medical marijuana and its use by the ...

original paper

MEDICAL MARIJUANA AND ITS USE BY THE IMMUNOCOMPROMISED John M McPartland, DO, MS, and Patty L Pruitt, DVM

John M McPartland, an osteopath who works with entrainment and medicinal herbs, is the medical director of Vermont Alternative Medicine in Middlebury, Vt. Patty L Pruitt is a veterinarian who uses herbs and nutriceuticals in her small-animal practice in Brandon, Vt.

Background • Those immunocompromised by AIDS or cancer chemotherapy use marijuana to allay symptoms of their disease or treatment. Some researchers believe that marijuana may further suppress the immune system. A list of immunological hazards that may be present in marijuana was collated and assessed, and clinical recommendations regarding the use of marijuana by immunocompromised individuals were made. Methods • Databases and other sources from 1964 to 1996 were searched using keywords (eg, cannabinoids, cannabis, hemp, marijuana). This was supplemented by a manual search of bibliographies, nonindexed books, and journals, and by consultation with experts. All reports were analyzed for antecedent sources. Data validity was assessed by source, identification methodology, and frequency of independent observations. Results • Substances implicated as potential immunological hazards in marijuana include endogenous constituents (cannabinoids, pyrolyzed gases, and particulates) and a longer list of exogenous contaminants, both natural (fungi and their metabolites) and synthetic (pesticides and adulterants). Conclusion • Burning of marijuana creates toxins of combustion. Particulate toxins (tars) are reduced by the use of vaporizer apparati. Gas-phase toxins are filtered by water pipes, but water pipes also filter some tetrahydrocannabinol, making this strategy counterproductive. Viable fungal spores in marijuana pose the greatest hazard to immunocompromised patients, though they can be sterilized by several methods. Pesticide residues and other adulterants may be present in black-market marijuana, but are absent in sources of marijuana that are approved by the Food and Drug Administration. (Alternative Therapies in Health and Medicine. 1997;3(3):39-45)

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Medical Marijuana and Its Use by the Immunocompromised

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f all the herbal medicines used in America, none engenders more debate than marijuana (Cannabis sativa—possibly also Cannabis indica and Cannabis afghanica, as there may be more species in the genus Cannabis). Anecdotes and clinical findings have documented marijuana’s efficacy in treating many ailments including glaucoma, asthma, migraine, and multiple sclerosis.1 Marijuana also allays nausea and anorexia associated with chemotherapy and AIDS.2 Nevertheless, the Drug Enforcement Agency (DEA) classifies marijuana as a prohibited Schedule I drug (“no currently accepted medical use”). The DEA will not reschedule marijuana without an official determ i n ation of safety and efficacy by the Food and Dru g Administration (FDA). The FDA requires controlled, doubleblinded clinical trials, and none have been conducted for marijuana. This deficit of clinical trials is partially due to the conundrum facing all herbal medicines: the lack of a patentable product. Other reasons are discussed below. Synthetic tetrahydrocannabinol (THC), the most psychoactive ingredient in marijuana, is available as a Schedule II prescription drug. It is used to treat nausea and anorexia. But many argue that purified THC is less effective than the polypharmaceutical herb.3 Since 1978, the federal government has provided patients with medical marijuana via a compassionate IND (investigational new drug) program. Seven state programs also have provided access to marijuana. Together, at least 800 patients have received marijuana from the National Institute of Drug Abuse (NIDA).4 In 1992, however, the Public Health Service stopped processing new applicants. In part, their justification for ending the program lay in marijuana’s posited health risks.5 Medical researchers proposed a controlled, clinical trial to determine whether this concern of health hazards was justified.6 Their study addressed a critical population: people with AIDS. Marijuana is in widespread use by those immunocompromised by AIDS or cancer chemotherapy. Use of marijuana by immunocompromised individuals is a critical question, because marijuana may further compromise the immune system.7 The clinical trial devised by Abrams and colleagues6 has been approved by the FDA (as well as the California Research Advisory Panel, the institutional review board of the University of California, and the scientific advisory board of the San Francisco Community Consortium). Unfortunately, the protocol was rejected by the DEA

