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Marihuana
Medicina
Workshop on the Medical Utility of Marijuana [dugacko]
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<blockquote data-quote="iz0t0p" data-source="post: 2748" data-attributes="member: 420"><p><u>nastavak</u></p><p></p><p>Use of Marijuana in Neurological and Movement Disorders</p><p></p><p></p><p>1. What research has been done and what is known about the possible medical uses of marijuana?</p><p></p><p>There have been numerous studies both in animals and in various clinical states on the use of cannabinoids on neurological and various movement disorders. These results range from anecdotal reports to surveys and clinical trials. Marijuana or tetrahydrocannabinol (THC) is reported to have some antispasticity, analgesic, antitremor, and antiataxia actions, as well as some activity in multiple sclerosis (MS) and in spinal cord injury patients.</p><p></p><p>The spasticity and nocturnal spasms produced by MS and partial spinal cord injury have been reported to be relieved by smoked marijuana and to some extent by oral THC in numerous anecdotal reports. The effect seems to appear rapidly with smoked marijuana; patients are able to titrate the dose by the amount they smoke. No large-scale controlled studies or studies to compare either smoked or oral THC with other available therapies have been reported. Several relatively good therapeutic alternatives exist. There is no published evidence that the cannabinoid drugs are superior or even equivalent.</p><p></p><p>Substantial experimental animal literature exists showing that various cannabinoids, given primarily by parenteral routes, have a substantial anticonvulsant effect in the control of various models of epilepsy, especially generalized and partial tonic-clonic seizures. Scant information is available about the human experience with the use of marijuana or cannabinoids for the treatment of epilepsy. This is an area of potential value, especially for cannabis therapies by other than the smoked route.</p><p></p><p>Several single case histories have been reported indicating some benefit of smoked marijuana for dystonic states. It must be remembered that dystonia is a clinical syndrome with numerous potential causes, and the information available now does not differentiate which causes are most likely to be improved. Smoked marijuana and oral THC have been tested in the treatment of Parkinson's disease and Huntington's chorea without success.</p><p></p><p>The cannabinoids also have been used as experimental immunologic modifiers to treat such conditions as the animal models of experimental allergic encephalomyelitis (EAE) and neuritis. Parenteral cannabinoids have been successful in modifying EAE in animals, suggesting that cannabinoids may be of value in a more fundamental way by altering the root cause of a disease such as MS rather than simply treating its symptoms. Smoked marijuana would not be acceptable for such a role because of the variability of dose with the smoked route.</p><p></p><p>2. What are the major unanswered scientific questions?</p><p></p><p>The discovery of dedicated systems of central nervous system (CNS) neurons approximately 8 years ago, which express receptors specific for the cannabinoids, is of major scientific interest and importance. The distribution of these cannabinoid receptor-bearing neurons corresponds well with the clinical effects of smoked marijuana; for instance, their presence in the forebrain may relate to adverse changes in short-term memory, but perhaps positively in the control of epilepsy. Cannabinoid receptors in the brainstem and cerebellum may relate to the recognized incoordination that accompanies smoked marijuana use. The discovery of intrinsic ligands for these receptors in the mammalian brain is also of great importance. This system of cannabinoid receptors and ligands may be analogous to the discovery of opiate receptors and endorphins, which linked various opium derivatives (heroin and morphine) to an intrinsic system of neurons in the CNS. That discovery was of major importance for pain research.</p><p></p><p>The major unanswered scientific questions are:</p><p></p><p>* How useful is smoked marijuana of known specific potency in controlling various neurologic conditions?</p><p></p><p>* In comparative studies, how useful is smoked marijuana in altering objective abnormalities such as spasticity versus current standard therapies that have already been approved for human use?</p><p></p><p>* Can alternative delivery systems (other than the oral route) be developed to provide rapidity of action with more safety than smoked marijuana?</p><p>* Can available or newly developed synthetic cannabinoids be used more effectively to stimulate or block receptor activity in the cannabinoid system of the CNS?</p><p>* What are the immune-modulating characteristics of the cannabinoids and can they be used for therapeutic human benefit?</p><p>* Can the long-term risks of daily smoked marijuana be quantified so that useful risk versus benefit ratios can be determined, especially when considering treatment of long-term conditions such as spasticity or epilepsy? </p><p></p><p>3. What are the diseases or conditions for which marijuana might have potential as a treatment and which merit further study?</p><p></p><p>Marijuana or the use of other cannabinoids as human therapies might be considered for treating spasticity and nocturnal spasms complicating MS and spinal cord injury, for various active epilepsy states, for some forms of dystonia, and perhaps most interestingly, for treating neuropathic pain (Zeltser et al. 1991). (Also see the chapter titled Analgesia.) Neuropathic pain complicates many CNS diseases. Few available therapies provide even partial relief.</p><p></p><p>Reference</p><p></p><p>Zeltser, R.; Seltzer, Z.; Eisen, A.; Feigenbaum, J.J.; and Mechoulam, R. Suppression of neuropathic pain behavior in rats by a non-psychotropic synthetic cannabinoid with NMDA receptor-blocking properties. Pain 47(1):95-103, October 1991.</p><p></p><p>Nausea and Vomiting</p><p></p><p></p><p>1. What research has been done and what is known about the possible medical uses of marijuana?</p><p></p><p>There is a large body of clinical research on the use of cannabinoids for chemotherapy-related nausea and vomiting. Most of this work was conducted during the early 1980s. The majority of reports deal with oral dronabinol rather than smoked marijuana. These studies demonstrated that dronabinol was superior to placebo in controlling nausea and vomiting caused by chemotherapy that induces a moderate amount of emesis (Sallan et al. 1975). Several studies compared oral dronabinol with prochlorperazine (Sallan et al. 1980). Mixed results were reported from these studies, but generally dronabinol was found equivalent.</p><p></p><p>Gralla and colleagues (1984) examined metoclopramide versus dronabinol in patients given cisplatin in a randomized double-blind trial. These investigators reported poorer antiemetic control and more side effects with dronabinol than with the metoclopramide.</p><p></p><p>None of these studies compared oral dronabinol or smoked marijuana with what are now considered the most effective antiemetic regimens, the combination of a specific serotonin antagonist (like ondansetron, granisetron, or dolasetron) plus dexamethasone, which were introduced in the early 1990s. This combination has demonstrated complete protection from vomiting during the initial 24 hours after cisplatin (the most potent emetic stimulus) in 79 percent of patients treated (Italian Group for Antiemetic Research 1995). Without antiemetic protection, 98 percent of similar patients vomit a median of six times within the first 24 hours alone after cisplatin (Kris 1996). Side effects of these newer antiemetic regimens are negligible and would permit a patient to drive or return to his or her job immediately after receiving chemotherapy.</p><p></p><p>Only two clinical trials have formally addressed the effectiveness of smoked marijuana. Levitt and colleagues (1984) conducted a random-order assignment crossover study comparing smoked marijuana and dronabinol in 20 subjects, 15 men and 5 women. Twenty-five percent of the subjects were free of vomiting and 15 percent were free of nausea. As to individual preference for the route of administration, 45 percent of the patients had no preference, 35 percent preferred oral dronabinol, and 20 percent preferred smoked marijuana.</p><p></p><p>Vinciguerra and colleagues (1988) studied smoked marijuana in an open trial in 74 patients who previously had no improvement with standard antiemetic agents. Nearly 25 percent of patients who initially consented to participate later refused treatment citing bias against smoking, harshness of smoke, and preference for oral dronabinol. Of the remaining 56 patients, 18 (34 percent) rated it very effective and 26 (44 percent) moderately effective. Twelve (22 percent) noted no benefit. Sedation occurred in 88 percent, dry mouth in 77 percent, and dizziness in 39 percent. Only 13 percent were free of adverse effects.</p><p></p><p></p><p></p><p>2. What are the major unanswered scientific questions?</p><p></p><p>No scientific questions have been definitively answered about the efficacy of smoked marijuana in chemotherapy-related nausea and vomiting. A comparison of the efficacy of smoked marijuana versus oral dronabinol would also be of interest. In addition, further information on appropriate dosage and frequency, side effects, tolerability, and patient acceptability for smoked marijuana would need to be established.</p><p></p><p>3. What are the diseases or conditions for which marijuana might have potential as a treatment and which merit further study?</p><p></p><p>Inhaled marijuana has the potential to improve chemotherapy-related nausea and vomiting. Because the combination of a serotonin antagonist plus dexamethasone prevents chemotherapy-related nausea and vomiting in the majority of patients, investigation of smoked marijuana as a treatment for the minority of patients who vomit despite receiving the current best regimens (i.e., rescue therapy in refractory patients) might be an initial focus. Another line of investigation could be the efficacy of inhaled marijuana in delayed nausea and vomiting due to chemotherapy.</p><p></p><p>An add-on design in which smoked marijuana or placebo would be administered to incomplete responders to standard combination therapy would be appropriate. A dronabinol capsule group should also be included. Stratification should be done for naive versus experienced marijuana smokers. Nausea severity, vomiting prevention, and CNS effects assessments should be primary endpoints.</p><p></p><p>Inhaled marijuana merits testing in controlled, double-blind, randomized trials for the above indications.</p><p></p><p>References</p><p></p><p>Gralla, R.J.; Tyson, L.B.; Bordin, L.A.; Clark, R.A.; Kelsen, D.P.; Kris, M.G.; Kalman, L.B.; and Groshen, S. Antiemetic therapy: A review of recent studies and a report of a random assignment trial comparing metoclopramide with delta-9-tetrahydrocannabinol. Cancer Treat Rep 68(1):163-172, January 1984.</p><p></p><p>Italian Group for Antiemetic Research. Ondansetron versus granisetron, both combined with dexamethasone, in the prevention of cisplatin-induced emesis. Ann Oncol 6:805-810, 1995.</p><p></p><p>Kris, M.G.; Cubeddu, L.X.; Gralla, R.J.; Cupissol, D.; Tyson, L.B.; Venkatraman, E., and Homesley, H.D. Are more antiemetic trials with a placebo necessary? Report of patient data from randomized trials of placebo antiemetics with cisplatin. Cancer 78:2193-2198, 1996.</p><p></p><p>Levitt, M.; Faiman, C.; Hawks, R.; and Wilson, A. Randomized double-blind comparison of delta-9-tetrahydrocannabinol (THC) and marijuana as chemotherapy antiemetics. Proc Am Soc Clin Oncol 3:91, 1984.</p><p></p><p>Sallan, S.E.; Zinberg, N.E.; and Frei, III, E. Antiemetic effect of delta-9-tetrahydrocannabinol in patients receiving cancer chemotherapy. N Engl J Med 293:795-797, 1975.</p><p></p><p>Sallan, S.E.; Cronin, C.; Zelen, M.; and Zinberg, N.E. Antiemetics in patients receiving chemotherapy for cancer--a randomized comparison of delta-9-tetrahydrocannabinol and prochlorperazine. N Engl J Med 302:135-138, 1980.</p><p></p><p>Vinciguerra, V.; Moore, T.; and Brennan, E. Inhalation marijuana as an antiemetic for cancer chemotherapy. NY State Med J 88(10):525-527, October 1988.</p><p></p><p>Glaucoma</p><p></p><p></p><p>1. What research has been done and what is known about the possible medical uses of marijuana?</p><p></p><p>Marijuana is not generally accepted as a safe and effective treatment for glaucoma. The American Academy of Ophthalmology (1992) stated: "There is evidence that marijuana (or its components), taken orally or by inhalation can lower intraocular pressure. However, there are no conclusive studies to date to indicate that marijuana (or its components) can safely and effectively lower intraocular pressure enough to prevent optic nerve damage. . . . The dose of marijuana necessary to produce a clinically relevant effect in the short term appears to produce an unacceptable level of undesirable side effects such as euphoria, systemic hypotension, and/or dry eye and conjunctival hyperemia in the majority of glaucoma patients in whom the drug has been carefully studied. No data have been published on studies of long-term ocular and systemic effects of the use of marijuana by glaucoma patients.