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( first: do no harm )



Janet B. Joy, Stanley J. Watson, Jr., and John A. Benson, Jr., Editors

Division of Neuroscience and Behavioral Health


Washington, D.C. 1999





Drug dynamics

There are many misunderstandings about drug abuse and dependence . The terms and concepts used in this report are as defined in the most recent Diagnostic and Statistical Manual of Mental Disorders (DSM-1V3 ), the most influential system in the United States for diagnoses of mental disorders, including substance abuse . 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).

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; others include panic, depression, dysphoria, depersonalization, delusions, illusions, and hallucinations. Of regular marijuana smokers, 17% report that they have experienced at least one of the symptoms, usually early in their use of marijuana. Those observations are particularly relevant for the use of medical marijuana in people who have not previously used marijuana.

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 12-month period:

  1. Tolerance, as defined by either of the following:
    1. A need for markedly increased amount of the substaiice to achieve intoxication or desired effect.
    2. Markedly diminished effect with continued use of the same amount of the substance.

  2. Withdrawal, as defined by either of the following:
    1. The characteristic withdrawal syndrome for the substance.
    2. The same (or a 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 (eg., visiting multiple doctors or driving long distances), use the substance (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 that is likely to have been caused or exacerbated by the substanc (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.

Table 3.2 Drug Withdrawal Symptoms


Decreased heart
Increased appetite
or weight gain


Sleep disturbance
Alcohol craving
Delirium tremens


Mild agitation
Sleep EEG


Cocaine craving


Increased sensitivity
to pain
Muscle aches
Nausea, cramps
Opioid craving

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. (Perceived risk ~ 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 Wend. The perceived risk of marijuana use did not change among California youth between 1996 and 1997. In sum, there is no evidence that the medical marijuana debate has altered perceptions among adolescents about the risks of marijuana use.

(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 in California, and changes in Arizona youth attitudes likely reflect factors peripheral to medical marijuana.)


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.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.

Psychiatric disorders

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, 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. There are clinical reports of marijuana-induced psychotic-like states (schizophrenia-like; depression and/or mania) lasting for a week or more. 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. 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. ' 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. Interestingly, schizophrenics prefer the effects of marijuana over those of alcohol and cocaine, which they generally use less often than does the general population. 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 effect from the use of cannabinoids.


As discussed earlier, acutely administered marijuana impairs cognition. PET imaging (positron emission tomography) allows investigators to measure the acute effects of marijuana smoking on active brain function. Human volunteers whe 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. Earlier studies purporting to show structural changes in the brains of heavy marijuana users (have not been replicated using more sophisticated techniques.)

Nevertheless, recent studies 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."9 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.'32 A consideration of the complex methodological issues facing research in this area is well reviewed in an article by Pope and colleagues. 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.

Psychomotor Performance

Marijuana administration has been reported to affect psychomotor performance on a number of different tasks. The review by Chait and Pierri 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 cigarette, their performance on flight simulator tests was impaired. Before the tests, however, they told the study investigators that they were sure their performance would be unaffected. 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.

Amotivational Syndrome

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. It is not enough to observe that a chronic marijuana user lacks motivation. Instead, relevant personality waits 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 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 would not be proven.


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. 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.

Immune System

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 marijuana use.

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.

HIV / AIDS Patients

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. (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 AIDS.

Marijuana use has been associated with a higher prevalence of HIV-seropositivity in cross-sectional studies, 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, or in the San Francisco Men's Health Study, in which 451 HIV-seropositive men were studied for 6 years. In contrast, the Sydney AIDS Project in Australia (386 HIV-seropositive men were studied for 12 months) 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.

The most compelling concerns regarding marijuana smoking in HIV/AIDS patients are the possible effects of marijuana on human immunity. Reports of opportunistic fungal and bacterial pneumonia in patients with AIDS who used marijuana suggest that marijuana smoking either suppresses the immune system, or that it exposes patients to an added burden of pathogens. In sum, patients with pre-existing 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.


