Marijuana and Medicine Assessing the Science Base (1999) / Chapter Skim
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3 First, Do No Harm: Consequences of Marijuana Use and Abuse
3 First, Do No Harm: Consequences of Marijuana Use and Abuse
Pages 83-136
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From page 83... ...
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 explores the negative health consequences of marijuana use, first with respect to drug abuse, then from a psychological perspective, and finally from a physiological perspective.
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From page 84... ...
Anxiety and paranoia are the most common acute adverse reactions;59 others include panic, depression, dysphoria, depersonalization, delusions, illusions, and hallucinations. 40 66 69 Of regular marijuana smokers, 17% report that they have experienced at least one of the symptoms, usually early in their use of marijuana.~45 Those observations are particularly relevant for the use of medical marijuana in people who have not previously used marijuana.
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From page 85... ...
CONSEQUENCES OF MARIJUANA USE AND ABUSE TABLE 3.1 Psychoactive Doses of THC in Humans 85 THC Delivery THC Dose Investigators System Resulting Plasma Concentrations Administered of THC Subjects' Reactions Heishman and One 2.75% co-workers THC (l990~62a cigarette smoked 0.32 mg/kga 50-100 ng/ml At higher level, subjects felt 100% "high" and psychomotor performance was decreased; at 50 ng/ml, subjects felt about 50% "high" Kelly and 1-g marijuana 0.25-0.50 Not measured Enough to feel co-workers cigarette mg/kga psychological effects (1993~85 smoked (2% or of THC 3.5% THC) Ohlsson and 19-mg THC About 0.22 100 ng/ml Subjects felt "high" co-workers cigarette mg/kgb (1980~8 smoked (about 1.9% THC)
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From page 86... ...
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.
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From page 87... ...
CONSEQUENCES OF MARIJUANA USE AND ABUSE 87 Reinforcement Drugs vary in their ability to produce good feelings in users, and the more strongly reinforcing a drug is, the more likely it will be abused (G. Koob, Institute of Medicine (IOM)
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From page 88... ...
The median forebrain bundle and the nucleus accumbens are associated with brain reward pathways.~8 Cocaine, amphetamine, alcohol, opioids, nicotine, and THC~44 all increase extracellular fluid dopamine in the nucleus accumbens region (reviewed by Koob and Le Moal88 and Nestler and Aghajanian~° 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.
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From page 89... ...
For example, daily marijuana smokers participated in a residential laboratory study to compare the development of tolerance to THC pills and to smoked marijuana. 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.
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From page 90... ...
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"~.3~ In a residential study of daily TABLE 3.2 Drug Withdrawal Symptoms Nicotine Alcohol Cocaine Opioids (e.g., heroin or morphine) Restlessness Irritability Impatience, hostility Dysphoria Depression Anxiety Difficulty concentrating Decreased heart rate Increased Irritability Sleep disturbance Nausea Tachycardia, hypertension Sweating Seizures Alcohol craving Delirium appetite or tremensa weight gain Tremor Perceptual distortion Restlessness Irritability Dysphoria Dysphoria Depression Anxiety Sleepiness, fatigue Bradycardia Insomnia Nausea C
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From page 91... ...
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.~5 Whether neurobiological conditions change during the manifestation of an abstinence syndrome remains an unanswered question in drug abuse research. The "liking" of sweet foods, for example, is
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From page 92... ...
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.
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From page 93... ...
lion 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.
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From page 94... ...
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)
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From page 95... ...
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 Robinson. 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.
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From page 96... ...
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)
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From page 97... ...
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. That is consistent with reports that the more symptoms of conduct disorders children have, the younger they begin drug abuse,~27 and that the earlier they begin drug use, the more likely it is to be followed by abuse or dependence.~25 Genetic factors are known to play a role in the likelihood of abuse for
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From page 98... ...
Drug dependence is more prevalent in some sectors of the population than others, but no group has been identified as particularly vulnerable to the drugspecific effects of marijuana. Adolescents, especially troubled ones, and people with psychiatric disorders (including substance abuse)
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From page 99... ...
The latter does not suggest that the pharmacological qualities of marijuana make it a risk factor for progression to other drug use. Instead, the legal status of marijuana makes it a gateway drug.82 Psychiatric disorders are associated with substance dependence and are probably risk factors for progression in drug use.
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From page 100... ...
The factors that best predict use of illicit drugs other than marijuana are probably the following: age of first alcohol or nicotine use, heavy marijuana use, and psychiatric disorders. However, progression to illicit drug use is not synonymous with heavy or persistent drug use.
