DHEAS and POMS measures identify cocaine dependence treatment outcome.

UNLABELLED: Early attrition is a significant problem in the treatment of cocaine dependence, but it is unclear why some patients succeed in treatment while others relapse or drop out of treatment without a demonstrated relapse. The goal of this study was to determine whether baseline levels of select hormones, including the adrenal hormone and excitatory neurosteroid dehydroepiandrosterone sulfate (DHEAS), would distinguish between treatment outcome groups. Based on the literature, completion of 90 days of treatment was established as a key outcome variable. METHODS: Quantitative urine levels of the cocaine metabolite benzoylecgonine (BE) and other substance of abuse analytes, plasma levels of DHEAS, DHEA, cortisol, and prolactin, and the profile of mood states (POMS) were serially measured in 38 male cocaine-dependent (DSM-IV) patients and in 28 controls of similar gender and age over a six month study. Exclusion criteria for the patients and controls included Axis I mood, anxiety or psychotic disorders. The patients could not manifest substance dependence except to cocaine. The patients and controls received remuneration for urine and blood collection. Blood samples for hormone levels were obtained between 8 and 10 a.m. on days 1, 14 and 21 of a 21-day inpatient treatment program and throughout 6 months of outpatient study visits at 45-day intervals. RESULTS: Attrition from treatment and study appointments occurred predominately at the junction between inpatient and outpatient programs. Forty percent of patients made the transition to outpatient treatment and remained abstinent and in treatment for a median of 103 days (ABST). Forty-two percent of patients dropped out of treatment during the inpatient stay or never returned after completing the inpatient program (DO) and 18% had a documented relapse either during, or within the first week after, the inpatient stay (REL). POMS total scores were elevated at treatment entry for both the ABST and DO groups. Plasma DHEAS levels in the DO patients were decreased compared to controls and increased in the ABST patients. POMS total scores for the REL patients at baseline were at control levels. Baseline cortisol levels were not statistically different between the outcome groups, though they were elevated for all cocaine patient groups. When treatment outcome was collapsed into whether patients completed (ABST) or did not complete 90 days of treatment (90N), ABST plasma DHEAS and cortisol were significantly elevated compared to the 90N patients and controls across the first 3 weeks of cocaine withdrawal. CONCLUSIONS: At treatment entry, each of the three patient outcome groups was identified by levels of circulating DHEAS and distressed mood. In the ABST patients, distressed mood during withdrawal may have been mitigated through antidepressant-like actions of enhanced endogenous DHEAS activity, thus contributing to improved abstinence and treatment retention. Patients, such as the DO group, with high levels of distressed mood at treatment entry and low DHEAS levels may benefit from adjunctive pharmacotherapy that targets DHEAS and POMS measures. Patients, such as the REL group, who lack distressed mood at treatment entry, may require intense application of motivational approaches plus residential treatment.

Achieving effective treatment of patients with chronic psychotic illness and comorbid substance dependence.

OBJECTIVE: The changing effectiveness of a treatment program for dual-diagnosis patients was evaluated over a 2-year period with the use of a sequential study group design. METHOD: The treatment outcome of 179 consecutively enrolled patients with chronic psychotic illness and comorbid substance dependence who entered a specialized day hospital dual-diagnosis treatment program from Sept. 1, 1994, to Aug. 31, 1996, was evaluated. The 24 months were divided into four successive 6-month periods for comparing the evolving effectiveness of the program for groups of patients entering the day hospital during these four periods. Treatment attendance, hospital utilization, and twice weekly urine toxicology analyses were used as outcome measures. RESULTS: The initial treatment engagement rate, defined as at least 2 days of attendance in the first month, increased significantly from group 1 to group 4, more than doubling. Thirty-day and 90-day treatment retention rates also substantially increased from group 1 to group 4. More patients had no hospitalization in the 6 months after entering the day hospital program than in the 6 months before entering the day hospital program. Urine toxicology monitoring indicated that the patients in group 4 were more likely than those in group 1 to remain abstinent at follow-up. CONCLUSIONS: The evolving clinical effectiveness of a developing program can be quantified by using a sequential group comparison design. The sequential outcome improvements may be related to the incremental contributions of assertive case management and skills training for relapse prevention.

Declarative and procedural memory functioning in abstinent cocaine abusers.

