Higher n-3 fatty acids are associated with more intense fenfluramine-induced ACTH and cortisol responses among cocaine-abusing men.

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intense FEN-induced ACTH response and higher EPA levels with a more intense cortisol response in cocaine-abusing men withdrawn from cocaine but not in control subjects.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.

Low plasma levels of docosahexaenoic acid are associated with an increased relapse vulnerability in substance abusers.

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.

Long-chain n-3 polyunsaturated fatty acids decrease feelings of anger in substance abusers.

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.

Associations between increases in plasma n-3 polyunsaturated fatty acids following supplementation and decreases in anger and anxiety in substance abusers.

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.

n-3 polyunsaturated fatty acids decrease anxiety feelings in a population of substance abusers.

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.

Efficacy of buspirone in the treatment of opioid withdrawal.

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.

Sensitization to the psychosis-inducing effects of cocaine compared with measures of cocaine craving and cue reactivity.

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.

Cocaine addicts with conduct disorder are typified by decreased cortisol responsivity and high plasma levels of DHEA-S.

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.

Polyunsaturated fatty acid status and aggression in cocaine addicts.

BACKGROUND: There is mounting evidence that low levels of some polyunsaturated fatty acids (PUFAs) play a role in the pathophysiology of aggressive disorders. PUFA status is influenced by nutritional factors and because of our observation that some substance abusers have poor dietary habits, we explored the possibility that the fatty acids (FA) profiles of cocaine addicts with and without aggressive tendencies would differ. We also explored the possibility that their FA levels would change after a 2 week stay on an inpatient unit where a standard diet would be provided. METHODS: Plasma levels of FAs were measured in 24 cocaine addicts admitted to an inpatient substance abuse unit. Six patients had a past history of aggression and 18 did not. RESULTS: A comparison of the FA levels of aggressive and non-aggressive patients performed 3.7+/-2.0 days after their admission did not reveal any significant difference in saturated FAs (SFAs) or monounsaturated FAs (MFAs). Aggressive patients had significantly lower levels of the n-6 PUFA docosapentaenoic acid (DPA), of total n-3 PUFAs and of the n-3 PUFA docosahexaenoic acid (DHA), and a marginally significant increase in the ratio of n-6 to n-3 PUFAs. Measurements performed 18.4+/-1.3 days after admission showed that most FAs had increased in the two patient groups. Some PUFAs, especially those of the n-3 series, increased more sharply in the aggressive patients. As a result, PUFA differences between groups that were present shortly after admission became non-significant. CONCLUSIONS: These data suggest that patients' diets prior to their hospitalization were less than optimal and that the diet of the aggressive individuals might have been particularly deficient in n-3 rich nutrients. These data also give additional support to evidence indicating a possible link between an n-3 deficiency and aggression in humans.

Polyunsaturated fatty acid status and relapse vulnerability in cocaine addicts.

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.

Effects of buspirone in withdrawal from opiates.

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.

Association between low plasma levels of cholesterol and relapse in cocaine addicts.

OBJECTIVE: In light of recent studies suggesting the existence of associations between low concentrations of cholesterol and various psychiatric disorders, we decided to explore relationships between cholesterol levels and relapse rates in a group of cocaine addicts who had undergone inpatient detoxification. METHODS: The total cholesterol levels of 38 non-opiate-dependent and non-alcohol-dependent cocaine addicts were determined while they were hospitalized. Drug use was subsequently assessed 3, 6, and 12 months after patients were discharged from the hospital. RESULTS: Comparisons of the cholesterol levels (obtained during hospitalization) of relapsers and nonrelapsers by analyses of covariance with age and weight as covariates revealed significantly lower cholesterol values in patients who relapsed at 3 months (p =.046), 6 months (p =.030), and 12 months (p =.019) after discharge. CONCLUSIONS: This study showed an association between a low total cholesterol level and relapse rates in detoxified cocaine addicts. Reasons for the predictive value of low cholesterol levels for relapse for up to 1 year after cholesterol measurements were made are unclear. These data are preliminary and in need of replication.

Perturbations of plasma cortisol and DHEA-S following discontinuation of cocaine use in cocaine addicts.

Changes in plasma levels of cortisol and dehydroepiandrosterone sulfate (DHEA-S) following cocaine discontinuation were assessed in hospitalized chronic cocaine users. Measurements were performed after 6, 9, 18 and 21 days of abstinence. Repeated measures ANOVAs revealed significant time effects for cortisol (P<0.02) and DHEA-S (P<0.001). Changes in the two hormones did not follow the same course. Levels of cortisol were highest on day 6 and then subsequently decreased, whereas DHEA-S levels were low on day 6 and highest on day 18. Repeated measures ANCOVAs were used to test the overall effects of total duration of cocaine use, daily or weekly cocaine amounts consumed, or frequency of use on cortisol secretion. Analyses revealed a significant effect of frequency of use only (P<0.04). More sustained cocaine use was associated with higher cortisol levels and less pronounced cortisol decline after discontinuation of cocaine use, but drug intake variables had no influence on DHEA-S. The effects of presence or absence of life-long histories of aggression were also assessed. Repeated measures ANOVAs revealed a near significant group x time interaction for cortisol, which declined more dramatically in aggressive addicts than in non-aggressive addicts after day 6. DHEA-S was consistently higher in aggressive cocaine addicts, although this effect did not reach statistical significance. There was a noticeable difference in the dynamics of normalization of adrenal hormones between the two groups, with DHEA-S/cortisol ratios rising more dramatically during cocaine abstinence in aggressive than in non-aggressive addicts. In conclusion, lingering neuroendocrine perturbations persist after discontinuation of cocaine use in addicts. Some of these changes could be associated with an increased relapse risk.