifested by three (or more) of the following,
occurring at any time in the same l2-month period:
(1) Tolerance, as defined by either of the following:
(a) A need for markedly increased amount of the
substance to achieve intoxication or desired effect.
(b) Markedly diminished effect with continued use of the
same amount of the substance.
(2) Withdrawal, as defined by either of the following:
(a) The characteristic withdrawal syndrome for
the substance to achieve intoxication or desired effect.
(b) The same (or closely related) substance is taken to
relieve or avoid withdrawal symptoms.
(3) The substance is often taken in larger amounts or over
a longer period than was intended.
(4) There is a persistent desire or unsuccessful efforts
to cut down or control substance use.
(5) A great deal of time is spent in activities necessary
to obtain the substance
(e.g. visiting multiple doctors driving long distances), use the
(e.g., chain-smoking), or recover from its effects.
(6) Important social occupational, or recreational activities
are given up or reduced because of substance use
(7) The substance use is continued despite knowledge of
having a persistent or recurrent physical or psychological problem
or exacerbated by the substance
(e.g., current cocaine use despite recognition of cocaine-induced
depression or continued drinking despite recognition that an ulcer
was made worse by alcohol consumption).
Substance abuse with physiological dependence is diagnosed
if there is evidence of tolerance or withdrawal.
Substance abuse without physiological dependence is
diagnosed if there is no evidence of tolerance or withdrawal.
Drugs vary in their ability to produce good feelings in the and the
more strongly reinforcing a drug is, the more likely it will be abused
(G. Koob, IOM workshop). Marijuana is indisputably reinforcing for many
people. The reinforcing properties of even so mild a stimulant as caffeine
are typical of reinforcement by addicting drugs (reviewed by Goldstein
54 in 1994). Caffeine is reinforcing for many people at low
doses (100-200 ma' the average amount of caffeine in one to two cups
of coffee), and aversive at high doses (600 mg the average amount of
caffeine in six cups of coffee). The reinforcing effects of many drugs
are different for different people. For example, caffeine was most reinforcing
for test subjects who scored lowest on tests of anxiety but tended not
to be reinforcing for the most anxious subjects.
As an argument to dispute the abuse potential of marijuana, some have
cited the observation that animals do not willingly self-administer
THC, as they will cocaine. Even if that were true, it would not be relevant
to human use of marijuana. The value in animal models of drug self-administration
is not that they are necessary to show that a drug is reinforcing, but
rather that they provide a model in which the effects of a drug can
be studied. Furthermore, THC is indeed rewarding to animals at some
doses but, like many reinforcing drugs, is aversive at high doses (4.0
mg/kg). 92 Similar effects have been found in experiments
conducted in animals outfitted with intravenous catheters that allow
them to self-administer WIN 55,212, a drug that mimics the effects of
A specific set of neural pathways has been proposed to be a "reward
system" that underlies the reinforcement of drugs of abuse 51
and other pleasurable stimuli. 51 Reinforcing properties
of drugs are associated with their ability to increase concentrations
of particular neurotransmitters in areas that are part of the proposed
brain reward system. The median forebrain bundle and the nucleus accumbens
are associated with brain reward pathways. 87 Cocaine, amphetamine,
alcohol, opioids, nicotine, and THC 143 all increase extracellular
fluid dopamine in the nucleus accumbens region (reviewed by Koob 87
and Nestler 109 in 1997). However, it is important to note
that brain reward systems are not strictly "drug reinforcement
centers". Rather, their biological role is to respond to a range
of positive stimuli, including sweet foods and sexual attraction.
The rate at which tolerance to the various effects of any drug develops
is an important consideration for its safety and efficacy.. For medical
use, tolerance to some effects of cannabinoids might be desirable. Differences
in the rates at which tolerance to the multiple effects of a drug develops
can be dangerous. For example, tolerance to the euphoric effects of
heroin develops faster than tolerance to its
respiratory depressant effects, so heroin users tend to increase
their daily doses to reach their desired level of euphoria, thereby
putting them at risk for respiratory arrest. Because tolerance to
the various effects of cannabinoids might develop at different rates,
it is important to evaluate independently their effects on mood, motor
performance, memory, and attention, as well as any therapeutic use
Tolerance to most of the effects of marijuana can develop rapidly
after only a few doses, and it also disappears rapidly. Tolerance to
large doses has been found to persist in experimental animals for long
periods after cessation of drug use. Performance impairment is less
among people who use marijuana heavily than it is among those who use
marijuana only occasionally, 29, 103, 123 possibly because
of tolerance. Heavy users tend to reach higher plasma concentrations
of THC than light users after similar doses of THC, arguing against
the possibility that heavy users show less performance impairment because
they somehow absorb less THC (perhaps due to differences in smoking
There appear to be variations in the development of tolerance to the
different effects of marijuana and oral THC. For example, a group of
daily marijuana smokers participated in a residential laboratory study
to compare the development of tolerance to THC pills and to smoked marijuana.
60, 61 One group was given marijuana cigarettes to smoke
four times per day for four consecutive days. Another group was given
THC pills on the same schedule. During the 4-day period, both groups
became tolerant to feeling "high" and what they reported as
a "good drug effect." In contrast, neither group became tolerant
to the stimulatory effects of marijuana or THC on appetite. Note that
tolerance does not mean the drug no longer produced those effects, simply
that the effects were less at the end than they were at the beginning
of the 4-day period. The marijuana smoking group reported feeling "mellow"
after smoking, and did not show tolerance to this effect. Interestingly,
the group who took THC pills did not report feeling "mellow,"
a difference that was also reported by many people who described their
experiences to the IOM study team.
