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This study was conducted in order to assess whether chronic excessive alcohol consumption affects the activity of the liver enzyme tryptophan oxygenase which is rate limiting along the most important pathway of catabolism. Five alcoholics were studied twice, once shortly after admission to an Inpatient unit and the second time 1 month later. On each study day patients were given a trptophan load of 50 mg/kg. Kynurenine in the urines (which reflects tryptophan oxygenase activity) was measured for a period of 8 hr following the load and showed a significantly enhanced activity of the enzyme shortly after cessation of drinking. This increased activity enzyme could explain the lowered tryptophan levels we have previously reported in alcoholics. The increase in enzyme activity may have been mediated by a rise in glucocorticoid hormones. In all instances, plasma cortisol measured hourly for 6 hr after the start of the experiment, was higher shortly after cessation of drinking than 1 month later. [ABSTRACT FROM AUTHOR]

The prevalence of alcoholism was assessed in veterans of the Vietnam and Korean wars. In addition, the role played by exposure to combat in excessive alcohol consumption was evaluated. One-third of patients attending clinics that were not devoted to the treatment of alcoholism had alcohol-related problems. This is far in excess of general population prevalence estimates. A significant association was found between combat exposure and excessive alcohol use. Close to 60% of a group of veterans exposed to combat drank excessively at the time of our study versus only 25% of a group of veterans of the Vietnam and Korean eras. An association between alcoholism and war experiences had already been observed by others in the early postwar era. Our data show that the effects of combat exposure can persist for more than a decade after the stressful events. [ABSTRACT FROM AUTHOR]

Apomorphine, a direct-acting dopamine agonist, stimulates release of growth hormone (hGH) and suppresses release of prolactin (PRL) from the anterior pituitary. Previous studies comparing the magnitude of these responses in schizophrenics and controls suggest that many acute (and some chronic) schizophrenics have exaggerated hGH responses; many chronic schizophrenics (and patients with tardive dyskinesia) have blunted hGH responses to apomorphine, and possibly blunted PRL responses. The present studies extend and confirm these findings in chronic schizophrenics; in addition, several studies were undertaken to further characterize these apomorphine-induced endocrine responses. Studies in which apomorphine was given on 2 or 3 separate occasions to each of five subjects indicate that the hGH response is a highly reproducible individual index, but PRL suppression is a less satisfactory measure. hGH responses to apomorphine were consistently antagonized by pretreatment with haloperidol, supporting the concept that the hGH-releasing effect of apomorphine is mediated by its action on dopamine receptors. Cyproheptadine pretreatment was associated with erratic increases or decreases in the hGH response to apomorphine, but did not alter PRL levels or apomorphine-induced PRL suppression. The relationship of these findings to biological hypotheses of schizophrenia and to neuroleptic-induced receptor changes is discussed. [ABSTRACT FROM AUTHOR]

Alcohol has been observed to alter various aspects of memory function. Some of the most extreme forms of memory impairment experienced by alcoholics are blackouts. There are at present very few data on the biological mechanisms underlying alcohol-related memory impairment A variety of mechanisms including the cholinergic and catecholaminergic systems have been implicated in learning and memory. More recently, however, the importance of the serotonergic system in memory function has been demonstrated. We investigated whether patients with a history of blackouts had lower plasma levels of the serotonin precursor tryptophan than patients without such a history. Tryptophan values were significantly lower in patients who had experienced blackouts than in patients who had not No significant differences between the two group of patients were observed for other amino adds sharing with tryptophan the same transport carrier into the brain. Drinking history variables did not differentiate among the two patient groups. Our data suggest that a decrease in plasma tryptophan (and concomitant lowered brain serotonin) could increase the vulnerability of certain individuals to manifestations of various aspects of memory impairment mdudrng one of its most extreme forms, the blackout [ABSTRACT FROM AUTHOR]

