Reproductive Toxicology, Vol. 5, pp. 389-390, 1991 0890-6238/91 $3.00 + .00 Printed in the U.S.A. Copyright © 1991 Pergamon Press plc

• Short Communication

THE FIRST INTERNATIONAL SYMPOSIUM ON THE PHYSIOPATHOLOGY OF ILLICIT DRUGS, HELD IN PARIS, FRANCE, ON MAY 31, 1990

GABRIEL G. NAHAS

College of Physicians & Surgeons of Columbia University, New York, New York

The first International Symposium on the "Physiopa- thology of Cannabis, Cocaine and Opiates" was held at the National Academy of Medicine of France, in Paris on May 31, 1990.* An important part of the program was devoted to the genotoxic and fetotoxic effects of these drugs. Finster (Columbia University College of Physicians and Surgeons) reported that while the terato- genic effects of cocaine are not evident, its toxic effects on mother and fetus are very damaging. Most of these effects may be attributed to sympathetic stimulation, re- suiting in vasoconstriction and hypoxia that will affect the fetus at all stages of its development. Infants born to cocaine-using mothers have lower weight, height, and head circumference. In New York City, reported mater- nal cocaine use rose from 1.0 to 21.1 per 1,000 live births between 1980 and 1988. It was also reported that cocaine-exposed infants, at two years of age, still had significantly smaller head circumference and greater at- tention deficit than a control group. Cocaine use in young men is associated with decreased sperm concen- tration and motility and increased abnormal morphol- ogy, as reported by Bracken (Yale University).

Parker (Boston City Hospital) reported that after controlling for potentially confounding variables, posi- tive maternal urine assay for marihuana was associated with a significant decrease in both weight and length of the newborn.

Neglia (University of Minnesota) reported a multi- center case-control study conducted by the Children's Cancer Study Group. This study dealt with potential in utero and postnatal exposures associated with acute

*Proceedings of this symposium titled Physiopathology of illicit drugs: cannabis, cocaine, opiates, have been published by Pergamon Press, New York-Oxford, 1991, as a volume in the series, Advances in the Biosciences.

nonlymphocytic leukemia (ANLL). Data were analyzed for 204 case--control pairs. Maternal use of mind-alter- ing drugs prior to and during pregnancy was found to be associated with an 11 fold increased risk (P = 0.003) of ANLL in offspring when compared to offspring of controls. Of the 11 mind-altering drug exposures, 10 were either marihuana exclusively (9) or included mari- huana (1). Mothers of ANLL cases were 10 times more likely to have used marihuana just preceding or during the pregnancy when compared to control mothers (P = 0.05). Marihuana-exposed cases of ANLL differed sig- nificantly from marihuana nonexposed cases with respect to age at diagnosis and morphologic subtype. The results of this previously reported study (Robison et al, 1989) suggest the possibility that maternal marihuana use during pregnancy may play an etiologic role in childhood ANLL.

Hutchings (Columbia University) reported that ma- ternal use of opiates (heroin, methadone), though not associated with increased teratogenicity, will cause pre- mature birth, lower birth weight, smaller head circum- ference, and serious withdrawal symptoms in the newborn that may persist for as long as 6 months and, if not treated, may be lethal. In the case of methadone, the withdrawal symptoms are biphasic and prolonged. Within the last 15 years, it has become increasingly ev- ident that the issue of drug safety and risk assessment goes far beyond structural defects and has come to en- compass a broad spectrum of adverse outcomes that in- clude neurobehavioral as well as other functional effects. Postnatal developmental defects include atten- tion deficit disorders and impairment of motor coor- dination.

Henrion (La Salp~tri~re) reported similar untoward effects of opiates on infants born in Paris from opiate- addicted mothers. He described, in addition, the high prevalence of HIV infection among opiate addicts,

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which exceeds 60% in his hospital, and affects one-half of all their offspring.

Auroux (Kremlin Bic~tre) reported experimental evidence suggesting that opiates, including methadone, affected development of the central nervous system by interfering with mRNA. Auroux also stated that opiates, including methadone, might be mutagenic and also af- fect male germ cells, which could transmit developmen- tal defects to the offspring. This possibility was elaborated on by Falek (Emory University), who de- scribed studies documenting the genotoxic and im- munodepressive effects of opiates; cytogenetic studies showed increased frequency of chromosome damage and sister chromatid exchange in opiate addicts, as well as a depression in DNA repair capacity.

Tuchmann-Duplessis (University of Paris) in his conclusion, emphasized the negative social impact of widespread addiction to these drugs, and how the trivi- alization of their use endangers future generations, which already have to contend with the damage wrought by tobacco and alcohol. These drugs also impair im- mune function, increasing viral and microbial infections as well as malignancies (H. Friedman, A. Cabral, B. Desoize). Morphine interacts with specific receptors of lymphocytes and inhibits lymphocyte proliferation and rosette formation. The inhibitory effects of cannabis on cells of the immune system, which require micromolar concentrations, seems to be mediated by the general nonspecific properties of cannabinoids and not by a ste- reospecific receptor like the one isolated in the brain, which is sensitive to nanomolar concentrations of THC. The effects of cocaine on immune mechanisms have not yet been thoroughly investigated.

Further documentation of the pathologic manifesta- tions of drug-induced immunodepression will require, as was the case for tobacco, long-term prospective epi- demiologic studies. Disseminated myocardial lesions, which have been temporally related to cocaine consump- tion in man, were produced experimentally (by Nahas and Trouve) in rats administered the pure drug. These lesions were attributed to the peripheral overstimulation by cocaine of the sympathoadrenal and renin angioten- sin systems. All these drugs impair basic brain mecha- nisms that control cerebral circulation, metabolism, and neurotransmission (neurotransmitter release, uptake,

synthesis, transport, and storage). The newer imaging techniques, which were so

clearly described by Dr. Volkow and her group at Brookhaven, have already shed light on some of these mechanisms that are impaired well beyond the acute pe- riod of intoxication. Three areas of the brain have been currently described as preferential targets of these drugs: the nucleus acumbens and striatum, which control plea- sure reward, the orbital frontal cortex and temporal lobe, which are involved in stereotyped automatic be- havior, and the hippocampus, a major relay of memory. Functional integrity of these areas is necessary for the performance of activities essential for the survival of the individual and the species. It appears that drug-induced neurotransmitter alterations in these areas impart rein- forcing patterns of drug-seeking, drug-consuming behav- ior which, in the presence of drug availability may become irreversible. Understanding how opiates, can- nabis, and cocaine produce (in nanomolar concentra- tions) an imbalance in the neurotransmitter systems of these areas, and how this imbalance relates to cognitive, emotional, and behavioral expressions, appears to be more important than specifying absolute changes in brain amine levels.

The most sobering reports of this colloquium de- scribed evidence of genotoxicity of opiates and cannabis in experimental and epidemiologic studies, respectively. Their confirmation should be a matter of priority. Fur- thermore, cocaine, cannabis, and opiates are fetotoxic. Fetotoxicity and perinatal toxicity consequent to mater- nal drug use will have to be gauged not only by somatic markers of weight and height, but also by cytogenetic studies of the newborn and long-term behavioral mea- surements that reflect the development of the central nervous system.

The gravity of the physiopathology of cannabis, cocaine, and opiates described in this volume, empha- sizes the importance of the prevention of drug depen- dence, as long as specific and effective therapies are not available. A close cooperation between clinicians, pa- thologists, epidemiologists, and experimental investiga- tors, somewhat neglected in the past, should be strengthened in order to better define the mechanisms of action of these drugs and find more effective ways of alleviating or limiting their use.