The oral and smoked doses were designed to deliver roughly equivalent
amounts to THC to the subject. Each smoked marijuana dose consisted
of five 10 second puffs of a 3.1% marijuana cigarette; the pills contained
30 mg of THC. Both groups also received placebo drugs during other four-day
periods. While the dosing of the two groups was comparable, different
routes of administration result in different patterns of drug effect.
The peak effect of smoked marijuana is felt within minutes, and declines
sharply after 30 minutes, 67, 94; the peak effect of oral
THC is usually not felt until about an hour and lasts for several hours.
A distinctive marijuana and THC withdrawal syndrome has been identified,
but it is mild and subtle compared to the profound physical syndrome
of alcohol or heroin withdrawal 31 73 The marijuana withdrawal
syndrome includes restlessness, irritability, mild agitation, insomnia,
sleep EEG disturbance, nausea, and cramping
(table 3.2). This syndrome, however, has only been reported in a
group of adolescents in treatment for substance abuse problems or
in a research setting where subjects were given marijuana or THC on
a daily basis 73
Table 3.2 Drug Withdrawal Symptoms
Decreased heart rate
Increased appetite or weight gain
Delirium tremens (severe agitation, confusion, visual hallucinations,
fever, profuse sweating, nausea, diarrhea, dilated pupils)
Sleep EEG disturbance
Increased sensitivity to pain
Table legend. This summary of withdrawal symptoms is from O'Brien's
1996 review. 112 In addition to the established symptoms
listed above, two recent studies have reported several more. A group
of adolescents under treatment for conduct disorders also reported
fatigue and illusions or hallucinations after marijuana abstinence
(this study is discussed further under the section on "Prevalence
and Predictors of Dependence"). 31 In a residential
study of daily marijuana users, withdrawal symptoms included sweating
and rhinorrhea (runny nose), in addition to those listed above (this
study is discussed further under the section on "Tolerance").
Withdrawal symptoms have been observed in carefully controlled laboratory
studies of people following use of both oral THC and smoked marijuana
(Haney and coworkers in press). In one study, subjects were given very
high doses of oral THC: 180-210 mg per day for 10 to 20 days, roughly
equivalent to smoking 9-10 two percent THC cigarettes per day. 73
During the abstinence period at the end of the study, the study subjects
were irritable and showed insomnia, rhinorrhea (runny nose), sweating,
and decreased appetite. The withdrawal symptoms, however, were short-lived.
After four days they had abated. This time course contrasts with another
study in which lower doses of oral THC were used (80-120 mg/day for
four days), and withdrawal symptoms were still near maximal after four
days (Haney and coworkers, in press).
In animals, simply discontinuing chronic heavy dosing of THC does
not reveal withdrawal symptoms However, in animal studies, the removal
of THC from the brain can be made abrupt by another drug that blocks
THC at its receptor when administered at the same time the chronic THC
is withdrawn. In this case, the withdrawal syndrome is quite pronounced,
and the behavior of the animals becomes hyperactive and disorganized.
152 The half-life of THC in brain is approximately one hour.
16, 24 Although traces of THC can remain in the brain for
much longer periods, the amounts are not physiologically significant.
Thus, the lack of a withdrawal syndrome seen if THC is abruptly withdrawn
without the addition of a receptor blocking drug is not likely due to
a prolonged decline in brain levels.
Craving, the intense desire for a drug, is the most difficult aspect
of addiction to overcome. Research on craving has focused on nicotine,
alcohol, cocaine, and opiates, but has not specifically addressed marijuana.
114 Thus, while this section briefly reviews what is known
about drug craving, its relevance to marijuana use has not been established.
Most individuals who suffer from addiction relapse within a year of
abstinence, and they often attribute their relapse to craving. 57
As addiction develops, craving increases even as maladaptive consequences
accumulate. Animal studies indicate that the tendency to relapse is
based on changes in brain function that continue for months or years
after the last use of the drug" 114 Whether the neurobiology
changes during the manifestation of an abstinence syndrome remains an
unanswered question in drug abuse research. 87 The liking
of sweet foods, for example, is mediated by certain opioid forebrain
systems and by brain-stem systems, whereas wanting seems to be mediated
by ascending dopamine neurons that project to the nucleus accumbens.
Anti-craving medications have been developed for nicotine and alcohol.
The antidepressant, bupropion, blocks nicotine craving, while naltrexone
blocks alcohol craving. 114 Another category of addiction
medication includes drugs that block
another drug's effects. Some of these addiction medication drugs
also block craving. For example, methadone blocks the euphoria effects
of heroin and also reduces craving.
Marijuana Use and Dependence
Prevalence of Use
Millions of Americans have tried marijuana, but most are not regular
users. In 1996, 68.6 million people or 32 % of the U.S. population over
12 years old had tried marijuana or hashish at least once in their lifetime,
but only 5 % were current users. 131 Marijuana use is most prevalent
among 18-25 year olds and declines sharply after age 34 (figure 3.1).
76, 131 Among adolescents, whites are more likely than blacks
to use marijuana' although this difference decreases by adulthood. 131
Most people who have used marijuana did so first during adolescence.
