Background
The present meeting
Reports and suggestions for important research needs
Cannabinoids from marihuana with variant length side chain (R) on the 16 carbon cannabinoid skeleton (C)
Summary of the chemistry of metabolic products
Important research needs
B. PHARMACOLOGICAL
Important research needs
C. CLINICAL
Important research and other needs
Pages: 37 to 48
Creation Date: 1973/01/01
Scientists from Japan and the United States who have been participating in the Japan-United States Cooperative Program met in Tokyo from 23 to 27 October 1972. A list of the participants is appended below. This meeting was concerned primarily with research on cannabis (marihuana) but other forms of drug dependence were discussed to some extent.
The background of this joint Japan-United States collaboration was reviewed in detail in the 1964-1969 report (Drug Dependence, Issue No. 4, June 1970) and need not be repeated in full in this report. Briefly, the work has been one part of the Japan-United States Cooperative Science Program which grew out of discussions between Prime Minister Hayato Ikeda and President John F. Kennedy in 1961. Under this programme the Japan Society for the Promotion of Science (JSPS) and United States National Science Foundation (NSF) collaborate in sponsoring and co-ordinating research in specific areas. Both countries must approve and participate in each project but each country supports the work carried out in that country.
The initial collaborative session on research on drug dependence was held in Tokyo on 16-27 November 1964. At that meeting the establishment of co-ordinating committees was recommended. These committees would make recommendations on exchange of personnel, development of basic and clinical researches, and the drafting of protocols for collaborative projects. At that meeting drug dependence of the morphine type was stressed.
A second meeting was held in Honolulu on 2-6 June 1969. The work accomplished between 1964 and 1969 was reviewed. Again drug dependence of morphine type was stressed but it was recommended that co-operative research on the chemistry, pharmacology, epidemiology, clinical features and public health aspects of cannabis should be emphasized in the subsequent years.
The meeting reported here reflected this increased emphasis on cannabis. As the individual reports of the different sections, which are appended below, show, a great deal of complementary work on the chemistry, basic pharmacology and investigations of dependence potential in animals was reported. It was also noted that use of cannabis has increased greatly in the United States and now involves millions of persons; use of the drug remained a small problem in Japan, but there were indications of involvement with cannabis by increasing numbers of Japanese.
* Report of Seminar on the Chemistry, Pharmacology, Clinical Effects and Use Characteristics of Cannabis, Tokyo, 23-27 October 1972, prepared by Harris Isbell and approved by the participants.
Other types of drug dependence were discussed. Marked differences between Japan and the United States respecting incidence of different forms of drug dependence and in the outcome of various medical, social and legal measures aimed at control and treatment were noted. For example, the Japanese have been able to reduce dependence of the amphetamine and morphine types to very Iow levels by a combination of strict legal controls, educational programmes and medical and social treatment. Similar measures in the United States have been singularly unsuccessful. On the other hand, use of inhalants (" glue ") has increased markedly in Japan but remains a minor problem in the United States. The reasons for these differences are not understood but present an opportunity for urgently needed research.
All of the participants in the 1972 meeting agreed that the collaborative effort had been very valuable to both the participating scientists and the two countries. The existence of the co-operative programme had facilitated exchanges of personnel for training and visits between scientists of the two countries. Research on drug dependence in both countries had been stimulated with the development of new hypotheses and methodologies. In addition, because of differing conditions in the two countries, the work had been complementary as well as duplicative. Accordingly, Japanese and American participants alike felt that the programme should continue to be supported by both countries.