ALTERNATIVE THERAPIES, MAy 1997, VOL. 3, NO. 3

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and NIDA.8 Political disingenuity involved in this rejection has frustrated members of Congress. Thus, a federal medical marijuana bill (HR-2618) currently is being sponsored by Rep Barney Frank (D-Mass). The legislation would overturn the DEA’s ruling, and is modeled after a 1981 bill sponsored by Rep Newt Gingrich (R-Ga). Meanwhile, the general public has turned to ballot initiatives, which overturn state laws but are still within the confines of federal prohibition. California’s Proposition 215 and Arizona’s Proposition 200 passed on November 5, 1996. These state-level initiatives allow patients to possess marijuana for medical use, contingent upon a physician’s recommendation. The federal government has threatened sanctions against physicians who make such recommendations. In the absence of a clinical trial, we conducted a literature review regarding the safety of marijuana. Our review focused on possible immunological hazards that may be present in marijuana; a list of this kind has never been collated. Databases beyond medicine were searched, including the agricultural and pharmacognical literature and the popular press. The article closes with some clinical recommendations regarding the use of medical marijuana by immunocompromised individuals. MATERIALS AND METHODS MEDLINE (1984–1994) and Index Medicus (1964–1994) were searched using the following MeSH keywords: “cannabinoids,” “cannabis abuse,” “marijuana,” and “tetrahydrocannabinol.” AGRICOLA (1990–1994) and Biological and Agricultural Index ( 19 6 4 – 1990) were searched using the keywords “c a n n a b i s , ” “hemp,” and “marijuana.” Current Contents (1964–1994) and Books in Print (1984–1994) were searched using the keyword “marijuana.” Two unindexed magazines (High Times and Sinsemilla Tips) w e re scanned by hand. Cataloged holdings at the follow i n g libraries were searched for theses and texts that were out of print: D a rtmouth, Harva rd, Michigan State Un i v e r s i t y, Nat i o n a l Agriculture Library, National Library of Medicine, Pennsylvania S t ate Un i v e r s i t y, Stanford Un i v e r s i t y, University of Illinois, University of Missouri, University of Michigan, University of Pennsylvania, and the University of Vermont. All reports of immunotoxins in marijuana were scanned for supporting citations and antecedent sources were retrieved. Data validity was assessed by source (peer-reviewed article vs popular press), identification methodology (analytical chemistry vs clinical history), and frequency of independent observations. RESULTS AND DISCUSSION Several potential challenges to the immune system emerged from our literature search. Health hazards cited more than once in well-documented studies are summarized in the Table. They are grouped as either endogenous constituents or exogenous contaminants of marijuana. Endogenous Constituents of Marijuana Turner et al9 listed more than 400 compounds present in marijuana. Of those, over 60 compounds were cannabinoids,

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List of potentially toxic constituents and contaminants of marijuana, cited more than once in peer-reviewed journals Endogenous Constituents Crude herb Cannabinoids Alcohols Aldehydes Ketones Terpenes Smoke, particulate phase Naphthalene Phenols Cresols Benzanthracine Benz(a)pyrene Smoke, gas phase Carbon monoxide Ammonia Hydrogen cyanide Isoprene Acetaldehyde Acetone Acrolein Acetonitrile Benzene Toluene Nitrosamines

Exogenous Contaminants Natural contaminants Alternaria alternata Aspergillus flavus, Aspergillus fumigatus, Aspergillus niger Cladosporium herbarum Enterobacter cloacae Epicoccum nigrum Fusarium spp. Klebsiella pneumoniae Mucor hiemalis Penicillium chrysogenum, Penicillium italicum Rhizopus stolonifer Salmonella muenchen Stemphylium botryosum Streptococcus, group D Fungal aflatoxins Mercury Adulterants Carbamate pesticides Formaldehyde Methaqualone Opium Paraquat PCP Stramonium

PCP, phencyclidine hydrochloride

which are unique to marijuana. The best-characterized cannabinoid is THC. Bouaboula et al10 demonstrated the presence of THC receptors in human leukocytes (THC can directly modulate leukocyte activity). They reported the greatest receptor densities on B cells, followed by natural killer cells, polymorphonuclear neutrophils, and T8 cells; then by monocytes and, finally, T4 cells. The direction of THC modulation remains uncertain. Nahas et al 11 showed in vitro suppression of human T lymphocytes by THC, which was not substantiated in subsequent studies.12-14 In two studies15, 16 it was suggested that THC suppresses macrophages, yet in a recent study 17 it was indicated that THC enhances macrophage secretion of interleukin-1. In some studies,18 THC inhibits B lymphocytes; in others,19 it does not. In a study by Derocq et al,20 it was found that THC actually enhances B-cell growth; in similar research,17,21 it was shown to increase levels of tumor necrosing factor. Cannabinoids other than THC may be immunosuppressive22 or have no effect.15 Hundreds more constituents of marijuana remain untested, including noncannabinoids unique to cannabis (eg, cannabisativine and sativic).9