</p><p></p><p>". . . Because the possibility exists that marijuana (or its components) may be useful in treating glaucoma, the American Academy on Ophthalmology Committee on Drugs believes that a long term clinical study, designed to test the safety and efficacy of marijuana in the prevention of progressive optic nerve damage and consequent visual field loss, appears appropriate."</p><p></p><p>The National Eye Institute (1997) has recently stated much the same thing. "Studies in the early 1970s showed that marijuana, when smoked, lowers intraocular pressure in people with normal pressure and those with glaucoma. . . . However, none of those studies demonstrated that marijuana--or any of its components--could safely and effectively lower intraocular pressure any more than a variety of drugs then on the market. . . . [and] some potentially serious side effects were noted. . . . Research to date has not investigated whether marijuana use offers any advantages over currently available glaucoma treatments or if it is useful when used in combination with standard therapies. . . . [t]he National Eye Institute stands ready to evaluate any well-designed studies for treatment of eye diseases, including those involving marijuana for treatment of glaucoma."</p><p></p><p>The initial observation that smoked marijuana lowered intraocular pressure (IOP) in humans in acute experiments was made by Hepler and Frank in 1971. Hepler and Petrus (1976) later reported in greater detail that 4 percent (tetrahydrocannabinol (THC)) marijuana cigarettes lowered the IOP about 27 percent more than did a placebo at 30 minutes in normal volunteers, and that 20 mg of oral THC lowered the IOP about 17 percent more than placebo at 30 minutes. They also reported that smoked marijuana lowered IOP much more dramatically in patients with poorly controlled glaucoma, with 10 of 12 responding, and presented graphs showing the timecourse. One patient demonstrated a reduction from 40 mm Hg to 10 mm Hg in one eye and from 35 mm Hg to 15 mm Hg in the other. Since patients with severe glaucoma did not discontinue their current therapy (pilocarpine - 4 percent, epinephrine - 2 percent, or oral acetazolamide) Hepler and Petrus concluded that smoked marijuana or oral THC were additive to the then-known classes of therapeutic agents, and presumably worked by an independent mechanism (Hepler and Petrus 1976). In these short-term studies, lasting up to 4 hours, 2 cigarettes were as effective as 20 cigarettes, and intoxication occurred. Others confirmed that the marijuana could have a significant adjunctive effect in glaucoma patients, with Cuendet and colleagues reporting that 12/16 eyes of 10 patients had a reduction of 15 percent or more (Cuendet et al. 1976).</p><p></p><p>Flom and colleagues (1975) concluded that in normal volunteers in acute studies the lowering of IOP was proportional to the "high," and that experienced users who did not experience a "high" did not have a lowering of IOP. Merritt and colleagues (1980) studied the blood pressure (BP) and IOP of 18 glaucoma patients in short-term studies, which compared smoking a single 2 percent THC cigarette versus a placebo cigarette of the same smell and taste and concluded that the IOP was reduced by 4 mm Hg at 30 minutes and by 6 mm Hg at 90 minutes (in patients with either open-angle or synechial angle-closure glaucoma), returning to baseline by 4 hours with THC, while there was no change with the placebo, but that the pulse rose from 82 beats per minute (bpm) to 123 bpm at 15 minutes, and the systolic BP fell 11 mm Hg and diastolic BP fell 5 mm Hg, suggesting that reduced perfusion of the ciliary body accounted for the reduction in IOP and that the adverse systemic effects, including postural hypotension, would limit the potential usefulness of marijuana. Indeed, Merritt concluded in an editorial in the Journal of the National Medical Association (1982) that "Systemic delta-9 THC therapies invariably produce a decreased perfusion pressure to the eye. This decreased perfusion to an already damaged optic nerve may not be of long-term benefit to glaucoma victims." However, there are several anecdotal reports that, on continued use, tolerance develops to the undesirable cardiovascular and mood effects of marijuana, while tolerance does not develop to the beneficial effects on IOP in patients with glaucoma (Palmberg 1997).</p><p></p><p>Efforts to avoid systemic effects of THC in glaucoma treatment led to studies of topical preparations, such as 1 percent THC in peanut oil. However, no effect of the preparation on IOP was found by Jay and Green (1983).</p><p></p><p>Animal studies have yielded conflicting results about the mechanism of action of THC on the IOP. The studies by Green in rabbits suggested central effects mediated through the adrenergic nervous system (Green 1979), but the studies of Colasanti (1990) in cats indicated no effect of either sympathetic or parasympathetic denervation on the action of THC. She also found that THC has no effect on aqueous production in anesthetized cats, but rather increased aqueous outflow facility threefold.</p><p></p><p>The mechanism in humans has never been investigated by modern means, including fluorophotometry, coupled with the older method of tonography, which could yield clear information about the mechanism of action, whether on inflow, conventional outflow, or uveo-scleral outflow. In addition, it would now be possible to test the additivity of marijuana to a wide variety of agents now available, including beta-1 and beta-2 agonists and antagonists, alpha-2 agonists, dorzolamide, and latanoprost, to see whether or not THC works by a separate mechanism.</p><p></p><p>2. What are the major unanswered scientific questions?</p><p></p><p>Researchers do not know the mechanism of action of cannabis on IOP, given either as smoked marijuana or as oral THC.</p><p></p><p>Additional studies of long-term marijuana use are needed to determine if there are or are not important adverse pulmonary, central nervous system (CNS), or immune system problems.</p><p></p><p>It needs to be determined if smoked or eaten marijuana is more effective in lowering IOP on a chronic basis than THC alone, as marijuana advocates maintain on the basis of anecdotal experience, or if pure THC, without the particulates and carcinogens of marijuana smoke, could be inhaled by means other than smoking, or taken orally, with equal long-term effect on IOP.</p><p></p><p>Researchers do not know if marijuana would be additive to the new, very potent types of eyedrops now available to treat glaucoma, including alpha-2 agonists, dorzolamide and latanoprost (a prostaglandin that increases uveoscleral outflow and, like THC, causes conjunctival hyperemia). If marijuana were not to be additive to one of these agents, marijuana would be obsolete, since these agents have no systemic side effects (other than slightly dry mouth in some patients with apraclonidine and bromonidine), and they have a duration of action of 12 to 24 hours.</p><p></p><p>What are the diseases or conditions for which marijuana might have potential as a treatment and which merit further study?</p><p></p><p>Further studies to define the mechanism of action and to determine the efficacy of delta-9-tetrahydrocannabinol and marijuana in the treatment of glaucoma are justified.</p><p></p><p>In glaucoma, there does not appear to be any obvious reason to use smoked marijuana as a primary " stand alone" investigational therapy, as there are many available agents for treatment, and these topical preparations seem to be potentially ideal. An approach that may be useful is to study smoked marijuana in incomplete responders to standard therapies. The suggested design for clinical studies is to add marijuana, oral THC, or placebo to standard therapy under double-blind conditions. Studies proposed should consider the following measures:</p><p></p><p>* Establish dose-response and dose-duration relationships for IOP and CNS effects.</p><p></p><p></p><p>* Relate IOP and blood pressure measurements longitudinally to evaluate potential tolerance development to cardiovascular effects.</p><p></p><p></p><p>* Evaluate CNS effects longitudinally for tolerance development.</p><p></p><p></p><p></p><p>References</p><p></p><p>American Academy of Ophthalmology. "The Use of Marijuana in the Treatment of Glaucoma." Statement by the Board of Directors of the American Academy of Ophthalmology, PO Box 7424, San Francisco, CA, June 1992.</p><p></p><p>Colasanti, B.K. Review: Ocular hypotensive effect of marijuana cannabinoids: Correlate of central action or separate phenomenon? J Ocular Pharmacol 6(4):259-269, 1990.</p><p></p><p>Cuendet, J.F.; Saprio, D.; Calanca, A.; Faggioni, R.; and Ducrey, N. Action of delta-9-tetrahydrocannabinol on ophthalmotonus. Opthalmologica 172:122-127, 1976.</p><p></p><p>Flom, M.C.; Adams, A.J.; and Jones, R.T. Marijuana smoking and reduced pressure in human eyes: Drug action or epiphenomenon? Invest Ophthalmol 14(1):52-55, 1975.</p><p></p><p>Green, K. Marihuana in ophthalmology--past, present and future. (Editorial). Ann Ophthalmol 11(2):203-205, 1979.</p><p></p><p>Hepler, R.S., and Frank, I.R. Marijuana smoking and intraocular pressure. (Letter). JAMA 217:1392, 1971.</p><p></p><p>Hepler, R.S., and Petrus, R.J. Experiences with administration of marihuana to glaucoma patients. In: Cohen, S., and Stillman, R.C., eds. The Therapeutic Potential of Marihuana. New York: Plenum Medical Books, 1976. pp. 63-75.</p><p></p><p>Jay, W.M., and Green, K. Multiple-drop study of topically applied 1% delta 9-tetrahydrocannabinol in human eyes. Arch Ophthalmol 101(4):591-593, 1983.</p><p></p><p>Merritt, J.C. Glaucoma, hypertension, and marijuana. (Editorial). J Natl Med Assn</p><p></p><p>74(8):715-716, 1982.</p><p></p><p>Merritt, J.C.; Crawford, W.J.; Alexander, P.C.; Anduze, A.L.; and Gelbart, S.S. Effect of marihuana on intraocular and blood pressure in glaucoma. Ophthalmology 87(3):222-228, 1980.</p><p></p><p>National Eye Institute. "The Use of Marijuana for Glaucoma." Statement of the National Eye Institute of the National Institutes of Health, February 18, 1997.</p><p></p><p>Palmberg, P. Unpublished observations presented at the Workshop on the Medical Utility of Marijuana, National Institutes of Health, Bethesda, MD, February 20, 1997.</p><p></p><p>Appetite Stimulation/Cachexia</p><p></p><p></p><p>What research has been done and what is known about the possible medical uses of marijuana?</p><p></p><p>It has been shown that there is a strong relationship between smoking marijuana and increased frequency and amount of eating.</p><p></p><p>Survey data on appetite stimulation (Haines and Green 1970) (N = 131) showed that 91 percent of marijuana users eat every time they smoke. Tart (1970) found that 93 percent of marijuana users (131) reported that marijuana made them enjoy eating very much and that they consequently ate a lot more. Foltin and colleagues (1986) reported that marijuana users eat more often. A study by Farrow and associates (1987) reported no hematologic changes or signs of nutrient deficiencies in marijuana users.</p><p></p><p>Marijuana is reported to enhance the sensory appeal of foods. Taste does not seem to be altered as measured by indexes of sourness (citric acid in lemonade), saltiness (NaCl in tomato juice), sweetness (sucrose in cherry-flavored drink), and bitterness (urea in tonic water). There does not appear to be impairment in the normal satiety mechanisms following marijuana ingestion.</p><p></p><p>Foltin and colleagues (1988) saw signs of a general increase in food intake on smoked marijuana days versus placebo days. The effect may not persist over an extended period of time, but long-term studies have not been done. Setting is important in appetite enhancement and social settings contribute heavily. Williams and associates (1946) did a chronic dosing study. They found that body weight went up and stayed up, possibly due to an effect of marijuana on fluid retention. Greenberg and colleagues (1976) saw a sharp increase in food intake followed by a leveling off. The increase in body weight may reflect a reduction in energy expenditure.</p><p></p><p>Food intake was greater after smoking, compared to oral and sublingual administration, but there was much individual variability. Marijuana seems to enhance appetite in the evening, whereas many cancer patients report having most of their appetite in morning. This would suggest a potential complementary use of marijuana.