BACKGROUND: We determined the nature and recovery of procedural and declarative memory functioning in a cocaine-abusing cohort in the 45-day period following use. METHODS: Thirty-seven cocaine abusers and 27 control subjects were administered the following memory and mood measures: California Verbal Learning Test, recall of the Rey-Osterrieth Complex Figure Test, Pursuit Rotor Task, and Profile of Mood States at 4 visits (within 72 hours of admission and at 10, 21, and 45 days following abstinence). RESULTS: Analysis of performance on the Rey-Osterrieth Complex Figure Test revealed that both groups improved in their recall over repeated administrations, though the control group recalled significantly more of the information than cocaine subjects during the 45-day interval. Results for the California Verbal Learning Test indicated improved learning for both subject groups over time, but no group x time interaction. On the Pursuit Rotor Task, cocaine abusers improved their performance at a faster rate than controls at visit 1. At day 45 (visit 4), cocaine abusers again showed improvement on the Pursuit Rotor Task, whereas controls demonstrated a relative plateau in rate of learning. CONCLUSIONS: This study documented a lasting detrimental effect on a sensitive nonverbal declarative memory task in cocaine-dependent subjects following abstinence of 45 days. In contrast, abstinence from cocaine during this 45-day period was associated with sustained improvement on a motor learning test in the cocaine abusers relative to controls.

Monetary reinforcement of abstinence from cocaine among mentally ill patients with cocaine dependence.

OBJECTIVE: The study investigated whether contingency management could reduce cocaine use by patients with schizophrenia. METHODS: An A-B-A research design, with two-month baseline, intervention, and follow-up phases, was used to study two homeless, treatment-resistant male outpatients with DSM-III-R diagnoses of schizophrenia and cocaine dependence. During the intervention phase, subjects provided daily urine specimens for testing for the cocaine metabolite benzoylecgonine (BE) and received $25 for each negative test. Concentrations of BE and metabolites of other illicit drugs were assayed twice a week to determine the amount of drug use in addition to frequency. Analysis of variance was used to compare drug use during the three study phases. RESULTS: During the intervention, the proportion of tests positive for cocaine was lower for both subjects. Mean urinary concentrations of BE were significantly lower during the intervention than during the baseline. CONCLUSIONS: These results suggest that modest monetary reinforcement of abstinence may decrease cocaine use among cocaine-dependent patients with schizophrenia.

Ultrafiltration using the Amicon MPS-1 for assessing methadone plasma protein binding.

The percent of protein-free and protein-bound methadone were separated in methadone-spiked bank and artificial plasma, and in plasma samples taken from methadone-maintained patients using the Amicon MPS-1 ultrafiltration device. Following the separation procedure, protein-bound and protein-free methadone were extracted from the protein-bound and free fractions, and their respective concentrations were determined by gas chromatography and nitrogen-phosphorus detection. Eighty-five patient samples from 38 men and 10 women receiving methadone maintenance were collected and subjected to the ultrafiltration methodology. Two independent procedures demonstrated that, following the ultrafiltration process, no proteins were measurable in the filtrate. In addition, the ultrafiltration process was found to function independently of the concentration of methadone and the volume of sample, assuming the amount filtered never exceeded 40% of the original volume. In the patient samples, the %-free methadone varied sixfold across all patients. Female patients were found to have a mean +/- SD %-free methadone of 11.9 +/- 3.8% vs. 10.1 +/- 3.4% for men. Pearson correlation values suggest that steady-state protein-free methadone levels (r = 0.521) and total methadone levels (r = 0.491) rise as methadone dose is increased. Corresponding to these results, free methadone levels are highly correlated with total methadone levels (Pearson r = 0.85). The Amicon MPS-1 ultrafiltration device appears to be a reliable and relatively easy system to use for separating protein-free from protein-bound methadone, though further study is required to clarify the clinical applications of free methadone levels.

Pharmacotherapy of schizophrenia patients with comorbid substance abuse.

Substance abuse worsens the course of schizophrenia and significantly impairs the relationship between the patient and the health care team. Recent advances in laboratory studies of substance abuse and the pharmacology of schizophrenia open up new possibilities for pharmacotherapy of substance abuse in schizophrenia patients. D1 dopaminergic receptor agonists may directly block the drive for stimulant use. D2 dopaminergic receptor antagonists may indirectly block the drive for stimulant and nicotine use, while opioid antagonists appear to reduce the drive to use alcohol. New generations of neuroleptics with serotonin (5-HT2) receptor antagonism and/or 5-HT1A agonist activity may reduce substance abuse in schizophrenia patients who self-medicate negative symptoms or neuroleptic side effects. Pharmacotherapy efficacy may be enhanced by adding contingency management, social skills training, and other manualized programs. Tables are provided of potentially useful medications. Preliminary results are presented of cocaine-abusing schizophrenia patient treated with desipramine and traditional neuroleptics.