JAPAN
Takemitsu Henmi, Psychiatrist
Assistant Professor
University of Tokyo, Tokyo
Eikichi Hosoya, * Pharmacologist
Professor and Chairman of Pharmacology
Keio University, Tokyo
Nobuo Ikekawa, Pharmaceutical Chemist
Assistant Professor
Tokyo Institute of Technology, Tokyo
Masaaki Kato, Psychiatrist
Head of the Division
National Institute for Mental Hygiene, Ichikawa
Akira Kasamatsu, Psychiatrist
Director
National Institute for Mental Hygiene, Ichikawa
Itsuo Nishioka, Pharmacognosist
Professor of Pharmacognosy
University of Kyushu, Fukuoka
Showa Ueki, Pharmacologist
Professor of Pharmacology
University of Kyushu, Fukuoka
* Co-ordinator
Tomoji Yanagita, Pharmacologist
Head of Pharmacology Division
Central Institute for Experimental Animal, Kawasaki
Hidetoshi Yoshimura, Pharmaceutical Chemist
Professor of Juridical Chemistry
University of Kyushu, Fukuoka
Keizo Watanabe, Pharmaceutical Chemist
Appraiser of Narcotics and Officer for the Control of Narcotics
Head of the Technical Division
The Ministry of Welfare, Tokyo
UNITED STATES
Henry Brill, Psychiatrist
Director, Pilgrim State
Psychiatric Hospital, New York, N. Y. 11717
Nathan B. Eddy, Pharmacologist
7055 Wilson Lane
Bethesda, Maryland 20034
Louis Harris, Pharmacologist
Professor of Pharmacology
University of North Carolina Medical School
Chapel Hill, North Carolina 27514
Leo Hollister, Clinical Pharmacologist
Associate Chief of Staff
Veterans Administration Hospital, Palo Alto, California 94304
Harris Isbell, Clinical Pharmacologist
Professor of Internal Medicine
University of Kentucky
Medical Center, Lexington, Kentucky 40506
Louis Lemberger
Biochemist and Clinical Pharmacologist
Eli Lilly and Company, Indianapolis, Indiana 46206
Herbert Raskin, Psychiatrist
Suite 309, 20100 W. 101/2 Mile Road
Southfiled, Michigan 48075
Maurice H. Seevers, * Pharmacologist
Professor Emeritus, Department of Pharmacology
The University of Michigan Medical School
Ann Arbor, Michigan 48104
Coy Waller, Pharmaceutical Chemist
Professor of Pharmacy, Institute of Pharmaceutical Sciences
University of Mississippi
University, Mississippi 38677
E. Leong Way, Pharmacologist
Professor of Pharmacology
University of California Medical Center
San Francisco, California 94122
* Co-ordinator.
A. CHEMICAL
In the report of the Conference in 1969, it was stated the U.S. national programme from NIMH had been redirected and that the chemical phase was to prepare fully defined materials for research in marihuana. In a large measure this has been accomplished. In defining these research materials, it has been realized that methods of analysis have to include not only gas chromatography (GC) but also thin layer chromatography (TLC). At times mass spectrometery and nuclear magnetic resonance are required. The following table summarizes the present knowledge of the chemistry of cannabinoids (THC and closely related compounds) in Cannabis sativa.
The structural variations in the cannabinoid skeleton are depicted in the Olivetol type.
I . Olivetol type - most abundant
R = -CH 2-CH 2-CH 2-CH 2-CH 3
II. Divarin type - second most abundant
R = -CH 2-CH 2-CH 3
Cannabivarin or Cannabivarol (CBV)
Cannabidivarin or Cannabidivarol (CBDV)
Tetrahydrocannabivarin or Tetrahydrocannabivarol (THCV)
III. Orcinol type
R = -CH 3
Cannabiorcol
Cannabidiorcol
IV. Sphaerophorin type
R = -CH 2-CH 2-CH 2-CH 2-CH 2-CH 2-CH 3
The cannabinoids in Cannabis sativa occur as their carboxylic acids in fresh plant material. Some strains have high THC content while certain others have high CBD content. Certain strains in southern Asia and South America have considerable cannabinoids of the Divarin type (propyl side chain). Some strains from South Africa and Japan have no CBD.
