Cocaine use disorder patients develop distinct patterns of regulation of acth secretion by a vasopressin agonist and oxytocin: Report on a laboratory study.

Background: : Oxytocin and Vasopressin systems in the brain sustain adaptation to stressors. Cocaine being a stressor, it may alter brain homeostatic function. This dysregulation may entrench cocaine use disorder. Method: : This is a human laboratory study of the effects of intranasal desmopressin (a Vasopressin 1b receptor agonist) and oxytocin on ACTH secretion in cocaine use disorder patients versus a control group. It consisted of two endocrine challenges performed on consecutive days. On day 1, the effect of intranasal desmopressin (80 IU) on ACTH secretion was measured. On day 2, a pre-treatment with intranasal oxytocin (24 IU) preceded intranasal desmopressin to monitor its effect on desmopressin-induced ACTH secretion. We hypothesized that the effect of intranasal oxytocin in controls would differ from the effect in cocaine use disorder patients. Results: : Forty-three patients were included in this study: 14 controls and 29 cocaine use disorder patients. Significant differences were noted in the direction of change of ACTH secretion between the two groups. In cocaine use disorder patients, overall ACTH secretion was on average 2.7 pg/ml/min higher after intranasal desmopressin than after intranasal oxytocin/desmopressin (t292 = 2.91, p = 0.004). The opposite was observed in controls: overall ACTH secretion averaged 3.3 pg/ml/min less after intranasal desmopressin than after intranasal oxytocin/desmopressin (t292 = -2.35, p = 0.02). Conclusion: : Intranasal oxytocin and desmopressin revealed a pattern of ACTH secretion in cocaine use disorder patients that is distinct from a non-addicted control group. (ClinicalTrial.gov00255357, 10/2014).

Dysregulation of diurnal cortisol secretion affects abstinence induction during a lead-in period of a clinical trial for depressed cocaine-dependent patients.

BACKGROUND AND OBJECTIVE: Hypothesizing that stress dysregulation may worsen cocaine dependence, we investigated the effect of diurnal cortisol secretion profile, suppression of cortisol secretion, and total cortisol secretion on retention, abstinence-based voucher earnings, days of cravings, and mood status of participants at the end of a 2-week medication-free lead-in prior to randomization in a clinical trial of mirtazapine (60 mg vs. placebo) for depressed cocaine-dependent patients. METHODS: We measured saliva cortisol levels at 9 AM, 2 PM, and 5 PM on the first two consecutive days of a 2-week medication-free lead-in period. Results from saliva samples were used to estimate the total daily level of cortisol, the diurnal profile of secretion (typical vs. atypical), and response to dexamethasone suppression (.1 mg). Seventy-seven patients collected saliva samples at baseline, and 65 (85%) were suitable for profile analysis. RESULTS: Patients with typical profiles (52%) collected significantly more abstinence-based voucher earnings during the lead-in (U = 299.50, p = .025). Diurnal secretion profile did not significantly affect mood status, days of craving, or retention. There were no significant effects of suppression of cortisol secretion or of total cortisol levels on any outcome measures. CONCLUSION: In a subgroup of cocaine-dependent patients, deviation of cortisol secretion away from the homeostatic diurnal pattern was associated with reduced success at achieving early abstinence, an important determinant of treatment success.

A randomized, double-blind, placebo-controlled trial of venlafaxine for the treatment of depressed cocaine-dependent patients.

OBJECTIVE: This study tested the hypothesis that the antidepressant venlafaxine would be an effective treatment for cocaine abusers with concurrent depressive disorders. METHODS: This was a randomized, 12-week, double-blind, placebo-controlled trial of outpatients (N = 130) meeting DSM-IIIR criteria for cocaine dependence and major depression or dysthymia (by SCID interview). Participants were treated with venlafaxine, up to 300 mg/day versus placebo. All patients received weekly individual manual-guided relapse prevention therapy. Weekly outcome measures included Clinical Global Impression Scale (CGI), self-reported cocaine use, urine toxicology and the Hamilton Depression Scale (Ham-D). RESULTS: Mood response, defined as a 50% reduction in the Ham-D between randomization and end of study, was 41% (26/64) on venlafaxine, and 33% (22/66) on placebo (p = .39). Measures of depression (Ham-D and CGI) improved more rapidly on venlafaxine than placebo, but these differences disappeared by weeks 6-8. Cocaine outcomes did not differ between treatment groups, and the proportion of patients achieving three or more consecutive weeks of urine-confirmed abstinence was low (venlafaxine: 16%; placebo: 15%). Reduction in cocaine use was associated with mood response. CONCLUSIONS: Overall, venlafaxine was not superior to placebo on either mood or cocaine use outcomes. Mood improvement was associated with improvement in cocaine use. However, placebo mood response was only moderate, and the proportion of patients achieving sustained abstinence was low. This suggests that the subgroup of cocaine-dependent patients with depressive disorders is relatively treatment resistant, and that further research is needed to improve outcomes for these patients.

Intermittent marijuana use is associated with improved retention in naltrexone treatment for opiate-dependence.