</p><p></p><p>Cachexia or wasting due to HIV infection is increasingly prevalent in the era of effective prophylaxis for Pneumocystis carinii pneumonia (Hoover et al. 1993). Significant weight loss, more than 20 percent of ideal body weight, is associated with shortened survival of HIV-infected patients (Kotler et al. 1989). The major causes of weight loss in HIV-infected patients are opportunistic infections, enteric infections associated with malabsorption, and reduced caloric intake. The latter is the most important cause of wasting in the absence of opportunistic infections and malabsorption (MacCallan et al. 1995).</p><p></p><p>Administration of the appetite stimulants megestrol acetate (VonRoenn et al. 1994) and dronabinol (Gorter et al. 1992) is associated with weight gain in HIV-infected patients. Anabolic steroids and recombinant human growth hormone produce an increase in lean body mass (Mulligan et al. 1993). In published studies, the weight gain produced by appetite stimulants or hormonal therapy has not been shown to be associated with an improved immunologic status or clinical outcome. All investigations, however, have been relatively short, 12 to 24 weeks in length. Although there is much anecdotal evidence of weight gain produced by use of smoked marijuana, no objective data relative to body composition alterations, HIV replication, or immunologic function in HIV-infected patients are available. An epidemiologic study demonstrated no alteration in the natural history of HIV infection with use of smoked marijuana (Kaslow et al. 1989), although other investigations in uninfected volunteers and animal models indicated that there are effects on components of the immune system. There have been no recent published studies of the impact of smoked marijuana on the immune system in HIV-infected patients using state-of-the-art immunologic assays.</p><p></p><p>Megestrol acetate (Oster et al. 1994, VonRoenn et al. 1994) produces weight gain that is predominantly fat, with very little increase in lean body mass. Dronabinol (9-THC) has been studied in patients with cancer (Nelson et al. 1994; Plasse et al. 1991) and AIDS (Gorter et al. 1992), who showed increased weight gain.</p><p></p><p>Beal and colleagues (1995) studied dronabinol as treatment for anorexia associated with weight loss in patients with AIDS. A significant increase in appetite was seen with a decrease in nausea, and a mood increase that was not significant. The 6-week study may have been too short to fully capture the effects of dronabinol.</p><p></p><p>In a survey looking at physicians' choice of drugs to treat wasting, the first line choice of 80 percent of the care providers was megestrol with dronabinol being used by 54 percent. Dronabinol was also the second line choice of most providers.</p><p></p><p>Problems that have been identified with dronabinol are that patients feel "too stoned"; are unable to titrate their dose properly; note delayed onset of effect, prolonged duration of effect, or problems with malabsorption; and "not the same feeling as smoked marijuana."</p><p></p><p>Several panelists pointed out that the weight gain is primarily an accumulation of water (sometimes of fat), but not of lean body mass. On the other hand, oncologists heard from patients with advanced cancer that increased appetite and weight gain are psychologically helpful, regardless of the nature of the added weight, and regardless of the impact (if any) on survival. Panelists also commented that very likely weight loss is an indicator rather than a cause of impending death.</p><p></p><p>2. What are the major unanswered scientific questions?</p><p></p><p>Some questions that need to be answered in future studies are:</p><p></p><p>Does smoking marijuana increase total energy intake in patients with catabolic illness?</p><p></p><p>Does marijuana use alter energy expenditure?</p><p></p><p>Does marijuana use alter body weight, and to what extent?</p><p></p><p>Does marijuana use alter body composition, and to what extent?</p><p></p><p>So far, it has not been shown that reversing wasting changes mortality risk. Another question is whether weight gain is associated with positive changes in psychological status. It seems related but has not been systematically addressed.</p><p></p><p>3. What are the diseases or conditions for which marijuana might have potential as a treatment and which merit further study?</p><p></p><p>Areas of study for the potential appetite-stimulating properties of marijuana include the cachexia of cancer, HIV/AIDS symptomatology, and other wasting syndromes. With an appropriate delivery system designed to minimize the health risks of smoking, studies of the appetite-stimulating potential of cannabinoids are justified. Such investigations should be designed to assess long-term effects on immunologic status, the rate of viral replication, and clinical outcomes in participants as well as weight gain.</p><p></p><p>In therapeutic trials for cachexia, research should attempt to separate out the effect of marijuana on mood versus appetite. Complex interactions likely are involved.</p><p></p><p>References</p><p></p><p>Beal, J.E.; Olson, D.O.; Laubenstein, L.; et al. Dronabinol as a treatment for anorexia associated with weight loss in patients with AIDS. J Pain Symptom Manage 10:89-97, 1995.</p><p></p><p>Farrow, J.A.; Rees, J.M.; and Worthington-Roberts, B.S. Health, developmental, and nutritional status of adolescent alcohol and marijuana abusers. Pediatrics 79:218, 1987.</p><p></p><p>Foltin, R.W.; Brady, J.V.; and Fischman, M.W. Pharmacol Biochem Behav 25:577-582, 1986.</p><p></p><p>Foltin, R.W.; Fischman, M.W.; and Byrne, M.F. Effects of smoked marijuana on food intake and body weight of humans living in a residential laboratory. Appetite 11:1-14, 1988.</p><p></p><p>Gorter, R.; Seifried, M.; and Volberding, P. Dronabinol effects on weight in patients with HIV infection. AIDS 6:127, 1992.</p><p></p><p>Greenberg, I.; Kuehnle, J.; Mendelson, J.H.; and Bernstein, J.G. Effects of marijuana use on body weight and caloric intake in humans. Psychopharmacology 49:79-84, 1976.</p><p></p><p>Haines, L., and Green, W. Marijuana use patterns. Br J Addict 65:347, 1970.</p><p></p><p>Hoover, D.R.; Saah, A.J.; Bacellar, H.; et al. Clinical manifestations of AIDS in the era of Pneumocystis prophylaxis. Multicenter AIDS Cohort Study. N Engl J Med 329:1922-1929, 1993.</p><p></p><p>Kaslow, R.A.; Blackwelder, W.C.; Ostrow, D.G.; et al. No evidence for a role of alcohol or other psychoactive drugs in accelerating immunodeficiency in HIV-1-positive individuals: A report from the Multicenter AIDS Cohort Study. JAMA 26:3424-3429, 1989.</p><p></p><p>Kotler, D.P.; Tierney, P.R.; Wang, J.; and Pierson, R.N., Jr. The magnitude of body cell mass depletion determines the timing of death from wasting in AIDS. Am J Clin Nutr 50:444-447, 1989.</p><p></p><p>MacCallan, D.C.; Noble, C.; Baldwin, C.; et al. Energy expenditure and wasting in human immunodeficiency virus infection. N Engl J Med 333:83-88, 1995.</p><p></p><p>Mulligan, K.; Grunfeld, C.; Hellerstein, M.K.; et al. Anabolic effects of recombinant human growth hormone in patients with wasting associated with human immunodeficiency virus infection. J Clin Endocrinol Metab 77:956-962, 1993.</p><p></p><p>Nelson, K.; Walsh, D.; Deeter, P.; and Sheehan, F. A phase II study of delta-9-tetrahydrocannabinol for appetite stimulation in cancer-associated anorexia (Review). J Palliat Care 10(1):14-18, Spring 1994.</p><p></p><p>Oster, M.H.; Enders, S.R.; Samuels, S.J.; Cone, L.A.; et al. Megestrol acetate in patients with AIDS and cachexia. Ann Intern Med 121:400-408, 1994.</p><p></p><p>Plasse, T.F.; Gorter, R.W.; Krasnow, S.H.; Lane, M.; Shepard, K.V.; and Wadleigh, R.G. Recent clinical experience with dronabinol. Pharmacol Biochem Behav 40:695-700, 1991.</p><p></p><p>Tart, C.T. Marijuana intoxication: Common experiences. Nature 226:701, 1970.</p><p></p><p>VonRoenn, J.; Armstrong, D.A.; Kotler, D.P.; et al. Megestrol acetate in patients with AIDS-related cachexia. Ann Intern Med 121:393-399, 1994.</p><p></p><p>Williams, E.G.; Himmelsbach, C.K.; Wikler, A.; and Rudle, D.C. Studies on marihuana and pyrahexyl compound. Publ Health Rep 61(29):1059, July 19, 1946.</p><p></p><p>Question 4.</p><p>What Special Issues Have To Be Considered in Conducting</p><p>Clinical Trials of the Therapeutic Uses of Marijuana?</p><p></p><p></p><p>Benefit and Risk Considerations</p><p></p><p>There are a number of guidelines and specific issues related to smoked marijuana that are important in planning trial designs and carrying out clinical studies. The current state of knowledge regarding the efficacy of smoked marijuana for a given disease/condition should be taken into account in designing clinical protocols. Investigators should give consideration to the range of potential questions that could be addressed and propose to address the most pertinent question(s) with the most appropriate study designs. This strategy should enhance the possibility of National Institutes of Health (NIH) funding support. In some instances, the initial question to be addressed may be whether smoked marijuana is efficacious in the treatment/management of a clinical condition. Such a proposed study may be a validation of clinical anecdotes or be proposed from basic research findings that suggest a potential benefit. In either case, the question should be formulated as a testable hypothesis. In other instances, the more germane question may be whether smoked marijuana possesses specific advantages over dronabinol capsules or other pharmacological therapies, has additional therapeutic effects in combination with standard therapies, has benefit in patients refractory to standard medications, or has benefit primarily in marijuana-experienced patients.</p><p></p><p>The risks of concern associated with the investigational use of marijuana differ depending on the patient populations being studied and with the proposed duration of administration. For example, there is a different level of risk of developing bacterial pneumonia associated with marijuana administration to immune-compromised patients compared with nonimmune-compromised subjects. On the other hand, some risks may decrease with continued use due to the rapid tolerance development to certain central nervous system (CNS) and cardiovascular effects of marijuana. Marijuana-experienced subjects may already have some level of tolerance to certain effects. Hence, it is critical to consider the side effects of marijuana, the proposed duration of administration, the previous and current level of marijuana use in the proposed study population, and any additional risks that may be conferred by the disease status of the population in the assessment of risks and the appropriate type and frequency of safety monitoring. Concerns regarding the long-term risks associated with smoking are less important in conditions where short-term use is being proposed or patients are terminally ill. However, such risks are of concern for conditions where chronic administration of smoked marijuana is likely. Regardless of whether short-term or long-term use is being studied, all clinical trials must monitor side effects.</p><p></p><p>Study Design Considerations</p><p></p><p>Beyond the benefit and risk considerations, there are some general and specific study design issues regarding the evaluation of the therapeutic effects of smoked marijuana.</p><p></p><p>There are two basic types of control groups to be considered in designing studies of the medical use of smoked marijuana: placebo control and active control groups. A placebo control is important in studying clinical conditions where there is no known effective therapy. Placebo controls are also desirable in studies where the question is whether smoked marijuana is effective or whether it is equivalent to another drug, and many study designs utilize both placebo and active control groups. This allows a determination as to whether a valid conclusion can be drawn about the efficacy of the test drug by providing a measure of assay sensitivity for the study; i.e., did any treatment show superiority to placebo. This design also allows comparison of marijuana with a standard therapy. If an effective standard treatment exists, there are conditions such as chemotherapy-related nausea and vomiting in which it would be unethical to include a placebo control group. On the other hand, in single-dose analgesic studies a placebo group can be incorporated in the design if appropriate provision is made for administration of a "rescue" analgesic if the study medication proves ineffective. Adding a placebo group increases the complexity of the study design and the number of subjects required and presents ethical questions that must be confronted and answered on a study-by-study basis, but a study without a placebo group may yield uninterpretable results unless some other measure of assay sensitivity is incorporated in the study.