ABSTRACT
Introduction
Discussion
Conclusion
Author: G. G. NAHAS
Pages: 57 to 62
Creation Date: 1990/01/01
Continuation of the practice of experimental administration of cocaine to cocaine-addicted volunteers has been recommended by some investigators. The author's view is that the risk of experimental use of cocaine outweighs its benefits and that this practice should not be pursued. The author describes the damaging effects of cocaine on the cardiovascular system, particularly its ability to induce myocardial band necrosis, and the unique reinforcing properties of the drug. The legal and ethical issues raised by the experimental use of cocaine are also discussed.
In 1987, an ad hoc committee of investigators on drug dependence recommended the continuation of experimental studies in which cocaine was administered to individuals under controlled conditions. It was argued that such studies would yield badly needed information relevant to the treatment of cocaine addicts [1] . The author disagrees with this view.
Over the past 10 years, sufficient studies have already been performed on human subjects who were administered cocaine orally [2] , intranasally [3] or intravenously [4] . The results of those experiments confirm the results of experiments performed on non-human primates: cocaine is spontaneously and repetitively self-administered; it rapidly induces tolerance; and it increases blood pressure and heart rate. The results of the experiments did not provide any information that was not already known from clinical observations [5] reported on at the turn of the century. These include palpitations and irregular velocity of the heart produced by cocaine, as well as the damaging effects of the drug on brain functions.
Subsequent experimental studies on animals and clinical observation of human subjects indicate that cocaine administration may produce acute vascular lesions of the coronary and cerebral vessels. Lethal doses of cocaine administered to rats by the intravenous or intraperitoneal route [6] and to dogs by the intravenous route [7] produce cardiac lesions identical to those produced by norepinephrine administration [8] .
For individuals using cocaine for therapeutic or "recreational" purposes, there is a considerable degree of difficulty in predicting what constitutes a fatal dose, as several authors have emphasized [9-11]. Fatalities related to cocaine intoxication have been recorded since the turn of the century [12-13]. In 1924, one author [14] reviewed 26 deaths resulting from cocaine usage as a local anaesthetic. In one study [11] , it was reported that "death may occur with as little as 20 mg intravenously". An otorhinolaryngologist [15] recommended that therapeutic (topical) application of cocaine be restricted to less than 200 mg and that dosage be minimized whenever possible.
In literature in the United States of America alone, from 1975 to 1987, it was found that a total of 140 cocaine-related deaths followed the "recreational" use of the drug [16-17]. The range of postmortem plasma concentrations varied from 0.8 to 800 mg per litre, indicating that lethality is not only produced by a very high dose of the drug. The summary of a recent report on the subject reads as follows:
"The cardiovascular effects of cocaine may culminate in clinical episodes of angina pectoris, myocardial infarction, arrhythmia, and intracranial hemorrhage. To clarify whether or not cocaine causes fatalities by these mechanisms, we studied 24 cases of sudden, apparently natural deaths as a result of coronary arteriosclerosis (15 cases), hypertensive cardiovascular disease (4 cases), and intracranial hemorrhage (5 cases) associated with cocaine use. In 11 cases, cocaine was found in the blood (average concentration: 0.57mg/litre; range: 0.05 to 1.45mg/litre), whereas in the remainder, cocaine or its major metabolite was found in the urine or other tissues. In the majority of [the deceased persons], autopsy disclosed the existence of severe natural disease which could have been exacerbated by the administration of stimulant drugs, including cocaine. These data, and a review of the current medical literature, indicate that cocaine may precipitate the sudden death of an individual with undiagnosed cardiovascular disease. A contributory role of cocaine should be considered in any apparently natural death occurring in a population where cocaine abuse is prevalent" [17] .
In addition, nine reports [17-20] relating recreational use of cocaine to coronary or cerebral vessel damage have appeared in United States medical journals since 1984.
Thus far, no such accident has been reported in experimentation with human cocaine addicts. But the subtle damage to myocardial and cerebral vessels, which cocaine administration may produce, must not be overlooked [21] . In a recent study [22] , contraction band necrosis was reported to be present [23] in 93 per cent of apparently normal hearts removed from subjects whose deaths were cocaine-related. Such damage may not be detectable by the methods of monitoring that are currently used on subjects in experiments involving cocaine administration (e.g. electrocardiograms, measurements by mood scales). Furthermore, some individuals are much more sensitive than others to the toxic effects of cocaine and so it is difficult to predict individual reactions to it. Thus, the potential risk to the experimental subject may greatly outweigh the hypothetical benefits derived from the experimental admini- stration of cocaine to human subjects.