Naltrexone is a theoretically promising alternative to agonist substitution treatment for opioid dependence, but its effectiveness has been severely limited by poor adherence. This study examined, in an independent sample, a previously observed association between moderate cannabis use and improved retention in naltrexone treatment. Opioid dependent patients (N = 63), admitted for inpatient detoxification and induction onto oral naltrexone, and randomized into a six-month trial of intensive behavioral therapy (Behavioral Naltrexone Therapy) versus a control behavioral therapy (Compliance Enhancement), were classified into three levels of cannabis use during treatment based on biweekly urine toxicology: abstinent (0% cannabis positive urine samples); intermittent use (1% to 79% cannabis positive samples); and consistent use (80% or greater cannabis positive samples). Intermittent cannabis users showed superior retention in naltrexone treatment (median days retained = 133; mean = 112.8, SE = 17.5), compared to abstinent (median = 35; mean = 47.3, SE = 9.2) or consistent users (median = 35; mean = 68.3, SE = 14.1) (log rank = 12.2, df = 2, p = .002). The effect remained significant in a Cox model after adjustment for baseline level of heroin use and during treatment level of cocaine use. Intermittent cannabis use was also associated with greater adherence to naltrexone pill-taking. Treatment interacted with cannabis use level, such that intensive behavioral therapy appeared to moderate the adverse prognosis in the consistent cannabis use group. The association between moderate cannabis use and improved retention on naltrexone treatment was replicated. Experimental studies are needed to directly test the hypothesis that cannabinoid agonists exert a beneficial pharmacological effect on naltrexone maintenance and to understand the mechanism.

Betting on change: modeling transitional probabilities to guide therapy development for opioid dependence.

This study investigated the process of change by modeling transitions among four clinical states encountered in 64 detoxified opiate-dependent individuals treated with daily oral naltrexone: no opiate use, blocked opiate use (i.e., opiate use while adhering to oral naltrexone), unblocked opiate use (i.e., opiate use after having discontinued oral naltrexone), and treatment dropout. The effects of baseline characteristics and two psychosocial interventions of differing intensity, behavioral naltrexone therapy (BNT) and compliance enhancement (CE), on these transitions were studied. Participants using greater quantities of opiates were more likely than other participants to be retained in BNT relative to CE. Markov modeling indicated a transition from abstinence to treatment dropout was approximately 3.56 times greater among participants in CE relative to participants in BNT, indicating the more comprehensive psychosocial intervention kept participants engaged in treatment longer. Transitions to stopping treatment were more likely to occur after unblocked opiate use in both treatments. Continued opiate use while being blocked accounted for a relatively low proportion of transitions to abstinence and may have more deleterious effects later in a treatment episode. (PsycINFO Database Record (c) 2009 APA, all rights reserved).

Dronabinol reduces signs and symptoms of idiopathic intracranial hypertension: a case report.

A case is presented in which a woman diagnosed with a longstanding history of idiopathic intracranial hypertension reported improvement of frontal headaches, photophobia, transient blindness, enlarged blind spots, and tinnitus after smoking marijuana. All these symptoms and signs were associated with increased intracranial pressure (220-425 mm of water). Treatment with dronabinol at a dose of 10 mg twice a day, then reduced to 5 mg twice a day, relieved all of her symptoms. Previously noted papilledema and enlargement of blind spots also resolved, and this, in the absence of psychoactive effect or weight gain.

Temperament characteristics, as assessed by the tridimensional personality questionnaire, moderate the response to sertraline in depressed opiate-dependent methadone patients.

During a randomized, double-blind, placebo controlled study of the effects of sertraline in depressed methadone-maintained patients, 82 completed the tridimensional personality questionnaire (TPQ) to assess whether temperament dimensions can affect treatment-related changes in mood and drug use. Mood outcome significantly differed according to scores on the reward dependence scale (RD). Low RD participants displayed a significantly better mood response to sertraline than high RD participants. Participants with high harm avoidance (HA) scores were more likely to be abstinent at the end of the 12 week trial of sertraline than low HA participants. High persistence (P) participants were less likely to be abstinent at the end of the 12-week trial. These results suggest that temperament dimensions may be important for identifying substance dependent patients more likely to benefit from pharmacological interventions for comorbid depressive disorders.

Gabapentin reduces cocaine use among addicts from a community clinic sample.

BACKGROUND: Individuals with chronic psychiatric conditions display a high rate of cocaine use. Gabapentin was hypothesized to reduce cocaine use by restoring inhibitory GABAergic feedback on ascending dopaminergic projections to nucleus accumbens neurons. METHOD: Nine participants with DSM-IV cocaine dependence were selected from patients attending a large community psychiatric clinic. During a 24-week open-label trial of gabapentin (800-2400 mg/day), qualitative urine drug screens were collected from the participants up to 3 times per week. Data were collected from September 1999 to May 2001. RESULTS: With gabapentin, the mean +/- SD number of cocaine-positive urine screens decreased from 53.11 +/- 13.23 to 35.22 +/- 14.84 (t = 3.58, N = 9, p <.01). The number of weeks of abstinence from cocaine increased from 2.1 +/- 1.5 to 8.0 +/- 5.5 (t = 3.21, N = 9, p <.01). CONCLUSION: Gabapentin appeared to be a safe and efficacious medication to reduce cocaine usage in a community sample of psychiatric patients.