As can be seen from above, various strains of cannabis have different chemical constituents. Strains of cannabis as used here means derived from seeds from various geographic locations. Since these strains of cannabis can be grown in various locations and under various conditions, while each maintains its own group of cannabinoids and in about the same ratio of concentration, these strains seem to represent genetic types. Thus differences in chemical constituents in different genetic types are genetically controlled.
There are certain chemical changes that are not genetically controlled.
These are:
Decarboxylation: Heat and storage cause the cannabinoidic acids to lose carbon dioxide and convert to the neutral cannabinoids (e.g. THCA transforms to THC).
Aromatization: Selective oxidation or dehydrogenation of THC results in loss of the psychotomimetic activity (e.g. the conversion of THC to CBN).
Recyclization; Cannabichromene is a cannabinoid that appears to be produced by biosynthesis, but is unstable and can be converted to cannabicyclol, which does not appear to be a natural biosynthetic product of cannabis.
Dr. Akira Yagi reported that using specific strains of cannabis in feeding experiments in which labelled precursors (malonic acid-2- 14C, dl-mevalonic acid-2- 14C, geraniol-l- 3H and nerol-l- 3H, CBG- 14COOH,CBD- 14COOH) were given, he obtained cannabigerolic acid as the first cannabinoid in the biosynthetic pathway which then was biosynthetically transformed into cannabidiolic acid (CBDA) and then into Δ 9- tetrahydro-cannabinolic acid (THCA). Cannabigerolic acid (CBGA) is also transformed into cannabigerolic acid monomethyl ether (CBGAM) and cannabichromenic acid (CBCA).
Differences in strains of cannabis cannot be determined by morphological characteristics. Dr. Itsuo Nishioka reported that by chemical analysis and an extensive strain selection programme, he had obtained a CBDA producing strain. This strain did not produce THCA due to a lack of the THCA synthesizing enzyme. The inability of the strain to produce THCA was demonstrated by tracer experiments. Furthermore cross pollination studies with a THCA producing strain, demonstrated that the CBDA producing strain was genetically recessive. The characteristic property to produce THCA in other strains appears to be genetically dominant.
A survey of the THC, CBN and CBD content of hemp from all parts of Japan was reported by Dr. Keizo Watanabe. Marihuana from Tochigi and Hokkaido regions contained a 3.9 per cent and 3.4 per cent THC, respectively.
It has been reported that hashish from Nepal contains CBV, CBDV and THCV, the propyl homologues of CBN, CBD and THC. Dr. Nobuo Ikekawa reported that marihuana from a Meo village, northern Thailand, contained high concentrations of THCV and CBDV and in addition some of the methyl homologues. Dr. Coy W. Waller reported that analysis of a fresh sample of an Indian strain (little leaf Indian cannabis) grown in Mississippi contained THCVA and CBDVA. Also other strains of marihuana grown in Mississippi were found by GC and TLC analysis to contain traces of the propyl and methyl homologues and possibly the heptyl homologue. Dr. Waller also reported that a south African strain grown in Mississippi contained CBC but no CBD. Since CBC and CBD give the same retention time in the GC, previously reported analysis of marihuana for CBD content may be in error.
The types of metabolic oxidation of the cannabinoids appear to be as outlined below:
The metabolites of Δ 9-THC that have been reported are:
|
1. 11-Hydroxy- Δ
9-THC Active
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2. 8β-Hydroxy- Δ
9-THC
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3. 8α-Hydroxy- Δ
9-THC
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4. 8α, l l-Dihydroxy- Δ
9-THC
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5. 8-Keto- Δ
9-THC
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6. 9,10-Epoxide of Δ
9-THC
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7. 11-Carboxy-1′-hydroxy- Δ
9-THC
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8. 11-Carboxy-2′-hydroxy- Δ
9-THC
|
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The metabolites of Δ
8-THC are:
|
|
|
1. 11-Hydroxy-Δ
8-THC
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2. 7β-Hydroxy-Δ
8-THC
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3. 7-Hydroxy-Δ
8-THC
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4. 1′-Hydroxy-Δ
8-THC
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5. 7α,11- Dihydroxy-Δ
8-THC
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6. 7β-Hydroxy-Δ
8-THC
|
|
7. 7-Keto-Δ
8-THC
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8. 3′-Hydroxy-Δ
8-THC
|
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The metabolites of cannabinol are:
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|
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1. 11-Hydroxy-CBN
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2. 11, 2′-Dihydroxy-CBN
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3. 2′-Hydroxy-CBN
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The metabolites of cannabidiol are:
Three monohydroxylated metabolites of CBD have been described. In two, the hydroxyl group is in the terpene portion and in the third it is in the 1' position of the pentyl side chain.