In 1987, the American Society for Pharmacology and Experimental Therapeutics and the Committee on Problems of Drug Dependence claimed to:
"... know virtually nothing about the effects of cocaine self- administered via the inhaled route [i.e. 'crack'] ... This route of administration, which has an onset of action as rapid as the intravenous route, but does not have the same problems, is a popular way to use cocaine. Carefully controlled studies in humans comparing the effects of cocaine when it is inhaled with the extensive data base already available for the intravenous route will provide sorely needed information relevant to treatment" [l].
And yet, one study published over 10 years ago showed that this form of administration resulted in rapid physical and mental damage and death [24] . Later studies by other authors [25] in the United States revealed similar effects.
It has been amply demonstrated since then that inhaling is the most reinforcing means of absorbing cocaine and the one most likely to produce serious physical and mental damage. It is, therefore, hazardous to perform the suggested experiments on "crack" users. In the opinion of the author, there is no scientific justification for administration of cocaine to humans in this form.
Cocaine-addicted subjects selected for such experiments are paid, and this raises legal as well as ethical problems. By law, a physician is only allowed to administer controlled substances for the purpose of treating an ailment; in the case of cocaine, it is legally used only to induce local surface anaesthesia. Cocaine administration to cocaine addicts for experimental purposes might be an infringement of the Harrison Act [26] . The broad interpretation of this Act, sustained twice by the United States Supreme Court, forbids a physician to prescribe for non-medicinal purposes any of the drugs falling under the jurisdiction of the Act (opiates and cocaine). The Supreme Court ruling specifically forbids physicians to prescribe addictive drugs to addicts, thus maintaining their addiction [27] .
From the point of view of the physician, in addition to the legal issue involved, there is an ethical one: the justification of giving cocaine to cocaine- addicted subjects. Provisions for follow-up of such subjects and attempts to help them become drug-free are not always explicitly stated in experimental protocols. In fact, cocaine administration will further reinforce the addictive behaviour that the physician would like to help eliminate.
The systematic continuation of studies of cocaine-consuming pregnant women and of their fetuses [28] is questionable, especially since other options are possible and it is known that continuous self-administration of cocaine by a pregnant woman will harm the fetus. Proposed studies of this kind implicitly accept the fact that cocaine use will not abate and that society will be burdened with the problem of major consumption of the drug for years to come.
In addition, such studies have a marginal effect on prevention and no impact on demand, contrary to what is implied by the authors of the ad hoc committee report. One of the members of the committee stated that some preliminary research questions might be tested by giving opiates and stimulant drugs to non-drug users for a long enough period of time to produce a sufficient state of dependence [29] .
Finally, such human studies might be conflicting with the following recommendations from the Declaration of Helsinki concerning non-therapeutic clinical research:
"The subject of clinical research should be in such a mental, physical and legal state as to be able to exercise fully his power of choice.
"...
"The investigator must respect the right of each individual to safeguard his personal integrity, especially if the subject is in a dependent relationship to the investigator" [30] .
These recommendations raise two questions: Is an addict, dependent on cocaine and paid to inject his drug of dependence, in a position to "exercise fully his power of choice"? Is an addict, dependent on cocaine and given cocaine by an investigator, in a "dependent relationship to the investigator"?
On the basis of current knowledge, and in view of the grave risk involved in administering cocaine to cocaine-addicted subjects, the author is of the view that its experimental use in humans should not be pursued. Instead, research emphasis should be directed towards in vitro and in vivo studies on animal preparations in order to investigate effects and mechanisms of cocaine toxicity on the brain, heart, vascular system, kidney and liver.
In view of the interactions of cocaine and catecholamines, the effects of acute and chronic cocaine administration on metabolism and turnover of central and peripheral catecholamine, stores and receptors should be inves- tigated as well as activity of the renin-angiotensin system. Such fundamental studies will permit a clearer definition of the mechanisms of acute and chronic cocaine toxicity, using biochemical markers as well as light and ultra- microscopic examination of brain, heart, kidney and liver specimens. Such studies have already led to a definition of antidotes [31, 32] and antagonist substances to the acute effects of cocaine intoxication. Such compounds, which are currently in clinical use for treating hypertension, might be tested for use in the management of cocaine addiction.
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27United States v. Doremus, 249 U.S. 86 (1919); and Nigro v. United States, 276 U.S. 232 (1928).
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29R. T. Jones, "Clinical and behavioral considerations in emission tomography study design", Neurobiology of Behavioral Control in Drug Abuse, National Institute on Drug Abuse, Research Monograph Series, No. 74, S. 1. Szara, ed. (Rockville, Maryland, 1986), pp. 117-123.
30Document issued by the National Institute of Health (Bethesda, Maryland).
31R. Trouv and G. G. Nahas, "Nitrendipine: an antidote to cardiac and lethal toxicity of cocaine", Proceedings of the Society for Experimental Biology and Medicine, vol. 183, 1986, pp. 392-397.
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