Preclinical studies have shown that diets supplemented with or deficient in n-3 polyunsaturated fatty acids (PUFAs) could influence serotonergic neurotransmission, but information about their effects on the serotonergic function of humans is scant. Therefore, simultaneous assessments of n-3 PUFAs and of the adrenocorticotropic hormone (ACTH) and cortisol responses to challenges with the serotonin (5-HT) probe d,l-fenfluramine (FEN) were performed in 25 cocaine-abusing men and 12 control subjects. Cocaine abusers were tested 18 days after their admission to a closed ward. ACTH and cortisol were measured in plasma samples collected on two testing days separated by 48 h following the random administration of 60 mg of FEN or placebo. Fatty acids were measured in the first test day samples. Patients' FEN-induced ACTH rises were significantly and positively correlated with docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). Patients' cortisol rises were positively and significantly correlated with EPA but not with DHA. There were no significant correlations between hormonal responses and pre-hospitalization cocaine use parameters. Control subjects' responses to FEN were not correlated with any PUFA. In conclusion, higher EPA and DHA levels were associated with a more intense FEN-induced ACTH response and higher EPA levels with a more intense cortisol response in cocaine-abusing men withdrawn from cocaine but not in control subjects. These findings support and expand existing evidence that EPA and DHA could influence 5-HT function in some human subgroups., (2011 Elsevier Ltd. All rights reserved.)

Low levels of some polyunsaturated fatty acids (PUFAs) could influence behaviors leading to the abuse of substances through their actions on serotonergic and dopaminergic mechanisms. Because substance abusers tend to have poor dietary habits, the possibility that a deficient intake of n-3 PUFAs, available from dietary sources only, and subsequent low n-3 plasma levels would predict their relapse rates was explored. Thirty-five patients admitted to substance abuse clinics were enrolled and followed for one year. Dietary questionnaires and blood samples were collected at baseline and on a quarterly basis, and relapse rates monitored on a monthly basis. Six patients dropped out shortly after study entry, 11 relapsed in the course of the study and dropped out, 7 relapsed but completed the study, and 11 did not relapse and completed the study. Non-relapsers were found to have significantly higher levels of docosahexaenoic acid (DHA) calculated as microg/ml and % TFA, when compared to relapsers (p = .031 and p = .010, respectively) and to relapsers and non-completers combined (p = .014 and p = .009, respectively). These pilot data suggest, but do not prove, the existence of a relationship between low levels of DHA and relapse vulnerability in some individuals who abuse substances. The study of the efficacy of n-3 supplements or of dietary modifications on relapse appears warranted.

Objective: Mounting evidence indicates that low levels of n-3 polyunsaturated fatty acids (PUFAs) play a role in the pathophysiology of a large number of psychiatric disorders. In light of the suboptimal n-3 PUFAs intake due to poor dietary habits among substance abusers and the strong associations between aggression, anxiety and substance use disorders we examined if insurance of adequate intakes of n-3 PUFAs with supplementation would decrease their anger and anxiety scores., Method: Substance abusers (n=22) were assigned to either 3 g of n-3 PUFAs, mainly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) or soybean oil in identically looking capsules. The trial was double-blind, randomized and lasted 3 months. Anger and anxiety scales were administered at baseline and once a month thereafter. Blood samples were collected at baseline and at the end of the trial., Results: Patients' dietary intakes of n-3 PUFAs fell below recommended levels. Assignment to n-3 PUFA treatment was accompanied by significant decreases in anger and anxiety scores compared to placebo assignment. These changes were associated with increases in plasma levels of both EPA and DHA but an increase in EPA was more robustly correlated with low end-of-trial anxiety scores and an increase in DHA was more robustly correlated with low end-of-trial anger scores., Conclusion: These pilot data indicate that ensuring adequate n-3 PUFA intake via supplementation benefits substance abusers by reducing their anger and anxiety levels. The strong correlations between an increase in plasma EPA and lower anxiety scores and between an increase in plasma DHA and lower anger scores suggests a need for the further exploration of the differential responses to these two n-3 PUFAs in different psychiatric conditions.

It has been suggested that low levels of n-3 polyunsaturated fatty acids (PUFAs) play a role in the pathophysiology of some psychiatric disorders. In light of the existence of strong associations between high-frequency and high-severity aggressive behaviors and substance use disorders and of our observation that substance abusers have poor dietary habits, the possibility that the administration of supplements of n-3 PUFAs would decrease their anger levels was explored. A lifelong history of aggressive behaviors and problems with the law was obtained in 24 patients. Thirteen patients received on a daily basis capsules containing 3 g of n-3 PUFAs (EPA+DHA). Eleven patients received placebo capsules. The trial was double-blind, randomized, and lasted 3 months. An anger scale was administered at baseline and every month thereafter. Six PUFA group patients and eight placebo group patients were followed for an additional 3 months after treatment discontinuation. Four patients in each group had a history of assaultive behavior. The baseline fish and n-3 PUFA intakes of these eight patients were significantly lower than those of the non-aggressive patients. When given for 3 months, n-3 PUFAs were superior to placebo in diminishing anger scores. Scores remained decreased for 3 months following treatment discontinuation. These data provide further support for emerging evidence indicating that supplementation with long-chain n-3 PUFAs could be beneficial in the treatment of some individuals with aggressive tendencies.