Quantitative urine levels of cocaine and other substances of abuse.

Used appropriately, quantitative levels can address research hypotheses and clinical issues that are otherwise untested by traditional qualitative urine results. Quantitative urine levels can provide new information in health services research, pharmacotherapy trials, studies of the interaction of cigarette smoking and substance abuse, additional studies of polysubstance abuse, and the linking of biological markers with phases of addiction and risk to relapse.

Effects of varying marijuana potency on deposition of tar and delta9-THC in the lung during smoking.

To determine whether smoking more, compared to less, potent marijuana (MJ) cigarettes to a desired level of intoxication ("high") reduces pulmonary exposure to noxious smoke components, in 10 habitual smokers of MJ, we measured respiratory delivery and deposition of tar and delta9-tetrahydrocannabinol (THC), carboxyhemoglobin (COHb) boost, smoking topography, including cumulative puff volume (CPV) and breathholding time, change in heart rate (deltaHR) and "high" during ad lib smoking of 0, 1.77, and 3.95% MJ cigarettes on 3 separate days. At each session, subjects had access to only a single MJ cigarette. On average, smoking topography and COHb boost did not differ across the different strengths of MJ, while THC delivery, as well as HR, were significantly greater (p < 0.01) and tar deposition significantly less (p < 0.03) for 3.95% than 1.77% MJ. Although individual adaptations in smoking topography for 3.95% compared to 1.77% MJ were highly variable, three subjects with the lowest 3.95% MJ:1.77% MJ ratios for CPV also displayed the lowest 3.95% MJ:1.77% MJ ratios for tar deposition. In vitro studies using a standardized smoking technique revealed a mean 25% lower tar yield from 3.95% than 1.77% MJ (p < 0.05), but no difference between 1.77% and 0% marijuana. Under the conditions of this study, we conclude that tar delivery is reduced relative to THC content in a minority of subjects, and this reduction appears to be due to a reduced intake of smoke (decreased CPV) and/or a reduced tar yield from the stronger MJ preparation.

Disability income, cocaine use, and repeated hospitalization among schizophrenic cocaine abusers--a government-sponsored revolving door?

BACKGROUND: Many patients with serious mental illness are addicted to drugs and alcohol. This comorbidity creates additional problems for the patients and for the clinicians, health care systems, and social-service agencies that provide services to this population. One problem is that disability income, which many people with serious mental illness receive to pay for basic needs, may facilitate drug abuse. In this study, we assessed the temporal patterns of cocaine use, psychiatric symptoms, and psychiatric hospitalization in a sample of schizophrenic patients receiving disability income. METHODS: We evaluated 105 male patients with schizophrenia and cocaine dependence at the time of their admission to the hospital. They had severe mental illness and a long-term dependence on cocaine, with repeated admissions to psychiatric hospitals; many were homeless. The severity of psychiatric symptoms and urinary concentrations of the cocaine metabolite benzoylecgonine were evaluated weekly for 15 weeks. RESULTS: Cocaine use, psychiatric symptoms, and hospital admissions all peaked during the first week of the month, shortly after the arrival of the disability payment, on the first day. The average patient spent nearly half his total income on illegal drugs. CONCLUSIONS: Among cocaine-abusing schizophrenic persons, the cyclic pattern of drug use strongly suggests that it is influenced by the monthly receipt of disability payments. The consequences of this cycle include the depletion of funds needed for housing and food, exacerbation of psychiatric symptoms, more frequent psychiatric hospitalization, and a high rate of homelessness. The troubling irony is that income intended to compensate for the disabling effects of severe mental illness may have the opposite effect.

Absence of acute cocaine interactions with the MAO-B inhibitor selegiline.

Selegiline, an irreversible monoamine oxidase-B (MAO-B) inhibitor, is under investigation as a treatment for cocaine relapse prevention. To evaluate its safety, human volunteers (n = 5) received intravenous cocaine (0, 20 and 40 mg, 1 h apart) following treatment with placebo or selegiline (10 mg, p.o.). Cocaine increased heart rate, blood pressure, pupil diameter and subjective indices of euphoria and craving. Selegiline produced no measureable effects, except for miosis, and did not alter the effects of cocaine. These data suggest that selegiline may be safely administered in combination with cocaine, and that selegiline is unlikely to increase reinforcing effects of cocaine.

Neuropsychological deficits in abstinent cocaine abusers: preliminary findings after two weeks of abstinence.

