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Student Use of Marijuana Linked to Perceptions of Risk

Many American teenagers today do not believe that smoking marijuana is dangerous. That was one of the conclusions of a recent study, by Dr. Jerald G. Bachman and colleagues at the University of Michigan in Ann Arbor, that examined changing attitudes of high school students toward the use of marijuana. The study is based on an extensive review of data from NIDA-supported annual surveys of 8th-, 10th-, and 12th-graders. The surveys, which together make up the ongoing Monitoring the Future project, have collected data on drug use from high school seniors since 1975. Data from 8th- and 10th-graders have been collected since 1991.

The percentage of high school seniors who used marijuana at least once during the past year decreased from 50.8 percent in 1979 to 21.9 percent in 1992, before rising steadily to 37.5 percent in 1998. While use rose, the perception of harm from use declined from 76.5 percent in 1992 to 58.5 percent in 1998. Those who disapproved strongly of regular use dropped from 90.1 percent in 1992 to 81.2 percent in 1998.

Dr. Bachman's group's statistical analysis showed that the simultaneous rise in use and decline in perceived harmfulness during the mid-1990s was more than simple coincidence. To account for this waning concern about the dangers of marijuana, the researchers suggest that the decline in drug use in the 1980s may have led to a "lowering of the guard" of government, schools, mass media, and families. News coverage of drug issues fell substantially in the early 1990s, and fewer antidrug messages were aired during prime-time television programs, the researchers note.

Young people pay close attention to realistically and creatively presented information about the risks of drug use, the researchers suggest. "Presenting this kind of information on the risks and consequences of marijuana use only once does not do the job," says Dr. Bachman. "The message must be repeated regularly so we don't lose students from one year to the next."

Marijuana Antagonist Reveals Evidence of THC Dependence in Rats

By Neil Swan, NIDA NOTES Contributing Writer

For the first time, researchers have demonstrated that marijuana may cause drug dependency in animals. This findingwas made possible by the recent development of a potent marijuana antagonist - an agent that blocks many effects of the drug. The marijuana antagonist appears to act like an on-off switch, allowing researchers to control the effects of withdrawal from delta-9-tetrahydrocannabinol (THC), the principal psychoactive ingredient of marijuana.

Dr. Billy Martin, a NIDA-funded marijuana researcher at Virginia Commonwealth University's Medical College of Virginia, who conducted one of two initial studies, presented his findings at NIDA's National Conference on Marijuana Use: Prevention, Treatment, and Research last summer. During his research, rats were exposed to THC for 4 days, then given a dose of the THC antagonist SR 141716A, which was developed by French scientists last year. The rats immediately and "dramatically" exhibited classic rodent behavioral withdrawal symptoms, indicating that they were dependent on THC, Dr. Martin said.

Within 10 minutes after administration of the marijuana antagonist, the rats exhibited behavior that included "wet-dog shakes" and facial rubbing, which constitute "definite evidence of withdrawal" from the effects of THC, said Dr. Martin. This behavior mimics long-observed opiate withdrawal symptoms in rodents.

The shakes and rubbing were so striking and frequent that they could be quantified by trained observers. Other, less frequent withdrawal-like behaviors included head shakes, biting, drooping eyelids, retropulsion (backing away), ear twitching, chewing, licking, and arching the back, Dr. Martin said.

The wet-dog shakes were dose-dependent, meaning they became more pronounced as dose levels of the antagonist were increased in the THC-exposed animals.

Dr. Martin acknowledged that such behavior is not like any marijuana withdrawal syndrome in humans.

"The fact that people do seek treatment for marijuana dependence is evidence of marijuana withdrawal in humans, but, even among those seeking treatment, we do not see dramatic withdrawal symptoms," said Dr. Martin. "That's because the withdrawal process in humans is so long and drawn out, evidenced chiefly by mild distress or anxiety. But with the rats, using SR 141716A as an effective antagonist, we compress and accentuate that withdrawal process.

"The challenge for us now is to use these animal data to design human studies-to determine how small a dose of THC is needed to become dependent on marijuana," said Dr. Martin.

Dr. Martin, senior investigator Dr. Mario D. Aceto, and colleagues at the Department of Pharmacology and Toxicology of Virginia Commonwealth University have published the results of their research.