</p><p></p><p>If smoked marijuana is being compared to a standard of care, placebo may not be needed if objective endpoints are being measured; e.g., number of vomiting episodes per day. Since many of the potential therapeutic uses of marijuana involve the use of the drug as an "add on" or adjunctive therapy administered concomitantly with a standard therapeutic regimen, a practical strategy for avoiding a placebo group is to administer the standard therapy to all patients in the study, and in addition administer marijuana to half the patients and a placebo marijuana to the other half. In that way, no patient would be deprived of standard effective therapy.</p><p></p><p>Some investigations address whether an effect is dose related. This type of design allows for the assessment of the dose range that produces therapeutic effects and the relationship between these effects and dose-related side effects. Although these designs do not exclude the addition of placebo groups, a placebo is often not used because the determination of a positive dose-response curve for an effect provides an internal measure of assay sensitivity. An obvious difficulty with this type of design for smoked marijuana is the inability to standardize dose delivery due to the inherent variability associated with pulmonary administration. One possible design is to compare self-titrated smoking with several fixed doses of THC capsules.</p><p></p><p>Selection of Patient Population</p><p></p><p>The selection of the patient population to be studied, and the inclusion /exclusion criteria for the defined population, are another critical set of decisions. Design choices include patients who are the general population of patients with the disorder, or one of the following groups: nonresponders or incomplete responders to other therapies, patients selected in open-trial designs who responded to marijuana, and naive versus experienced marijuana smokers.</p><p></p><p>One proposed strategy, selecting subsets responsive to marijuana in an open manner (i.e., "enrichment design"), assumes that there may be subpopulations that are difficult to recognize, except on the basis of their prior putative response to marijuana. Once identified, such patients are randomly assigned to a study drug or control group and are evaluated in a prospective manner. This approach is useful in situations where responses are variable and/or modest, making it difficult to demonstrate an effect, and where it would be of interest to know if a drug was useful even in a subset of the patient population. However, the limitation of this approach is the difficulty of estimating the size of the population to which study results can be generalized.</p><p></p><p>Single-patient (N = 1) studies utilize multiple periods of a study drug-control, within-subject, crossover design. Evidence of efficacy in single patients can be determined in such designs, although carryover effects from the long plasma half-life of cannabinoids may confound interpretation of results.</p><p></p><p>Blinding or Masking Treatment Assignments</p><p></p><p>The issue of "blinding" or "masking" marijuana cigarettes was discussed at some length. Blinding may be difficult, even with identical-looking placebo cigarettes. Experienced marijuana users may be able to discern from the subjective effects whether they received active or placebo cigarettes. Nonetheless, there should be an effort to mask treatment assignment from both the patient and investigator, i.e., the double-blind technique. The effectiveness of blinding can be evaluated to some extent by querying patients after the study about their guess as to the identity of their treatment. In order to maintain double-blind conditions when comparing smoked marijuana with a control treatment in tablet or capsule form, a double-dummy technique is used. The marijuana treatment group would receive active marijuana plus dummy tablets or capsules, while the control group would receive dummy marijuana (i.e., with little or no THC) plus active tablets or capsules.</p><p></p><p>Selection of Clinical Endpoints</p><p></p><p>The choice of clinical endpoints for evaluation of potential efficacy should be guided by the desire to obtain objective data, if such endpoints can be obtained and are clinically relevant. Examples of such endpoints would be the number of vomiting episodes associated with a particular chemotherapy, intraocular pressure (IOP) measurements in glaucoma trials, and weight gain and percent changes in body composition in AIDS-wasting syndrome studies. The frequency of measurements should be dictated by the clinical condition being studied.</p><p></p><p>While blinding may not be as important in studies with clear objective endpoints, some potential indications for marijuana are in conditions that involve subjective responses, e.g., treating the symptoms and improving the quality of life in very sick or dying patients. Scientific evidence can be generated on the basis of subjective responses. These therapeutic areas should not be avoided on the grounds that studies involving objective endpoints would be easier to quantitate or would be more immune to bias.</p><p></p><p>Because of the importance of the questions of the medical utility of marijuana and the inherent difficulties in designing a definitive study with clinically important endpoints, a mechanism could be considered, such as a forum where experts in the subject areas and experts in clinical trial methodology, Government scientists, and applicable physicians and patients could engage in dialog regarding appropriate study designs prior to their adoption.</p><p></p><p>Possible Role of the NIH in Facilitating Clinical Evaluation of the Medical Utility of Marijuana</p><p></p><p>There are several mechanisms whereby the NIH can facilitate clinical trials with marijuana.</p><p></p><p>Adequate supplies of marijuana of various and consistent strengths and placebos should be made available to investigators. The NIH should consider using its facilities and influence to assure the availability of comparator compounds and appropriate placebos (e.g., active and identical placebo amitriptyline tablets to permit a randomized trial versus smoked marijuana/smoked marijuana placebo for the control of neuropathic pain).</p><p></p><p>Because of the broad range of potential uses of marijuana cutting across many NIH Institutes, a centralized mechanism should be considered to facilitate the design, approval, and conduct of trials supported by the NIH. Consideration should be given to supporting mechanisms whereby experts in multiple areas and physicians and patients could engage in dialog regarding study designs prior to their commencement. In addition, to permit the most rapid and accurate determination of marijuana's medical utility, the NIH should coordinate with efforts in individual States and by research organizations also conducting peer-reviewed research studying marijuana (e.g., American Cancer Society, Multiple Sclerosis Society). The NIH should also work closely with the Drug Enforcement Administration (DEA) and the U.S. Food and Drug Administration (FDA) to ensure that FDA regulations are followed and that clinical trials supported are adequate for submission as part of an FDA approval package should marijuana prove effective for a particular indication.</p><p></p><p>The NIH should use its resources and influence to rapidly develop a smoke-free inhaled delivery system for marijuana or THC. This effort will remove a significant health hazard during clinical testing and future potential use. This will also bring this research effort in line with other Government initiatives to curtail cigarette smoking, the number-one preventable cause of premature death and disability in America. Until this is done, the testing of smoked marijuana would be difficult in smoke-free healthcare and municipal facilities. In addition, study of smoked marijuana in private facilities such as community medical offices or patients' homes, where smoking is not prohibited, would still present an environmental hazard of secondhand smoke for healthcare workers and family members. "Taking the smoke" out of an inhaled dosage form of marijuana or THC would remove an important obstacle to the accurate determination of inhaled marijuana's beneficial and deleterious effects.</p><p></p><p>Appendix: The Effect of Controlled Substances Scheduling on Marijuana Research</p><p></p><p></p><p>(Although not discussed at the meeting, this section is provided as background regarding research with Schedule I substances.)</p><p></p><p>In addition to the requirements of the U.S. Food and Drug Administration (FDA) and sponsoring organizations such as the National Institutes of Health (NIH) concerning the conduct of clinical research, U.S. investigators are subject to specific FDA and Drug Enforcement Agency (DEA) regulations concerning research with controlled substances. Under the Controlled Substances Act (21 USC 822 (a)(1)) and implementing DEA regulations, persons conducting clinical research with any controlled substance must register with the DEA, keep specific types of records, and periodically report to the DEA. Marijuana is currently classified at the highest (most restrictive) level as a Schedule I drug (no accepted medical use, high potential for abuse). Attempts by various petitioners to have marijuana rescheduled have not been successful.</p><p></p><p>Therefore, there is at least one extra layer (many States have their own laws modeled after the Controlled Substances Act (CSA), which add further complexity) for any investigator undertaking clinical trials with controlled substances. In the case of research conducted under an Investigational New Drug Application (IND), recordkeeping requirements are exempt from the CSA but must be kept in accordance with the Food, Drug and Cosmetic Act (FDCA). Under the FDCA, a sponsor or investigator must make its records concerning shipment, delivery, receipt, and disposition available for inspection and copying at DEA's request. Additionally, FDA regulations require that sponsors and investigators conducting clinical trials take special precautions to prevent diversion, including storage in a secure place with limited access. In the case of some investigator sites, this may require acquisition of a safe and/or other physical space changes and/or procedures to insure security and accountability of the substance.</p><p></p><p>The CSA also mandates reporting procedures when conducting research with controlled substances. A DEA registration for controlled substances also authorizes (within specified limits) the manufacture and distribution of the substances. If a researcher engages in manufacture or distribution, then he or she is held to the reporting standard of manufacturers and distributors. Presumably, the manufacturer/distributor reporting requirements would not apply in most studies, as the source of marijuana would be the National Institute on Drug Abuse (NIDA) and most studies would not be using the plant material to manufacture other forms or products.</p><p></p><p>Where research studies of Schedule I substances are not conducted under an IND, the DEA requires a copy of the research protocol be submitted for approval and identify in the registration applications the extent to which the research will involve manufacture or importation. Where research is conducted under an IND, however, the sponsor need only provide the DEA with a copy of the IND and a statement of security precautions. The FDA has ultimate authority to decide whether the research may proceed either under its jurisdiction over INDs (FDCA) or in the case of non-IND research, under the CSA (21CFR1301.42). Where non-IND research is undertaken, the FDA must consult with the DEA concerning the adequacy of the applicant's diversion control procedures. If a researcher desires to increase the amount of Schedule I material it has previously received permission to use, it must apply to the DEA for the increase, and the DEA will forward the request to the FDA for approval/denial, taking into account DEA comments on the adequacy of the researcher's security against diversion control.</p><p></p><p>Some States may have their own registration requirements for Schedule I substances above and beyond the Federal requirements. Each researcher must check his or her own State authorities to see if other regulatory requirements need to be met. Given the small amounts of research material used by researchers in comparison to the additional regulatory burden and time delays, many researchers have been discouraged from pursuing research with these substances. Indeed, one of the recommendations of the Institute of Medicine Report entitled The Development of Medications for the Treatment of Opiate and Cocaine Addictions: Issues for the Government and Private Sector (National Academy Press, Washington, DC 1995, pp. 168-171) was that the current regulatory system be modified to remove barriers to undertaking clinical research with controlled substances.</p><p></p><p>Ad Hoc Group of Experts</p><p></p><p></p><p>William T. Beaver, M.D.</p><p>Professor Emeritus of</p><p>Pharmacology and Anesthesia</p><p>Georgetown University School of Medicine</p><p>Washington, DC</p><p></p><p></p><p>Julie Buring, Sc.D.</p><p>Associate Professor of Preventive Medicine</p><p>Harvard Medical School</p><p>and</p><p>Deputy Director</p><p>Division of Preventive Medicine</p><p>Brigham and Women's Hospital</p><p>Boston, MA</p><p></p><p></p><p>Kobaja Goldstein, M.D.</p><p>Professor Emeritus of Pharmacology</p><p>Stanford University</p><p>Stanford, CA</p><p></p><p></p><p>Kenneth Johnson, M.D.</p><p>Professor and Chairman</p><p>Department of Neurology</p><p>University of Maryland Hospital</p><p>Baltimore, MD</p><p></p><p></p><p>Reese Jones, M.D.</p><p>Professor of Psychiatry</p><p>Langley Porter Psychiatric Institute</p><p>University of California, San Francisco</p><p>San Francisco, CA</p><p></p><p></p><p>Mark G. Kris, M.D.</p><p>Attending Physician</p><p>Memorial Sloan-Kettering Cancer Center</p><p>and</p><p>Professor of Medicine</p><p>Cornell University Medical College</p><p>New York, NY</p><p></p><p></p><p>Kathi Mooney, Ph.D.</p><p>Program Director</p><p>Graduate Programs in Oncology</p><p>Nursing</p><p>and</p><p>Professor</p><p>University of Utah College of Nursing</p><p>Salt Lake City, UT</p><p></p><p></p><p>Paul Palmberg, M.D., Ph.D.</p><p>Professor of Ophthalmology</p><p>Bascom-Palmer Eye Institute</p><p>University of Miami School of Medicine</p><p>Miami, FL</p><p></p><p></p><p>John Phair, M.D.</p><p>Professor of Medicine</p><p>Northwestern University Medical School</p><p>Chicago, IL</p></blockquote><p></p>