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.

Reproductive System

Human Studies

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, no 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 pulse during the luteal phase (the phase after ovulation and before menses). 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. Except for adolescent mothers, there is little evidence that gestation is shorter in mothers who smoke marijuana. Several studies of women who smoked marijuana regularly during pregnancy show that they tend to give birth to lower weight babies. 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. 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 men who use marijuana rarely smoke it, but instead prepare it as tea. 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. 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. Since 1978, the Ottawa Prenatal Prospective Study has been measuring the cognitive functions of children born to mothers who smoked marijuana during pregnancy. 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 years.

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. In another study, 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 incompatib1e with a current goal. 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.

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.

Bronchial-pulmonaiy Damage

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. However, the incidence of 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.

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.'45 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.'45 Similar findings were reported by Bloom and coworkers,15 and these investigators noted an additive effect of smoking both marijuana and tobacco.

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. 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 cellse 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. 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.

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. 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 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. Tenant and coworkers 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 epidemiologicad data, indirect evidence, such as nonspecific airway hyperresponsiveness and measures of lung function, offers an indicator of the vulnerability of marijuana smokers to COPD. 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. On the other hand, Tashkin and coworkers 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. 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.

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 areconsistent 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 of 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?

Three factors influence the safety of marijuana or cannabinoid drugs for medical uses: the delivery system, the use of plant material, and the side effects of cannabinoid drugs. (1) 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 be contraindicated.

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.

Market Outlook for Marijuana

The market outlook for the development of marijuana as a new drug, based on foregoing analysis, is not favorable for a host of scientific, regulatory, and commercial reasons.

From a scientific point of view, research is difficult due to the rigors of obtaining an adequate supply of legal, standardized marijuana for study. Further scientific hurdles to overcome relate to satisfying the exacting requirements for FDA approval of a new drug. These hurdles are even more exacting for a botanical product due to inherent problems with purity, consistency, and other factors (noted above). Finally, the health risks associated with smoking represent another barrier to FDA approval, unless a new, smoke-free route of administration is demonstrated to be safe. Depending on the route of administration, an additional overlay of regulatory requirements may have to be satisfied.

From a commercial point of view, uncertainties abound. The often-cited cost new drug development, about $200-300 million, may not fully apply but there are likely additional costs needed to satisfy FDA's requirements for a botanical product. As noted above, no botanical products have ever been approved new drugs by FDA under today's stringent standards for safety and efficacy. Satisfying the legal requirements of the CSA also will add significantly to the cost of development. On the positive side, so much research already has been done that some development costs will be lower. The cost of bringing dronabinol to market, for example, was curtailed dramatically as a result of clinical trials supported with government funding. Nevertheless, for these reasons it is impossible to estimate the cost of developing marijuana as a new drug. Estimating return on investment is similarly difficult. A full-fledged market analysis would be required for the indication being sought. Such an analysis would take into account the market limitations resulting from drug scheduling restrictions, stigma, and patentability.

The plant does not constitute patentable subject matter under US patent law because it is unaltered from what is found in nature. So-called 'products of nature' are not generally patentable. New marijuana strains, on the other hand, could be patentable in the U.S. under a product patent or a plant patent because they are altered from what is found in nature. (A product patent prohibits others from manufacturing, using, or selling each strain for 20 years; whereas, a plant patent carries somewhat less protection.) Thus far, HortaPharm has not sought any type of patent for its marijuana strains in the U.S., but it has received approval for a plant registration in Europe.

In short, the development of the marijuana plant is beset by significant scientific, regulatory, and commercial obstacles and uncertainties. The prospects for its development as a new drug are unfavorable, unless return on investment is not a driving force. It is noteworthy that no pharmaceutical firm has sought to bring it to market in the U.S. The only interest in its development appears to be in England by a small pharmaceutical firm and in the U.S. from physicians without formal ties to pharmaceutical firms.