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From page 101... ...
Kandel and co-workers also included nonmedical use of prescription psychoactive drugs in their study of drug use progression.82 In contrast with the use of alcohol, nicotine, and illicit drugs, there was not a clear and consistent sequence of drug use involving the abuse of prescription psychoactive drugs. The current data on drug use progression neither support nor refute the suggestion that medical availability would increase drug abuse among medical marijuana users.
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From page 102... ...
. That scheduling also signals to physicians that a drug has abuse potential and that they should monitor its use by patients who could be at risk for drug abuse.
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From page 103... ...
In contrast with marijuana use, rates of other illicit drug use among ER patients were substantially higher in states that did not decriminalize marijuana use. Thus, there are different possible reasons for the greater increase in marijuana use in the decriminalized states.
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From page 104... ...
The Medical Marijuana Debate The most recent National Household Survey on Drug Abuse showed that among people 12-17 years old the perceived risk associated with smoking marijuana once or twice a week had decreased significantly between 1996 and 1997.~32 (Perceived risk is measured as the percentage of survey respondents who report that they "perceive great risk of harm" in using a drug at a specified frequency.) At first glance, that might seem to validate the fear that the medical marijuana debate of 1996 before passage of the California medical marijuana referendum in November 1997 had sent a message that marijuana use is safe.
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From page 105... ...
These psychological domains should therefore be considered in assessing the relative risks and therapeutic benefits related to 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.
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From page 106... ...
~7 Marijuana smoking increases blood flow in other brain regions, such as the frontal lobes and lateral cerebellum.~0~ ~55 Earlier studies purporting to show structural changes in the brains of heavy marijuana users22 have not been replicated with more sophisticated techniques.28 89 Nevertheless, recent studies ~22 have found subtle defects in cognitive tasks in heavy marijuana users after a brief period (19-24 hours) of marijuana abstinence.
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From page 107... ...
When heavy marijuana use accompanies these symptoms, the drug is often cited as the cause, but no convincing data demon
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From page 108... ...
Because such research can only be done on subjects who become heavy marijuana users on their own, a large population studysuch as the Epidemiological Catchment Area study described earlier in this chapter would be needed to shed light on the relationship between motivation and marijuana use. Even then, although a causal relationship between the two could, in theory, be dismissed by an epidemiological study, causality could not be proven.
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From page 109... ...
Assays of Leukocytes from Marijuana Smokers. One of the more common approaches has been to isolate peripheral blood leukocytes from people who have smoked marijuana in order to evaluate the immune
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From page 110... ...
The major problem with the approach is that after blood samples are drawn from the study subjects the leukocytes must be isolated from whole blood before they are tested. That is done by high-speed centrifugation followed by extensive washing of the cells, which removes the cannabinoid; perhaps for this reason no adverse effects have been demonstrated in peripheral blood leukocytes from marijuana smokers.75 9~ ~23 ~60 Leukocyte Responses to THC.
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From page 111... ...
Marijuana cigarettes usually do not have filters, and marijuana smokers typically develop a larger puff volume, inhale more deeply, and hold their breath several times longer than tobacco smokers.~9 However, a marijuana cigarette smoked recreationally typically is not packed
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From page 112... ...
The reduction in ability to destroy fungal organisms was similar to that seen in tobacco smokers. The inability to kill pathogenic bacteria was not seen in tobacco smokers.~° Furthermore, marijuana smoking depressed production of proinflammatory cytokines, such as TNF-I and IL-6, but not of immunosuppressive cytokines.~° Cytokines are important regulators of macrophage function, so this marijuana-related decrease in inflammatory cytokine production might be a mechanism whereby marijuana smokers are less able to destroy fungal and bacterial organisms, as well as tumor cells.
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From page 113... ...
. When marijuana smokers were compared with nonsmokers and tobacco smokers in a group of 446 volunteers, 15-20% of the marijuana smokers reported symptoms of chronic bronchitis, including chronic *
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From page 114... ...
The damage is greater in people who smoke both marijuana and tobacco.~30 Overproduction of mucus by the increased numbers of mucous-secreting cells in the presence of decreased numbers of ciliated cells tends to leave coughing 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.~48 A 1998 study has shown that both marijuana and tobacco smokers have significantly more cellular and molecular abnormalities in bronchial epithelium cells than nonsmokers; these 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.
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From page 115... ...