Social influences, such as peer pressure and Prevalence of use by peers,
are highly predictive of initiation into marijuana use. 9
Initiation is not, of course, synonymous with continued or even regular
use. A cohort of 456 students who experimented with marijuana during
their high school years were surveyed about their reasons for initiating,
continuing, and stopping drug use. 9 Students who began as
heavy users were excluded from the analysis, Those who did not become
regular marijuana users cited two types of reasons for discontinuing.
The first was related to their health and well-being, that is, they
felt marijuana was bad for their health or their family and work relationships.
The second type was based on age-related changes in circumstances, including
increased responsibility and less regular contact with other marijuana
users. Interestingly, among high school students who quit, parental
disapproval was a stronger influence than peer disapproval in discontinuing
marijuana use. In the initiation of marijuana use, the reverse was true.
The reasons cited by those who continued to use marijuana were to "get
in a better mood or feel better.'' Social factors were not a significant
predictor of continued use after initiation. Data on young adults show
similar trends. Those who use drugs in response to social influences
are more likely to stop using them than those who also use drugs for
psychological reasons. 79
The age distribution of marijuana users among the general population
contrasts with that of medical marijuana users. Marijuana use generally
declines sharply after age 34, whereas medical marijuana users tend
to be over 35 (figure 3.1). This raises the question as to what, if
any, relationship exists between abuse and medical use of marijuana,
however, there are no studies reported in the scientific literature
that address this question.
Figure 3.1 Age distribution of marijuana users among the general
Prevalence and Predictors of Drug Dependence
Many factors influence the likelihood that a particular person will
become a drug abuser or an addict: the user, the environment, and the
drug are all important factors (table 3.3). 113 The first
two categories apply to potential abuse of any substance; that is, someone
who is vulnerable to drug abuse for individual reasons, and who finds
themselves in an environment that encourages drug abuse, is initially
likely to abuse the most readily available drug - regardless of its
unique set of effects on the brain.
The third category includes drug-specific effects that influence the
abuse liability of a particular drug. As discussed earlier in this chapter,
the more strongly reinforcing a drug is, the more likely it will be
abused. The abuse liability of a drug is enhanced by how quickly its
effects are felt, and this is determined by how the drug is delivered.
In general, the effects of drugs that are inhaled or injected are felt
within minutes, those that are ingested take half an hour or more. The
proportion of people who become addicted varies among drugs (table 3.4).
Table 3.3 Factors that are correlated with drug dependence
- Pharmacological effects of the drug
- Genetic factors
- Individual risk-taking propensities
- History of prior drug use
- Availability of the drug
- Acceptance of the use of that drug within society
- Balance of social reinforcements and punishments for use
- Balance of social reinforcements and punishments for abstinence
Source: Crowley and Rhine (1985)32
Table legend. Factors that can influence the likelihood that an individual
will become dependent on a drug.
Table 3.4 Prevalence of Drug Use and Dependence Among the General
||Proportion Who have Ever Used Different Types of Drugs
||Proportion Of Users That Ever Became Dependent
and hypnotic drugs)
Table legend. The table shows estimates for the proportion
of people among the general population who used or became dependent
on different types of drugs. The proportion of users that ever
became dependent includes anyone who was ever dependent -
whether it was for a period of weeks or years - and thus includes
more than those who are currently dependent. The diagnosis of drug
dependence used in this study was based on DSM-III-R criteria. 2
Adapted from table 2 in Anthony and coworkers (1994). 8
Compared to most other drugs listed in this table, dependence among
marijuana users is relatively rare. This might be due to differences
in the specific drug effects; in the availability of, or penalties associated
with the use of, the different drugs -- or, some combination of these
Note that the percent listed are from the Epidemiological Catchment
Area study, and (of people who ever used marijuana) (46 %), are higher
than that reported by the National Household Survey on Drug abuse (32%).
The differences are likely due to different survey methods (for discussion
see Kandel 199275).
Daily use of most illicit drugs is extremely rare in the general population.
In 1989 daily use of marijuana among high school seniors was less than
that of alcohol (2.9% and 4.2 %, respectively) 75
Drug dependence is more prevalent in certain sectors of the population
than others. Age, gender, and race or ethnic group are all significant
factors.8 Excluding tobacco and alcohol, the following trends of drug
dependence are statistically sigruficant:8 Men are 1.6 times more likely
than women to become drug dependent. Non-Hispanic whites are about twice
as likely as African-Americans to become drug dependent. (The difference
between non-Hispanic and Hispanic whites was not significant.) Lastly,
people aged 25-44 years are more than three times as likely as those
over 45 years to become drug dependent.
More often than not, drug dependence co-occurs with one or more other
psychiatric disorders. The majority of individuals diagnosed with a
drug dependence disorder are also diagnosed with another psychiatric
disorder (76 % of men, 65 % of women). 75 The most frequent
co-occurring disorder is alcohol abuse; 60 % of men and 30 % for women
diagnosed as drug dependent also abuse alcohol. For women who are drug
dependent, phobic disorders and major depression are almost equally
common (29 % and 28 %, respectively). Note that this study distinguished
only between alcohol, nicotine and "other drugs," the category
that included marijuana. The frequency with which drug dependence and
other psychiatric disorders co-occur might not be the same for marijuana
and other drugs that were included in that category of "other drugs."