"We have been searching for a marijuana antagonist for many years," said Dr. Martin, who has been a marijuana researcher for 22 years.

Sources

Aceto, M.D.; Scates, S.M.; Lowe, J.A.; and Martin, B.R. Canna-binoid-precipitated withdrawal by a selective antagonist: SR 141716A. Eur. J. Pharmacol. 282(1-3):R1-R2, 1995.

Rinaldi-Carmona, M., et al. SR 141716A, a potent and selective antagonist of the brain cannabinoid receptor. FEBS (Federation of European Biochemical Societies) Letters 350(2-3):240-244, 1994.

Tsou, K.; Patrick, S.; and Walker, M.J. Physical withdrawal in rats tolerant to delta-9-tetrahydrocannabinol precipitated by a cannabinoid receptor antagonist. Eur. J. Pharmacol. 280:R13-R15, 1995.

From NIDA NOTES, November/December, 1995

Marijuana Impairs Driving-Related Skills and Workplace Performance

By Robert Mathias, NIDA NOTES Staff Writer

Marijuana use impairs driving-related functions and is linked to a pattern of behaviors that leads to poor job performance, according to two NIDA-supported studies on the effects of marijuana on human performance. Findings from the studies were presented at NIDA's first National Conference on Marijuana Use.

"Driving and marijuana do not mix; that's the bottom line," said Dr. Stephen J. Heishman, a research psychologist in the Clinical Pharmacology Branch of NIDA's Division of Intramural Research. Figures from previous studies of automobile accident victims show that from 6 to 12 percent of nonfatally injured drivers and 4 to 16 percent of fatally injured drivers had tetrahydrocannabinol (THC), the psychoactive ingredient in marijuana, in their bloodstream, Dr. Heishman said. One study showed that 32 percent of drivers in a shock trauma unit in Baltimore had marijuana in their bloodstream, he noted. However, in most of these studies, the majority of subjects who tested positive for THC also tested positive for alcohol, making it difficult to single out THC's effect on driving.

In a laboratory study at NIDA's Addiction Research Center in Baltimore that controlled for alcohol's confounding effect, Dr. Heishman tested marijuana's effects on the functional components of driving. Study subjects smoked a marijuana cigarette, waited 10 minutes, then smoked another cigarette. Both cigarettes contained either 0, 1.8, or 3.6 percent THC. Twenty minutes after smoking the cigarettes, the subjects were given a standard sobriety test similar to a roadside sobriety test. The test showed that marijuana significantly impaired their ability to stand on one leg for 30 seconds or touch their finger to their nose. As the dose of THC increased, the subjects swayed more, raised their arms, and had to put their feet down in an attempt to maintain their balance. Subjects also committed 2.5 times more errors when they attempted to touch their nose with their finger.

The data from these laboratory studies show that marijuana impairs balance and coordination - functional components important to driving - in a dose-related way, said Dr. Heishman. These effects may be related to reported marijuana-induced impairment of automobile driving, he stated.

Highway and urban driving studies conducted in the Netherlands show less impact on actual driving. However, these driving studies used very low doses of marijuana for safety reasons, Dr. Heishman said. Future research using appropriate safety measures should test the effect of higher doses of marijuana on driving as well as the combined effect of marijuana and alcohol on driving, he concluded.

In another study, Dr. Wayne Lehman of Texas Christian University looked at how marijuana affects job performance. A series of surveys he conducted among 4,600 municipal employees in four cities in the Southwest indicated that 8 percent of employees had smoked marijuana in the past year, and a large percentage of these users had smoked marijuana in the past month, Dr. Lehman said.

"Employees who report marijuana use are different from nonusers," said Dr. Lehman. They are much more likely than nonusers to have arrest histories, low self-esteem, high rates of depression, and friends who are deviant. Many marijuana smokers also have alcohol-related problems. One-third of marijuana users in the surveys reported they drank frequently, one-half said they got drunk, and 60 percent reported a problem with alcohol use, according to Dr. Lehman.

This behavioral pattern in the personal backgrounds of marijuana-smoking employees was associated with negative attitudes toward work and job performance, Dr. Lehman said. The surveys found that marijuana users were less likely than nonusers to commit to the organization, had less faith in management, and experienced low job satisfaction. These workers reported more absenteeism, tardiness, accidents, workers' compensation claims, and job turnover than workers who had not used marijuana. They were also more likely to report to work with a hangover, miss work because of a hangover, and be drunk or use drugs at work.

