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PEDIATRICS Vol. 109 No. 2 February 2002, pp. 284-289

Marijuana: A Decade and a Half Later, Still a Crude Drug With Underappreciated Toxicity

Richard H. Schwartz, MD

From the Department of Pediatrics, Inova Fairfax Hospital for Children, Falls Church, Virginia

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	ABSTRACT

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In 1984, I published in this journal a review entitled "Marijuana: A Crude Drug With a Spectrum of Underappreciated Toxicity."¹ In the introduction to that article, I disclosed that our son Keith, who was 15 years old at the time, was in a long-term, modified outpatient adolescent drug and alcohol rehabilitation program because he had become dependent on marijuana with its associated behavioral, interpersonal, scholastic, and antisocial problems. Keith and most of his friends had experimented several times with LSD, beer, and several other drugs but never used injection drugs. Marijuana was clearly Keith’s drug of choice and the only drug he used with regularity. Approximately 1 year later, Keith graduated from the treatment program. He completed the early aftercare component, relapsed several times, and completed a 4-month refresher drug rehabilitation program in another state. Nine years after admission to the first rehabilitation program, Keith finally attained some adult goals. Now 34 years old, he has been drug-free for 10 years. He is the president and owner of a successful discount cellular phone business that he started. More important, a decade ago, he reestablished an excellent and close relationship with his parents. As far as I can tell, Keith remains drug-free except for an occasional beer.

Key Words: marijuana • cannabis • drug abuse

Abbreviations: THC, -9-tetrahydrocannabinol • AIDS, acquired immunodeficiency syndrome

	INTRODUCTION

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Several general or specialized reviews of marijuana have been published in the medical literature in the past decade.^2–12 The United States Institute of Medicine, the Canadian Addiction Research Foundation, and the Australian government also have published comprehensive reviews of marijuana.^13–15 The purpose of this review article is to describe 15 years of advances in knowledge about marijuana.

	SOURCES AND POTENCY OF MARIJUANA

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Fifteen years ago, <40% of seized marijuana was grown in the United States. Colombia and Mexico were the sources of most marijuana, and much of the Mexican-grown product was low-potency marijuana compressed into a kilobrick.^16,17 Today, regular-grade marijuana is more potent than that of 15 years ago, yielding a product that contains >5% -9-tetrahydrocannabinol (THC). At present, domestic marijuana accounts for >60% of seized and analyzed marijuana. Marijuana is currently grown and cultivated predominantly in northern California and the Pacific northwest, particularly in British Columbia.¹⁸ In 2000, >4000 pounds of highly potent marijuana grown in British Columbia was seized by US and Canadian customs. In barns, townhouses, and detached houses ("grow houses"), it is grown hydroponically, without soil, under powerful 1000-watt halide lamps with ventilation and exhaust systems to reduce the heat from the lamps and the smell from the vegetation.¹⁹ Each lamp illuminates a section of plants that started as hybrid clones. Hybrid seeds are now easily purchased on-line through the Internet or from High Timesand other magazines, from sources in Canada and the Netherlands. Selected high-potency strains of hydroponically grown buds such as B.C. bud now contain >12% THC. Hybrid seeds from highly potent strains of cannabis plants are easily obtained from seed banks in British Columbia or the Netherlands, where 10 seeds can cost $0.80 to $1.50 per seed (www.sensiseeds.com). The specially grown buds (small, packed, resin-rich flowers) can be >8 inches long and sell for >$300 per ounce. Sinsemilla buds grown outdoors can sell for >$250 per ounce. By means of comparison, 15 years ago, the average potency of Mexican or common domestic marijuana was only 3%, and that of Colombian grown sinsemilla was 4.6%.^2,4

	INTERNET WEB SITES RELATED TO MARIJUANA

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In the past decade, there has been an exponential growth of Web sites related to marijuana (see, eg, marijuana.com, www.theamsterdam.com, www.smokin420.com). These sites often are dominated by marijuana advocacy groups, and the information contained in them minimizes the dangers of marijuana smoking and highlights the advantages of medical marijuana, the costs of the failed federal "War on Drugs," the injustice of imprisonment for possession of small quantities of marijuana, and the crushing of civil liberties that has occurred because adults are not permitted to light up a marijuana cigarette in the privacy and security of their own homes. Several Web sites contain information on purchasing hybrid marijuana seeds and tips for growing the plants outdoors or indoors, using special equipment that can also be purchased over the Internet.²⁰ A high school or college student who is using the Internet might get a very opinionated yet seemingly factual view of the benefits and harm from smoking marijuana.

