HIV-Risk Behavior Among Adults with Opioid Use Disorder During 12 Months Following Pre-trial Detention: Results from a Randomized Trial of Methadone Treatment.

This was a three group randomized clinical trial of interim methadone and patient navigation involving 225 pre-trial detainees with opioid use disorder in Baltimore. The HIV Risk Assessment Battery (RAB) was administered at baseline (in jail), and at 6 and 12 months post-release. Generalized linear mixed model analyses indicated the condition × time interaction effect failed to reach significance (ps > .05) for both the drug risk and sex risk subscale scores. Therefore, findings suggest that there were no intervention effects on drug or sex risk behaviors. However, increased use of cocaine at baseline was associated with increases in drug- (b = .04, SE = .02) and sex-risk (b = .01, SE = .003) behaviors. These results suggest that interventions targeting cocaine use among pre-trial detainees may serve as a means of reducing HIV risk associated with drug- and sex-risk behaviors.Clinical Trials Registration: Clinicaltrials.gov NCT02334215.

Methadone treatment of arrestees: A randomized clinical trial.

BACKGROUND: Opioid use disorder is common among detainees in US jails, yet methadone treatment is rarely initiated. METHODS: This is a three-group randomized controlled trial in which 225 detainees in Baltimore treated for opioid withdrawal were assigned to: (1) interim methadone (IM) with patient navigation (IM + PN); (2) IM; or (3) enhanced treatment-as-usual (ETAU). Participants in both IM groups were able to enter standard methadone treatment upon release, while ETAU participants received an assessment/referral number. Follow-up assessments at 1, 3, 6, and 12 months post-release determined treatment enrollment, urine drug testing results, self-reported days of drug use, criminal activity, and overdose events. Generalized linear mixed modelling examined two planned contrasts: (1) IM groups combined vs. ETAU; and (2) IM + PN vs. IM. RESULTS: On an intention-to-treat basis, compared to ETAU, significantly more participants in the combined IM groups were in treatment 30 days post-release, while the IM + PN vs. IM groups did not significantly differ. By month 12, there were no significant differences in the estimated marginal means of enrollment in any kind of drug treatment (0.40 and 0.27 for IM + PN and IM groups, respectively, compared to 0.29 for ETAU). There were no significant differences for either contrast in opioid-positive tests, although all groups reported a sharp decrease in heroin use from baseline to follow-up. There were five fatal overdoses, but none occurred during methadone treatment. CONCLUSION: Initiating methadone treatment in jail was effective in promoting entry into community-based drug abuse treatment but subsequent treatment discontinuation attenuated any potential impact of such treatment.

Steroid binding at sigma receptors suggests a link between endocrine, nervous, and immune systems.

Specific sigma binding sites have been identified in the mammalian brain and lymphoid tissue. In this study, certain gonadal and adrenal steroids, particularly progesterone, were found to inhibit sigma receptor binding in homogenates of brain and spleen. The findings suggest that steroids are naturally occurring ligands for sigma receptors and raise the possibility that these sites mediate some aspects of steroid-induced mental disturbances and alterations in immune functions.

1-delta9-tetrahydrocannabinol: neurochemical and behavioral effects in the mouse.

Administration of pure 1-delta(9)-tetrahydrocannabinol to mice had the following dose-dependent nzeurochemical and behavioral effects: a slight but significant increase in concentrations of 5-hydroxytryptamine in whole brain; a decrease in concentration of norepinephrine in brain after administration of low doses and an increase after high doses; diminished spontaneous activity, mloderate hypothermnia, hypersetisitivity to tactile and auditory stimiuli, and ataxia after low doses; and sedation, pronounced hypothermia, and markedly diminished spon taneous activity and reactivity after high doses. The duration of the effects on body temperature and spontaneous activity correlated generally with the changes in brain amines. The characteristic changes in brain amines do not correspond exactly to those observed with other psychotropic drugs.

Suspiciousness induced by four-hour intravenous infusions of cocaine. Preliminary findings.

Cocaine hydrochloride was administered to experienced users as an intravenous (IV) loading dose of 40 to 80 mg, followed by four-hour continuous IV infusions of either cocaine or placebo. Rates of cocaine infusion were individualized to maintain steady-state cocaine concentrations for the duration of the infusion. During the infusions, subjects rated themselves on questions that assessed their suspiciousness and paranoia, and nurse-observers took descriptive notes on the subjects' behavior; these notes were later scored on a scale for guarded, suspicious, and paranoid behavior. Nurses observed and rated moderately suspicious behavior when cocaine IV bolus loading doses were followed by cocaine infusions, but not when loading doses were followed by saline solution infusions; subjects did not rate themselves as suspicious during any of the study conditions. Suspiciousness during low-dose cocaine infusions significantly correlated with the amount of cocaine previously administered to the subjects. Suspiciousness during infusions was not related to plasma cocaine concentrations, preadmission drug use, or psychiatric symptoms and history. Cocaine infusions may be a useful tool to pursue the biology of stimulant psychoses.

Cocaine-induced reduction of glucose utilization in human brain. A study using positron emission tomography and [fluorine 18]-fluorodeoxyglucose.

We examined the effects of cocaine hydrochloride (40 mg intravenously) on regional cerebral metabolic rates for glucose and on subjective self-reports of eight polydrug abusers in a double-blind, placebo-controlled, crossover study. The regional cerebral metabolic rate for glucose was measured by the [fluorine 18]-fluorodeoxyglucose method, using positron emission tomography. With eyes covered, subjects listened to a tape that presented white noise, "beep" prompts, and questions about subjective effects of cocaine or saline. Cocaine produced euphoria and reduced glucose utilization globally (mean reduction, 14%). Twenty-six of 29 brain regions (all neocortical areas, basal ganglia, portions of the hippocampal formation, thalamus, and midbrain) showed significant decrements (5% to 26%) in the regional cerebral metabolic rate for glucose. No significant effects of cocaine were observed in the pons, the cerebellar cortex, or the vermis. Right-greater-than-left hemispheric asymmetry of regional cerebral metabolic rates for glucose occurred in the lateral thalamus. The findings demonstrate that reduced cerebral metabolism is associated with cocaine-induced euphoria.