[QUOTE="iz0t0p, post: 2748, member: 420"] [u]nastavak[/u] Use of Marijuana in Neurological and Movement Disorders 1. What research has been done and what is known about the possible medical uses of marijuana? There have been numerous studies both in animals and in various clinical states on the use of cannabinoids on neurological and various movement disorders. These results range from anecdotal reports to surveys and clinical trials. Marijuana or tetrahydrocannabinol (THC) is reported to have some antispasticity, analgesic, antitremor, and antiataxia actions, as well as some activity in multiple sclerosis (MS) and in spinal cord injury patients. The spasticity and nocturnal spasms produced by MS and partial spinal cord injury have been reported to be relieved by smoked marijuana and to some extent by oral THC in numerous anecdotal reports. The effect seems to appear rapidly with smoked marijuana; patients are able to titrate the dose by the amount they smoke. No large-scale controlled studies or studies to compare either smoked or oral THC with other available therapies have been reported. Several relatively good therapeutic alternatives exist. There is no published evidence that the cannabinoid drugs are superior or even equivalent. Substantial experimental animal literature exists showing that various cannabinoids, given primarily by parenteral routes, have a substantial anticonvulsant effect in the control of various models of epilepsy, especially generalized and partial tonic-clonic seizures. Scant information is available about the human experience with the use of marijuana or cannabinoids for the treatment of epilepsy. This is an area of potential value, especially for cannabis therapies by other than the smoked route. Several single case histories have been reported indicating some benefit of smoked marijuana for dystonic states. It must be remembered that dystonia is a clinical syndrome with numerous potential causes, and the information available now does not differentiate which causes are most likely to be improved. Smoked marijuana and oral THC have been tested in the treatment of Parkinson's disease and Huntington's chorea without success. The cannabinoids also have been used as experimental immunologic modifiers to treat such conditions as the animal models of experimental allergic encephalomyelitis (EAE) and neuritis. Parenteral cannabinoids have been successful in modifying EAE in animals, suggesting that cannabinoids may be of value in a more fundamental way by altering the root cause of a disease such as MS rather than simply treating its symptoms. Smoked marijuana would not be acceptable for such a role because of the variability of dose with the smoked route. 2. What are the major unanswered scientific questions? The discovery of dedicated systems of central nervous system (CNS) neurons approximately 8 years ago, which express receptors specific for the cannabinoids, is of major scientific interest and importance. The distribution of these cannabinoid receptor-bearing neurons corresponds well with the clinical effects of smoked marijuana; for instance, their presence in the forebrain may relate to adverse changes in short-term memory, but perhaps positively in the control of epilepsy. Cannabinoid receptors in the brainstem and cerebellum may relate to the recognized incoordination that accompanies smoked marijuana use. The discovery of intrinsic ligands for these receptors in the mammalian brain is also of great importance. This system of cannabinoid receptors and ligands may be analogous to the discovery of opiate receptors and endorphins, which linked various opium derivatives (heroin and morphine) to an intrinsic system of neurons in the CNS. That discovery was of major importance for pain research. The major unanswered scientific questions are: * How useful is smoked marijuana of known specific potency in controlling various neurologic conditions? * In comparative studies, how useful is smoked marijuana in altering objective abnormalities such as spasticity versus current standard therapies that have already been approved for human use? * Can alternative delivery systems (other than the oral route) be developed to provide rapidity of action with more safety than smoked marijuana? * Can available or newly developed synthetic cannabinoids be used more effectively to stimulate or block receptor activity in the cannabinoid system of the CNS? * What are the immune-modulating characteristics of the cannabinoids and can they be used for therapeutic human benefit? * Can the long-term risks of daily smoked marijuana be quantified so that useful risk versus benefit ratios can be determined, especially when considering treatment of long-term conditions such as spasticity or epilepsy? 3. What are the diseases or conditions for which marijuana might have potential as a treatment and which merit further study? Marijuana or the use of other cannabinoids as human therapies might be considered for treating spasticity and nocturnal spasms complicating MS and spinal cord injury, for various active epilepsy states, for some forms of dystonia, and perhaps most interestingly, for treating neuropathic pain (Zeltser et al. 1991). (Also see the chapter titled Analgesia.) Neuropathic pain complicates many CNS diseases. Few available therapies provide even partial relief. Reference Zeltser, R.; Seltzer, Z.; Eisen, A.; Feigenbaum, J.J.; and Mechoulam, R. Suppression of neuropathic pain behavior in rats by a non-psychotropic synthetic cannabinoid with NMDA receptor-blocking properties. Pain 47(1):95-103, October 1991. Nausea and Vomiting 1. What research has been done and what is known about the possible medical uses of marijuana? There is a large body of clinical research on the use of cannabinoids for chemotherapy-related nausea and vomiting. Most of this work was conducted during the early 1980s. The majority of reports deal with oral dronabinol rather than smoked marijuana. These studies demonstrated that dronabinol was superior to placebo in controlling nausea and vomiting caused by chemotherapy that induces a moderate amount of emesis (Sallan et al. 1975). Several studies compared oral dronabinol with prochlorperazine (Sallan et al. 1980). Mixed results were reported from these studies, but generally dronabinol was found equivalent. Gralla and colleagues (1984) examined metoclopramide versus dronabinol in patients given cisplatin in a randomized double-blind trial. These investigators reported poorer antiemetic control and more side effects with dronabinol than with the metoclopramide. None of these studies compared oral dronabinol or smoked marijuana with what are now considered the most effective antiemetic regimens, the combination of a specific serotonin antagonist (like ondansetron, granisetron, or dolasetron) plus dexamethasone, which were introduced in the early 1990s. This combination has demonstrated complete protection from vomiting during the initial 24 hours after cisplatin (the most potent emetic stimulus) in 79 percent of patients treated (Italian Group for Antiemetic Research 1995). Without antiemetic protection, 98 percent of similar patients vomit a median of six times within the first 24 hours alone after cisplatin (Kris 1996). Side effects of these newer antiemetic regimens are negligible and would permit a patient to drive or return to his or her job immediately after receiving chemotherapy. Only two clinical trials have formally addressed the effectiveness of smoked marijuana. Levitt and colleagues (1984) conducted a random-order assignment crossover study comparing smoked marijuana and dronabinol in 20 subjects, 15 men and 5 women. Twenty-five percent of the subjects were free of vomiting and 15 percent were free of nausea. As to individual preference for the route of administration, 45 percent of the patients had no preference, 35 percent preferred oral dronabinol, and 20 percent preferred smoked marijuana. Vinciguerra and colleagues (1988) studied smoked marijuana in an open trial in 74 patients who previously had no improvement with standard antiemetic agents. Nearly 25 percent of patients who initially consented to participate later refused treatment citing bias against smoking, harshness of smoke, and preference for oral dronabinol. Of the remaining 56 patients, 18 (34 percent) rated it very effective and 26 (44 percent) moderately effective. Twelve (22 percent) noted no benefit. Sedation occurred in 88 percent, dry mouth in 77 percent, and dizziness in 39 percent. Only 13 percent were free of adverse effects. 2. What are the major unanswered scientific questions? No scientific questions have been definitively answered about the efficacy of smoked marijuana in chemotherapy-related nausea and vomiting. A comparison of the efficacy of smoked marijuana versus oral dronabinol would also be of interest. In addition, further information on appropriate dosage and frequency, side effects, tolerability, and patient acceptability for smoked marijuana would need to be established. 3. What are the diseases or conditions for which marijuana might have potential as a treatment and which merit further study? Inhaled marijuana has the potential to improve chemotherapy-related nausea and vomiting. Because the combination of a serotonin antagonist plus dexamethasone prevents chemotherapy-related nausea and vomiting in the majority of patients, investigation of smoked marijuana as a treatment for the minority of patients who vomit despite receiving the current best regimens (i.e., rescue therapy in refractory patients) might be an initial focus. Another line of investigation could be the efficacy of inhaled marijuana in delayed nausea and vomiting due to chemotherapy. An add-on design in which smoked marijuana or placebo would be administered to incomplete responders to standard combination therapy would be appropriate. A dronabinol capsule group should also be included. Stratification should be done for naive versus experienced marijuana smokers. Nausea severity, vomiting prevention, and CNS effects assessments should be primary endpoints. Inhaled marijuana merits testing in controlled, double-blind, randomized trials for the above indications. References Gralla, R.J.; Tyson, L.B.; Bordin, L.A.; Clark, R.A.; Kelsen, D.P.; Kris, M.G.; Kalman, L.B.; and Groshen, S. Antiemetic therapy: A review of recent studies and a report of a random assignment trial comparing metoclopramide with delta-9-tetrahydrocannabinol. Cancer Treat Rep 68(1):163-172, January 1984. Italian Group for Antiemetic Research. Ondansetron versus granisetron, both combined with dexamethasone, in the prevention of cisplatin-induced emesis. Ann Oncol 6:805-810, 1995. Kris, M.G.; Cubeddu, L.X.; Gralla, R.J.; Cupissol, D.; Tyson, L.B.; Venkatraman, E., and Homesley, H.D. Are more antiemetic trials with a placebo necessary? Report of patient data from randomized trials of placebo antiemetics with cisplatin. Cancer 78:2193-2198, 1996. Levitt, M.; Faiman, C.; Hawks, R.; and Wilson, A. Randomized double-blind comparison of delta-9-tetrahydrocannabinol (THC) and marijuana as chemotherapy antiemetics. Proc Am Soc Clin Oncol 3:91, 1984. Sallan, S.E.; Zinberg, N.E.; and Frei, III, E. Antiemetic effect of delta-9-tetrahydrocannabinol in patients receiving cancer chemotherapy. N Engl J Med 293:795-797, 1975. Sallan, S.E.; Cronin, C.; Zelen, M.; and Zinberg, N.E. Antiemetics in patients receiving chemotherapy for cancer--a randomized comparison of delta-9-tetrahydrocannabinol and prochlorperazine. N Engl J Med 302:135-138, 1980. Vinciguerra, V.; Moore, T.; and Brennan, E. Inhalation marijuana as an antiemetic for cancer chemotherapy. NY State Med J 88(10):525-527, October 1988. Glaucoma 1. What research has been done and what is known about the possible