A strong association between drug dependence and antisocial personality
or its precursor, conduct disorder, is also widely reported in children
and adults (reviewed by Robins 125 in 1998). Although the
causes of this association are still uncertain, Robins recently concluded
that it is more likely that conduct disorders generally lead to substance
abuse than the reverse. 125 Such a trend might, however,
depend on the age at which the conduct disorder is manifested.
A longitudinal study by Brooks and coworkers indicated that while
childhood conduct disorder may lead to later drug use for older adolescents
there is no evidence that depression, anxiety, or conduct disorders
precede heavy drug use. 18 Rather, the drug use preceded
the psychiatric disorders. In contrast to tobacco and other illicit
drugs, moderate (less than once a week, more than once a month) to heavy
marijuana use did not predict anxiety or depressive disorders, but was
consistent with those other drugs in predicting antisocial personality
disorder. The rates of disruptive disorders increased with increased
levels of drug use. Thus, heavy drug use among adolescents can be a
warning sign for later psychiatric disorders, whether it is an early
manifestation of symptoms for those disorders or a causal factor remains
to be determined.
Psychiatric disorders are more prevalent among adolescents who use
drugs including alcohol and nicotine. 78 Table 3.5 indicates
that daily cigarette smoking among adolescent boys is associated with
an approximately tenfold increase in the likelihood of being diagnosed
with a psychiatric disorder compared to those who do not smoke. Note,
however, that the table does not compare equivalent intensity of use
among the different drug classes. Thus, although daily cigarette smoking
among adolescents is more strongly associated with psychiatric disorders
than is any use of illicit substances, it does not follow that this
comparison is true for every amount of cigarette smoking. 78
Table 3.5 Psychiatric disorders associated with drug use among
|Relative prevalence of diagnoses for psychiatric
disorders associated with drug use among children
Relative Prevalence Estimates
|Weekly alcohol use
|Daily cigarette smoking
|Any illicit substance use
Table legend. The subjects ranged in age from 9-18 years,
with an average age of 13 years.
A ratio of one means that the relative prevalence of the disorder
is equal among those who do and those who do not use the particular
type of drug, that is, there is no measurable association. A ratio
greater than one indicates that the factor is associated. Thus boys
who smoke daily are as almost ten times more often diagnosed as having
a psychiatric disorder (not including substance abuse) as those who
smoke less. Substance abuse was excluded from this analysis since
the subjects being analyzed were already grouped by their high drug
use. Except where noted (n.s.) all values are statistically significant..
Data are from table 4 in Kandel and coworkers 1997 78
Few marijuana users become dependent (table 3.4), but those who do
encounter problems similar to those associated with dependence on other
drugs.19 142 The severity of dependence appears to be less
among people who use only marijuana than among those who abuse cocaine
or abuse marijuana with other drugs (including alcohol). 19, 142
Data gathered in 1990-1992 from the National Comorbidity Study of
over 8,000 persons aged 15-54 years indicate that 4.2 % of the general
population were dependent on marijuana at one time in their life. 8
Similar results for the frequency of substance abuse among the general
population were obtained from the Epidemiological Catchment Area Program,
a survey of over 19,000 people. Based on data collected in the early
1980s for that study, 4.4% of adults have, at one time, met the criteria
for marijuana dependence. For comparison, 13.8% of adults met the criteria
for alcohol-dependence and 36.0% met them for tobacco. After alcohol
and nicotine, marijuana was the substance most frequently associated
with a diagnosis of substance dependence.
In a fifteen-year study begun in 1979 of 1,201 adolescents and young
adults in suburban New Jersey, 7.3% of those subjects, at one time,
met the criteria for marijuana dependence, indicating that the rate
of marijuana dependence might be even higher in some groups of adolescents
and young adults than for the general population. 70 Adolescents
meet the criteria of drug dependence at lower rates of marijuana use
than do adults, suggesting that they are more vulnerable to dependence
than adults 25 (see box on Criteria for Substance Abuse).
Youths who are already dependent on other substances are particularly
vulnerable to marijuana dependence. For example, Crowley and coworkers
31 interviewed a group of 229 adolescent patients in a residential
treatment program for delinquent, substance-involved youth, and found
that those patients were dependent on an average of 3.2 different substances.
The adolescents in this study had previously been diagnosed as dependent
on at least one substance (including nicotine and alcohol) and had three
or more conduct disorder symptoms during their life. Among those troubled
adolescents, about 83% of those who had previously used marijuana at
least six times went on to develop marijuana dependence. Approximately
equal numbers of youths in this study were diagnosed as marijuana dependent
as were diagnosed as alcohol-dependent, fewer were diagnosed as nicotine-dependent.
However, comparisons between the dependence potential of different drugs
should be made cautiously. The probability that a particular drug will
be abused is influenced by many factors, including the specific drug
effects and availability of the drug.