Pyrolysis produces at least 200 additional compounds in marijuana smoke.23 As Vachon24 emphasized, it may be the smoke in marijuana smoking that produces immunotoxic effects. In one study, Huber et al2 5 summarized smoke literature. They divide smoke into two parts: an insoluble particulate (tar) phase and a gas phase. Tar contains cannabinoids and other polyc yc l i c hydrocarbons, many of which are mutagenic by the Ames test.26 Phenol is one such mutagenic hydrocarbon, and marijuana tar contains approximately 50% more phenols than does tobacco tar.2 7 Other mutagenic hydrocarbons in marijuana tar include b e n z a n t h racene, benzo[a] p y rene, naphthalene, and severa l c re s o l s .2 3 The gas phase contains acetaldehyde, acetonitrile, ammonia, benzene, carbon monoxide, hyd rogen cya n i d e , nitrosamines, and toluene. The presence of immunotoxins in marijuana smoke does not necessarily indicate that toxins reach the smoker. To test this hypothesis, Huber et al 25 blew gas-phase marijuana smoke into a model lung. Wet filter-lined tubes, comparable to those lining the mouth and trachea, re m oved all gas-phase components before they reached the lung. The model lung experiment, therefore, suggests that in vitro bioassays may have no genuine in vivo effects. Exogenous Contaminants in Marijuana Exogenous contaminants in marijuana can be classified as either adulterants or natural contaminants. Both groups contain hazardous materials, including potential immunotoxins. Ad u l t e ra n t s . H i s t o r i c a l l y, cannabis has been laced with t ob a c c o, betel nut, fox g l ove leaves, henbane leaves, D a t u ra leaves, and powdered Strychnos nux-vomica seeds.28 More recently, in the United States, Nahas2 9 has cited oregano, lawn clippings, and hay in marijuana. Jones and Lovinger3 0 assembled a less benign list including hair spray, phencyclidine hydrochloride (PCP), cocaine, and opium. Gold 31 , 3 2 listed rat poison, amphetamines, lysergic acid diethylamide (LSD), strychnine, and stramonium leaves. The origin of such data is uncertain. Gold cited two studies erroneously—Yamaguchi and Kandel’s3 3 and Jessor and Jessor’s3 4—because these sources make no mention of cannabis contaminants. Forensic studies began in 1857 when Bell 35 analyzed a specimen of Cannabis indica containing approximately 25% opium, plus camphor. During the 1970s and early 1980s, several health agencies and private corporations conducted anonymous streetdrug analyses to protect consumers from misrepresented and potentially toxic substances. Submissions of marijuana were the least adulterated of all street drugs.3 6 Lundberg et al3 7 reported that 95% of the samples were pure marijuana, with no mixtures. In another study, Johnson et al38 analyzed nearly 8000 samples of marijuana. In decreasing frequency of occurrence, adulterants included tob a c c o, PCP, cat n i p, heroin, methamphetamines, parsley, LSD, oregano, tea, opium, alfalfa, peyote, mescaline, bell a donna, water hemlock, cinquefoil, wild carrot, ye l l ow chamomile, thyme, stramonium, incense, rabbit tobacco, and mugwort.