Dr. Nobuo Ikekawa described a system for the detection and quantitation of cannabinoids and their metabolites at nanogram levels. He used the mass fragmentography method. The single ion detection procedure using the LKB-9000 mass spectrometer equipped with the Accelerating Voltage Alternator (AVA) system was applied to the sample after it was trimethylsilylated. He demonstrated the procedure using rabbit urine hexane extract with a silicagel column clean-up step. After intravenous administration of Δ 9-THC to rabbits, he detected in the urine 75 ng of Δ 9-THC and 7.5 ng of 11-hydroxy-Δ 9-THC.
Dr. Hidetoshi Yoshimura determined the distribution, metabolism and elimination of 14C-labelled Δ 9-THC in the Donryu strain of male rats. Forty-eight hours after i.p. injection, radioactivity was still detectable in adipose tissue, gastrointestinal tract and its contents, skin, adrenals and liver. A portion of the radioactivity was shown by the TLC method to have chromatographical properties characteristic of 11-hydroxy-Δ 9-THC.
Miss Aiko Sawa and Eikichi Hosoya injected Δ 9-THC into rats (20 mg/kg i.p.) and into rabbits (20 mg/kg i.v.). The urines of these animals were collected every 24 hours for 3 days. The urine was extracted with n-hexane and ether (pH 5). The ether extract was treated with p-TSA in refluxing benzene. Δ 9-THC was detected from n-hexane extract, and Δ 8-THC and CBN were detected from p-TSA treated ether extract of 24 and 48 hour urine by TLC and GC.
Dr. Louis Lemberger described and summarized investigations from various research laboratories dealing with the in vitro and in vivo metabolism and physiological disposition of Δ 9-THC in animals and man.
After the intravenous administration of Δ 9-THC to various animal species, highest concentrations of radioactivity are present in lung, liver, adrenals, and spleen; whereas the lowest concentrations are found in blood, brain, and spinal cord. With time, levels of radio-activity in all of these tissues decrease; however, there is an increase in the concentration of radioactivity in fat. A small percentage of the radio-activity is localized in brain. There is no selective distribution in any specific brain region; however, it appears that the radioactivity is localized in general in the gray matter, very little being in the white matter.
Δ 9-THC is bound to human plasma protein primarily in the lipoprotein fraction, and its 11-OH metabolite is bound primarily to the albumin fraction. After intravenous administration to several species, the plasma levels of Δ 9-THC disappear in a biphasic fashion. The initial rapid phase represents uptake and redistribution to tissues, and the secondary slow phase represents metabolism and excretion. The plasma half-lives of Δ 9-THC of the slow phase range from approximately 2 hours in the rabbit to as much as 57 hours in naive human subjects. Δ 9-Tetrahydrocannabinol is extensively metabolized in all species examined, and its metabolites are excreted in both urine and faeces. Rat excretes a major portion in the faeces, whereas rabbit excretes the majority of radioactivity in the urine. Man is intermediate, excreting about 25 per cent of a radioactive dose of 14C-Δ 9-THC in the urine and 50 per cent in the faeces in the first week.
