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"In summary, 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 dependence on other drugs. Drug dependence is more prevalent in some sectors of the population than others, but no group has been identified as particularly vulnerable to the drug-specific effects of marijuana. Adolescents, especially troubled ones, and people with psychiatric disorders (including substance abuse) appear to be more likely than the general population to become dependent on marijuana."

Tolerance

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 themselves 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 under investigation.

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,29,104,124 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 behavior).95

There appear to be variations in the development of tolerance to the different effects of marijuana and oral THC. For example, daily marijuana smokers participated in a residential laboratory study to compare the development of tolerance to THC pills and to smoked marijuana.61,62 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 four-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. "Tolerance" does not mean that the drug no longer produced the effects but simply that the effects were less at the end than at the beginning of the four-day period. The marijuana smoking group reported feeling "mellow" after smoking and did not show tolerance to this effect; the group that took THC pills did not report feeling "mellow." The difference 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 of THC to a subject. Each smoked marijuana dose consisted of five 10-second puffs of a marijuana cigarette containing 3.1% THC; the pills contained 30 mg of THC. Both groups also received placebo drugs during other four-day periods. Although the dosing of the two groups was comparable, different routes of administration resulted in different patterns of drug effect. The peak effect of smoked marijuana is usually felt within minutes and declines sharply after 30 minutes68,95; the peak effect of oral THC is usually not felt until about an hour and lasts for several hours.118

Withdrawal

A distinctive marijuana and THC withdrawal syndrome has been identified, but it is mild and subtle compared with the profound physical syndrome of alcohol or heroin withdrawal.31,74 The symptoms of marijuana withdrawal include restlessness, irritability, mild agitation, insomnia, sleep EEG disturbance, nausea, and cramping (Table 3.2). In addition to those symptoms, two recent studies noted 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 in the section on "Prevalence and Predictors of Dependence on Marijuana and Other Drugs").31 In a residential study of daily marijuana users, withdrawal symptoms included sweating and runny nose, in addition to those listed above.62 A marijuana withdrawal syndrome, however, has been reported only in a group of adolescents in treatment for substance abuse problems31 and in a research setting where subjects were given marijuana or THC daily.62,74

Withdrawal symptoms have been observed in carefully controlled laboratory studies of people after use of both oral THC and smoked marijuana.61,62 In one study, subjects were given very high doses of oral THC: 180-210 mg per day for 10-20 days, roughly equivalent to smoking 9-10 2% THC cigarettes per day.74 During the abstinence period at the end of the study, the study subjects were irritable and showed insomnia, runny nose, sweating, and decreased appetite. The withdrawal symptoms, however, were short lived. In four days they had abated. The time course contrasts with that in 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.61,62

In animals, simply discontinuing chronic heavy dosing of THC does not reveal withdrawal symptoms, but the "removal" of THC from the brain can be made abrupt by another drug that blocks THC at its receptor if administered when the chronic THC is withdrawn. The withdrawal syndrome is pronounced, and the behavior of the animals becomes hyperactive and disorganized.153 The half-life of THC in brain is about an 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 when THC is abruptly withdrawn without administration of a receptor-blocking drug is probably not due to a prolonged decline in brain concentrations.

Craving 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.115 Thus, while this section briefly reviews what is known about drug craving, its relevance to marijuana use has not been established.

Most people who suffer from addiction relapse within a year of abstinence, and they often attribute their relapse to craving.58 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.115 Whether neurobiological conditions change during the manifestation of an abstinence syndrome remains an unanswered question in drug abuse research.88 The "liking" of sweet foods, for example, is mediated by opioid forebrain systems and by brain stem systems, whereas "wanting" seems to be mediated by ascending dopamine neurons that project to the nucleus accumbens.109

Anticraving medications have been developed for nicotine and alcohol. The antidepressant, bupropion, blocks nicotine craving, while naltrexone blocks alcohol craving.115 Another category of addiction medication includes drugs that block other drugs' effects. Some of those drugs also block craving. For example, methadone blocks the euphoric 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--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.132 Marijuana use is most prevalent among 18- to 25-year-olds and declines sharply after the age of 34 (Figure 3.1).77,132 Whites are more likely than blacks to use marijuana in adolescence, although the difference decreases by adulthood.132

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 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 their marijuana 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 health and well-being; that is, they felt that marijuana was bad for their health or for their family and work relationships. The second type was based on age-related changes in circumstances, including increased responsibility and decreased regular contact with other marijuana users. 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. 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 them for psychological reasons.80

The age distribution of marijuana users among the general population contrasts with that of medical marijuana users. Marijuana use generally declines sharply after the age of 34 years, whereas medical marijuana users tend to be over 35. That raises the question of what, if any, relationship exists between abuse and medical use of marijuana; however, no studies reported in the scientific literature have addressed this question.

Prevalence and Predictors of Dependence on Marijuana and Other Drugs

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).114 The first two categories apply to potential abuse of any substance; that is, people who are vulnerable to drug abuse for individual reasons and who find themselves in an environment that encourages drug abuse are 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 that 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, and the effects of drugs that are ingested take a half hour or more.