These data indicate that marijuana use is strongly associated with problematic alcohol use and a pattern of general deviance that leads to impaired behaviors and poor workplace performance, Dr. Lehman concluded.

From NIDA NOTES, January/February, 1996

Studies Show Cognitive Impairments Linger in Heavy Marijuana Users

By Robert Mathias, NIDA NOTES Staff Writer

Students who smoke marijuana heavily may be limiting their ability to learn, according to a NIDA-funded study. The study found that college students who used marijuana regularly had impaired skills related to attention, memory, and learning 24 hours after they had last used the drug. The finding supports the results of previous NIDA-funded research that reported that adults who were chronic heavy marijuana users showed residual impairment in cognitive abilities a day after they had last used marijuana.

"Now we know that for students who smoke marijuana heavily, the ability to learn is affected not just while they are high, but for at least a day after," says NIDA Director Dr. Alan I. Leshner. Together with other NIDA-funded research that has shown a marked increase in daily marijuana use among young people in recent years, this finding underlines the importance of the Marijuana Use Prevention Initiative launched by Health and Human Services Secretary Dr. Donna Shalala last year, Dr. Leshner says. NIDA is playing a leading role in the initiative by providing science-based information to educate the public about the consequences of marijuana use. (For more information, see NIDA NOTES, November/December 1995, Marijuana Conference Advances HHS Secretary's Marijuana Initiative and March/April 1996, Facts About Marijuana and Marijuana Use.)

In the study conducted among college students, Dr. Pope and Dr. Deborah Yurgelun-Todd, also of McLean Hospital, tested the cognitive functioning of 65 heavy cannabis users, most of whom had smoked marijuana at least 27 out of the previous 30 days. The researchers compared the heavy users' cognitive functioning to that of a comparison group of 64 light users, most of whom had smoked marijuana on no more than 3 of the previous 30 days. Heavy users ranged in age from 18 to 24 years and light users from 18 to 28 years. The two groups were similar demographically and had comparable numbers of men and women. Subjects in both groups had smoked marijuana for at least 2 years, and none had smoked regularly for more than a decade.

To ensure that the subjects did not smoke marijuana or use other illicit drugs or alcohol during the study, researchers monitored them for 19 to 24 hours. Then the subjects performed a battery of standard tests designed to assess their ability to pay attention, learn, and recall new information. The tests indicated that heavy marijuana users had more difficulty than light users in sustain-ing and shifting attention and hence in registering, organizing, and using information. Heavy users exhibited these cognitive deficits by being less able than light users were to learn word lists; by making a greater number of errors in sorting cards by different characteristics, such as by color or shape; and by making more errors when the rules for sorting the cards were changed without warning. Men in the heavy users group showed somewhat greater impairment than women in the same group.

While the residual cognitive impairments detected in the study were not severe, they could be significant in the day-to-day life of chronic users, Dr. Pope says. The diminished ability to pay attention and decreased mental flexibility exhibited in these tests may cause chronic marijuana users important difficulties in adapting to intellectual and interpersonal tasks, he says.

The residual cognitive impairments
found in the study could be
significant in the day-to-day
life of chronic users.

"This is a fairly definitive study because it was methodologically sound and controlled for a wide number of factors, including the possible confounding effects of alcohol and other drug use," says Dr. Jagjitsing Khalsa of NIDA's Division of Clinical and Services Research.

Previous studies have produced mixed findings about the residual effects of heavy marijuana use on neuropsychological performance, notes Dr. Khalsa. Methodological problems such as ambiguous terminology, failing to take into account cognitive differences in study participants prior to initiation of marijuana use, and failing to note the possible effect of alcohol and other drugs have raised questions about the results of many of these studies. (For more information about methodological issues, see the Pope, Gruber, Yurgelun-Todd article listed below.)