The in vitro metabolism of the cannabinoids has been extensively studied. Δ 9-THC is hydroxylated to 11-OH-Δ 9-THC and 8,11-diOH-Δ 9-THC. Both of these metabolites are more polar than the parent compound. Metabolic studies in vivo confirmed the in vitro finding that l 1-OH was an important route of metabolism. This compound and its metabolic products are excreted in urine and faeces in animals and man. The predominant metabolic product present in rabbit and human urine appears to be a polar carboxylic acid derivative of Δ 9-tetrahydrocannabinol.
Dr. Lemberger then discussed in greater detail some of his clinical studies. In man, Δ 9-THC is absorbed after inhalation or oral administration. And the plasma levels of the metabolite appeared to be temporally correlated with the psychologic effects. Further studies demonstrated support for the hypothesis that Δ 9-THC, present in marihuana or hashish, could be metabolized in vivo to 11-hydroxy-Δ 9-THC which appears to be responsible in part for the psychologic effects.
The metabolism of Δ 9-THC occurs predominantly in the liver microsomal enzyme systems, and perhaps to a lesser extent in extra hepatic tissues. The microsomal systems metabolize other drugs and interactions with these and Δ 9-THC have been reported in animals. Some of these interactions include agents such as hexobarbital and amphetamine, in addition to other constituents of cannabis such as cannabidiol.
Continue the search for better methods for the detection of cannabinoids and their metabolites in body tissues and fluids.
Pure THCA and other naturally occurring acids should be prepared and tested for psychotropic properties.
Continue to define the biosynthetic pathways to cannabinoids in cannabis.
Prepare other metabolic products and test them for psychotropic activity.
The isolation and identification of Δ 9-THC (see report of chemistry section) as the chief psychoactive substance in marihuana ( Cannabis sativa) have been major achievements. Much credit should be accorded the many distinguished chemists, particularly those from Israel, Germany, Japan and the United States who carried out studies on the structure and synthesis of Δ 9-THC, and to the clinical pharmacologists in the United States for the demonstration that the pharmacological properties of Δ 9-THC are essentially identical with those of cannabis. In the wake of these pioneering discoveries, Japanese and American chemists have synthetized Δ 9-THC and some related derivatives in amounts sufficient for carrying out thorough pharmacologic evaluations. The availability of these substances has greatly facilitated the studies reported today, which augment our knowledge of marihuana.
Mouse-killing behavior (muricide) was found to be induced in the rat after chromic administration of Δ 9-THC. According to Ueki, Fujiwara, and Ogawa, the muricidal behaviour elicited by Δ 9-THC becomes manifest in the rat housed individually even on the first day of administration, and persists for a long period after the drug has been discontinued. Indeed, long lasting muricidal behaviour was induced even after single administration. In contrast, rats housed in a group did not exhibit muricidal behaviour, even though other acute responses to THC such as catalepsy, hypothermia and a decrease in exploratory activity were similar to those observed in animals housed individually.
In studies designed to assess the physical dependence liability of marihuana in the rat, Hosoya and Nozaki found that by the tests used Δ 9-THC did not cause physical dependence. Unlike after morphine, the injection of the narcotic antagonist, naloxone, following repeated administration Δ 9-THC, failed to elicit a decrease in body temperature, body weight and spontaneous locomotor activity. Furthermore, the fall in body weight which occurs following abrupt withdrawal in morphine-dependent animals was not prevented by Δ 9-THC. In these respects, marihuana and cocaine appeared to be similar.
Psychopharmacological studies of Δ 9-THC by Yanagita and Ando reveal that the reinforcing effect of Δ 9-THC on monkey's drug-seeking behaviour, if any, appears to be weak compared with other classes of compounds known to produce drug dependence. This was concluded from experiments on intravenous self-administration of Δ 9-THC in rhesus monkeys. Nevertheless, they found that acute administration of Δ 9-THC in the rat inhibits operant responding using the behavioural effect of Δ 9-THC on Sidman avoidance and DRL schedules. The effects of Δ 9-THC were different from those of other major psychotropic agents such as amphetamines, chlorpromazine, or LSD.