The proportion of people who become addicted varies among drugs. Table 3.4 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. Compared to most other drugs listed in this table, dependence among marijuana users is relatively rare. This might be due to differences in specific drug effects, the availability of or penalties associated with the use of the different drugs, or some combination.

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).76

Drug dependence is more prevalent in some sectors of the population than in others. Age, gender, and race or ethnic group are all important.8 Excluding tobacco and alcohol, the following trends of drug dependence are statistically significant:8 Men are 1.6 times as likely than women to become drug dependent, non-Hispanic whites are about twice as likely as blacks to become drug dependent (the difference between non-Hispanic and Hispanic whites was not significant), and people 25-44 years old are more than three times as likely as those over 45 years old to become drug dependent.

More often than not, drug dependence co-occurs with other psychiatric disorders. Most people with a diagnosis of drug dependence disorder also have a diagnosis of a another psychiatric disorder (76% of men and 65% of women).76 The most frequent co-occurring disorder is alcohol abuse; 60% of men and 30% of women with a diagnosis of drug dependence also abuse alcohol. In 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"; marijuana was grouped among "other drugs." 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.

A strong association between drug dependence and antisocial personality or its precursor, conduct disorder, is also widely reported in children and adults (reviewed in 1998 by Robins126). Although the causes of the association are uncertain, Robins recently concluded that it is more likely that conduct disorders generally lead to substance abuse than the reverse.126 Such a trend might, however, depend on the age at which the conduct disorder is manifested.

A longitudinal study by Brooks and co-workers noted a significant relationship between adolescent drug use and disruptive disorders in young adulthood; except for earlier psychopathology, such as childhood conduct disorder, the drug use preceded the psychiatric disorders.18 In contrast with use of other illicit drugs and tobacco, moderate (less than once a week and more than once a month) to heavy marijuana use did not predict anxiety or depressive disorders; but it was similar to those other drugs in predicting antisocial personality disorder. The rates of disruptive disorders increased with increased drug use. Thus, heavy drug use among adolescents can be a warning sign for later psychiatric disorders; whether it is an early manifestation of or a cause of those disorders remains to be determined.

Psychiatric disorders are more prevalent among adolescents who use drugs--including alcohol and nicotine--than among those who do not.79 Table 3.5 indicates that adolescent boys who smoke cigarettes daily are about 10 times as likely to have a psychiatric disorder diagnosis as those who do not smoke. However, the table does not compare intensity of use among the different drug classes. Thus, although daily cigarette smoking among adolescent boys 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.79

Few marijuana users become dependent on it (Table 3.4), but those who do encounter problems similar to those associated with dependence on other drugs.19,143 Dependence appears to be less severe among people who use only marijuana than among those who abuse cocaine or those who abuse marijuana with other drugs (including alcohol).19,143

Data gathered in 1990-1992 from the National Comorbidity Study of over 8,000 persons 15-54 years old indicate that 4.2% of the general population were dependent on marijuana at some time.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. According to data collected in the early 1980s for that study, 4.4% of adults have, at one time, met the criteria for marijuana dependence. In comparison, 13.8% of adults met the criteria for alcohol dependence and 36.0% for tobacco dependence. After alcohol and nicotine, marijuana was the substance most frequently associated with a diagnosis of substance dependence.

In a 15-year study begun in 1979, 7.3% of 1,201 adolescents and young adults in suburban New Jersey at some time met the criteria for marijuana dependence; this indicates that the rate of marijuana dependence might be even higher in some groups of adolescents and young adults than in the general population.71 Adolescents meet the criteria for drug dependence at lower rates of marijuana use than do adults, and this suggests that they are more vulnerable to dependence than adults25 (see Box 3.2).

Youths who are already dependent on other substances are particularly vulnerable to marijuana dependence. For example, Crowley and co-workers31 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 substances. The adolescents 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. About 83% of those who had used marijuana at least six times went on to develop marijuana dependence. About equal numbers of youths in the study had a diagnosis of marijuana dependence and a diagnosis of alcohol dependence; fewer were nicotine dependent. Comparisons of dependence potential between 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 co-workers developed conduct disorders before marijuana abuse. That is consistent with reports that the more symptoms of conduct disorders children have, the younger they begin drug abuse,127 and that the earlier they begin drug use, the more likely it is to be followed by abuse or dependence.125

Genetic factors are known to play a role in the likelihood of abuse for drugs other than marijuana,7,129 and it is not unexpected that genetic factors 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 statistically significant influence on whether a person finds the effects of marijuana pleasant.97 Not surprisingly, people 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 a person will continue using marijuana. Similar results were found in a study of female twins.86 Family and social environment strongly influenced the likelihood of ever using marijuana but had little effect on the likelihood of heavy use or abuse. The latter were more influenced by genetic factors. Those results are consistent with the finding that the degree to which rats find THC rewarding is genetically based.92

In summary, 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 dependence on other drugs. Drug dependence is more prevalent in some sectors of the population than others, but no group has been identified as particularly vulnerable to the drug-specific effects of marijuana. Adolescents, especially troubled ones, and people with psychiatric disorders (including substance abuse) appear to be 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 at high risk for substance dependence. Some controlled substances that are approved medications produce dependence after long-term use; this, however, is a normal part of patient management and does not generally present undue risk to the patient.