	METHODS OF SMOKING: FROM JOINTS AND BOWLS TO BONGS AND BLUNTS

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Fifteen years ago, marijuana was usually smoked in tiny pipes called bowls or in small, hand-rolled marijuana cigarettes called joints.²⁰ The dried plant material sold in zip-lock bags contained small twigs and many tiny seeds (achenes), which required time-consuming cleaning of the rough product. Now, sinsemilla (seedless marijuana) or buds are easily purchased in every American town and suburb, at a cost of $100 to $200 per ounce, double the cost of 15 years ago. Rich in resin, the crumbled or chopped dried material is often smoked in water or dry bongs that resemble Turkish water pipes but come in many ornate shapes and colors. They can easily be purchased over the Internet. The irritating smoke is thereby cooled and highly concentrated, permitting a "super high." Although not a new way of smoking marijuana, the widespread availability of bongs and their reported use by groups of younger middle school students is a change from 15 years ago. Blunts are inexpensive cigars, often Phillies Blunts, that are sliced in half longitudinally. One well-rolled blunt is equal to 5 marijuana cigarettes in quantity. A new verb, to be blunted, refers to smoking blunts to get high. The idea originated in Jamaica, where the outer wrapper can be common brown bag paper instead of tobacco leaf. The inner tobacco leaves are removed and either refilled with marijuana alone or mixed with tobacco. Obviously, there is a big difference between the amount of marijuana contained in a joint or a bowl and the amount inhaled in a blunt. Sometimes the potency of the smoke is increased even more by the addition of hashish to the crumbled marijuana filler.

Every issue of High Times magazine contains at least 10 advertisements for products such as Tommy Chong’s Detoxifying Tea (Spectrum Laboratories, Cincinnati, OH) that are alleged to sanitize a "dirty" urine specimen.²¹ In contrast to 15 years ago, many employers now require preemployment drug tests before acceptance, and parents can purchase drug test kits for home urine testing. Some of the sanitizing beverages (Urine Luck) contain chemicals that nullify confirmatory tests by gas chromatography/mass spectrometry; other products are alleged to inactivate screening tests for THC.

Clinical Laboratory Improvement Act-waved rapid immunoassay tests for detection of THC metabolites are now easily available from pharmacies and by mail for use by physicians and parents for detection of recent marijuana use. I have tested several of these products and compared the results against gas chromatography/mass spectrometry, the reference standard for detection of drugs in urine. The Clinical Laboratory Improvement Act-waved tests performed well, and there were no false-positive test results in the 10 paired tests that we performed.

	AMERICAN ACADEMY OF PEDIATRICS POLICY STATEMENT ON URINE DRUG TESTING

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In 1996, the American Academy of Pediatrics published a policy statement, "Testing for Drugs of Abuse in Children and Adolescents" (RE9628), strongly recommending voluntary consent before urine testing for adolescents with decision-making capacity.²² "Involuntary diagnostic testing is not deemed appropriate in adolescents with decisional capacity—even with parental consent—and should be performed only if there are strong medical or legal reasons to do so." Involuntary diagnostic testing would be justified only if the adolescent were at risk of serious harm that could be averted if the specific drug were identified. If the treatment and therapy would not be changed, then involuntary testing would not be justified. Consent from the older adolescent may be waived—in circumstances in which information gained by history or physical strongly suggests that the young person is at high risk of substance abuse. The appropriate response to the suspicion of drug testing in a young person would be referral to a qualified health care professional for comprehensive evaluation.

