Reprinted from 24 April 1970, volume 168, pages 507-509 SCIENCE Chronic Non-Psychiatric Hazards of Drugs of Abuse A conference on Chronic Non- Psychiatric Hazards of Drugs of Abuse was held in San Francisco, 29-30 Oc- tober 1969. The conference was co- sponsored by the Center for Studies of Narcotic and Drug Abuse of the Na- tional Institute of Mental Health and by the recently formed Environmental Mutagen Society, The conference focused on biological hazards of drugs of abuse and excluded their psychiatric and psychopharmaco- logical effects. The major categories of hazards considered were toxicity, carci- nogenicity, teratogenicity, and muta- genicity. The object was to review ex- isting toxicological information on these drugs and to identify productive strat- egies for future research, A particular effort was made to interpret current data on biological hazards due to LSD. Hazards posed by drugs of abuse were viewed against the perspective of therapeutic and prophylactic drugs, as well as from the wider perspective of environmental chemical pollutants. Drugs of abuse, however, present un- usual toxicological problems. Their use, which has increased dramatically over the last decade, is generally re- stricted to young adults. Such drugs are self-administered in a variety of ways, including ingestion, injection, and inhalation; they are generally admin- istered in unquantitated doses, They are often administered in highly impure or contaminated states in combination with a variety of other drugs and chemicals, and for prolonged periods of time. Finally, intercurrent infection and mal- nutrition are sometimes prevalent in user populations. In part, as a result of the restricted availability of these drugs, their chronic biological effects have been less well studied than other cate- gories of drugs or environmental pol- lutants. The concept of matching ben- efits against hazards, generally con- sidered appropriate in toxicological evaluation of therapeutic drugs, pesti- cides, or food additives, is complicated by other concerns implicit in the con- cept of “drug abuse.” Chemical structures of major cate- gories of drugs of abuse were reviewed. The chemical crudity of most synthetic and semisynthetic formulations, and also the possibility of important bio- logical activity of misidentified or un- identified chemical contaminants were emphasized. For example, the anesthetic Sernyl is commonly sold on the streets as synthetic marihuana. Background in- formation on psychiatric, sociological, and pharmacological aspects of drug addiction and dependence were con- sidered, Barbiturate dependence merited particular concern in view of the high mortality associated with abrupt with- drawal of this drug. Biological interactions between dif- ferent drugs of abuse and between them and other environmental pollutants were considered in relation to hepatic microsomal enzyme function. For ex- ample, barbiturates are potent inducers of detoxifying microsomal enzymes; conversely, microsomal enzyme func- tions are inhibited by cannabinol con- stituents of marihuana and by 3,4- methylenedioxyamphetamine (structur- ally related to piperonyl butoxide, a pesticide synergist and potent micro- somal enzyme inhibitor). While population surveys are helpful in establishing shifts in usage patterns of various drugs of abuse, they are un- likely to be useful in monitoring or detecting chronic hazards. Epidemio- logical approaches were discussed both generally and in specific relation to mutagenic effects. Detecting such haz- ards typically requires very large popu- lation samples, which practical con- siderations limit. However, valuable epidemiologic data on drugs of abuse, as well as on a variety of other environ- mental influences, could well accrue from a uniform nationwide registration for congenital anomalies. For example, if LSD was a powerful teratogen, this might manifest by a significant cluster- ing of birth defects in younger mothers in metropolitan districts. No such fluc- tuations have been observed. However, present systems of data collection are only marginally capable of detecting gross effects, The scientific literature on carcino- genicity, teratogenicity, and mutagenic- ity of drugs of abuse is almost non- existent, with the notable exception of that on cytogenetic effects of LSD. Carcinogenicity was discussed with particular reference to problems of bio- transformation of precarcinogens and carcinogens, the need for enhancing the sensitivity of standard animal tests, and their high degree of human rele- vance, Feeding or other appropriate administration of high test doses to rodents, from early infancy onward, may help to reduce the insensitivity of current carcinogenicity tests which must use numbers of rodents incom- parably smaller than the large human populations at presumptive risk. The recent Bionetics study on pesticides (sponsored by the National Cancer In- stitute) demonstrates that such _tech- niques do not produce false positives. With regard to teratogenicity testing, while standard protocols are available, these could be made less empirical if modified in light of data on metabolic transformation and on the duration of sensitivity of any particular developing organ to any drug. Infeamammalian moder 10% genicity testing—bacteria, Neurospora, Drosophila, and in vitro cytogenetics— were considered to yield useful infor- mation. Mammalian methods, however, provide information with a higher de- gree of presumptive human relevance. Such systems, which are both sensitive and practical, include in vivo cyto- genetics, the host-mediated assay, in which bacteria or Neurospora are tested in a mammalian milieu, and the dominant lethal assay. A combination of mammalian and ancillary submam- malian tests are likely to detect all chemicals producing point mutations or chromosome anomalies. Early cytogenetic studies on LSD were reviewed and found difficult to interpret because of poor experimental design, inadequate controls, drug con- taminants, and unresolved sampling problems. These studies reflect diffi- culties, sometimes inevitable, in the use of humans, notably the likelihood of previous or concurrent exposure to other drugs. It was considered that these problems would be avoided by well-planned serial in vivo animal studies. Recently, more adequate hu- man studies have suggested that pure LSD administered under controlled conditions may not produce cytogenetic effects. Needless to say, such findings have no bearing on the psychiatric haz- ards of these drugs. The confusion in regard to LSD underscores the critical need for pro- grammatic development of information on genetic and other hazards of drugs of abuse, quite apart from other drugs and chemical pollutants, with currently available methods that are sensitive, relevant, and practical. Standard uni- form reference samples of crude and synthetic drugs of abuse should be made more easily available to toxicolo- gists. The possibility of integrating vari- ous methods—for example, the use of single animal groups for concurrent tests such as carcinogenicity tests, in vivo cytogenetics, the host-mediated assay, the dominant lethal assay, and psycho- pharmacological studies—should also be explored. The proceedings of the conference will be published by the National In- stitute of Mental Health in monograph form. SAMUEL S, EPSTEIN Children’s Cancer Research Foundation, Inc. and Harvard Medical School, Boston, Massachusetts 02115 JosHuA LEDERBERG Stanford University Medical Center, Stanford, California 94305 Copyright © 1970 by the American Association for the Advancement of Science