There is mounting evidence that low levels of n-3 polyunsaturated fatty acids (PUFAs) play a role in the pathophysiology of a number of psychiatric disorders. Preclinical studies have shown that n-3 PUFAs decrease anxietylike behaviors, but there is a paucity of information about their effects on anxiety in humans. In light of our observation that substance abusers have poor dietary habits and the strong association between anxiety disorders and substance use disorders, the possibility that the administration of supplements of n-3 PUFAs would decrease the anxiety level of a group of substance abusers was explored. Thirteen patients were given on a daily basis capsules containing 3 g of n-3 PUFAS (eicosapentaenoic acid + docosahexaenoic acid). Eleven patients received similarly looking placebo capsules containing vegetable oil. The trial was double-blind, randomized, and lasted 3 months. A scale assessing anxiety feelings was administered at baseline and on a monthly basis thereafter. Six PUFA group patients and 8 placebo group patients were followed for an additional 3 months after treatment discontinuation and administered the same questionnaire monthly. Patients who received n-3 PUFAs for 3 months showed a progressive decline in anxiety scores. This was not the case for patients who received placebos. A comparison of the 2 groups was significant (P = 0.010). Anxiety scores remained significantly decreased in the PUFA group for 3 months after treatment discontinuation. A comparison of the 2 groups followed for 6 months was also significant (P = 0.042). In conclusion, these preliminary data indicate that n-3 PUFA supplementation could be beneficial in the treatment of some patients with anxiety disorders.

In an attempt to develop a new opiate detoxification approach, the authors assessed the efficacy of buspirone in the treatment of acute heroin withdrawal. Buspirone, a drug interacting with the serotonergic system, was selected because there is evidence that a decrease in serotonergic neurotransmission may be involved in opiate withdrawal symptoms. Twenty-nine hospitalized heroin addicts were randomized to 4 groups: (1) placebo; (2) methadone; (3) buspirone 30 mg daily; (4) buspirone 45 mg daily. The double-blind trial started in all patients with a 5-day methadone stabilization period ending with a 30-mg dose. This was followed from days 6 through 12 by placebo in group 1 and by a methadone taper in group 2. Because of its delayed action, buspirone was started on day 1 in groups 3 and 4 and was continued, after methadone discontinuation, through day 12. On day 13, drugs and placebo were discontinued and patients were observed through day 14. Withdrawal symptoms were assessed with the "Subjective Opiate Withdrawal Scale" (SOWS) and the "Objective Opiate Withdrawal Scale" (OOWS). The SOWS and OOWS scores were significantly higher in the placebo group than in the methadone, buspirone 30 mg, and buspirone 45 mg groups. There were no significant differences in SOWS or OOWS scores when the methadone group was compared with each of the two buspirone groups or when the two buspirone groups were compared with one another. In conclusion, buspirone, a nonopiate drug with no abuse potential, a safe side effect profile and no withdrawal symptoms, at doses of 30 and 45 mg, was as effective as a methadone taper in alleviating the withdrawal symptoms of heroin addicts stabilized for 5 days with, and then withdrawn from, methadone. The use of buspirone could be particularly helpful in outpatient settings where the duration of the methadone taper recommended for detoxification can be lengthy.

A previous study has suggested that sensitization to the psychosis-inducing effects of cocaine may be a marker of vulnerability to relapse in cocaine addiction. In this report, cocaine-dependent subjects participating in a study on naturally occurring and cue-induced cocaine craving were interviewed about prior experience of cocaine-induced psychosis and the degree to which this effect had become more frequent or severe or had occurred at lower cumulative doses. Sensitization to cocaine-induced psychosis was negatively correlated with baseline measures of drug dependence severity and indices of cocaine craving over the preceding 24 hours but not with measures of cocaine cue reactivity.