Adulteration with PCP was reportedly widespread in the late 1970s,39 but forensic studies have rarely found PCP in marijuana.4 0 Likewise, descriptions of marijuana mixed with scopolamine appear in clinical literature,41 but not in forensic surveys. Adulteration with overt poisons such as cyanide and parathion, reported in the popular press, have never been detected in forensic studies.4 0 More recent analysis of marijuana has detected a d u l t e ration with psychoactive pharmaceuticals such as methaqualone and benzodiazepines. 4 2 According to one gas chromatography/mass spectrometry study,2 3 government-produced NIDA cigarettes were once contaminated with nicotine. Farmers may contaminate plants during cultivation. Plants treated with liquid foliar fertilizer may contain N-nitrosamines.43 Pesticides used on NIDA marijuana grown by the University of Mississippi included sulfur dusts, Bordeaux mixture, and Ceresan M, a mercuric compound.44 According to J McChesney, PhD, no pesticides are currently used on NIDA marijuana (written communication, January 1995). In Holland, state-controlled cultivators use carbamate fungicides to control gray mold in marijuana. Historically, Indian entomologists sprayed marijuana with lead arsenate 45; the residue in 100 g of marijuana equaled 2 mg of arsenic, “allowed as a medical dose.”45(p263) Illegal cultivators of marijuana often use pesticides in an unrestricted fashion. Common pesticides include acephate, aldicarb, carbaryl, diazinon, malathion, maneb, parathion, and zineb. 46 Urban myth suggests that certain pesticides enhance the “ h i g h” of marijuana, hence N e w s w e e k re p o rted ( J a n u a ry 20, 1986) drug dealers treating marijuana with insecticides like Black Flag or Raid. Drug dealers call this product “wac.” “Amp” marijuana is sprayed with formaldehyd e . 4 7 In one study, Donald48(p43) described a 19-year-old smoker “dipping joints in embalming fluid.” Paraquat, a dipyridilium herbicide, has been sprayed on marijuana by police.49 The contaminated crop may then be harvested and sold by unscrupulous drug dealers. This problem peaked around 1978, when 21% of marijuana tested in the southwestern United States was contaminated with paraquat.49 Other herbicides used on marijuana include glyphosate,5 0 amitrole, atrazine, simazine, 2,4-dichlorophenoxyacetic acid,51 karbutilate, diuron, amiben, alachlor, dicamba, propachlor, linuron, silvex, 2 , 4 , 5 - t r i c h l o ro p h e n ox yacetic acid, 5 2 bentazon, diquat , metribizin, phenmedipham, ioxynil, and bromoxynil. 53 Natural contaminants. Like all plants, cannabis accumulates metals from the soil. Siegel et al 5 4 have documented mercury bioaccumulation in Hawaiian marijuana. Jurkowska et al 55 found lithium levels of 1.04 mg/kg in hemp plants, which is higher than any other crop plant tested. Cannabis is cultivated in areas contaminated with cadmium and copper. The plants extract these metals from the soil, then the metals are recovered from harvested plants.56 Microbial contamination of marijuana exposes users to microbial toxins and possible infection by pathogenic organisms. Bacterial contaminants include Klebsiella pneumoniae, Enterobacter c l o a c a e , and group D S t re p t o c o c c u s f rom NIDA marijuana



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cigarettes57; and Salmonella muenchen,58 Thermoactinomyces candidus, Thermoactinomyces vulgaris, and Micropolyspora faeni5 9 from illicit marijuana. Nicholls et al60 found that hemp plants contain 10 times the bacteria population present in other plants. They isolated Enterobacter cloacae and four other species of Enterobacteriaceae, three species of Pseudomonas, and assorted Bacillus, Corynebacterium, Staphylococcus, and Acinetobacter species. Regarding fungi, Ramírez61 reported policemen developing pulmonary histoplasmosis after pulling up a plot of marijuana. Cannabis plants can be infected by scores of plant-pathogenic fungi.6 2 Some of these organisms—Aspergillus niger, Aspergillus fumigatus, Aspergillus flavus, Penicillium chrysogenum, Penicillium italicum, Rhizopus stolonifer, Mucor hiemalis—commonly cause opportunistic infections in immunosuppressed people.59,63,64 Less common opportunists found on illicit marijuana include Alternaria alternata, Cladosporium herbarum, Epicoccum nigrum, and Stemphylium botryosum.62,64,65 Kurup et al59 demonstrated that spores of Aspergillus fumigatus and Mucor species survive in smoke drawn from pyrolyzed marijuana cigarettes. Cases of marijuana smokers contracting pulmonary fungal infections appear in the literature.66-72 In a small cohort of AIDS patients with pulmonary aspergillosis, four of six patients questioned were marijuana smokers.73 These rare reports can hardly be considered a trend, though they have been misinterpreted as such.70 An uncontrolled clinical trial of 56 immunocompromised patients smoking marijuana did not report any cases of pulmonary infections,74 nor has an increased rate of opportunistic infections been reported in an epidemiological study.75 To facilitate infections, fungi release toxic metabolites. Aspergillus flavus, for instance, produces aflatoxins in marijuana; the aflatoxins survive combustion in cigarettes.7 6 Fusarium species produce many mycotoxins; at least seven species infest marijuana.6 2 One Fusarium toxin, zearalenone, causes a mycotoxicosis marked by nausea, vomiting, diarrhea, headache, chills, and convulsions.7 7 Another group of Fusarium toxins, the trichothecenes, cause a hemorrhagic syndrome, and gained media attention for their reputed use in chemical warfare (“yellow rain”). Alternaria alternata frequently blights marijuana62,64,65 and produces a mycotoxin called alternariol. Alternariol causes mutations in human esophageal epithelium, and may play an important role in cancer of the aerodigestive tract.7 8 Aerodigestive tract tumors are the most common malignancies affecting marijuana smokers.79-90 Interestingly, cancers of the aerodigestive tract have not been reported in marijuana smokers from traditional Islamic and Hindu cultures, where cannabis has been used for centuries. Conceivably the most potent immunotoxins in marijuana are unique to our modern era. CONCLUSIONS AND RECOMMENDATIONS Reviewing this list of immunotoxins suggests a potential albeit moderate risk in using medical marijuana. The potential hazards listed in the Table may be separated into two groups: those applicable to FDA-approved sources of marijuana, and those potential hazards found in illicit or street supplies of marijuana.

