RESEARCH NEEDS AND FUTURE DIRECTIONS

This section is intended to give some indication of future research needs and of the Department's program to provide the data needed to adequately explore the health implications of marihuana use. It should be emphasized that the issue of marihuana use in our society is complex and also involves moral, philosophical and legal questions which are unlikely to be resolved by scientific research. Whatever the ultimate resolution of these issues of values, it is essential that there be adequate understanding of the health implications of millions of Americans using marihuana in order that the individual and the society may more rationally approach the issue.

In retrospect, much has already been accomplished in expanding our understanding of marihuana since the Department, through its National Institute of Mental Health, embarked on a high priority marihuana research program. An adequate supply of well standardized natural and synthetic materials has been developed and a comprehensive program of research is currently being supported. The results of some of this ongoing research are summarized m this report. As time passes, additional information will become available so as to provide a more complete picture of the implications of marihuana use at various dosage levels and in differing use patterns.

While much has already been learned about the chemistry and the acute physiological effects of cannabis and related synthetics, much remains to be learned. More careful study is needed of the known psychoactive compounds, how they are metabolized and the role of their metabolic products in producing a range of acute and chronic effects. It is also important to understand the possiblis influence of other constituents of cannabis which may not in themselves be psychoactive but may nevertheless influence the action of those constituents which are.

The question "what is the active component of marihuana" has been partially resolved. Delta-9-THC, probably acting through a metabolite (11-hydroxy-THC) appears to be the principal compound
in the plant producing psychic effects. However, the influence of many ingredients ngredients of marihuana, such as cannabinol, cannabidiol and
the various acid precursor forms of these compounds and THC must be investigated as they may affect the psychoactivity of THC (or hydroxy:THC). There may be other substances which are water soluble, in contrast to the oil soluble cannabinoids, which may also contribute to the overall drug action.

Some of the effects which may be due to chronic heavy marihuana use are changes in personality, motivation, short-term memory and other disturbances of thinking. The possibility that some substances, remaining in the body longer than THC (or even hydroxy-THC), may be causally related to these effects must be entertained. If this is so, these substances should be isolated or made synthetically and their effects and influence on THC action studied.

A major difficulty encountered in the early portion of the metabolism studies was that of measuring THC after it has entered the body. This was found to be due to its rapid transformation into hydroxy-THC and other degradation products. However, as THC is metabolized it becomes a more polar compound more difficult to separate from other body constituents.

Several ways can be recommended to deal with this. Further development of the very sensitive techniques of radio-immunoassay (immune reactions using radiolabelled compounds) should be capable of achieving the selective and sensitive determination of THC and its metabolites. Other techniques which may be useful are combining gas chromatography with mass spectrometry and the use of spectrofluorometric analysis.

It is important to develop convenient techniques which quantitatively measure the amount of psychoactive material which is absorbed into the body following marihuana smoking or ingestion. Such measures would be analogous to present blood alcohol tests used to determine levels of alcohol intoxication.

The use of marihuana by man is seldom divorced completely from the use of other drugs. One of the principal difficulties in studying; marihuana is that users frequently also use LSD, amphetamines, alcohol, heroin and other drugs. In addition, most people use an extremely long list of common drugs such as aspirin, tranquilizers, caffeine, antihistamines, antihypertensives, antibiotics, etc. The possible interactive effects of these varibus drugs are not now known and need study.

The interactions between barbiturates and marihuana, especially in the brain and liver, should certainly be studied in order to anticipate problems such as now occur in the simultaneous use of alcohol and barbiturates. In fact, the admixture of all three—alcohol, barbiturates and marihuana—will predictably occur and must also be studied.

Despite the increase of marihuana research papers since 1968, some actions of marihuana are incompletely understood and their possible significance for health cannot at present be evaluated. These areas are discussed under the classical organ systems approach commonly used in medicine.

(1) Cardiovascular system.—One of the most reliably reproducible indicators of marihuana action is the characteristic acceleration of the heart beat. In addition, large or toxic doses produce a fall in blood pressure. Despite repeated observations of these effects in animals and man, their mechanisms and toxic significance is largely a matter of speculation.

A few basic studies on the mechanisms of these actions have been done but they do not yet provide adequate explanation. Studies are needed on isolated and intact hearts and cardiovascular systems as well as a careful checking of the cardiac performance of human marihuana-using subjects. An authoritative evaluation of the risk of this drug for those with heart disease is needed. The risk involved in marihuana use by older people being treated for cardiac conditions with drugs such as digitalis should also be studied.