There is evidence that children with antisocial behaviors have increased plasma levels of the adrenal androgen dehydroepiandrosterone sulfate (DHEA-S) and either a decreased level of another adrenal steroid, cortisol, or a decreased cortisol responsivity to stress. Low levels of cortisol have also been reported in antisocial adults but their levels of DHEA-S have not been studied. The present study was designed to perform in adult cocaine addicts simultaneous assessments of DHEA-S and cortisol as a function of a diagnosis of antisocial personality disorder (adult symptoms) and of a retrospective diagnosis of conduct disorder (CD). Basal cortisol and DHEA-S were determined in the plasma samples of 40 hospitalized men. The patients' cortisol responsivity was also assessed while they were being exposed to a stressful situation. Patients who had a retrospective CD diagnosis had significantly increased DHEA-S levels and secreted less cortisol when stressed. Comparisons between patients who did and did not meet the antisocial personality disorder adult criteria did not reveal any significant difference in DHEA-S or in cortisol responsivity. This could be attributed to the nature of the criteria used to define the adult disorder, which focus mostly on a failure to conform to social norms, whereas a number of CD criteria involve displays of some degree of violence. In conclusion, adults who retrospectively qualified for a CD diagnosis had increased DHEA-S levels and a decreased cortisol reactivity, confirming observations made in children and indicating that mechanisms underlying adrenal steroid alterations in childhood could still be at play in adulthood.

There is mounting evidence that low levels of some polyunsaturated fatty acids (PUFAs) play a role in the pathophysiology of depressive and aggressive disorders, including homicides. There is also evidence derived mostly from the animal literature that PUFAs could play a role in the abuse of substances through their action on central serotonergic and dopaminergic systems that are both known to play a role in reward mechanisms. In this study, we explored the possibility that the relapse rates of cocaine addicts discharged after a period of detoxification on an inpatient unit would be associated with their PUFA status. Thirty-eight patients were enrolled in the study. PUFA status was assessed only at baseline, shortly after admission. Resumption of substance use was assessed 3 months, 6 months and 1 year following discharge. Thirty-two patients remained available for follow-up for the duration of the study. Subjects who relapsed at 3 months had significantly lower baseline levels of total n-6 PUFAs, linoleic acid (LA, 18:2n-6), arachidonic acid (AA, 20:4n-6) and total n-3 PUFAs when compared to non-relapsers by ANCOVAs with age and weight as covariates. Lower baseline total n-6 PUFAs, LA and AA continued to predict relapse 6 months and 12 months following discharge. Age, marital status, educational level, cocaine use parameters or psychopathology did not differ between relapsers and non-relapsers. In conclusion, low PUFA status at baseline was a better predictor of relapse than cocaine use, sociodemographic or clinical parameters. These data suggest, but do not prove, the existence of a causal relationship between n-6 or n-3 status and relapse vulnerability in cocaine addicts, and provide a rationale for the exploration of possible relationships between relapse to addictive disorders and PUFA status in observational and interventional trials.

The purpose of this study is to evaluate the effectiveness of buspirone in attenuating withdrawal symptoms in heroin addicts and methadone-maintained patients following cessation of heroin or methadone use. Subjects were twenty hospitalized male chronic opiate users aged 30-55 who did not present any DSM-IV Axis I disorder with the exception of opioid dependence. For the first five days, patients received doses of methadone that were decreased to 30 mg and were maintained on this dose for the following three days. Methadone was then discontinued, and patients were randomly assigned to buspirone or placebo treatment from day nine to seventeen. The buspirone dose was 15 mg on day nine and 30 mg from day ten to day seventeen. Treatment was double-blind. Withdrawal symptoms were measured with the Objective Opiate Withdrawal Scale (OOWS) and the Subjective Opiate Withdrawal Scale (SOWS). Buspirone-treated patients had significantly lower scores on the OOWS on days thirteen (p=.040), fourteen (p=.025), fifteen (p=.035), and seventeen (p=.035). They also had lower scores on the SOWS on days sixteen (p=.050). It is concluded that buspirone was effective in attenuating the objective and subjective withdrawal symptoms that follow opiate use cessation.

The authors studied the effects of a challenging dose of the serotonin (5-HT)-releaser/reuptake inhibitor d,l-fenfluramine (FEN) on spontaneous cocaine craving in a group of cocaine-addicted users in order to evaluate the involvement of serotonergic pathways in the modulation of craving for cocaine. Nineteen cocaine-dependent male inpatients received 60 mg of FEN or placebo (double-blind). Data were compared with those obtained in a previous study of another serotonergic probe, the partial postsynaptic agonist meta-chlorophenyl-piperazine (m-CPP). FEN significantly reduced cocaine craving and increased cortisol and prolactin when compared with placebo. When the responses to the two drugs were compared, there were no differences in the cortisol and prolactin rises, but m-CPP was a more potent inhibitor of cocaine craving than FEN. These data suggest that 5-HT releasers/reuptake inhibitors and serotonergic agents with greater postsynaptic activity should be further examined.

