Ethical, scientific and clinical issues in ethanol administration research involving alcoholics as human subjects.

Research involving the administration of ethanol to human subjects has been conducted with some regularity since the 1960s. The purpose of this paper is to provide a broader discussion of the ethical and clinical issues pertaining to the administration of ethanol to subjects with a history of alcohol dependence and to assess the potential benefits and risks of ethanol administration research. Three kinds of investigation are reviewed: (1) basic scientific research on alcohol dependence and related disabilities; (2) clinical research that involves ethanol administration as part of the treatment; and (3) studies that have evaluated the short- and long-term effects of ethanol administration on the health and wellbeing of alcoholic research participants. It is concluded that ethanol administration research has not only contributed to the fund of knowledge about basic mechanisms of alcohol dependence; it has also advanced the scientific understanding of treatment. Moreover there is no compelling evidence that participation in ethanol administration research per se has adverse effects on alcoholic research subjects. In the interests of developing a practical approach to the ethical dilemmas posed by ethanol administration research, an ethical review process is suggested that takes into account the principles of respect for people, beneficence, and justice by tailoring the risk/benefit analysis to four types of research subjects: alcoholics recruited directly from the community, subjects recruited from residential treatment settings, recovering alcoholics, and alcoholics in outpatient treatment.

Types of alcoholics: concurrent and predictive validity of some common classification schemes.

This study evaluated the discriminative power and predictive validity of five common typological schemes used to classify alcoholics for theoretical or clinical purposes. A heterogenous sample of 321 alcoholics was classified according to primary vs secondary alcoholism, parental alcoholism, Fellinek's gamma-delta distinction, gender, and subtypes derived from MMPI profiles. A prospective longitudinal cohort design was employed to compare the relative ability of these typologies to differentiate alcoholics according to natural history, alcohol-related consequences, response to treatment, and post-treatment adjustment. The findings indicate that while 'one-dimensional' typologies discriminate subgroups in terms of etiological variables, presenting symptoms, and drinking patterns, none of the classification systems emerges as a strong predictor of outcome status. In addition, these typologies do not discriminate well with respect to the alcoholic's drinking patterns and presenting symptoms, except in areas closely connected with the model (e.g. alcoholics with antisocial personality (ASP) indicate more social problems related to alcohol use than do primary alcoholics). Because there is a great deal of overlap among certain subtypes identified within different typological models (e.g. alcoholics with primary ASP tended to have a positive family history and a gamma pattern of impaired control), we hypothesize that empirical clustering techniques that search for naturally occurring commonalities among alcoholics may be a better way to identify homogeneous subtypes.

Types of alcoholics, I. Evidence for an empirically derived typology based on indicators of vulnerability and severity.

An empirical clustering technique was applied to data obtained from 321 male and female alcoholics to identify homogeneous subtypes having discriminative and predictive validity. The clustering solution identified two "types" of alcoholics who differed consistently across 17 defining characteristics in the male and female samples. One group, designated type A alcoholics, is characterized by later onset, fewer childhood risk factors, less severe dependence, fewer alcohol-related problems, and less psychopathological dysfunction. The other group, termed type B alcoholics, is characterized by childhood risk factors, familial alcoholism, early onset of alcohol-related problems, greater severity of dependence, polydrug use, a more chronic treatment history (despite their younger age), greater psychopathological dysfunction, and more life stress. The two types also differed with respect to treatment outcome assessed prospectively at 12 and 36 months. The results are consistent with historical and contemporary typological theories that have postulated similar subgroups of alcoholics. The findings suggest that an empirically derived, multivariate typology of alcoholism has theoretical implications for explaining the heterogeneity among alcoholics and may provide a useful basis for predicting course and estimating treatment response.

Ethanol beverage anticipation: effects on plasma testosterone and luteinizing hormone levels--a pilot study.

Levels of plasma testosterone (T) and luteinizing hormone (LH) were evaluated in alcoholic and control subjects while they smelled a real beer and then drank a placebo beer which they believed contained alcohol. Plasma T and LH differed in the alcoholics and controls during beverage presentation and T levels also differed during drink consumption. Although these results suggest a role for conditioned responses, the lack of concordance between the hormone levels and psychophysiological responses or self-report desire to drink does not support a conditioning hypothesis that could account clearly for consumption behavior. Alternative hypotheses are discussed.

Discriminant function analysis of clinical laboratory data. Use in alcohol research.