	TRENDS IN MARIJUANA USE BY ADOLESCENTS

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According to data collected by the National Monitoring the Future Survey, annual marijuana use among adolescents of all ages steadily fell between 1979 and the early half of the 1990s.^23,24 In 1992, annual use was at a low of 22% among 12th graders nationwide. Between 1992 and 1999, the percentages of high school students who had used marijuana at least once (lifetime use), used it in the past month (current use), and used it 4 or more times per week (daily use) rapidly increased, peaking in 1996 among 8th graders and in 1997 for 10th and 12th graders. During the same period, there was a reduction in the perceived risk associated with smoking marijuana. A reduction in the perceived risk to smoking marijuana usually precedes actual increases in use of the drug and is a leading indicator of change in frequency of use. In 1999 and 2000, rates of use by 8th-, 10th-, and 12th-grade high school students leveled off, simultaneous with the percentage of each grade that saw great risk in using marijuana regularly. Data from a 1999 to 2000 survey of 7th-, 9th-, and 11th-grade students in California substantiated the decrease in lifetime or annual use of marijuana but showed no change in weekly use of the drug.²⁵

Fifteen years ago it was widely believed that marijuana was a critical gateway drug to illicit drug use.²⁶ Young adolescents experimented with and became dependent on tobacco, learned how to drink alcohol and enjoyed its intoxicating effect, and progressed to marijuana and then to cocaine and other "hard drugs." Data from Golub and Johnson²⁷ and from Simmons and Tashkin²⁸ suggested that marijuana smoking may precede tobacco smoking or abusing alcohol, at least in girls, and that smoking potent marijuana may not be a forerunner to learning how to smoke heroin and cocaine base.^29,30 Although the modified gateway theory is not accepted by many marijuana advocates, the research is well done and reproducible.³¹

Data from the 1992 to 1999 National Institute of Justice reports on positive drug tests at the time of arrest showed during that 7-year period that there was a 100% increase in urine tests that were positive for marijuana use among youths 18 to 20 years.³⁰ Arrestees born since 1970 seemed much less likely to progress to harder drugs such as cocaine or heroin than older arrestees.

A recent study of 1228 German adolescents who were followed from baseline at 14 years of age to 17 years of age and reevaluated serially for a mean of 20 months found that 74% of the adolescents continued some regular use of marijuana over time.³² The higher the baseline use pattern, the higher the probability of continued or heavier use during follow-up. Frequent use of cannabis during adolescence seems to be less transient than many people believe.³¹

	MECHANISMS OF ACTION OF MARIJUANA

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In the past 15 years, there have been several exciting advances in the understanding of how marijuana exerts its effect on short-term memory, appetite, sleep, motivation, coordination, and emotions.^33,34 Marijuana seems to produce its effects through specific binding with endogenous THC receptors. Euphoria occurs when marijuana stimulates the dopamine pathway to the nucleus accumbens of the medial forebrain, postulated to be the reward center of our brain. This is the same reward center that is highly stimulated by cocaine. There are 2 endogenous cannabinoid receptors: CB1, a G-protein-linked receptor, found in highest concentrations in the hippocampus and cerebellum, and CB2, which is found in the spleen and other organs. The hippocampus THC receptors are particularly numerous, and this may explain why marijuana causes impairment of short-term memory.^35,36 Cerebellar binding of THC may also explain impairment in coordination and motor vehicle operation. A recently developed, unique CB1 cannabinoid receptor-antagonist produced in humans a dose-dependent blockade of marijuana-induced intoxication/euphoria and tachycardia.³⁷ Pretreatment of human volunteers with an oral dose of SR141716 before smoking marijuana significantly reduced by 50% to 75% the subjective rating of being "high."³⁷ Anandamide (arachidodonyl ethynol-amide) is believed to be one of the endogenous analgesic drugs, similar to endorphins. This compound, isolated from pigs, binds to endogenous CB1 binding sites and may be useful in elucidating some of the mechanisms of action of marijuana. It is hypothesized that these endogenous anandamide compounds, when linked to THC binding sites, play some role in modulation or inhibition of nociception (pain). Binding of exogenous cannabinoids to brain and spinal cord receptors has been shown to cause alterations in neurotransmitters, changes in quantity of adenyl cyclase and dopamine, and modulation of the -amino butyric acid system.

