"Vivisection is barbaric, useless and a hindrance to medical progress." - Dr. med. Werner Hartinger, surgeon, Germany, past president of the Internatonal League of Doctors Against Vivisection (ILDAV), April 15, 1988, Third Symposium of the ILDAV in Woudschoten, the Netherlands.
A Critique of Drug Addiction ResearchMurry J. Cohen, M.D.
The following is an examination and critique of two abstracts of research grants – Marilyn E. Carroll principal investigator. These grants are 5RO1DA02486-19 – Primate Model of Drug Abuse-Intervention Strategies, and 5R37DA03240-16 – Environmental and Pharmacological Control of Drug Abuse.
Carroll states that "animal models of drug administration have been useful for identifying variables that control drug taking behaviour in humans…" This is a highly debatable statement. In my extensive experience working with drug addicts, it is experience working with human addicts that has accomplished this goal - albeit quite insufficiently - not animal studies. Little has changed with respect to advances based on animal models since clinical pharmacologist Vincent Dole’s 1986 statement, "Some 60 years of offering alcohol to animals has produced no fundamental insights into the causes of this self-destructive behaviour or even a convincing analogue of pathological drinking." Now Carroll plans to use the same dubious animal model approach to study factors that predispose to the acquisition of drug abuse and that relate to the uniquely human phenomena of abstinence, craving and relapse. Her approach is misguided, however, for it is impossible to reproduce human drug abuse in the laboratory - nonhuman primate or human - because clinical human drug use reflects psychological factors that change from day to day, as well as factors that do not have laboratory correlates, such as drug costs, drug purity, drug availability, drug mixtures, the setting, users’ physical health, and many other variables. Animal models of drug addiction are fundamentally ill-conceived, failing to reflect crucial social, hereditary, and spiritual factors. Furthermore, fundamental differences between both humans and rats, and humans and nonhuman primates, including intra-uterine environment, sensitivity periods, and rates of growth, are among the many physiological factors that undermine extrapolating from one species to another. These factors invalidate non-human primate research in general, in the area of substance-abuse as well as in other areas of research.
Carroll states that subtle factors related to previous drug use may alter performance, long after drug use has stopped, that contribute to the high rate of relapse. This, of course, is true. Many of these factors are known by clinicians who treat and study human drug addicts. Carroll’s attempt to manipulate laboratory variables in rats in order to study such subtle and complex phenomena as drug-seeking behaviour, drug-rewarded behaviour, abstinence, craving, and relapse in humans is absurd. These human states and conditions reflect intricate bio-chemical, environmental, psycho-social, economic, cultural, and psycho-pathological factors in humans that simply cannot be replicated by the simplistic manipulation of laboratory conditions in rats. For example, Carroll’s rat animal model of craving -a distinctly human state that consists of much more than mere behaviour - by substituting saline for cocaine, is an example of reductio ad absurdum. Relapse - another complex human condition - cannot be "modelled" simply by "replacing cocaine with saline and then priming the rats with one injection of cocaine." This kind of thinking is like regarding a two-dimensional diagram of a section of human anatomy as human anatomy itself. The almost limitless number of factors resulting in human drug abuse, and the many and varied treatment approaches, cannot be reduced to "behavioural interventions such as food satiation, food deprivation, or access to an alternative reinforcer….." Humans don’t get addicted, or develop cravings, or relapse, because they eat too much, eat too little, or are hypo- or hyperglycemic.
Carroll’s plan of studying performance deficits in rats undergoing cocaine abstinence in order to understand the great difficulty human cocaine addicts have in remaining abstinent, in addition to the extrapolation problem, seems to depend exclusively on a behavioural, operant conditioning paradigm. But, as any clinician who treats human drug addicts knows, the clinical problem is much more complicated in humans than simple application of behavioural theory. If a behavioural approach were all that were necessary, then the many tried, and failed, behavioural approaches already applied to humans would have solved the problem. Applying this incorrect paradigm in rats removes it even further from the reality of substance abuse treatment, and cannot possibly either improve the paradigm or render it more relevant in humans, for humans in the real world, and rats in the laboratory, have different agendas for their cocaine use. Anyway, the paradigm doesn’t apply. It is extremely doubtful that Carroll will succeed in her grandiose claim of discovering "successful strategies for altering behaviour in all phases of drug addiction" that would "have considerable health related consequences for the prevention of initial illicit drug use, in treatment and in the prevention of relapse in human drug users." This claim might succeed in selling the grant to the funding authority, but it will not succeed in helping clinicians treating substance abusers. It does succeed in betraying the health needs of people suffering from drug addiction.