The study by Dr. Pope and Dr. Yurgelun-Todd joins a growing body of well-controlled and well-designed studies that indicate protracted cognitive impairment among heavy marijuana users, says Dr. Khalsa. For example, in 1993, Dr. Robert Block of the University of Iowa College of Medicine compared adult heavy marijuana users and nonusers ranging in age from 18 to 42 years who had been matched on the basis of their intellectual functioning before the onset of drug use. Subjects who used marijuana frequently-7 or more times weekly for at least 2 years-showed deficits in mathematical skills and verbal expression and selective impairments in memory retrieval processes, the study reported. Although the two studies used different neuropsycho-logical tests, "in general, both studies showed some impairments in cognitive abilities among heavy marijuana users," Dr. Block says.

The study joins a growing body
of research that indicates protracted
cognitive impairment among heavy
marijuana users.

It remains unclear whether marijuana's short-term residual cognitive impairments are due either to a residue of the drug that remains in the brain after marijuana's acute effects have dissipated, to a withdrawal effect from abrupt discontinuation of the drug, or to a neurotoxic effect of the drug on brain structure or function. Research has yet to demonstrate conclusively that chronic heavy marijuana use results in cognitive deficits that persist after a prolonged period of abstinence. However, NIDA-supported animal studies do show structural damage to the hippocampus, a structure critical in learning and memory, from the principal psychoactive ingredient in marijuana.

To help answer these and other questions about the long-term effects of marijuana, both Dr. Pope and Dr. Block plan followup studies to examine the effects of chronic heavy marijuana use on cognition and brain function after longer periods of abstinence. Dr. Block proposes to use neuroimaging techniques to look at heavy users' brains while they perform cognitive tasks to determine whether brain function or structure is altered after abstinence from marijuana for a minimum of 30 hours. Dr. Pope is planning a study to determine if cognitive impairments persist in long-time heavy marijuana users for up to 28 days after they have stopped using marijuana.

Sources

Block, R.I., and Ghoneim, M.M. Effects of chronic marijuana use on human cognition. Psychopharmacology 110:219-228, 1993.

Pope, H.G., Jr.; Gruber, A.J.; and Yurgelun-Todd, D. The residual neuropsychological effects of cannabis: The current status of research. Drug and Alcohol Dependence 38:25-34, 1995.

Pope, H.G., Jr., and Yurgelun-Todd, D. The residual cognitive effects of heavy marijuana use in college students. JAMA 275(7):521-527, 1996.

From NIDA NOTES, May/June, 1996

Smoking Any Substance Raises Risk of Lung Infections

By Michael D. Mueller, NIDA NOTES Staff Writer

Smoking any substance- tobacco, marijuana, or "crack," a smokable form of cocaine-increases a smoker's risk of developing bacterial pneumonia and other infections of the lungs, according to the findings of drug abuse, smoking and health, and AIDS researchers.

Although some drugs seem to have specific damaging effects when smoked, smoking anything appears to damage or paralyze the cilia, the hair-like projections in the lungs that sweep out microbes and other matter that can cause disease, according to NIDA-funded studies. Damaging the lung's cilia, the respiratory system's first line of defense, can have severe consequences for people with weak immune systems, the studies note.

A NIDA workshop held in August 1995 examined current research at that time on the cardio-pulmonary complications of crack cocaine use. In a report summarizing the major findings presented at the workshop, Dr. Pushpa V. Thadani, a pharmacologist in NIDA's Division of Basic Research, notes that smoking cocaine appears to weaken the crack smoker's natural resistance to infection in the lungs.

"Pulmonary alveolar macro-phages-cells that protect the lungs from infectious agents-are exposed to the highest concentrations of cocaine," says Dr. Thadani. NIDA-funded studies show that alveolar macrophages from crack cocaine smokers are less active than are alveolar macrophages from nonsmokers in destroying Staphylococcus aureus, a common cause of bacterial lung infection. Preliminary findings also indicate that alveolar macro-phages of cocaine smokers are more susceptible to HIV-related infections than are alveolar macrophages of people who do not smoke cocaine.

"Much remains unknown about the effects of crack smoking on the alveolar macrophages and other cells of defense in the lungs," says Dr. Thadani. "However, it appears that there are profound effects, and this needs to be further explored," she says.

Smoking anything appears to damage or paralyze the cilia, the hair-like projections in the lungs that sweep out microbes and other matter that can cause disease.