Although parents often state that marijuana caused their children
to be rebellious, the troubled adolescents in the study by Crowley and
coworkers developed conduct disorders before marijuana abuse. This is
consistent with reports showing that the more symptoms of conduct disorders
children have, the younger they begin drug abuse, 126 and
that the younger they begin drug use, the more likely it is to be followed
by abuse or dependence. 124
Genetic factors are known to play a role in the likelihood of substance
abuse for drugs other than marijuana, 7 128 and it is not
unexpected that genetic factors might play a role in the marijuana experience,
including the likelihood of abuse. A study of over 8,000 male twins
listed in the Vietnam Era Twin Registry indicated that genes have a
significant influence on whether an individual finds the effects of
marijuana pleasant. 96 Not surprisingly, individuals who
found marijuana to be pleasurable used it more often than those who
found it unpleasant. The study suggested that, although social influences
play an important role in the initiation of use, individual differences
- perhaps associated with the brain's reward system - influence whether
an individual will continue using marijuana. Similar results were found
in a study of female twins. 85 Family and social environment
strongly influenced the likelihood of ever using marijuana, but had
little impact on the likelihood of heavy use or abuse. The latter were
more influenced by genetic factors. These results are consistent with
the finding that the degree to which rats find THC rewarding is genetically
In sum, although few marijuana users develop dependence, some do.
But, they appear to be less likely to do so than users of other drugs
(including alcohol and nicotine), and marijuana dependence appears to
be less severe than it is for other drugs. Drug dependence is more prevalent
in certain sectors of the population, but no group has been identified
as being particularly vulnerable to the drug-specific effects of marijuana.
Adolescents, especially troubled adolescents, and people with psychiatric
disorders (including substance abuse) appear to more likely than the
general population to become dependent on marijuana.
If marijuana or cannabinoid drugs were approved for therapeutic uses,
it would be important to consider the possibility of dependence, particularly
for patients in high risk groups for substance dependence. Certain controlled
substances that are approved medications produce dependence after long
term use. This is, however, a normal part of patient management and
does not generally present undue risk to the patient.
The fear that marijuana use might cause, as opposed to merely precede,
the use of drugs that are more harmful of great concern. Judging from
comments submitted to the IOM study team, this appears to be an even
greater concern than the harms directly related to marijuana itself.
The discussion that marijuana is a gateway drug implicitly recognizes
that other illicit drugs might inflict greater damage to health or social
relations than marijuana. Although the scientific literature generally
discusses drug use progression between a variety of drug classes, including
alcohol and tobacco, the public discussion has focused on marijuana
as a gateway drug that leads to abuse of more harmful illicit drugs
such as cocaine and heroin.
There are strikingly regular patterns in the progression of drug use
from adolescence to adulthood. Because it is the most widely used illicit
drug, marijuana is predictably the first illicit drug most people encounter.
Not surprisingly, most users of other illicit drugs have used marijuana
first. 80, 81 In fact, most drug users do not begin their
drug use with marijuana; they begin with alcohol and nicotine and usually
when they are too young to do so legally. 81, 89
The gateway analogy evokes two ideas that are often confused. The
first, more often referred to as the stepping stone hypothesis, is the
idea that progression from marijuana to other drugs arises from pharmacological
properties of marijuana itself. 81 The second interpretation
is that marijuana serves as a gateway to the world of illegal drugs
in which youths have greater opportunity and are under greater social
pressure to try other illegal drugs. This is the interpretation most
often used in the scientific literature, and is supported by -- although
not proven by the available data.
The stepping stone hypothesis applies to marijuana only in the broadest
sense. People who enjoy the effects of marijuana are, logically, more
likely to be willing to try other mood-altering drugs than are people
who are not willing to try marijuana or who dislike its effects. In
other words, many of the factors associated with a willingness to use
marijuana are, presumably, the same as those associated with a willingness
to use other illicit drugs. Those factors include physiological reactions
to the drug effect, which are consistent with the stepping stone hypothesis,
but also psychosocial factors that are independent of drug-specific
effects. There is no evidence that marijuana serves as a stepping stone
on the basis of its particular drug effect. One might argue that marijuana
is generally used before other illicit mood-altering drugs, in part,
because its effects are milder, but in that case, marijuana is a stepping
stone only in the same sense as taking a small dose of a particular
drug and then increasing that dose over time is a stepping stone to
increased drug use.
Whereas the stepping stone hypothesis presumes a predominantly physiological
component to drug progression, the gateway theory is a social theory.
The latter does not suggest that the pharmacological qualities of marijuana
make it a risk factor for progression to other drug use. Instead it
is the legal status of marijuana that makes it a gateway drug. 81
Psychiatric disorders are associated with substance dependence, and
are likely risk factors for progression in drug use. For example, the
troubled adolescents studied by Crowley and coworkers 31
were dependent on an average of 3.2 substances, suggesting that their
conduct disorders are associated with increased risk of progressing
from one drug to another. Substance abuse of a single substance is also
a likely risk factor for subsequent multiple drug use. For example,
in a longitudinal study that examined drug use and dependence, about
26% of problem drinkers report they first used marijuana after the onset
of alcohol-related problems (R. Pandina, IOM workshop). This study also
found that 11% of marijuana users developed chronic marijuana problems,
although most also had alcohol problems.
Intensity of drug use is also an important risk factor in progression.
Daily marijuana users are more likely than their peers to be extensive
users of other substances (for review see Kandel and Davies 77
). Seventy-five percent of 34-35 year old men who had used marijuana
10-99 times by age 24-25 never used any other illicit drug; 53% of those
who had used it more than 100 times did progress to using other illicit
drugs 10 or more times. 77 Comparable proportions for women
are 64% and 50%.