The rhesus monkey experiment is invalid by definition. Carroll herself states the monkeys must be trained to consume drugs orally and by inhalation. No one has to train humans intent on abusing drugs. The notion that these monkeys can serve as animal models of prevention by testing factors that influence acquisition is simplistic and wrong. Why? Because laboratory conditions have no relation to human street conditions, monkey and human physiology differ, causes of cocaine use between the two differ, and the many subtle factors effecting humans cannot even be conceived of, no less duplicated in the artificial and mechanistic environment of the laboratory. The attempt to "establish measures of reinforcing efficacy that can be used to evaluate behavioural and pharmacological interventions" again reduces this complex behaviour we call addiction to a mere behavioural paradigm. And use of food deprivation to induce increased drug self-administration again ignores the characteristics of the human problem, where food deprivation is barely relevant to substance abuse.
There are many difficulties inherent in the presumptions and suppositions that support using monkeys to "model" human diseases or disorders, in this case addictive disorders. Among these are:
There is no evidence that the biochemical effects of cocaine on humans and monkeys are the same;
The dopaminergic receptors thought to be effected by cocaine - at least six different types in humans - may differ in the two species;
Humans with dopamine depletion secondary to chronic cocaine use often show other disordered neuro-transmitter states, from both use of other drugs and other psychological disorders that might accompany cocaine abuse, thereby differing from the "pure" cocaine-addicted monkeys in the laboratory.
These differences are not just theoretical. They are real, and ignoring them in research protocol design can result in real disasters for humans. Such differences can result in different actions of the same drug in the two species. For example, fialuridine as a treatment for hepatitis B appeared safe in tests in monkeys, but it caused liver failure is seven of 15 humans taking the drug, five of whom died and two of whom required liver transplants. The analgesic Opren (benoxaprofen), which showed no toxicity in rhesus monkeys, produced liver failure, skin photosensitivity, and 61 deaths in humans. And Flosint, for the treatment of arthritis, was well tolerated by monkeys, but caused eight deaths in humans.
Carroll’s expressed desire to use animal models because studying these phenomena is difficult in humans is illogical. Just because a given approach is difficult doesn’t justify substituting another approach - easier, more do-able, and potentially productive of reams of data - if that approach is irrational and invalid, and is unlikely to uncover anything about human drug addiction. Difficult does not mean impossible, and rather then tinkering with simplistic variables in nonhuman species from artificial environments in order to learn about humans, common sense would dictate that humans themselves should be studied. Were the ingenuity, talent, and economic resources enjoyed by animal researchers applied to solving this difficult problem, it would be solved. But, despite its major scientific shortcomings, and despite its poor track record of success, animal experimentation continues as the paradigm of choice because the apparatus is there, the money is there, the data bases are there, and its supporters run the show.
Carroll’s research seems to confirm the validity of two slogans, one descriptive of animal research, the other critical. The first is: "Inject a chemical into a rat and produce a research paper." The second is: "Only when rats start to hide their bottles can they model human alcoholism."
Based on these considerations, it would appear that the 86 nonhuman primates used in research by 20 or so researchers at the niversity of Minnesota, and the approximately 16 used by Marilyn Carroll herself, are contributing nothing significant to medical science. I call for revocation of the NIH grants supporting this research, and for the immediate termination of Marilyn Carroll’s irrelevant and inhumane research..
(Source: MRMC Newsletter - Vol.12 No.3 Aug 1999 . For further information please contact MRMC Medical Research Modernization Committee, P.O. Box 2751, New York, NY 10163 - Ph:(212) 579-3477 - Fax: (212) 283 6702 - E-mail: stkaufman@pol.net - Website: http://www.mrmcmed.org/