	Short-Term Memory Impairment

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Impairment of short-term memory is one of the least debatable and most troublesome adverse effects of marijuana.^38–43 During the past 15 years, there has been important research in this area in adults, high school students, and college students. The single most marked effect of marijuana smoking seems to be an impairment of our ability to process newly learned material and store it for future use. Given the increase in use of marijuana by 8th-grade students since 1992, this has alarming potential significance.

Seven of 8 studies published before 1988 found lingering selective deficits in recent memory in adult, chronic marijuana smokers as compared with control subjects.³⁸ Two of those 8 studies initially found no evidence of memory impairment. However, on reevaluation of the same subjects 1 decade later, short-term memory impairment was demonstrable. Does impairment of short-term memory linger after the marijuana euphoria has passed? In real life, as in the laboratory setting, short-term memory impairment secondary to smoking marijuana has been documented to cause major problems. Having trouble remembering things is the most bothersome adverse effect mentioned by 100 adult, daily marijuana smokers.⁴⁴ In a study of 10 high school students who had been daily marijuana smokers for a mean of 7 months, marijuana use was confirmed by twice-weekly tests for urine THC.⁴⁵ Excluded from the study were those who were heavy drinkers and those with low IQ test scores. During the 6-week study period, participants were supervised 24 hours a day to ensure that they could not continue to smoke marijuana. A neuropsychology masters-level candidate administered auditory and visual short-term memory tests after a 48-hour washout period and again 6 weeks later. Impairment of both visual and auditory short-term memory was demonstrated. Control groups did not show this impairment. In a well-publicized study of 65 college students who smoked marijuana frequently and 64 who smoked it occasionally, daily use of the drug was associated with impairment of "executive functions" such as learning of lists and attention to homework.⁴⁶ Residual neuropsychological impairment of executive functions was found to carry over well past the period of intoxication. Verbal fluency was noted to be impaired in many of the daily marijuana smokers. In the accompanying editorial to this published study, it was suggested that the most plausible interpretation of the findings was that heavy marijuana smoking produces alterations of cannabinoid-specific brain function or structure.⁴⁷

	Additional Adverse Effects of Marijuana

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In the past 15 years, we have substantiated the adverse respiratory effects of smoking marijuana.^48–52 A chronic cough, often productive, deepening of the voice, high co-association with tobacco smoking, recurrent bronchitis, and irritation of the respiratory tree from the posterior choanae to the bronchi are accepted effects of marijuana smoking. Frequent marijuana smoking can cause significant impairment of pulmonary function tests (spirometry) after only a few years of heavy use of the drug. Wheezing, exercise-induced shortness of breath, nocturnal wakening with chest tightness, and early morning sputum production were more frequent than in the control group. The cannabis-dependent group had 60% to 70% more symptoms than the control group of nonsmokers.⁵² That study of 91 young New Zealanders (age 21 years) was controlled for tobacco smoking and bronchial asthma.

Early and frequent use of marijuana seems to be associated with the adoption of an anticonventional lifestyle in an appreciable percentage of young adolescents. This is characterized by affiliations with delinquent and substance-using peers and early school dropout, leaving parental home during teenage years, and early parenthood.⁵³ There is also some evidence that marijuana use is associated with an increased frequency of unprotected sex.⁵⁴ The effects of marijuana on spermatogenesis, fertility, and development of gynecomastia, as well as teratogenic effects on the fetus, seem to have been overemphasized.^55–57 Although THC is capable of crossing the placenta into the fetus of experimental animals, data now show that cannabinoids do not produce gross fetal malformations. There seems to be an increasing amount of evidence to support subtle impairment of executive functions in preschool and primary school years.⁵⁷ Similarly, the in vitro evidence of impairment of cellular immunity has not been born out in vivo. Data from the Abrahams, San Francisco study of marijuana smoking by patients with acquired immunodeficiency syndrome (AIDS) have not shown a deterioration in patients’ immunity to fungi or other opportunistic organisms. There is incontrovertible evidence that intoxication from marijuana impairs driving skills under controlled conditions.^58–60 A recent study performed in the Netherlands assessed the separate and combined effects of marijuana and alcohol on driving performance in real driving situations.⁶¹ Eighteen licensed drivers who were experienced in smoking marijuana and in drinking alcohol participated. The Road Tracking Test measured a driver’s capability to maintain a constant speed of 100 km/hour and a steady lateral position between the boundaries of the right traffic lane. The Car Following Test measured drivers’ reaction times and distance between vehicles while driving 50 m behind a vehicle that executed a series of alternating accelerations and decelerations. Smoking marijuana alone or drinking alcohol alone significantly impaired performances on both road tests compared with the baseline without marijuana or alcohol. Marijuana use alone caused reaction time to increase 36% above that of an unimpaired driver, which translated to an additional 139 feet more at a speed of 59 mph. There was a diminished ability to perceive and/or respond to changes in the relative velocities of other vehicles and to adjust one’s own vehicle’s speed accordingly.⁶¹ Whether marijuana impairs real-life driving skills is still debatable. However, in 1997, the World Health Organization concluded, "There is sufficient consistency and coherence from the experimental studies and studies of cannabinoid levels among accident victims ... to conclude that there is an increased risk of motor vehicle accidents among persons who drive when intoxicated with cannabis."² There is an obvious need for more research in this area.