The factors that best predict illicit drug use other than marijuana
are likely the following: age of first alcohol or nicotine use, heavy
marijuana use, and psychiatric disorders. However, it is important to
keep in mind that progression to illicit drug use is not synonymous
with heavy or persistent drug use. Indeed, although the age of onset
for licit drug alcohol and nicotine) use predicts later illicit drug
use, age of first use of licit drugs does not appear to predict persistent
or heavy use of those drugs. 89
Data on the gateway phenomenon are frequently over-interpreted. For
example, one study reports that "marijuana's role as a gateway
drug appears to have increased" (Golub and Johnson 1994). This
was a retrospective study based on interviews of drug abusers who reported
smoking crack or injecting heroin on a daily basis. Those data provide
no indication of what proportion of marijuana users become serious drug
abusers. Rather, they indicate that serious drug abusers usually use
marijuana before they smoke crack or inject heroin. Only a small percent
of the adult population use crack or heroin on a daily basis; during
the five-year period from 1993-1997, an average of three people per
1000 had used crack and about two per 1000 had used heroin in the past
Many of the data on which the gateway theory is based do not measure
dependence. Instead they measure use, even once-only use. Thus those
data show only that, compared to people who never use marijuana, marijuana
users are more likely to use those drugs (maybe even only once), not
that they become dependent or even frequent users. Note that the authors
of these studies are careful to point out that their data should not
be used as evidence of an inexorable, causal progression. Rather they
note that identifying stage-based user groups makes it possible to identify
the specific risk factors that predict movement from one stage of drug
use to the next - this is the real issue in the gateway discussion.
In the sense that marijuana use typically precedes rather than follows
initiation into the use of other illicit drugs, it is indeed a gateway
drug. However, it does not appear to be a gateway drug to the extent
that it is the most significant predictor or even the cause of heavy
drug abuse; that is, care must be taken not to attribute cause to association.
The most consistent predictors of heavy drug use appear to be the intensity
of marijuana use, and co-occurring psychiatric disorders or a family
history of psychopathology including alcoholism. 77, 82
An important caution is that data on drug use progression pertain
to nonmedical drug use. It does not follow from those data that if marijuana
were available by prescription for medical use, the pattern of drug
use would be the same. Kandel and coworkers also studied nonmedical
use of prescription psychoactive drugs in their study of drug use progression.
81 In contrast to alcohol, nicotine, and illicit drugs, there
was not a clear and consistent sequence of drug use involving the abuse
of prescription psychoactive drugs. At present, the data on drug use
progression neither support nor refute the suggestion that medical availability
would increase drug abuse among medical marijuana users. It is, admittedly,
another question as to whether the medical use of marijuana might encourage
drug abuse among the general community - not among medical marijuana
users themselves, but among others simply because of the fact that marijuana
is used for medical purposes.
The Link Between Medical Use and Drug Abuse
Almost everyone who spoke or wrote to the IOM study team about the
potential harms of the medical use of marijuana felt that it would send
the wrong message to children and teenagers. They stated that information
about the harms of marijuana is undermined by claims that marijuana
might have medical value. Yet, many of our powerful medicines are also
dangerous medicines. These two facets of medicine -effectiveness and
risk - are inextricably linked.
The question here is not whether marijuana can be both harmful and
helpful, but whether the perception of its benefits will increase its
abuse. For now, any answer to the question remains conjecture. Because
marijuana is not an approved medicine, there is little information about
the consequences of its medical use in modern society. The following
are three examples from which reasonable inferences might be drawn.
Opiates such as morphine and codeine are an example of a class of drugs
that is both abused to great harm and used to great medical benefit,
and it 'would be useful to examine the relationship between medical
use and abuse. Another example is the natural experiment during 1973-1978
in which some states decriminalized marijuana, and others did not. Finally,
one can examine the short term consequences of the publicity surrounding
the 1996 medical marijuana campaign in California. Did this have any
measurable impact on the marijuana consumption among youth in California?
The consequences of this "message" that marijuana might have
medical use are examined below.
Medical Use and Abuse of Opiates
Two highly influential papers published in the 1920s and 1950s led
to a widespread concern among physicians and medical licensing boards
that liberal use of opiates would result in many addicts reviewed by
Moulin and coworkers 105 in 1996. Such fears have proven
unfounded; it is now recognized that fear of producing addicts through
medical treatment resulted in needless suffering among patients with
pain, as physicians needlessly limited appropriate doses of medications.
27, 44 Few individuals begin their drug addiction problems
by misuse of drugs that have been prescribed for medical use. 113
In general, opiates are carefully regulated in the medical setting and
diversion of medically prescribed opiates to the black market is not
generally considered to be a major problem.
There is no evidence to suggest that the use of opiates or cocaine
for medical purposes has increased the perception that the illicit
use of these drugs is safe or acceptable. Clearly, there are risks
that patients may abuse marijuana for its psychoactive effects as
well as risks of diversion of marijuana from legitimate medical channels
into the illicit market. Again, this does not differentiate marijuana
from many accepted medications that are abused by some patients or
diverted from medical channels for non-medical use. Where this has
taken place, medications have been placed in Schedule II of the Controlled
Substances Act, which brings the drug under stricter control, including
quotas on the amount that can be legally manufactured (see chapter
5 for discussion of the Controlled Substances Act). This scheduling
also signals to physicians that the drug has abuse potential and that
they should monitor the use of the medication by patients that may
be at risk for drug abuse.