Harris reported that ninety-day chronic toxicity studies in the monkey and rat with THC and marihuana extract produced only minor histopathologic changes. Amounts up to 500 mg/kg of Δ 9-THC orally resulted in adrenal and gonadal atrophy, but no detectable lesions in the CNS. Tolerance to the depressant effects of Δ 9-THC developed and after 30 days hyperactivity was noted in rats. Although some animals convulsed on this high dose regimen, no deaths were recorded. As a result of these studies, the United States Food and Drug Administration now permits continuous studies in man on THC for a period of one year.
The effect of Δ 9-THC is inconsistent in tests for antinociceptive activity and such findings are difficult to extrapolate to human situations. In the anesthetized animal, low doses of Δ 9-THC sensitize the cardiovascular system to norepinephrine and epinephrine. High doses produce hypotension and the action appears to be centrally mediated.
Studies on Δ 9-THC indicate that tolerance develops rapidly to certain pharmacologic effects, and to a high degree. Operant behaviour tests in the pigeon using fixed-interval and fixed-ratio schedules reveal decrements in performance for relatively small doses of Δ 9-THC. Tolerance to these depressant effects occur after a few administrations and doses exceeding 10 times the lethal level have been attained. Tolerance also occurs to operant behaviour in the rat and to overt behavioural effects in the dog. Cross tolerance between Δ 8-THC and Δ 9-THC was also demonstrated.
Studies indicate that the tolerance is not primarily due to drug disposition factors. No difference in plasma levels of Δ 9-THC or its metabolites was found between tolerant and non-tolerant animals. Radioactivity was still present in the plasma 14 days after the termination of chronic administration. Repeated doses of material with radioactivity at 48 hour intervals led to increasing plasma, brain, and liver concentrations. The buildup was mainly in residue fractions which contained the more polar water soluble metabolites.
Bile cannulation studies in rats revealed a large entero-hepatic circulation for Δ 9-THC. Seventy per cent of an intravenous dose was excreted in the bile in 12 hours.
Some new water soluble esters of Δ 9-THC were discussed. These compounds show a very similar pharmacological profile to Δ 9-THC, but have not yet been tested in man. A number of other nitrogen-analogs of Δ 9-THC were described which have potent antinociceptive activity in animals.
Greater emphasis on the development of methodology for the detection of Δ 9-THC and its metabolites in body fluids and tissues.
Additional studies on the interaction of Δ 9-THC with other pharmacologic agents that are commonly abused should be encouraged.
Studies on the pharmacology and pharmacokinetics of Δ 9-THC metabolites should be expanded.
Studies should search for neurochemical changes that may occur in the CNS after single and repeated Δ 9-THC administrations.
Studies on the crude plant and plant extract in comparison with Δ 9-THC are needed. For studies on the crude plant and plant extract, a uniform plant source should be utilized. Supplies are available from the United States National Institute of Mental Health.
Long-term behavioural studies with Δ 9-THC should be initiated.
Studies to ascertain whether drug-seeking behaviour is modified by tolerance to Δ 9-THC or by its repeated administration should be made.
The individual papers on clinical findings are not summarized but the general trend of the discussions and the principal conclusions and recommendations which emerged are presented.
Attention centred primarily on cannabis but the full range of drug dependence problems came under discussion because of the close relationship among all forms of drug dependence. The topic was discussed from a variety of viewpoints including epidemiology, clinical pharmacology, clinical medicine, and psychiatry.
The experiences of Japan and the United States were examined and compared in an effort to gain a better understanding of the nature of the problem and its prevention and treatment. The general state of knowledge in this field was also reviewed. At virtually every point serious gaps in our knowledge were identified.