medical uses of marijuana? Marijuana is not generally accepted as a safe and effective treatment for glaucoma. The American Academy of Ophthalmology (1992) stated: "There is evidence that marijuana (or its components), taken orally or by inhalation can lower intraocular pressure. However, there are no conclusive studies to date to indicate that marijuana (or its components) can safely and effectively lower intraocular pressure enough to prevent optic nerve damage. . . . The dose of marijuana necessary to produce a clinically relevant effect in the short term appears to produce an unacceptable level of undesirable side effects such as euphoria, systemic hypotension, and/or dry eye and conjunctival hyperemia in the majority of glaucoma patients in whom the drug has been carefully studied. No data have been published on studies of long-term ocular and systemic effects of the use of marijuana by glaucoma patients. ". . . Because the possibility exists that marijuana (or its components) may be useful in treating glaucoma, the American Academy on Ophthalmology Committee on Drugs believes that a long term clinical study, designed to test the safety and efficacy of marijuana in the prevention of progressive optic nerve damage and consequent visual field loss, appears appropriate." The National Eye Institute (1997) has recently stated much the same thing. "Studies in the early 1970s showed that marijuana, when smoked, lowers intraocular pressure in people with normal pressure and those with glaucoma. . . . However, none of those studies demonstrated that marijuana--or any of its components--could safely and effectively lower intraocular pressure any more than a variety of drugs then on the market. . . . [and] some potentially serious side effects were noted. . . . Research to date has not investigated whether marijuana use offers any advantages over currently available glaucoma treatments or if it is useful when used in combination with standard therapies. . . . [t]he National Eye Institute stands ready to evaluate any well-designed studies for treatment of eye diseases, including those involving marijuana for treatment of glaucoma." The initial observation that smoked marijuana lowered intraocular pressure (IOP) in humans in acute experiments was made by Hepler and Frank in 1971. Hepler and Petrus (1976) later reported in greater detail that 4 percent (tetrahydrocannabinol (THC)) marijuana cigarettes lowered the IOP about 27 percent more than did a placebo at 30 minutes in normal volunteers, and that 20 mg of oral THC lowered the IOP about 17 percent more than placebo at 30 minutes. They also reported that smoked marijuana lowered IOP much more dramatically in patients with poorly controlled glaucoma, with 10 of 12 responding, and presented graphs showing the timecourse. One patient demonstrated a reduction from 40 mm Hg to 10 mm Hg in one eye and from 35 mm Hg to 15 mm Hg in the other. Since patients with severe glaucoma did not discontinue their current therapy (pilocarpine - 4 percent, epinephrine - 2 percent, or oral acetazolamide) Hepler and Petrus concluded that smoked marijuana or oral THC were additive to the then-known classes of therapeutic agents, and presumably worked by an independent mechanism (Hepler and Petrus 1976). In these short-term studies, lasting up to 4 hours, 2 cigarettes were as effective as 20 cigarettes, and intoxication occurred. Others confirmed that the marijuana could have a significant adjunctive effect in glaucoma patients, with Cuendet and colleagues reporting that 12/16 eyes of 10 patients had a reduction of 15 percent or more (Cuendet et al. 1976). Flom and colleagues (1975) concluded that in normal volunteers in acute studies the lowering of IOP was proportional to the "high," and that experienced users who did not experience a "high" did not have a lowering of IOP. Merritt and colleagues (1980) studied the blood pressure (BP) and IOP of 18 glaucoma patients in short-term studies, which compared smoking a single 2 percent THC cigarette versus a placebo cigarette of the same smell and taste and concluded that the IOP was reduced by 4 mm Hg at 30 minutes and by 6 mm Hg at 90 minutes (in patients with either open-angle or synechial angle-closure glaucoma), returning to baseline by 4 hours with THC, while there was no change with the placebo, but that the pulse rose from 82 beats per minute (bpm) to 123 bpm at 15 minutes, and the systolic BP fell 11 mm Hg and diastolic BP fell 5 mm Hg, suggesting that reduced perfusion of the ciliary body accounted for the reduction in IOP and that the adverse systemic effects, including postural hypotension, would limit the potential usefulness of marijuana. Indeed, Merritt concluded in an editorial in the Journal of the National Medical Association (1982) that "Systemic delta-9 THC therapies invariably produce a decreased perfusion pressure to the eye. This decreased perfusion to an already damaged optic nerve may not be of long-term benefit to glaucoma victims." However, there are several anecdotal reports that, on continued use, tolerance develops to the undesirable cardiovascular and mood effects of marijuana, while tolerance does not develop to the beneficial effects on IOP in patients with glaucoma (Palmberg 1997). Efforts to avoid systemic effects of THC in glaucoma treatment led to studies of topical preparations, such as 1 percent THC in peanut oil. However, no effect of the preparation on IOP was found by Jay and Green (1983). Animal studies have yielded conflicting results about the mechanism of action of THC on the IOP. The studies by Green in rabbits suggested central effects mediated through the adrenergic nervous system (Green 1979), but the studies of Colasanti (1990) in cats indicated no effect of either sympathetic or parasympathetic denervation on the action of THC. She also found that THC has no effect on aqueous production in anesthetized cats, but rather increased aqueous outflow facility threefold. The mechanism in humans has never been investigated by modern means, including fluorophotometry, coupled with the older method of tonography, which could yield clear information about the mechanism of action, whether on inflow, conventional outflow, or uveo-scleral outflow. In addition, it would now be possible to test the additivity of marijuana to a wide variety of agents now available, including beta-1 and beta-2 agonists and antagonists, alpha-2 agonists, dorzolamide, and latanoprost, to see whether or not THC works by a separate mechanism. 2. What are the major unanswered scientific questions? Researchers do not know the mechanism of action of cannabis on IOP, given either as smoked marijuana or as oral THC. Additional studies of long-term marijuana use are needed to determine if there are or are not important adverse pulmonary, central nervous system (CNS), or immune system problems. It needs to be determined if smoked or eaten marijuana is more effective in lowering IOP on a chronic basis than THC alone, as marijuana advocates maintain on the basis of anecdotal experience, or if pure THC, without the particulates and carcinogens of marijuana smoke, could be inhaled by means other than smoking, or taken orally, with equal long-term effect on IOP. Researchers do not know if marijuana would be additive to the new, very potent types of eyedrops now available to treat glaucoma, including alpha-2 agonists, dorzolamide and latanoprost (a prostaglandin that increases uveoscleral outflow and, like THC, causes conjunctival hyperemia). If marijuana were not to be additive to one of these agents, marijuana would be obsolete, since these agents have no systemic side effects (other than slightly dry mouth in some patients with apraclonidine and bromonidine), and they have a duration of action of 12 to 24 hours. What are the diseases or conditions for which marijuana might have potential as a treatment and which merit further study? Further studies to define the mechanism of action and to determine the efficacy of delta-9-tetrahydrocannabinol and marijuana in the treatment of glaucoma are justified. In glaucoma, there does not appear to be any obvious reason to use smoked marijuana as a primary " stand alone" investigational therapy, as there are many available agents for treatment, and these topical preparations seem to be potentially ideal. An approach that may be useful is to study smoked marijuana in incomplete responders to standard therapies. The suggested design for clinical studies is to add marijuana, oral THC, or placebo to standard therapy under double-blind conditions. Studies proposed should consider the following measures: * Establish dose-response and dose-duration relationships for IOP and CNS effects. * Relate IOP and blood pressure measurements longitudinally to evaluate potential tolerance development to cardiovascular effects. * Evaluate CNS effects longitudinally for tolerance development. References American Academy of Ophthalmology. "The Use of Marijuana in the Treatment of Glaucoma." Statement by the Board of Directors of the American Academy of Ophthalmology, PO Box 7424, San Francisco, CA, June 1992. Colasanti, B.K. Review: Ocular hypotensive effect of marijuana cannabinoids: Correlate of central action or separate phenomenon? J Ocular Pharmacol 6(4):259-269, 1990. Cuendet, J.F.; Saprio, D.; Calanca, A.; Faggioni, R.; and Ducrey, N. Action of delta-9-tetrahydrocannabinol on ophthalmotonus. Opthalmologica 172:122-127, 1976. Flom, M.C.; Adams, A.J.; and Jones, R.T. Marijuana smoking and reduced pressure in human eyes: Drug action or epiphenomenon? Invest Ophthalmol 14(1):52-55, 1975. Green, K. Marihuana in ophthalmology--past, present and future. (Editorial). Ann Ophthalmol 11(2):203-205, 1979. Hepler, R.S., and Frank, I.R. Marijuana smoking and intraocular pressure. (Letter). JAMA 217:1392, 1971. Hepler, R.S., and Petrus, R.J. Experiences with administration of marihuana to glaucoma patients. In: Cohen, S., and Stillman, R.C., eds. The Therapeutic Potential of Marihuana. New York: Plenum Medical Books, 1976. pp. 63-75. Jay, W.M., and Green, K. Multiple-drop study of topically applied 1% delta 9-tetrahydrocannabinol in human eyes. Arch Ophthalmol 101(4):591-593, 1983. Merritt, J.C. Glaucoma, hypertension, and marijuana. (Editorial). J Natl Med Assn 74(8):715-716, 1982. Merritt, J.C.; Crawford, W.J.; Alexander, P.C.; Anduze, A.L.; and Gelbart, S.S. Effect of marihuana on intraocular and blood pressure in glaucoma. Ophthalmology 87(3):222-228, 1980. National Eye Institute. "The Use of Marijuana for Glaucoma." Statement of the National Eye Institute of the National Institutes of Health, February 18, 1997. Palmberg, P. Unpublished observations presented at the Workshop on the Medical Utility of Marijuana, National Institutes of Health, Bethesda, MD, February 20, 1997. Appetite Stimulation/Cachexia What research has been done and what is known about the possible medical uses of marijuana? It has been shown that there is a strong relationship between smoking marijuana and increased frequency and amount of eating. Survey data on appetite stimulation (Haines and Green 1970) (N = 131) showed that 91 percent of marijuana users eat every time they smoke. Tart (1970) found that 93 percent of marijuana users (131) reported that marijuana made them enjoy eating very much and that they consequently ate a lot more. Foltin and colleagues (1986) reported that marijuana users eat more often. A study by Farrow and associates (1987) reported no hematologic changes or signs of nutrient deficiencies in marijuana users. Marijuana is reported to enhance the sensory appeal of foods. Taste does not seem to be altered as measured by indexes of sourness (citric acid in lemonade), saltiness (NaCl in tomato juice), sweetness (sucrose in cherry-flavored drink), and bitterness (urea in tonic water). There does not appear to be impairment in the normal satiety mechanisms following marijuana ingestion. Foltin and colleagues (1988) saw signs of a general increase in food intake on smoked marijuana days versus placebo days. The effect may not persist over an extended period of time, but long-term studies have not been done. Setting is important in appetite enhancement and social settings contribute heavily. Williams and associates (1946) did a chronic dosing study. They found that body weight went up and stayed up, possibly due to an effect of marijuana on fluid retention. Greenberg and colleagues (1976) saw a sharp increase in food intake followed by a leveling off. The increase in body weight may reflect a reduction in energy expenditure. Food intake was greater after smoking, compared to oral and sublingual administration, but there was much individual variability. Marijuana seems to enhance appetite in the evening, whereas many cancer patients report having most of their appetite in morning. This would suggest a potential complementary use of marijuana. Cachexia or wasting due to HIV infection is increasingly prevalent in the era of effective prophylaxis for Pneumocystis carinii pneumonia (Hoover et al. 1993). Significant weight loss, more than 20 percent