The purpose of this study was to determine if cerebral blood flow (CBF) alterations are associated with discontinuation of heroin in chronic heroin users, and whether these alterations are reversible during abstinence. Ten physically healthy opioid-dependent males, hospitalized on an inpatient drug rehabilitation unit, were studied. Each patient had an initial single photon emission computed tomographic (SPECT) scan with the radiotracer technetium-99m-d,l-hexamethylpropyleneamine oxime (99mTc-HMPAO) 1 week after opiate discontinuation and a repeat scan 2 weeks later. The initial scans in 9 of the 10 subjects demonstrated significant, often discrete, perfusion defects, especially in the frontal, parietal, and temporal cortices. Two weeks later, repeat brain perfusion SPECT scans showed improvement in all nine subjects who had abnormal scans. Comparisons of the first scan with the second scan showed an increase in cortical uptake on the repeat SPECT study. All subjects had normal computed tomographic or magnetic resonance imaging scans. The results of this preliminary study suggest that the chronic use of opiates, like chronic use of cocaine, results in perfusion abnormalities without corresponding abnormalities on imaging studies of cerebral anatomy and morphology. This study also documents that these perfusion defects are partially reversible with short-term abstinence.

In view of recent trends toward the replacement of traditional inpatient rehabilitation programs with nonresidential services, we examined the extent to which patients currently admitted to inpatient rehabilitation for alcohol or drug abuse/dependence met published criteria suggesting a preferential need for inpatient or residential care. Over 90% of almost 300 veterans with a primary DSM-III R diagnosis of alcohol or substance abuse/dependence, admitted to six New York Metropolitan Area Veterans Administration Medical Centers for inpatient rehabilitation, met at least one criterion dimension considered indicative of a need for such services, with over two-thirds meeting two or more dimensions. These findings suggest a continuing need for initial primary inpatient or residential rehabilitation for such patients.

The morbidity risks for alcoholism in the first-degree relatives of a cohort of male cocaine addicts with or without alcoholism comorbidity were studied. Of the 71 patients who participated in our study, 40 (56.3%) had a history of alcoholism and 37 (59.1%) a history of opioid abuse. Twenty-two patients (30.1%) also met criteria for a lifetime diagnosis of a major psychiatric disorder. Significant increases in morbidity risks for alcoholism were found among male relatives of cocaine addicts with comorbid alcohol dependence when compared with relatives of cocaine addicts with no alcohol comorbidity. Among fathers, risks were .69 vs .32 (z = 2.98, p < .003). Among brothers, risks were .38 vs .15 (z = 2.35, p < .03). Significantly increased risks were also observed in male relatives when probands with a psychiatric diagnosis were excluded from the analyses. Among female relatives, increases in morbidity risks were found but they failed to reach statistical significance. Two interpretations are consistent with these findings. One of these interpretations is that alcoholism is a disorder distinct from other addictions and has its own mode of transmission. The second interpretation is that the transmission of substance use disorders lacks specificity and that the substances selected are influenced by sociocultural or biological factors.

The effect of chronic ethanol consumption on plasma and erythrocyte membrane lipids were studied in rats fed a liquid diet containing ethanol for 4 weeks and intubated with the same diet 90 min prior to killing. Control animals underwent the same treatment, except that their liquid diet did not contain ethanol, but an isocaloric amount of carbohydrates. Plasma total cholesterol, free (unesterified) cholesterol and HDL cholesterol were higher in ethanol-fed animals than in controls. Phospholipids were also higher in the plasma of ethanol-fed animals when compared to controls so that the plasma cholesterol/phospholipid ratio (Ch/PL ratio) of the two groups did not differ significantly, regardless of the cholesterol fraction considered. Experimental and control animals did not differ either in the Ch/PL ratio of their erythrocyte membranes. In view of the fact that it has been suggested that the factor determining the direction of the cholesterol exchanges between plasma and erythrocyte membranes is the equilibrium between their respective Ch/PL ratios, these results are interpreted as being compatible with the hypothesis that the effect of chronic ethanol intake on erythrocyte membrane lipids is mediated through changes in plasma lipids.