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FDA-Approved Sources Currently the only FDA-approved source of marijuana is from NIDA. The University of Mississippi provides NIDA with “pure and unadulterated and standardized marijuana … without any contaminants or pesticides” (written communication, J McChesney, PhD, January 1995). Thus, FDA-approved sources of marijuana are free from any exogenous adulterants listed in the Table. Endogenous constituents of marijuana, however, may still pose hazards. Although THC appears to be immunosuppressive, in vitro experiments have produced contradictory results. It is important to note that clinical trials of dronabinol (synthetic THC) in AIDS patients did not produce evidence suggesting that THC was immunosuppressive (verbal communication, D Visconti, PhD, December 1996). Burning marijuana cre ates many new toxins in smoke. Some patients avoid smoke toxins by eating marijuana in baked goods. Unfortunately, oral marijuana shares the drawbacks of o ral THC capsules: erratic bioavailability and slow onset of action, which make dosage difficult to titrate. Furthermore, the eating of marijuana may become difficult for patients who are anorexic, nauseous, or vomiting. THC taken by mouth is converted to an 11-hydroxy metabolite by hepatocytes before entering the systemic bloodstream. Pharmacological activity of the metabolite is quite different from that of free THC; the metabolite, for instance, is four to five times more psychoactive.91 Marijuana smokers have implemented several strategies to decrease smoke exposure. The most important strategy is to smoke marijuana containing an adequate concentr ation of THC. Less smoking is re q u i red. We realize this re c o m m e n d at i o n directly contradicts official government warnings about “dangerous high-potency marijuana,” but here we are dealing with medicaments, not inebriants. Product preparation also may increase THC concentration. The concentration of THC in marijuana only averages 2% to 12% because marijuana contains much plant material lacking THC (eg, xylem and phloem, which still burn and produce smoke), whereas hashish consists of almost pure plant resin glands, containing up to 45% THC. Other strategies incorporate special pyrolysis techniques and various smoking apparati. Many people filter marijuana smoke in water pipes. As Huber et al2 5 have demonstrated, drawing smoke through a water filter removes gas-phase smoke toxins. Unfortunately, particulate-phase smoke toxins such as tar are not as readily removed by water pipes. Gieringer9 2 found that water pipes actually removed more THC than tar. He hypothesized that this would induce users to smoke more marijuana to compensate for THC loss, making water pipes counterproductive. Gieringer concluded that vaporizer devices are superior to water pipes. Vaporizers heat marijuana to 155˚C, the point at which THC vaporizes (but below the burning point of combustible plant material). Vaporizers delivered a higher cannabinoid-to-tar ratio than did cigarettes or pipes. The best vaporizer delivered a 1:10 ratio, whereas cigarettes averaged 1:13 and pipes averaged 1:27 (the worst water pipe delivered 1:40).9 2


Cannabinoid and tar delivery are modulated by inhalation parameters (eg, deepness of inhalation, duration of breathhold, time between inhalations). Zacny and Chait93,94 found that prolonged breathholding did not intensify the physiological and subjective effects of marijuana. It did, however, increase carbon monoxide (CO) concentrations in smokers, as the authors note: “Our results suggest that marijuana smokers could achieve the same level of intoxication while lowering their exposure to CO and other possibly toxic smoke constituents simply by modifying a single aspect of their smoking behavior.”9 4 These findings were not confirmed by Tashkin et al,9 5 who reported that prolonged bre athholding increased the THC level in smokers’ bloodstreams. Viable spores of opportunistic fungi such as Aspergillus, Penicillium, Rhizopus, and Mucor species are the greatest hazards facing immunocompromised users of marijuana (see Figure). Microbiological contamination of NIDA cigarettes is well documented57,59,63 and poses a serious risk. Smoking marijuana with a water pipe does not protect smokers. Moody et al96 tested water pipes with Aspergillus-contaminated marijuana and found that transmission of fungal spores was reduced by only 15%.