of ideal body weight, is associated with shortened survival of HIV-infected patients (Kotler et al. 1989). The major causes of weight loss in HIV-infected patients are opportunistic infections, enteric infections associated with malabsorption, and reduced caloric intake. The latter is the most important cause of wasting in the absence of opportunistic infections and malabsorption (MacCallan et al. 1995). Administration of the appetite stimulants megestrol acetate (VonRoenn et al. 1994) and dronabinol (Gorter et al. 1992) is associated with weight gain in HIV-infected patients. Anabolic steroids and recombinant human growth hormone produce an increase in lean body mass (Mulligan et al. 1993). In published studies, the weight gain produced by appetite stimulants or hormonal therapy has not been shown to be associated with an improved immunologic status or clinical outcome. All investigations, however, have been relatively short, 12 to 24 weeks in length. Although there is much anecdotal evidence of weight gain produced by use of smoked marijuana, no objective data relative to body composition alterations, HIV replication, or immunologic function in HIV-infected patients are available. An epidemiologic study demonstrated no alteration in the natural history of HIV infection with use of smoked marijuana (Kaslow et al. 1989), although other investigations in uninfected volunteers and animal models indicated that there are effects on components of the immune system. There have been no recent published studies of the impact of smoked marijuana on the immune system in HIV-infected patients using state-of-the-art immunologic assays. Megestrol acetate (Oster et al. 1994, VonRoenn et al. 1994) produces weight gain that is predominantly fat, with very little increase in lean body mass. Dronabinol (9-THC) has been studied in patients with cancer (Nelson et al. 1994; Plasse et al. 1991) and AIDS (Gorter et al. 1992), who showed increased weight gain. Beal and colleagues (1995) studied dronabinol as treatment for anorexia associated with weight loss in patients with AIDS. A significant increase in appetite was seen with a decrease in nausea, and a mood increase that was not significant. The 6-week study may have been too short to fully capture the effects of dronabinol. In a survey looking at physicians' choice of drugs to treat wasting, the first line choice of 80 percent of the care providers was megestrol with dronabinol being used by 54 percent. Dronabinol was also the second line choice of most providers. Problems that have been identified with dronabinol are that patients feel "too stoned"; are unable to titrate their dose properly; note delayed onset of effect, prolonged duration of effect, or problems with malabsorption; and "not the same feeling as smoked marijuana." Several panelists pointed out that the weight gain is primarily an accumulation of water (sometimes of fat), but not of lean body mass. On the other hand, oncologists heard from patients with advanced cancer that increased appetite and weight gain are psychologically helpful, regardless of the nature of the added weight, and regardless of the impact (if any) on survival. Panelists also commented that very likely weight loss is an indicator rather than a cause of impending death. 2. What are the major unanswered scientific questions? Some questions that need to be answered in future studies are: Does smoking marijuana increase total energy intake in patients with catabolic illness? Does marijuana use alter energy expenditure? Does marijuana use alter body weight, and to what extent? Does marijuana use alter body composition, and to what extent? So far, it has not been shown that reversing wasting changes mortality risk. Another question is whether weight gain is associated with positive changes in psychological status. It seems related but has not been systematically addressed. 3. What are the diseases or conditions for which marijuana might have potential as a treatment and which merit further study? Areas of study for the potential appetite-stimulating properties of marijuana include the cachexia of cancer, HIV/AIDS symptomatology, and other wasting syndromes. With an appropriate delivery system designed to minimize the health risks of smoking, studies of the appetite-stimulating potential of cannabinoids are justified. Such investigations should be designed to assess long-term effects on immunologic status, the rate of viral replication, and clinical outcomes in participants as well as weight gain. In therapeutic trials for cachexia, research should attempt to separate out the effect of marijuana on mood versus appetite. Complex interactions likely are involved. References Beal, J.E.; Olson, D.O.; Laubenstein, L.; et al. Dronabinol as a treatment for anorexia associated with weight loss in patients with AIDS. J Pain Symptom Manage 10:89-97, 1995. Farrow, J.A.; Rees, J.M.; and Worthington-Roberts, B.S. Health, developmental, and nutritional status of adolescent alcohol and marijuana abusers. Pediatrics 79:218, 1987. Foltin, R.W.; Brady, J.V.; and Fischman, M.W. Pharmacol Biochem Behav 25:577-582, 1986. Foltin, R.W.; Fischman, M.W.; and Byrne, M.F. Effects of smoked marijuana on food intake and body weight of humans living in a residential laboratory. Appetite 11:1-14, 1988. Gorter, R.; Seifried, M.; and Volberding, P. Dronabinol effects on weight in patients with HIV infection. AIDS 6:127, 1992. Greenberg, I.; Kuehnle, J.; Mendelson, J.H.; and Bernstein, J.G. Effects of marijuana use on body weight and caloric intake in humans. Psychopharmacology 49:79-84, 1976. Haines, L., and Green, W. Marijuana use patterns. Br J Addict 65:347, 1970. Hoover, D.R.; Saah, A.J.; Bacellar, H.; et al. Clinical manifestations of AIDS in the era of Pneumocystis prophylaxis. Multicenter AIDS Cohort Study. N Engl J Med 329:1922-1929, 1993. Kaslow, R.A.; Blackwelder, W.C.; Ostrow, D.G.; et al. No evidence for a role of alcohol or other psychoactive drugs in accelerating immunodeficiency in HIV-1-positive individuals: A report from the Multicenter AIDS Cohort Study. JAMA 26:3424-3429, 1989. Kotler, D.P.; Tierney, P.R.; Wang, J.; and Pierson, R.N., Jr. The magnitude of body cell mass depletion determines the timing of death from wasting in AIDS. Am J Clin Nutr 50:444-447, 1989. MacCallan, D.C.; Noble, C.; Baldwin, C.; et al. Energy expenditure and wasting in human immunodeficiency virus infection. N Engl J Med 333:83-88, 1995. Mulligan, K.; Grunfeld, C.; Hellerstein, M.K.; et al. Anabolic effects of recombinant human growth hormone in patients with wasting associated with human immunodeficiency virus infection. J Clin Endocrinol Metab 77:956-962, 1993. Nelson, K.; Walsh, D.; Deeter, P.; and Sheehan, F. A phase II study of delta-9-tetrahydrocannabinol for appetite stimulation in cancer-associated anorexia (Review). J Palliat Care 10(1):14-18, Spring 1994. Oster, M.H.; Enders, S.R.; Samuels, S.J.; Cone, L.A.; et al. Megestrol acetate in patients with AIDS and cachexia. Ann Intern Med 121:400-408, 1994. Plasse, T.F.; Gorter, R.W.; Krasnow, S.H.; Lane, M.; Shepard, K.V.; and Wadleigh, R.G. Recent clinical experience with dronabinol. Pharmacol Biochem Behav 40:695-700, 1991. Tart, C.T. Marijuana intoxication: Common experiences. Nature 226:701, 1970. VonRoenn, J.; Armstrong, D.A.; Kotler, D.P.; et al. Megestrol acetate in patients with AIDS-related cachexia. Ann Intern Med 121:393-399, 1994. Williams, E.G.; Himmelsbach, C.K.; Wikler, A.; and Rudle, D.C. Studies on marihuana and pyrahexyl compound. Publ Health Rep 61(29):1059, July 19, 1946. Question 4. What Special Issues Have To Be Considered in Conducting Clinical Trials of the Therapeutic Uses of Marijuana? Benefit and Risk Considerations There are a number of guidelines and specific issues related to smoked marijuana that are important in planning trial designs and carrying out clinical studies. The current state of knowledge regarding the efficacy of smoked marijuana for a given disease/condition should be taken into account in designing clinical protocols. Investigators should give consideration to the range of potential questions that could be addressed and propose to address the most pertinent question(s) with the most appropriate study designs. This strategy should enhance the possibility of National Institutes of Health (NIH) funding support. In some instances, the initial question to be addressed may be whether smoked marijuana is efficacious in the treatment/management of a clinical condition. Such a proposed study may be a validation of clinical anecdotes or be proposed from basic research findings that suggest a potential benefit. In either case, the question should be formulated as a testable hypothesis. In other instances, the more germane question may be whether smoked marijuana possesses specific advantages over dronabinol capsules or other pharmacological therapies, has additional therapeutic effects in combination with standard therapies, has benefit in patients refractory to standard medications, or has benefit primarily in marijuana-experienced patients. The risks of concern associated with the investigational use of marijuana differ depending on the patient populations being studied and with the proposed duration of administration. For example, there is a different level of risk of developing bacterial pneumonia associated with marijuana administration to immune-compromised patients compared with nonimmune-compromised subjects. On the other hand, some risks may decrease with continued use due to the rapid tolerance development to certain central nervous system (CNS) and cardiovascular effects of marijuana. Marijuana-experienced subjects may already have some level of tolerance to certain effects. Hence, it is critical to consider the side effects of marijuana, the proposed duration of administration, the previous and current level of marijuana use in the proposed study population, and any additional risks that may be conferred by the disease status of the population in the assessment of risks and the appropriate type and frequency of safety monitoring. Concerns regarding the long-term risks associated with smoking are less important in conditions where short-term use is being proposed or patients are terminally ill. However, such risks are of concern for conditions where chronic administration of smoked marijuana is likely. Regardless of whether short-term or long-term use is being studied, all clinical trials must monitor side effects. Study Design Considerations Beyond the benefit and risk considerations, there are some general and specific study design issues regarding the evaluation of the therapeutic effects of smoked marijuana. There are two basic types of control groups to be considered in designing studies of the medical use of smoked marijuana: placebo control and active control groups. A placebo control is important in studying clinical conditions where there is no known effective therapy. Placebo controls are also desirable in studies where the question is whether smoked marijuana is effective or whether it is equivalent to another drug, and many study designs utilize both placebo and active control groups. This allows a determination as to whether a valid conclusion can be drawn about the efficacy of the test drug by providing a measure of assay sensitivity for the study; i.e., did any treatment show superiority to placebo. This design also allows comparison of marijuana with a standard therapy. If an effective standard treatment exists, there are conditions such as chemotherapy-related nausea and vomiting in which it would be unethical to include a placebo control group. On the other hand, in single-dose analgesic studies a placebo group can be incorporated in the design if appropriate provision is made for administration of a "rescue" analgesic if the study medication proves ineffective. Adding a placebo group increases the complexity of the study design and the number of subjects required and presents ethical questions that must be confronted and answered on a study-by-study basis, but a study without a placebo group may yield uninterpretable results unless some other measure of assay sensitivity is incorporated in the study. If smoked marijuana is being compared to a standard of care, placebo may not be needed if objective endpoints are being measured; e.g., number of vomiting episodes per day. Since many of the potential therapeutic uses of marijuana involve the use of the drug as an "add on" or adjunctive therapy administered concomitantly with a standard therapeutic regimen, a practical strategy for avoiding a placebo group is to administer the standard therapy to all patients in the study, and in addition administer marijuana to half the patients and a placebo marijuana to the other half. In that way, no patient would be deprived of standard effective therapy. Some investigations address whether an effect is dose related. This type of design allows for the assessment of the dose range that produces therapeutic effects and the relationship between these effects and dose-related side effects. Although