Effect of Marijuana Decriminalization
Monitoring the Future, the annual survey of values and life-styles
of high school seniors, revealed that high school seniors in decriminalized
states reported using no more marijuana than did their counterparts
in states where marijuana was not decriminalized. 71 Another
study reported somewhat conflicting evidence indicating that decriminalization
had increased marijuana use. 104 That study used data from
the Drug Awareness Warning Network (DAWN), which has collected data
since 1975 on drug-related emergency (ER) room cases. Among states
that had decriminalized marijuana in 1975-1976, there was a greater
increase from 1975 to 1978 in the proportion of ER patients who had
used marijuana than in states that did not decriminalize marijuana
(table 3.6). Despite the greater increase among decriminalized states,
by 1978, the proportion of marijuana users among ER patients was about
equal in states that did and states that did not decriminalize marijuana.
This is because the non-decriminalized states had higher rates of
marijuana use before decriminalization. In contrast to marijuana use,
rates of other illicit drug use among ER patients were substantially
higher among states that did not decriminalize
marijuana use. Thus, there are different possible reasons for the
relatively greater increase in marijuana use in the decriminalized
states. On the one hand, decriminalization might have led to an increased
use of marijuana (at least among people who seek health care in hospital
emergency rooms). On the other hand, the lack of decriminalization
might have encouraged greater use of drugs that are even more dangerous
than marijuana. Interpretations are ambiguous.
The differences between the results for high school seniors from the
Monitoring the Future study and DAWN data are unclear, although the
author of the latter study suggests the reasons might lie in limitations
inherent in how the DAWN data are collected. 104 In sum,
there is not strong evidence that decriminalization causes a significant
increase in marijuana use.
In 1976, the Dutch adopted a policy of toleration for possession of
up to 30 g of marijuana. There was little change in marijuana use during
the seven years following this policy change, suggesting that the policy
change itself had little impact; however, in 1984 when Dutch "coffee
shops" that sold marijuana commercially spread throughout Amsterdam,
marijuana use began to increase. 97 During the 1990s, marijuana
use has continued to increase in the Netherlands at the same rate as
in the United States and Norway two countries that strictly forbid marijuana
sale and possession. Further, during this period, approximately equal
percentages of American and Dutch 18-year olds used marijuana; Norwegian
18-year olds were approximately half as likely to have used marijuana.
The authors of this study conclude that there is little evidence that
the Dutch marijuana depenalization policy led to increased levels of
marijuana use, although they note that commercialization of marijuana
might have contributed to its increased use.
In sum, there is little evidence that decriminalization of marijuana
use necessarily leads to a substantial increase in marijuana use.
Table 3.6 Decriminalization and Marijuana Use
|Effect of Decriminalization on Marijuana Use
in ER Cases
||Total Reports of Drug Use per ER
||Time Period (States the decriminalized so after 1975 and before
||States that decriminalize marijuana.
||States that did not Decriminalized marijuana
|Other drug use
Table legend. The values shown indicate the frequency of drug use
among ER patients in states that decriminalized marijuana from July
1975- July 1977 and in those that did not. Data are based on patient
self-reports. The 1975 values reflect ER marijuana reports before
or in the first months of decriminalization, whereas the 1978 values
reflect ER reports when decriminalization laws had been in effect
at least one year. The 1978 levels are median values for quarters
in 1978, and are derived from figures 1 and 2 in Model (1993). 104
The values in the column for states that did not decriminalize represent
what might have been seen if the states in the first column had not
Effect of the Medical Marijuana Debate
The most recent National Household Survey on Drug Abuse showed that
among youth ages 12-17 the perceived risk of smoking marijuana once
or twice a week had decreased significantly between 1996 and 1997. 131
(Perceived risk is measured as the percent of survey respondents who
report that they "perceive great risk of harm" in using a
drug at a specified frequency.) At first glance, this might seem to
validate the fear that the medical marijuana debate of 1996 - prior
to the passage of the California medical marijuana referendum in November
1997 - had sent a message that marijuana use is safe. But a closer analysis
of the data shows that Californian youth were an exception to the national
trend. The perceived risk of marijuana use did not change among California
youth between 1996 and 1997. 131 a. In sum, there
is no evidence that the medical marijuana debate has altered perceptions
among adolescents about the risks of marijuana use. 131 a
In assessing the relative risks and benefits of the medical use of
marijuana, the psychological effects of marijuana may be viewed both
as unwanted side effects as well as potentially desirable end points
in medical treatment. However, the vast majority of research on the
psychological effects of marijuana has been done in the context of assessing
the drug's intoxicating effects when used for non-medical purposes.
Thus the literature does not directly address what effects will occur
when marijuana is taken for medical purposes.
There are some important caveats to consider in attempting to extrapolate
from this research to the medical use of marijuana. The circumstances
under which psychoactive drugs are taken are an important influence
on the psychological effects produced. Further, research protocols to
study marijuana's psychological effects in most instances were required
to use participants who had prior experience with marijuana. Clearly,
people who might have had adverse reactions to marijuana would either
choose to not participate in this type of study or would be screened
out by the investigator. Therefore, the incidence of adverse reactions
to marijuana that might occur in individuals with no marijuana experience
cannot be estimated from such studies. A further complicating factor
concerns the dose regimen used for laboratory studies. In most instances
laboratory research studies have looked at the effects of single doses
of marijuana which might be different than that observed when the drug
is taken repeatedly for a chronic medical condition.
Nonetheless, laboratory studies are useful in suggesting what psychological
functions might be studied when marijuana is evaluated for medical purposes.
a Although Arizona also passed a medical marijuana
referendum, it was embedded in a broader referendum concerning prison
sentencing. Hence the debate in Arizona did not focus on medical marijuana
the way it did m California, and changes in Arizona youth attitudes
likely reflect factors peripheral to medical marijuana.)