There has been a growing interest in the use of discriminant function analysis of routinely collected laboratory data to differentiate between alcoholic and nonalcoholic individuals. However, no consensus has been reached concerning the validity and reliability of this form of analysis regarding the diagnosis of, or screening for, alcoholism. In addition, this technique may provide important information concerning the multivariate nature of the pathophysiological effects of alcohol. However, this issue is seldom discussed. Because of differences in methodology across studies and the growing confusion regarding conceptual issues associated with this statistical technique, there have been few critical reviews. This chapter is directed at critically evaluating the current literature, particularly with respect to the methodological and conceptual issues associated with the use of discriminant function analysis in alcohol research. As part of this approach we suggest guidelines for future research in this area.

Psychopathology as a predictor of treatment outcome in alcoholics.

We performed a one-year follow-up study of 266 alcoholics who had received extensive psychiatric assessment, including diagnosis with the National Institute of Mental Health Diagnostic Interview Schedule and DSM-III criteria, during their index treatment episode. The aims were to evaluate the relationship between additional DSM-III diagnoses in alcoholics and outcome at follow-up, assess the relative prognostic power of different ways of measuring psychopathology by comparing categorical DSM-III diagnoses and a global symptom severity measure, and assess whether ratings of psychopathology add to the prognostic power of an alcohol-dependence measure. While coexistent psychiatric diagnoses generally predicted poorer treatment outcome, there were significant interactions in the relationship between diagnoses and treatment outcome for men and women. For men, having an additional diagnosis of major depression, antisocial personality, or drug abuse was associated with poorer outcome. For women, having major depression was associated with a better outcome in drinking-related measures, while antisocial personality and drug abuse were associated with poorer prognosis. The value of determining psychiatric diagnosis was supported by covariance analyses that suggested that prognostic significance of specific disorders was not accounted for by general psychopathology or general dependence dimensions.

Neuroendocrine, psychophysiological and subjective reactivity to an alcohol placebo in male alcoholic patients.

Alteration in neuroendocrine activity associated with the regulation of energy metabolism and food intake may play a role in characterizing the alcohol dependent state. Alcoholics, when compared to controls, demonstrated significantly larger and more rapid glucose and insulin responses following the consumption of a placebo beer, which they believed contained alcohol. The existence of significant correlations between peak neuroendocrine responses and desire to drink, anxiety, as well as psychophysiological responses in alcoholics suggests the potential multivariate nature of the biological/behavioral state associated with alcohol dependence.

The progression of behavioral and pathological effects of the parasite Toxocara canis in the mouse.

Toxocara canis, the parasitic roundworm of the dog may infect aberrant hosts including mice and humans. The present study examined the behavioral and pathological changes at each of three postintubation periods (Period 1: 8-10 days, 2: 49-51 days, and 3: 84-86 days postintubation, respectively) in independent groups of mice intubated with 1000 eggs of T. canis. Eight-ten days after intubation Toxocara infected animals typically showed depressed levels of activity relative to saline-intubated controls. The scope and severity of behavioral changes were attenuated when different mice were tested 49-51 days after infection, and then became more severe when the third set of animals was tested 84-86 days after intubation. While brain pathology increased over the three periods, visceral organs showed marked pathology 8-10 days after intubation followed by a decrease in severity. These data suggest that Toxocara associated pathological changes in visceral organs and in the brain have behavioral consequences in mice. Given the similarity in migratory pathways of this parasite in rodents and humans, and the findings of T. canis larvae in human brain tissue, the results of this animal study may have implications concerning the possible etiology of behavioral disorders for children who have a known history of pica for dirt.

Basic aspects of blood platelet monoamine oxidase activity in hospitalized men alcoholics.

Platelet MAO activity (tryptamine as substrate) was assessed in 44 hospitalized men alcoholics to examine the relationships between MAO levels and variables related to alcohol misuse and physiological status. Mean MAO levels were lower in this population than in normal controls and hospitalized psychiatric patients. MAO activity correlated with age but was independent of variables derived from self-reported drinking histories and scales of alcohol dependence. Similarly, platelet MAO activity was not related to the misuse of other drugs. Of the variance in MAO activity, 38% could be accounted for by age, and the values of Mg++, low density lipoproteins and eosinophil combined. The significance of low platelet MAO activity in alcoholics is discussed.

Elevated endogenous breath acetaldehyde levels among abusers of alcohol and cigarettes.