Dr. Donald P. Tashkin, a professor of medicine at the University of California at Los Angeles School of Medicine, and his colleagues recently examined the effects that habitual smoking of tobacco, marijuana, and/or cocaine has on the lining of the lung's air passages. The NIDA-funded study included 53 nonsmokers, 14 smokers of crack cocaine only, 40 smokers of marijuana only, and 31 regular tobacco smokers. In addition, there were 16 smokers of both cocaine and marijuana, 12 smokers of cocaine and tobacco, and 44 smokers of both marijuana and tobacco. Thirty-one patients smoked all three substances.

The researchers found that smoking either marijuana or tobacco produces significant damage to the cilia in the lining of the airways. Among smokers of both marijuana and tobacco, it appears that the effects of marijuana add to the effects of tobacco, and vice versa. "The damage to the ciliated cells in the lining of the airways caused by smoking tobacco, and/or marijuana weakens the ability of the lungs to remove inhaled particles, making the lungs more vulnerable to infection," says Dr. Tashkin.

Cocaine smokers had fewer significant abnormalities than marijuana or tobacco smokers did- but more abnormalities than were detected among nonsmokers, Dr. Tashkin says. Among people who smoke both tobacco and cocaine, cocaine smoking appears to produce injury to the mucosal lining of the airways beyond that caused by smoking tobacco alone.

A NIDA-supported study by Dr. Waleska T. Caiaffa and her colleagues at Johns Hopkins University in Baltimore compared the medical records of 40 HIV-positive injecting drug users (IDUs) who had suffered from one bout of bacterial pneumonia with those of 197 HIV-positive IDUs with no history of bacterial pneumonia. The study found that HIV-positive IDUs who smoked illicit drugs were almost twice as likely to develop bacterial pneumonia as were their counterparts who did not smoke illicit drugs. This association was independent of age, degree to which the natural immune system had been suppressed, and cigarette smoking. Among the 77 HIV-positive IDUs who reported smoking drugs, 87.9 percent indicated that they had smoked marijuana, 25.9 percent said that they had used cocaine, and 9.1 percent admitted smoking crack.

Smoking is a serious issue among AIDS patients, according to several NIDA-supported studies. The health effects of smoking illicit drugs are above and beyond those caused by smoking cigarettes, the studies note. People with AIDS often die of pneumonia and other lung problems, and smoking tobacco and/or illicit drugs increases the risks for these diseases.

"The effect that smoking has on the lungs is more serious than most people realize. Smoking anything is bad for your health, especially if your immune system has been weakened," says Dr. Tashkin.

Sources

Caiaffa, W.T.; Vlahov, D.; Graham, N.M.; Astemborski, J.; Solomon, L.; Nelson, K.E.; and Munoz, A. Drug smoking, Pneumo-cystis carinii pneumonia, and immunosuppression increase risk of bacterial pneumonia in human immunodeficiency virus-seropositive injection drug users. Am. J. of Respiratory and Critical Care Medicine 150:1493-1498, 1994.

Fligiel, S.E.; Roth, M.D.; Kleerup, E.C.; Barsky, S.H.; Simmons, M.S.; and Tashkin, D.P. Tracheobronchial histopathology in habitual smokers of cocaine, marijuana, and/or tobacco. Chest, in press.

Thadani, P.V., et al. NIDA conference report on cardiopulmonary complications of "crack" cocaine use: Clinical manifestations and pathophysiology. Chest 110:1072-1076, 1996.

From NIDA NOTES, January/February, 1997

Research Must Determine Medical Potential of Marijuana, NIH Expert Panel Concludes

By Robert Mathias, NIDA NOTES Staff Writer

A National Institutes of Health (NIH) panel of experts has concluded that critical questions about the therapeutic usefulness of marijuana remain largely unanswered by studies that have been conducted to date. The panel called for NIH to facilitate rigorous, well-designed clinical studies to evaluate marijuana's potential to treat a variety of medical conditions. Such studies must address the many potential short- and long-term hazards of smoked marijuana, the panel stressed.

The panel of eight experts, who have broad experience in clinical studies and therapeutics, expressed their opinions in a 37-page report that NIH issued in August 1997. NIH had convened the experts at a 2-day meeting earlier in the year to consider wide-ranging claims about the therapeutic usefulness of marijuana, particularly smoked marijuana, and the need for and feasibility of additional research. At the meeting, the panel reviewed the published scientific data on the medical use of marijuana and considered comments, including those from patients and advocacy groups.