Sixteen subjects hospitalized for treatment of cocaine dependence were administered a battery of neuropsychological tests within 72 h of last cocaine use and again approximately 2 weeks later. Twenty-one non-cocaine using control subjects, matched for age, gender, ethnicity and education, also received neuropsychological testing. Abstinence from mood altering substances during the 2-week study period was verified for both groups on three occasions using quantitative urine analysis. The results suggest that recent cocaine use is associated with impairment in memory, visuospatial abilities, and concentration during the acute phase of withdrawal, independent of withdrawal-related depression. Furthermore, many of these deficits appear to persist at least 2 weeks beyond cessation of cocaine use.

Hypothalamic-pituitary function during alcohol exposure and withdrawal and cocaine exposure.

This chapter examines the neuroendocrine effects of acute exposure to and withdrawal from alcohol and cocaine, with special emphasis on the hypothalamic-pituitary-adrenal (HPA) axis. We present the results from two preliminary controlled inpatient studies that document HPA dysfunction during acute exposure to alcohol and cocaine and during withdrawal from alcohol. We discuss the methodological approach of these studies in comparison to related attempts in the literature to use measures of thyroid and prolactin regulation to predict risk of relapse to alcohol and cocaine use, respectively. Our data and the results of related studies are presented in the context of a proposed index of HPA axis dysfunction that may provide a useful clinical measure of susceptibility to relapse during protracted abstinence from alcohol or cocaine.

Brain, lung, and cardiovascular interactions with cocaine and cocaine-induced catecholamine effects.

The pathophysiologic effects of cocaine on neuronal, pulmonary, and cardiovascular tissue are related to the drug's interaction with select catecholamine and neuroendocrine systems. Cocaine has been shown to alter circulating levels of the neurotransmitters, dopamine, norepinephrine, epinephrine, as well as the hypothalamic-pituitary-adrenal axis hormones corticotropin-releasing factor (CRF), adrenocorticotropic hormone (ACTH), and cortisol. Furthermore, brain and lung tissue have been identified as primary sites of cocaine sequestration and metabolism. This paper reviews evidence suggesting that steroid-potentiated actions of catecholamines on vascular tissues contributes to the etiology of cocaine-related medical complications, including ischemic stroke, coronary ischemia, and ischemia-based renal failure.

CSF and endocrine studies of premenstrual syndrome.

Eight women with prospectively documented premenstrual syndrome (PMS) underwent multiple samplings for estradiol, progesterone, prolactin, cortisol, and plasma 3-methoxy-4-hydroxyphenylglycol (MHPG) during an asymptomatic midcycle (late follicular) and a symptomatic premenstrual (late luteal) phase of the menstrual cycle. Cerebrospinal fluid (CSF) was collected for analysis of MHPG, norepinephrine (NE), 5-hydroxyindoleacetic acid (5-HIAA), dihydroxyphenylacetic acid (DOPAC), gamma-aminobutyric acid (GABA), homovanillic acid (HVA), tyrosine, tryptophan, beta-endorphin, prostaglandins, adrenocorticotropic hormone (ACTH), and arginine vasopressin (AVP). In subsequent months, a dexamethasone suppression test (DST) and a thyrotropin-releasing hormone (TRH) stimulation test were performed during midcycle and premenstrual phases. Significant results included increased CSF concentrations of MHPG in the premenstrual, as compared with the midcycle, phase of the cycle, and increased plasma cortisol concentrations during the midcycle phase. The DST showed a 62% overall rate of nonsuppression, irrespective of menstrual cycle phase. Though there were no abnormalities of thyrotropin-stimulating hormone (TSH) after TRH stimulation, the mean delta maximum prolactin values after TRH stimulation were higher than reported normal values both at midcycle and premenstrually. These pilot data suggest hormonal axes that might be worthy of further systematic investigation in future studies of PMS.

Transdermal nicotine and smoking behavior in psychiatric patients.

The authors used a double-blind crossover design to observe the effect of transdermally administered nicotine on the smoking behavior of 13 psychiatric patients who were not trying to stop smoking. The patients smoked significantly fewer cigarettes while receiving nicotine than while receiving placebo. These data suggest that transdermally administered nicotine can be a useful adjunct in treating nicotine-addicted psychiatric patients in a non-smoking environment.

Discrepancies between patient report, clinical assessment, and urine analysis in psychiatric patients during inpatient admission.

