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Title:
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National Institutes of Health -- Workshop on the Medical Utility of Marijuana | ||
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Author:
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Ad Hoc Group of Experts |
Date:
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Feb. 19-20, 1997 |
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Summary:
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Over the past 18 months there has been wide-ranging public discussion on the potential medical uses of marijuana, particularly smoked marijuana. To contribute to the resolution of the debate | ||
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TOC | Part 1 | Part 2 | Part 2a | Part 3 | Part 4 | Part 5 | ||
Part 4 of 5
TOC | Part 1 | Part 2 | Part 2a | Part 3 | Part 4 | Part 5
NAUSEA AND VOMITING1. 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.
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.
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.
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