these designs do not exclude the addition of placebo groups, a placebo is often not used because the determination of a positive dose-response curve for an effect provides an internal measure of assay sensitivity. An obvious difficulty with this type of design for smoked marijuana is the inability to standardize dose delivery due to the inherent variability associated with pulmonary administration. One possible design is to compare self-titrated smoking with several fixed doses of THC capsules. Selection of Patient Population The selection of the patient population to be studied, and the inclusion /exclusion criteria for the defined population, are another critical set of decisions. Design choices include patients who are the general population of patients with the disorder, or one of the following groups: nonresponders or incomplete responders to other therapies, patients selected in open-trial designs who responded to marijuana, and naive versus experienced marijuana smokers. One proposed strategy, selecting subsets responsive to marijuana in an open manner (i.e., "enrichment design"), assumes that there may be subpopulations that are difficult to recognize, except on the basis of their prior putative response to marijuana. Once identified, such patients are randomly assigned to a study drug or control group and are evaluated in a prospective manner. This approach is useful in situations where responses are variable and/or modest, making it difficult to demonstrate an effect, and where it would be of interest to know if a drug was useful even in a subset of the patient population. However, the limitation of this approach is the difficulty of estimating the size of the population to which study results can be generalized. Single-patient (N = 1) studies utilize multiple periods of a study drug-control, within-subject, crossover design. Evidence of efficacy in single patients can be determined in such designs, although carryover effects from the long plasma half-life of cannabinoids may confound interpretation of results. Blinding or Masking Treatment Assignments The issue of "blinding" or "masking" marijuana cigarettes was discussed at some length. Blinding may be difficult, even with identical-looking placebo cigarettes. Experienced marijuana users may be able to discern from the subjective effects whether they received active or placebo cigarettes. Nonetheless, there should be an effort to mask treatment assignment from both the patient and investigator, i.e., the double-blind technique. The effectiveness of blinding can be evaluated to some extent by querying patients after the study about their guess as to the identity of their treatment. In order to maintain double-blind conditions when comparing smoked marijuana with a control treatment in tablet or capsule form, a double-dummy technique is used. The marijuana treatment group would receive active marijuana plus dummy tablets or capsules, while the control group would receive dummy marijuana (i.e., with little or no THC) plus active tablets or capsules. Selection of Clinical Endpoints The choice of clinical endpoints for evaluation of potential efficacy should be guided by the desire to obtain objective data, if such endpoints can be obtained and are clinically relevant. Examples of such endpoints would be the number of vomiting episodes associated with a particular chemotherapy, intraocular pressure (IOP) measurements in glaucoma trials, and weight gain and percent changes in body composition in AIDS-wasting syndrome studies. The frequency of measurements should be dictated by the clinical condition being studied. While blinding may not be as important in studies with clear objective endpoints, some potential indications for marijuana are in conditions that involve subjective responses, e.g., treating the symptoms and improving the quality of life in very sick or dying patients. Scientific evidence can be generated on the basis of subjective responses. These therapeutic areas should not be avoided on the grounds that studies involving objective endpoints would be easier to quantitate or would be more immune to bias. Because of the importance of the questions of the medical utility of marijuana and the inherent difficulties in designing a definitive study with clinically important endpoints, a mechanism could be considered, such as a forum where experts in the subject areas and experts in clinical trial methodology, Government scientists, and applicable physicians and patients could engage in dialog regarding appropriate study designs prior to their adoption. Possible Role of the NIH in Facilitating Clinical Evaluation of the Medical Utility of Marijuana There are several mechanisms whereby the NIH can facilitate clinical trials with marijuana. Adequate supplies of marijuana of various and consistent strengths and placebos should be made available to investigators. The NIH should consider using its facilities and influence to assure the availability of comparator compounds and appropriate placebos (e.g., active and identical placebo amitriptyline tablets to permit a randomized trial versus smoked marijuana/smoked marijuana placebo for the control of neuropathic pain). Because of the broad range of potential uses of marijuana cutting across many NIH Institutes, a centralized mechanism should be considered to facilitate the design, approval, and conduct of trials supported by the NIH. Consideration should be given to supporting mechanisms whereby experts in multiple areas and physicians and patients could engage in dialog regarding study designs prior to their commencement. In addition, to permit the most rapid and accurate determination of marijuana's medical utility, the NIH should coordinate with efforts in individual States and by research organizations also conducting peer-reviewed research studying marijuana (e.g., American Cancer Society, Multiple Sclerosis Society). The NIH should also work closely with the Drug Enforcement Administration (DEA) and the U.S. Food and Drug Administration (FDA) to ensure that FDA regulations are followed and that clinical trials supported are adequate for submission as part of an FDA approval package should marijuana prove effective for a particular indication. The NIH should use its resources and influence to rapidly develop a smoke-free inhaled delivery system for marijuana or THC. This effort will remove a significant health hazard during clinical testing and future potential use. This will also bring this research effort in line with other Government initiatives to curtail cigarette smoking, the number-one preventable cause of premature death and disability in America. Until this is done, the testing of smoked marijuana would be difficult in smoke-free healthcare and municipal facilities. In addition, study of smoked marijuana in private facilities such as community medical offices or patients' homes, where smoking is not prohibited, would still present an environmental hazard of secondhand smoke for healthcare workers and family members. "Taking the smoke" out of an inhaled dosage form of marijuana or THC would remove an important obstacle to the accurate determination of inhaled marijuana's beneficial and deleterious effects. Appendix: The Effect of Controlled Substances Scheduling on Marijuana Research (Although not discussed at the meeting, this section is provided as background regarding research with Schedule I substances.) In addition to the requirements of the U.S. Food and Drug Administration (FDA) and sponsoring organizations such as the National Institutes of Health (NIH) concerning the conduct of clinical research, U.S. investigators are subject to specific FDA and Drug Enforcement Agency (DEA) regulations concerning research with controlled substances. Under the Controlled Substances Act (21 USC 822 (a)(1)) and implementing DEA regulations, persons conducting clinical research with any controlled substance must register with the DEA, keep specific types of records, and periodically report to the DEA. Marijuana is currently classified at the highest (most restrictive) level as a Schedule I drug (no accepted medical use, high potential for abuse). Attempts by various petitioners to have marijuana rescheduled have not been successful. Therefore, there is at least one extra layer (many States have their own laws modeled after the Controlled Substances Act (CSA), which add further complexity) for any investigator undertaking clinical trials with controlled substances. In the case of research conducted under an Investigational New Drug Application (IND), recordkeeping requirements are exempt from the CSA but must be kept in accordance with the Food, Drug and Cosmetic Act (FDCA). Under the FDCA, a sponsor or investigator must make its records concerning shipment, delivery, receipt, and disposition available for inspection and copying at DEA's request. Additionally, FDA regulations require that sponsors and investigators conducting clinical trials take special precautions to prevent diversion, including storage in a secure place with limited access. In the case of some investigator sites, this may require acquisition of a safe and/or other physical space changes and/or procedures to insure security and accountability of the substance. The CSA also mandates reporting procedures when conducting research with controlled substances. A DEA registration for controlled substances also authorizes (within specified limits) the manufacture and distribution of the substances. If a researcher engages in manufacture or distribution, then he or she is held to the reporting standard of manufacturers and distributors. Presumably, the manufacturer/distributor reporting requirements would not apply in most studies, as the source of marijuana would be the National Institute on Drug Abuse (NIDA) and most studies would not be using the plant material to manufacture other forms or products. Where research studies of Schedule I substances are not conducted under an IND, the DEA requires a copy of the research protocol be submitted for approval and identify in the registration applications the extent to which the research will involve manufacture or importation. Where research is conducted under an IND, however, the sponsor need only provide the DEA with a copy of the IND and a statement of security precautions. The FDA has ultimate authority to decide whether the research may proceed either under its jurisdiction over INDs (FDCA) or in the case of non-IND research, under the CSA (21CFR1301.42). Where non-IND research is undertaken, the FDA must consult with the DEA concerning the adequacy of the applicant's diversion control procedures. If a researcher desires to increase the amount of Schedule I material it has previously received permission to use, it must apply to the DEA for the increase, and the DEA will forward the request to the FDA for approval/denial, taking into account DEA comments on the adequacy of the researcher's security against diversion control. Some States may have their own registration requirements for Schedule I substances above and beyond the Federal requirements. Each researcher must check his or her own State authorities to see if other regulatory requirements need to be met. Given the small amounts of research material used by researchers in comparison to the additional regulatory burden and time delays, many researchers have been discouraged from pursuing research with these substances. Indeed, one of the recommendations of the Institute of Medicine Report entitled The Development of Medications for the Treatment of Opiate and Cocaine Addictions: Issues for the Government and Private Sector (National Academy Press, Washington, DC 1995, pp. 168-171) was that the current regulatory system be modified to remove barriers to undertaking clinical research with controlled substances. Ad Hoc Group of Experts William T. Beaver, M.D. Professor Emeritus of Pharmacology and Anesthesia Georgetown University School of Medicine Washington, DC Julie Buring, Sc.D. Associate Professor of Preventive Medicine Harvard Medical School and Deputy Director Division of Preventive Medicine Brigham and Women's Hospital Boston, MA Kobaja Goldstein, M.D. Professor Emeritus of Pharmacology Stanford University Stanford, CA Kenneth Johnson, M.D. Professor and Chairman Department of Neurology University of Maryland Hospital Baltimore, MD Reese Jones, M.D. Professor of Psychiatry Langley Porter Psychiatric Institute University of California, San Francisco San Francisco, CA Mark G. Kris, M.D. Attending Physician Memorial Sloan-Kettering Cancer Center and Professor of Medicine Cornell University Medical College New York, NY Kathi Mooney, Ph.D. Program Director Graduate Programs in Oncology Nursing and Professor University of Utah College of Nursing Salt Lake City, UT Paul Palmberg, M.D., Ph.D. Professor of Ophthalmology Bascom-Palmer Eye Institute University of Miami School of Medicine Miami, FL John Phair, M.D. Professor of Medicine Northwestern University Medical School Chicago, IL [/QUOTE]
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