	MARIJUANA AS MEDICINE: LET THE FACTS SPEAK FOR THEMSELVES

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Although a discussion of medical marijuana seems inappropriate for a pediatric journal, access to and legal possession of marijuana by adults for various common diseases can model exposure and access to and use of the drug by children and adolescents. In November 1996, California voters passed the Compassionate Use Act (Proposition 215) by a wide margin (56% to 44%). This law permits seriously ill patients and their primary caregivers to possess and to cultivate marijuana for the patients’ personal medical use if they have the written or oral recommendations or approval of a physician. Use of marijuana is not limited to any diagnostic list, and there is no restriction of use by adolescents or children. Since then, 8 other states (Washington, Oregon, Alaska, Hawaii, Arizona, Colorado, Nevada, and Maine) and the District of Columbia have passed medical marijuana laws, some more restrictive than others. Oregon alone currently has an estimated 2350 individuals who have a license to smoke and grow medical marijuana. An internal audit of the medical marijuana program taken in June 2001 found that a single physician accounted for 890 applications and only 13 other physicians signed more than 10 applications each. At least 12 other states have medical marijuana laws in various legislative committees for probable vote this or next November). Some organizations, including the American Public Health Association, the Federation of American Scientists, and several activist AIDS groups, have demanded that certain patients have access to medical marijuana. Medical marijuana has been advocated in editorials and op-ed opinions in the Journal of the American Medical Association⁶² and the New England Journal of Medicine.⁶³ Several books have been published promoting medical marijuana for many maladies, including dysmenorrhea, clinical depression, fibromyalgia, chronic fatigue syndrome, and bronchial asthma.^64,65 There is no lack of poignant anecdotes concerning marijuana’s therapeutic efficacy in providing relief from migraine headaches and other painful conditions, relief of spasticity associated with spinal cord injury, and reduction of seizure frequency in epilepsy. Of all of the diseases mentioned in medical journals and books, there is some credible objective evidence, obtained by clinical investigations, only for marijuana’s effectiveness as an antiemetic against emetogenic types of cancer chemotherapy and for use in treating AIDS-related wasting syndrome.¹³

A search of the English-language literature found 14 studies that evaluated cannabinoids for the treatment of chemotherapy-induced nausea and vomiting.^66,67 Only 1 article and 2 abstracts described smoked marijuana in the protocol. Eleven study protocols used synthetic dronabinol (THC), administered orally as a capsule. In abstract given at the 20th Annual Meeting of the American Society of Clinical Oncology in 1984, of 20 patients who were evaluated by double-blind crossover paradigm to compare smoked marijuana with oral THC, only 5 patients were free of vomiting and 3 others were free of nausea, regardless of whether they smoked or swallowed the drug. In the single published peer-reviewed study, Vinciguerra et al⁶⁸ evaluated the effectiveness of smoked marijuana in 56 adult cancer patients who were receiving emetogenic chemotherapy. Twelve patients had no relief of nausea or vomiting. Smoked marijuana was found to be moderately effective by 26 patients (46%) and very effective by 18 patients (32%). The study protocol called for deep and sustained inhalation of the marijuana smoke with the breath held for 10 seconds after a deep inhalation. Most of the patients had not been receiving the most emetogenic of the chemotherapeutic agents at the time of the study, and many of today’s effective antiemetic agents were not available to cancer patients at the time of the study.⁶⁹ In multiple studies involving a total of 329 adult cancer patients who took oral cannabinoid drugs to prevent nausea or vomiting, the adverse effects of THC included somnolence (32%) and ataxia (9%). Adverse effects happened significantly more often in those who were taking cannabinoids than in those who were taking other antiemetic drugs.^66,67