, showed an accelerated rate of decline in tobacco smokers but not in marijuana smokers.~47 Thus, the question of whether usual marijuana smoking habits are enough to cause COPD remains open. Conclusion.
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From page 116... ...
Marijuana use has been associated with a higher prevalence of HIV seropositivity in cross-sectional studies,84 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.
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From page 117... ...
Most studies lack the necessary comparison groups to calculate the isolated effect of marijuana use on cancer risk. Many marijuana smokers also smoke tobacco, so when studies lack information regarding cigarette smoking status, there is no way to separate the effects of marijuana smoke and tobacco smoke.
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From page 118... ...
were markedly higher in the marijuana smokers than in the nonsmokers and the tobacco smokers. Moreover, the effects of marijuana and tobacco were additive.~3~ Thus, in relatively young smokers of marijuana, particularly those who smoke both marijuana and tobacco, marijuana is implicated as a risk factor for lung cancer.
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From page 119... ...
Preliminary findings suggest that marijuana smoke activates cytochrome P4501A1 (CYPlAl) , the enzyme that converts PAHs, such as benz~ocipyrene, into active carcinogens.99 Bronchial epithelial cells in tissue biopsies taken from marijuana smokers show more binding to CYPlA1 antibodies than do comparable cells in biopsies from nonsmokers (D.
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From page 120... ...
2. Molecular markers of respiratory cancer progression in marijuana smokers.
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From page 121... ...
Similarly, further studies on cell cultures of peripheral blood mononuclear cells could be used to assess the effects of exposure to THC on HIV infectivity and replication. Cardiovascular System Marijuana smoke and oral THC can cause tachycardia (rapid heart beat)
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From page 122... ...
Acute treatments with cannabinoids including THC, CBD, cannabinol, and anandamide can decrease the fertilizing capacity of sea urchin sperm.~35~~37 The sea urchin is only a distant relative of humans, but the cellular processes that regulate fertilization are similar enough that one can expect a similar effect in humans. However, the effect of cannabinoids on the capacity of sperm to fertilize eggs is reversible and is observed at concentrations of 6-100 ,uM,~36 ~37 which are higher than those likely to be experienced by marijuana smokers.
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From page 123... ...
The results of studies of the relationship between prenatal marijuana exposure and birth outcome have been inconsistent (reviewed in 1995 by Cornelius and co-workers30~. Except for adolescent mothers, there is little evidence that gestation is shorter in mothers who smoke marijuana.30 Several studies of women who smoked marijuana regularly during pregnancy show that they tend to give birth to lower weight babies.4665 Mothers who smoke tobacco also give birth to lower weight babies, and the relative contributions of smoking and THC are not known from these studies.
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From page 124... ...
, there was no difference in weight between babies born to women who reported themselves as marijuana smokers and those born to women who reported that they did not smoke marijuana. That raises an important concern about the methods used to measure the effects of marijuana smoking in any study, perhaps even more so in studies on the effects of marijuana during pregnancy, when subjects might be less likely to admit to smoking marijuana.
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From page 125... ...
The 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 the mothers' use of marijuana during pregnancy.
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From page 126... ...
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, and people with psychiatric disorders, or problems with substance abuse appear to be at greater risk for marijuana dependence than the general population.
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From page 127... ...
CONCLUSION: Numerous studies suggest that marijuana smoke is an important risk factor in the development of respiratory disease. RECOMMENDATION: Studies to define the individual health risks of smoking marijuana should be conducted, particularly among populations in which marijuana use is prevalent.
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From page 128... ...
1987. Differential examination of bronchoalveolar ravage cells in tobacco cigarette and marijuana smokers.
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From page 129... ...
1991. Advanced malignancy in the young marijuana smoker.
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From page 130... ...
1979. Observations on the effects of four weeks of heavy marijuana smoking on group interaction and individual behavior.
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From page 131... ...
1992. Characterization of the absorption phase of marijuana smoking.
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From page 132... ...
1993. Effects of smoked marijuana on heart rate, drug ratings and task performance by humans.
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From page 133... ...
1991. Altered serum immunoglobulin concentration in chronic marijuana smokers.
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From page 134... ...
1993. Health care use by frequent marijuana smokers who do not smoke tobacco.
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From page 135... ...
1996. Endobronchial injury in young tobacco and marijuana smokers as evaluated by visual, pathologic and molecular criteria.
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From page 136... ...
1988. Peripheral blood lymphocyte subpopulations and mitogen responsiveness in tobacco and marijuana smokers.
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