Endogenous (fasting) breath acetaldehyde levels were assessed as a discriminator between alcoholic and non-alcoholic subjects. The influence of smoking as a potential confounding variable on breath acetaldehyde was determined. Individuals with a history of smoking and/or drinking had higher endogenous breath acetaldehyde levels as compared to controls. Mean acetaldehyde levels revealed an additive (noninteractive) pattern associated with combined abuse of these substances. The similarity in acetaldehyde levels between alcoholic non-smokers and non-alcoholic smokers limits the usefulness of endogenous breath acetaldehyde for the purpose of early diagnosis of alcoholism. Results support hypotheses that elevations in acetaldehyde could be a common factor in disease associated with alcohol and cigarette abuse.

Dietary ascorbic acid deficiency in guinea pigs: no effect on ethanol preference, spiroperidol binding, or monoamine oxidase activity.

Ascorbic acid levels are commonly reported to be decreased in alcoholics. Although this deficiency could be due to dietary factors, there is evidence that ascorbic acid may be involved in the metabolism and acute effects of ethanol, possibly related to the pathogenesis of alcoholism. Therefore, we examined ethanol preference in guinea pigs receiving an ascorbate deficient vs a normal diet. Brain and spleen ascorbic acid levels were dramatically decreased, but ethanol preference was not altered by the acute dietary deficiency of this vitamin. In addition, an acute stressor (cold water swim), alone or in combination with ascorbate deficiency, had no effect on ethanol preference. At termination of the experiment, two measures of brain aminergic function (MAO activity and 3H-spiroperidol binding), purportedly altered by ethanol or ascorbic acid or both, were not associated with tissue ascorbate levels.

Neuropathological studies of experimental toxocariasis in lead exposed mice.

Binghamton Heterogeneous stock mice intubated with embryonated eggs from the common parasite of dogs, Toxocara canis, display dramatic alterations in behavior. Many of these behavioral changes are markedly attenuated if mice are maintained also on a drinking solution containing lead acetate. The data presented here, however, show that the extensive neural degeneration of the CNS occurs after T. canis infection and that the nature and extent of this degeneration is similar, regardless of whether mice had been administered parasites alone or in combination with lead. Thus the neuropathological data reported in detail here cannot account for the striking interactive influence of T. canis and lead on behavior.

Behavioral changes in mice following lead administration during several stages of development.

How lead ingestion during different developmental periods influences activity of mice was investigated. Binghamton Heterogenous Stock (HET) mice were assigned to one of four groups defined by a 2 X 2 factorial in which the only available drinking fluid was either lead (L) or water (C) from the time of mating to birth or from birth to the end of the experiment. Thus, a control group (CC) received water throughout, whereas the other three groups received a 0.5% lead acetate solution at the time they were mated (LC) or when pups were discovered (group CL), or throughout the experiment (group LL). The effects of these exposure regimes on activity were assessed in an open field or a running wheel when the mice were 25 days of age and then again when they were 55 days old. Aspects of agonistic behavior were also examined in these animals. Mice that received lead only following birth (CL group) appeared most affected in the open field and in running wheels. But, both the direction and degree of this effect were influenced by the specific test situation and measures as well as by the age of the mouse when tested. For example, the CL group crossed the most squares in the open field at both ages. However, the CL group was less active during their first day in the running wheels when 25 days old, but not when 55 days old. In general, activity of the LC group was least affected by administration of lead, but the effects of continued exposure to this toxic substance (LL group) were not simply additive. In contrast to measures of activity, agonistic testing at 60 days of age showed that all groups that had been or were being exposed to lead (CL, LC, LL) displayed a shorter latency to fight when compared to the control group (CC).

Behavioral effects of lead and Toxocara canis in mice.

Adult mice were administered the common parasite Toxocara canis or lead or both. The parasite clearly altered mouse performance on tests of exploration, activity, learning, and motor coordination; behavioral effects in mice receiving lead alone were less general. Consequence of Toxocara administration appeared attenuated in animals receiving both agents. Parasite larvae were found in the central nervous system in all infected mice.

Toxocara canis and lead alter consummatory behavior in mice.

Ingestion of palatable and unpalatable solutions was measured in adult mice in which had been administered the common parasite of the dog, Toxocara canis alone, or in combination with lead. In addition, response to hot plate and susceptibility to electroconvulsive seizure were also measured. Results from the palatability test indicated that either lead or Toxocara may alter the mouse's mode of interacting with its environment. However, the two agents in combination interacted in their effects on consummatory behavior. Results from the hot plate and ECS measures were less clear with respect to how lead and/or Toxocara influence temperature reactivity and seizure susceptibility. Histological examination of the CNS in parasite infected animals revealed Wallerian Type degeneration of fiber pathways including the corpus callosum, olfactory tract, and cerebellar penduncles.