An exhaustive review of cannabinoids for control of chemotherapy-induced nausea and vomiting concluded that the cannabinoids tested in the trials may be useful as mood-enhancing adjuvants for controlling chemotherapy-related sickness, but potentially serious adverse effects, even when taken short-term, are likely to limit their widespread use.⁶⁹ A comprehensive review of cannabinoid analgesia concluded that there is little proven evidence for efficacy and much evidence for adverse effects greater than most existing analgesic drugs. An editorial in the British Medical Journal stated that on current evidence, cannabinoids can be recommended only for use in controlled clinical trials in carefully selected conditions for which there is no effective treatment.^70,71

In 1997, a panel of scientists assembled by the National Institutes of Health examined all of the evidence for medical marijuana.¹³ Although the panel agreed that there was a suggestion of marijuana’s therapeutic value for a few diseases as noted above, it concluded that sound research studies supporting the claims of drug effectiveness were lacking. A summary of the findings of the Institute of Medicine report follows:

1. Marijuana’s future as medicine does not involve smoking it. If there is any future for marijuana as medicine, it lies in its isolated components, the cannabinoids and their synthetic derivatives.
   
2. There is no compelling evidence that marijuana should be used to treat glaucoma and little evidence for treating migraine headaches.
   
3. Medical marijuana should be tried only when there is failure of all approved medications to provide relief and always under medical supervision.
   
4. Medical marijuana should be used only in short-term (<6 months’ duration) trials.
   

	CONCLUSION

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Much has been learned in the past 15 years about marijuana’s increasing potency, new methods of smoking it, transborder shipments from north as well as south, the presence of endogenous binding sites in selected parts of our brains, its adverse effect on short-term memory, and an alarming increase in its use by 8th-grade students. The question of medical marijuana seems to have shifted from the medical trial court to the court of public opinion through referendums, largely through poignant anecdotes of individuals who plead for unimpeded access to marijuana, without fear of penalty. Currently, evidence is weak to moderate for the antiemetic effect of synthetic cannabinoids and quite weak for the superiority of smoked marijuana for treatment of nausea and vomiting secondary to emetogenic chemotherapy. For some unexplained reason, we continue to fail to appreciate that marijuana is a crude drug with underappreciated toxicity.

	Suggestions for State Medical Marijuana Laws

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1. Medical use marijuana should, at present, be limited to the 2 disease entities that have at least some objective evidence of effectiveness, ie, nausea and vomiting caused by highly emetogenic cancer chemotherapy and AIDS, and palliation of the AIDS wasting syndrome; it should not be recommended or prescribed for those who are HIV positive.
   
2. Restriction of use by minors except for individualized compassionate reasons.
   
3. Documentation of cancer and need for emetogenic chemotherapy.
   
4. Required reevaluation at least every 3 to 4 months.
   
5. Repeated documentation of continued need for smoked marijuana.
   
6. Exclusion or careful supervision of individuals with a record of psychotic diseases, panic disorder, or a history of abuse of alcohol or drugs and those convicted of a felony.
   
7. Oral and written warnings about operation of a motor vehicle, motor boat, or dangerous machinery.
   
8. Instructions about reporting adverse effects and the legal liability for prescribing or dispensing the drug must be spelled out.
   

	FOOTNOTES

 
Received for publication Jun 28, 2001; Accepted Aug 27, 2001.

Reprint requests to (R.H.S.) 115 Park St, SE, Suite 203, Vienna, VA 22180. E-mail: rhs738{at}aol.com

	REFERENCES

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