Self-report and clinical assessment of substance use were compared with urine analysis results in 56 male patients consecutively admitted for inpatient psychiatric treatment. All subjects received DSM-III-R Axis I diagnosis and were classified into diagnostic groups. Urine samples were tested for cocaine, marijuana, opiates, phencyclidine (PCP), amphetamines, and barbiturates. Thirty-five of the 56 patients (62%) produced urine samples that were positive for at least 1 substance of abuse. Of this group, 15 patients (27% of total sample) denied substance use during the week prior to admission. In addition, the admitting physician did not identify intoxication in 23 of the 35 patients (66%) with positive urines. The admitting physician's assessment matched the patient's answers regarding recent substance use in 79 percent of the patients. This association was especially apparent with the 26 patients who denied recent substance use, all but one of whom received a drug-negative assessment from the admitting physician.

Myocardial ischemia during cocaine withdrawal.

STUDY OBJECTIVE: To determine the prevalence of myocardial ischemia in patients with cocaine addiction. DESIGN: Myocardial ischemia in chronic cocaine users was detected by serial 24-hour electrocardiographic ambulatory (Holter) monitoring and exercise treadmill testing in chronic cocaine users. The Holter tapes were coded, scanned in a blinded manner, and mixed with the tapes of 42 normal volunteers and 119 patients with either stable or unstable angina. SETTING: A 28-day inpatient, substance abuse treatment program followed by an outpatient treatment program. PATIENTS: Twenty-one consecutive male chronic cocaine users. MAIN RESULTS: Eight of the 21 patients with cocaine addiction had frequent episodes of ST elevation during Holter monitoring; these episodes occurred almost exclusively during the first 2 weeks of withdrawal. None of the volunteers and patients with stable angina and only 4% of the patients with unstable angina had episodes of ST elevation during Holter monitoring (cocaine users compared with volunteers, P = 0.0004). Of the 20 cocaine patients who had exercise treadmill testing, only 1 had a positive test for ischemia. CONCLUSIONS: Cocaine users frequently develop silent myocardial ischemia manifesting as episodes of ST elevation during the first weeks of withdrawal. The underlying mechanisms for these changes remain unknown, but our observations support the hypothesis that coronary vasospasm plays an important role in cocaine-related ischemic syndromes.

Outpatient treatment of PCP abusers.

Despite the persistence of phencyclidine (PCP) abuse as a public health problem in many urban areas of the United States, there are no published data on outpatient treatment outcome. We studied 37 unselected male PCP abusers (mean age 32 years, 73% Black, 19% married, 68% unemployed) who attended at least one outpatient treatment session at the Brentwood Division, West Los Angeles VA Medical Center. Subjects had smoked PCP for an average of 7 years, with 84% using it at least weekly (38% daily) and 76% using other drugs (alcohol, marijuana, or cocaine). All subjects reported psychological dependence on PCP (i.e., liking PCP use and difficulty stopping despite adverse consequences), while none reported a physiological withdrawal syndrome when stopping PCP use. Subjects stayed in treatment an average of 21 weeks (range 1-155 weeks), attending an average of 68% of the group meetings. PCP was detected in weekly urine samples 78% of the time, with verbal self-report of recent PCP use occurring before 29% of the group meetings. Four subjects (11%) achieved at least 1 year of abstinence, 10 (30%) transferred to residential treatment or a community recovery home, 16 (48%) dropped out of treatment, and two (6%) were jailed. Treatment outcome was not significantly associated with subject characteristics. Age was the only subject characteristic that significantly predicted length of stay (r = .40).

Desipramine increases circulating growth hormone in elderly depressed patients: a pilot study.

Serial blood samples were collected from 15 elderly depressed inpatients, ages 62 to 95 years, following random assignment to a 50 mg oral test dose of desmethylimipramine (DMI) or amitriptyline (AMI). Nine female and six male subjects began the 210-min study at 0800h. Serum growth hormone (hGH), cortisol, and prolactin (hPRL) were determined by radioimmunoassay. Baseline hormone concentrations were related to self and observer ratings of anxiety and depression. There was a trend for the hGH, cortisol, and hPRL concentrations to decline during the period of study. This trend for all three hormones reversed in those subjects receiving DMI, beginning approximately 90 min after drug ingestion. The DMI-induced increase of hGH reached statistical significance at the very end of the sampling period. There was an apparent latency in the DMI-induced effect for all three hormones. There was no stimulatory effect of AMI on hGH, cortisol, or hPRL. The female subjects had higher baseline hGH levels than the men. In addition, a significant negative correlation was found between baseline hPRL levels and self ratings of anxiety.