The Japanese experience with a succession of drugs since 1945 was reviewed and brought up-to-date and was examined with relation to economic and social events such as the disruptions of the post World War II period, the rapid further industrialization of the country, and influences from abroad. Evidence was cited that the shift from one drug to another might be an expression of the changing mood of society using popular songs as an indicator. Questions were also raised as to specific affinities between certain personality types and certain drugs as, for example, the use of hallucinogens by passive individuals.
The recent experience with heroin and marihuana in the United States was described and it was noted that the Japanese had encountered an increasing problem with marihuana since 1969 when 100 arrests were made; in 1971, 700 arrests were recorded. The problem is still minuscule in Japan compared to that in the United States, where cannabis suddenly in the last few years came to be used by some millions of young persons, but the potential for further increase may exist in Japan. The use of volatile inhalants, e.g., glue sniffing, on the other hand was described as a major problem in Japan and a minor one in the United States. Originally the Japanese cases were young teenagers as they still are in the United States but now the Japanese users of inhalants range up to 25 years of age. The interpretation of these and many other differences and similarities of national experience still remains to be clarified and further research on this question may provide valuable leads as to the nature and prevention of the processes underlying drug dependence. The recent rise of methamphetamine arrests among delinquents in Japan was cited as an example of events that call for further study.
From the point of view of clinical psychiatry the users of marihuana and other drugs may be divided into experimenters, users and abusers (heavy and very heavy users).
Individual psychopathology plays a key role, in drug dependence generally, and can be seen as a pathological reaction to life demands, a form of withdrawal from reality. More specifically a wide variety of psychiatric syndromes have been reported to be associated with abuse of drugs including marihuana but this entire important subject is still highly controversial and even emotional, and urgently requires further study by all available techniques. We have abundant proof of the ability of marihuana to involve vast numbers of persons but we still know too little about the future effects of this massive involvement.
Attention was drawn to the fact that drug dependence and abuse have many of the characteristics of a contagious disorder. Transmission occurs along social lines and drug dependence is no respecter of international boundaries. A purely local interpretation of the environmental factors is simplistic and incomplete and the course of a drug epidemic appears to be influenced by many environmental factors at home and from abroad, and from the past as well as the present.
Attention was repeatedly drawn to the far greater effectiveness of law enforcement as a preventive measure in Japan as compared with the United States and the interpretation of this fact remained unclear. The outcome of treatment seemed also to be more favourable in Japan than in the United States and the cases do not seem to trend so strongly toward intractable chronicity. The better prognosis may be related to a greater social cohesion and family support in Japan and to a better follow-up system but the reason is not clear. More investigation is urgently needed.
Finally it was noted that much is now known about the long-term effects of marihuana on the individual but the direct and indirect effects of long-term heavy use are still very uncertain.
Reports from the United States Army in Germany describe pulmonary damage and cognitive changes in heavy hashish users and studies now in progress in Jamaica, Greece, Egypt and elsewhere on populations that have used the drug heavily may be expected to cast light on this subject. Interference with complex mental functioning under the influence of marihuana is well established, but the effect on driving capacity is yet to be completely evaluated. Additionally, though it seems that the various constituents differ in their potency, the nature of their effect on humans seems much the same. Here also a vast amount of experimental work remains to be done.
In view of the potential public health implications of cannabis due to its propensity to involve large numbers of people, a fuller evaluation of this drug is urgently recommended. The following specific points may be listed.
Further epidemiological, environmental, sociological, and clinical studies should be carried out at national and international levels and the subjects should not be limited to marihuana abusers but should include multiple drug users and non-drug users. More adequate and more complete case study techniques must be developed for such studies.
Research concerning the effects of chronic high doses of cannabis is urgently required. Well designed prospective and retrospective studies comparing heavy users of marihuana with non-drug using groups should be initiated.
The importance of international co-operation in clinical matters was stressed and it was recommended that active channels of communication be maintained in order to make the clinical experiences fully available between the two countries on a current basis.