Marijuana should be sterilized before smoking. The simplest method of sterilization uses dry heat. Baking marijuana in home ovens at 150˚C (300˚F) for 5 minutes kills spores of Aspergillus fumigatus, Aspergillus flavus, and Aspergillus niger.7 2 THC is neither degraded nor vaporized by this method.72 Ungerleider et al5 7 gas-sterilized marijuana in a mix of 12% ethylene oxide and 88% dichlorodifluoromethane at 8.5 to 10 psi for 4.5 to 5 hours. They reported no loss of THC from fumigation, though gas residues remained in air pockets of fumigated material, posing another health hazard. They also sterilized marijuana with high-dose cobalt 60 irradiation (with up to 20,000 Gy), again without THC reduction. This is the method currently under investigation by government-regulated growers in Holland (written communication, R Clarke, MS, November 1993). Illicit Marijuana Sources Black-market marijuana contains more microbiological contaminants and a greater variety of opportunistic fungi than does NIDA marijuana.9 7 Strategies to avoid microorganisms include careful cultivation, harvesting, and storage of marijuana.64 Grossly contaminated marijuana is easy to diagnose89 and should not be

Left to right: Rhizopus stolonifer, Mucor hiemalis, Penicillium chrysogenum, Penicillium italicum, Aspergillus flavus, Aspergillus niger, Aspergillus fumigatus. Top row: Sporophores cross-sectioned to reveal internal structures (approximately 400x). Bottom row: Natural habitat of above fungi (approximately 25x). Opportunistic fungi isolated from marijuana Line drawing by JM McPartland. Reprinted from Myocology Society of America Newsletter. 1989;40:1. Used with permission.



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used. Sw e at- c u red marijuana (commonly imported fro m Colombia) maintains a “tradition” of Aspergillus contamination.64,97 Bl a c k- m a rket marijuana also may contain adultera n t s . Although some adulterants reported in marijuana are very toxic (eg, PCP), the validity of many reports is questionable. Citation tracking proved that some reports were unsubstantiated or fabricated.31,32 Underground grower’s guides promote the unlabeled use of pesticides on marijuana, but pesticide residues are rarely detected in forensic studies (exceptions include paraquat and other deliberate adulterants). Exposure to black-market adulterants could be eliminated by smoking marijuana from FDA-approved sources. For this reason, the US Public Health Service should not curtail availability of government-grown marijuana. The philosophy guiding our efforts is one of harm reduct i o n .9 8 It is the same philosophy behind needle exc h a n g e s , methadone maintenance, and condom distribution. The use of marijuana remains illegal, but its widespread use makes harm reduction an appropriate strategy for identifying and reducing health hazards facing individuals who do consume it. We do not condone the use of illicit marijuana. We do call for clinical trials of medical marijuana, however, so that researchers can answer lingering questions about efficacy and safety. In response to Propositions 215 and 200, federal officials have awarded $1 million to the Institute of Medicine of the National Academy of Sciences to “gather scientific evidence on the effectiveness of marijuana as a medical treatment” (New York Times. January 9, 1997:B10). Unfortunately, this grant was not earmarked for clinical research, but to fund a blue-ribbon panel of experts to conduct yet another comprehensive literat u re review. Such a review99 was recently completed for the Australian Minister of Justice and published on the 100th anniversary of the first comprehensive literature review.100 Many other reviews h ave been published including one by the Institute of M e d i c i n e .101 L i t e rat u re re v i ews can be biased; for example, General Barry McCaffrey has vowed to “capture data” on marijuana’s effects on workplace accidents and rising teen pregnancy rates ( The Nation. January 6, 1997:14-17). What we need now is proof by clinical trial, as General McCaffrey agrees (Newsweek. February 3, 1997:27). The DEA cannot refuse to reschedule marijuana because of a lack of clinical research while simultaneously refusing to permit such research. After clearing bureaucratic hurdles for 5 years, Abrams’s clinical research faces one final barrier: NIDA’s refusal to supply marijuana for the study. These decisions should be based on scientific merit and not held hostage to political considerations. In February an NIH panel recommended that further clinical trials be undertaken; hopefully the DEA and NIDA will comply with this mandate. Acknowledgments The authors thank Carlo Calabrese for his early encouragement. Adriane Fugh-Berman, Dale Gieringer, and two anonymous reviewers shared their

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insights. Earlier versions of this paper appeared in Sinsemilla Tips, an alternative agronomy journal.

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