(2) Liver funetion.—The primary clue linking THC with the liver has been the involvement of this organ in transforming THC into hydroxy-THC and other metabolites. Although marihuana use appears nowhere near as hepatotoxic as alcohol, the function of this organ should be carefully evaluated by well known clinical tests and in special cases by biopsy. Again, the risk of marihuana in persons with disease-limited liver function should be assessed.

(3) Gastrointestinal function.—Since some users take marihuana orally, the gastrointestinal effects of this drug must be evaluated. There is evidence that the drug in large amounts can slow gastrointestinal passage of an experimental meal and relax an isolated intestine. The sometimes reported increase in appetite following marihuana smoking may also be related to gastrointestinal effects in the gastrointestinal tract.

Observations made during metabolism studies have shown a marked persistence in the gastrointestinal tract of certain derivatives of THC, particularly di-hy•1roxy THC. This appears to be caused by a cyclic process in which the liver secretes metabolic products into the bile and then into the intestine where they remain or may be reabsorbed for recycling. This, and the fact that eating is a primary route of marihuana intake, suggest the need for a careful research consideration of marihuana and gastrointestinal function in the future.

(4) Neuroendocrine effects of marihuana.—Little research has been done on the neuroendocrinological effects of chronic marihuana use. Almost all other drugs with strong psychotropic action such as tranquilizers, antidepressants and alcohol can elicit disturbances of those systems controlling stress reactions, gonadal function, growth and the like. Careful studies will be needed in order to evaluate possible risks to patients with all sorts of mild endocrine disorders of the pituitary, thyroid, adrenal and other glands.

(5) Lung function.—Because smoking is the typical mode of use of marihuana in America, studies of its effects on lung function are of considerable potential importance. Carcinogenic liability of marihuana should be investigated using dogs and other animals trained to inhale smoke. Detailed microscopic investigation into the effects of chronic marihuana smoking on the living cells of ;the trachea and bronchi must be completed, even though preliminary experiments have not shown this form of smoking to be as damaging as tobacco smoking.

(6) Brain function.—This is the most important area of future research. It is of critical importance to know the role of chronic marihuana use in some of the behavioral and intellectual changes that have been reported as associated with use. Apart from the implications of chronic, heavy use of such materials as hashish, it is of critical importance to know what, if any, are the implications of use at the much lower levels already occurring or likely to occur for substantial numbers of the population.

Although laboratory research is an important aspect of the study of the relationship of marihuana and health, it must be emphasized that the answers are not ultimately to be found in animal research or in laboratory studies of acute human administration. While such research may provide important clues as to the questions to be posed, the most important of these can only be answered by careful observation and testing of the many users, here and abroad, who are, in effect, experimenting on themselves. To date long-term chronic studies have not generally been possible with American populations. It will be some time before long-term users exist in adequate numbers to assess the impact of American using habits and exposure to cannabis. Meanwhile continuing efforts are being made to develop a series of overseas studies with a range of human user populations at different levels of use so as to learn the health implications of varying patterns of use. Two such studies are now in progress. In order to control for different variables and to cope with the inevitable deficiencies of any one study, several more will be needed.   

In evaluating patterns and histories of use it is important to know more about differences which may be associated with particular ethnic and subcultural aspects.   

Little is at present known about the factors that play a role in determining long-term patterns of drug use such as patterns of child rearing, parental attitudes and their personal drug use. How do these affect the use patterns of children? There is evidence that the ways in which parents use tobacco and alcohol are correlated with their children's use Almost certainly parental attitudes and behavior are related to the use of illicit drugs as well.   

To date marihuana use has been largely confined to the youthful portion of the American population—an age group in some respects least likely to show ill effects of a drug. As more representative portions of the population experiment with the drug, it becomes increasingly important that we know the implications of use for individuals who may be less physiologically or psychologically resilient and who may have a variety of disabilities. This is important not only from the standpoint of chronic use, but also to understand the implications of acute usage for various types of performance and functioning, including such everyday tasks as driving.   

Finally, it is of importance to develop effective methods of prevention and education that are likely to deter individuals of all backgrounds and at all levels of risk from adopting pernicious pattern-of drug use whether of marihuana or of other drugs abused in our, society. To do so we need to better understand the factors in our o" and in other cultures which help to socially control drug use and to inhibit drug abuse. Although research in these areas frequently lack-the precision possible in laboratory sciences, it may prove to be • g the end the most important in averting drug abuse and its healt • consequences. Such research should certainly include a better understanding of those aspects of individuals' lives that serve to make dim! abuse less attractive and provide tenable alternatives to drug use.