Laboratory studies indicate that acute and chronic marijuana use has
pronounced effects on mood, psychomotor, and cognitive functions. These
psychological domains should, therefore' be considered in assessing
the relative risks and benefits of the therapeutic use of marijuana
or cannabinoids for any medical condition.
A major question remains as to whether marijuana can produce lasting
mood disorders or psychotic disorders such as schizophrenia. Georgotas
and Zeidenberg reported that smoking 10-22 marijuana cigarettes per
day was associated with a gradual waning of the positive mood and social
facilitating effects of marijuana and an increase in irritability, social
isolation and paranoid thinking. Considering that smoking one cigarette
is enough to make a person feel "high" for about one to three
hours, 67, 94, 117 the subjects in that study were taking
very high doses marijuana. Reports have described the development of
apathy, lowered motivation and impaired educational performance in heavy
marijuana users who do not appear to be behaviorally impaired in other
ways. 12, 121 There are clinical reports of marijuana induced
psychotic-like states (schizophrenia like; depression and/or mania)
lasting for a week or more. 111 Hollister suggests that because
of the varied nature of the psychotic states induced by marijuana, there
is no specific "marijuana psychosis." Rather, the marijuana
experience may trigger latent psychopathology of many types. 65
More recently, Hall and colleagues concluded that "there is reasonable
evidence that heavy cannabis use, and perhaps acute use in sensitive
individuals, can produce an acute psychosis in which confusion, amnesia,
delusions, hallucinations, anxiety, agitation and hypomanic symptoms
predominate." Regardless of which of these interpretations is correct,
both reports agree that there is little evidence that marijuana alone
produces a psychosis that persists after the period of intoxication.
The association between marijuana and schizophrenia is not well understood.
The scientific literature indicates general agreement that heavy marijuana
use can precipitate schizophrenic episodes, but not that marijuana use
can cause the underlying psychotic disorder. 58, 95, 150
As noted earlier, drug abuse is common among people with psychiatric
disorders. Estimates of the prevalence of marijuana use among schizophrenics
vary considerably, but are in general agreement that it is greater than
or equal to use among the general population. 133 Interestingly,
schizophrenics prefer the effects of marijuana over those of alcohol
and cocaine, 35 which they generally use less often than
does the general population. 133 The reasons for this are
unknown, but it raises the possibility that schizophrenics might obtain
some symptomatic relief from moderate marijuana use. But overall, compared
with the general population, individuals with schizophrenia or with
a family history of
schizophrenia are likely to be at greater risk of suffering adverse
psychiatric effects from the use of cannabinoids.
As discussed earlier, acutely administered marijuana impairs cognition.
59, 65, 111 PET imaging (positron emission tomography) allows
investigators to measure the acute effects of marijuana smoking on active
brain function. Human volunteers who perform auditory attention tasks
before and after smoking a marijuana cigarette show impaired performance
while under the influence of marijuana; this is associated with substantial
reduction in blood flow to the temporal lobe of the brain, an area that
is sensitive to such tasks. 115 116 In other brain regions, such as
the frontal lobes and lateral cerebellum, marijuana smoking increases
blood flow. 100, 154 Earlier studies purporting to show structural
changes in the brains of heavy marijuana users 22 (have not
been replicated using more sophisticated techniques. 28, 88
Nevertheless, recent studies 121, 14 have found subtle
defects in cognitive tasks in heavy marijuana users after a brief period
(19-24 hours) of marijuana abstinence. Longer term cognitive deficits
in heavy marijuana users have also been reported. 139 Although
these studies have attempted to match heavy marijuana users with subjects
with similar cognitive abilities prior to exposure to marijuana use,
the adequacy of this matching has been questioned. 132 A
consideration of the complex methodological issues facing research in
this area is well reviewed in an article by Pope and colleagues. 120
Care must be exercised in this area so that studies are designed to
differentiate between changes in brain function caused by the illness
for which marijuana is being given and the effects of marijuana. AIDS
dementia is an obvious example of this possible confusion. It is also
important to determine whether the repeated use of marijuana at therapeutic
dosage levels produces any irreversible cognitive effects.
Marijuana administration has been reported to affect psychomotor performance
on a number of different tasks. The review by Chait and Pierri 23
details not only the studies which have been done in this area but also
points out the inconsistencies across studies, the methodological shortcomings
of many studies, and the large individual differences among the studies
attributable to subject, situational and methodological factors. Those
factors must be considered when designing studies of psychomotor performance
in participants involved in a clinical trial of the efficacy of marijuana.
The types of psychomotor functions that have been shown to be disrupted
by the acute administration of marijuana include: body sway, hand steadiness,
rotary pursuit, driving and flying simulation, divided attention, sustained
attention, and the digit-symbol substitution test. A study of experienced
airplane pilots showed that, even 24 hours after a single marijuana
performance on flight simulator tests was impaired (Yesavage and
coworkers 1985 162). Before the tests, however, they told
the study investigators that they were sure their performance would
Clearly, cognitive impairments associated with acutely administered
marijuana limit the activities that individuals being treated with marijuana
would be able to do safely or productively. For example, no one under
the influence of marijuana or THC should drive a vehicle or operate
potentially dangerous equipment.