Under U.S. law, marijuana has been classified in the most restrictive category of controlled substances since 1970. This means that the drug in its usual form has a high potential for abuse and has no commonly accepted medical use in this country. However, advocates for the medical use of smoked marijuana claim it is effective in such areas as reducing nausea associated with cancer chemotherapy, counteracting the wasting syndrome associated with AIDS, and treating glaucoma. An oral form of marijuana's principal active ingredient, delta-9-tetrahydrocannabinol (THC), called dronabinol, is approved as a treatment for nausea and vomiting related to cancer chemotherapy. Dronabinol also is used to stimulate the appetite of AIDS patients.

The NIH panel noted that the current debate over using marijuana as a medicine centers on claims that smoked marijuana offers therapeutic advantages over dronabinol and that it has potential to treat other conditions, such as pain and glaucoma. However, little data from clinical trials are available to support or refute these claims, the panel's review showed.

Most previous studies of marijuana's therapeutic potential have used THC in capsule form. Such studies do not answer questions about the potential benefits or risks of smoked marijuana, which has substantially different dose absorption and pharmacological activity from the oral dosage form, the panel noted. In addition, although THC is the principal psychoactive component of the cannabis leaf, other compounds in the leaf may have therapeutic properties, the panel said.

The panel called for more studies to properly evaluate marijuana's medical potential in five areas: analgesia, or pain relief; neurological and movement disorders; nausea and vomiting associated with cancer chemotherapy; glaucoma; and appetite stimulation to counteract weight loss in patients with AIDS or cancer. In addition to dronabinol, effective treatments already are available for many of these indications, the panel noted. For example, a number of medications can treat pain without risking marijuana's adverse effects.

However, even where effective medications exist, marijuana could be studied for its potential to offer relief to patients who do not respond fully to such treatments, the panel stated. Other reasons for studying marijuana's medical potential include determining whether it is useful in treating diseases or conditions for which treatments are not currently available, such as nerve pain caused by disease or tissue injury, and whether it could enhance the therapeutic effects of currently available treatments.

Any studies of marijuana's medical potential need to consider both the short- and long-term risks associated with smoked marijuana, the panel stressed. Among the short-term risks cited by the panel are cardiovascular effects, effects on the lungs, and undesirable mental and behavioral effects. Other concerns would come into play if marijuana were used to treat patients with chronic diseases, such as the possibility that frequent and prolonged marijuana use might significantly impair the functioning of the body's immune system. Examining that aspect is particularly important for patients who already have compromised immune systems, such as cancer patients undergoing chemotherapy and HIV/AIDS patients, the panel noted.

To address health concerns about using smoked marijuana for longer term therapy, the panel suggested that researchers strive to develop alternative dosage forms for marijuana, such as a smoke-free inhaled delivery system. Such a system could deliver purer forms of THC and related cannabinoids and permit better control of doses, the panel stated.

For More Information

The full text of the expert panel's report on the medical utility of marijuana is available at http://www.nih.gov/news/medmarijuana/MedicalMarijuana.htm

Chronic Marijuana Abuse May Increase Risk of Stroke

Dr. Ronald I. Herning and Dr. Jean Lud Cadet, with colleagues at NIDA's Intramural Research Program in Baltimore, report preliminary evidence suggesting that chronic abuse of marijuana can restrict blood flow to the brain and increase the risk of stroke for young men aged 18 to 30.

The investigators used transcranial Doppler sonography, a noninvasive technology that uses sound waves to take measurements and create images, to calculate the pulsatility index -- a measure of resistance to blood flow -- in cerebral arteries of 35 male participants, 16 long-term marijuana users and 19 nonusers of marijuana. Marijuana users had higher resistance to blood flow to their brains than did nonusers upon initial measurement, and the deficits persisted after the marijuana abusers remained abstinent for a month, well past the time when acute withdrawal symptoms were reported. As a result, the deficits do not appear to be related to a temporary withdrawal syndrome.

The findings suggest that, at least within the first 4 weeks of marijuana abstinence, blood flow in the brain in young marijuana abusers is comparable to that of 60-year-olds, which may be of clinical importance because advancing age increases the risk of stroke.

The study was published in the June 2001 Annals of the New York Academy of Science.