Impulsivity, aggression, and neuroendocrine responses to serotonergic stimulation in substance abusers.

Alterations in the activity of central serotonergic systems have been implicated in impulsive and aggressive behavior. We examined the neuroendocrine and psychological responses of 24 substance users with differing levels of aggressiveness and impulsivity to the oral administration of an indirect serotonin agonist fenfluramine (60 mg) or placebo given in a double-blind crossover design. All subjects were volunteers on a closed research ward and were abstinent from drugs for a minimum of 5 days. Baseline plasma prolactin (PRL) levels were greater in the groups with higher levels of self-reported aggressiveness and impulsivity. When adjusted for the baseline, PRL and cortisol responses 180 min after fenfluramine administration were significantly elevated in subjects with higher levels of aggressiveness and impulsivity. Peak cortisol levels were correlated with impulsivity. PRL and cortisol responses to fenfluramine were more strongly correlated with impulsivity than aggressiveness. Also, the more impulsive subjects reported a decrease in subjective states of depression, hostility and anxiety after drug treatment. These data further support the hypothesis of altered serotonergic activity in aggressive and impulsive behaviors.

Auditory event-related potentials in adolescents at risk for drug abuse.

We evaluated sensory and cognitive information processing in noninstitutionalized delinquent male adolescents and in age-matched low delinquency controls. Detailed psychometric testing documented the nature of the aggressive behavior of these young men. Deficits in information processing, as assessed by event-related potential (ERP) techniques, were observed at several levels of the auditory system in the delinquent group. The delinquent group showed delays in wave V of the brainstem auditory evoked potential, shorter N100 latency, and decreased slow wave amplitude of cognitive event-related potentials when subjects were asked to perform a mental task in a noisy environment. It remains to be determined whether or not such information-processing deficiencies are common among delinquent populations and how they might influence the development of delinquent behavior and drug abuse.

Cardiovascular responses to cocaine placebo in humans: a preliminary report.

Cardiovascular responses after placebo-cocaine injections were in the same direction as the effect of cocaine iv in 22 male volunteers. Subjects received iv placebo in a room where they had been given repeated doses of iv cocaine. The placebo response consisted of an increase from baseline values of systolic and diastolic blood pressure and pulse rate. The control group, 8 subjects, which was not exposed to a conditioning phase, showed a smaller increase in the pulse rate and systolic blood pressure after the placebo injection. The results, in accordance with animal literature, suggest the existence of cocaine-conditioned effects in humans.

EEG and brainstem auditory evoked response potentials in adult male drug abusers with self-reported histories of aggressive behavior.

Auditory brainstem evoked response (BAER) and spontaneous electroencephalogram (EEG) were measured in 124 adult male drug abusers. We examined the relationships among psychiatric diagnoses, paper and pencil measures of aggression and hostility, and electrophysiological features. Subjects meeting criteria for antisocial personality disorder (ASP), as defined by DSM-III, were not significantly different from non-ASP subjects for either BAER or spontaneous EEG measures. The more overtly aggressive subjects had significant delays in BAER latency. Aggressive subjects also had more delta activity and less alpha activity in the spontaneous EEG, as have been observed in "psychopaths" and "criminals." Although ASP and aggression are related, these data indicate that aggressiveness may be a separate, albeit overlapping, trait. As both early aggression and a diagnosis of ASP are predictors of later drug use, the findings that only aggression was associated with EEG slowing and brainstem delays may indicate that ASP and aggression make independent contributions to vulnerability to the development of drug abuse.

Abuse potential of loperamide.

Effects of the currently marketed form of loperamide (Imodium capsules) that might relate to abuse potential were examined. Study I was a double-blind "dose run-up" in adult male subjects with a history of illicit drug use but no history of opioid addiction. Subjective responses to doses of loperamide ranging from 12 to 60 mg were compared with responses to 120 mg codeine sulfate (96 mg base) and to placebo. Based on study I, loperamide (60 mg) was used in study II and its effects were compared with those of codeine (96 mg base) and placebo in an exaddict subject group. Study II subjects had had extensive opioid experience but were not actively addicted at the time of this double-blind, inpatient study. In study II, as in study I, unlike loperamide and placebo, codeine induced pupillary constriction. Loperamide (60 mg) induced a detectable subjective effect in somewhat over half the subjects, was "liked" little or not at all, and was identified as "dope" at a frequency less than that for a threshold dose of oral codeine. It was concluded that in its present form, i.e., capsules containing loperamide mixed with magnesium stearate, loperamide poses little threat of potential abuse.

Low nicotine cigarettes: cigarette consumption and breath carbon monoxide after one year.

Subjects who took part in a 12-wk study of switching behavior were observed during the subsequent year. Data were obtained for 96 smokers every 3 mo. A sample of smokers who, at 12 wk, had switched to a brand delivering less than half the nicotine of their baseline brand were offered continued monetary incentives to participate for an additional 6 mo (maintenance study). In the maintenance study, subjects continued to smoke low-nicotine cigarettes during the 6-mo period in which money and contact reinforcement were continued; maintenance control subjects increased their tar and nicotine exposure significantly. In the follow-up study of those who had not changed by more than 50%, the original control group, nonswitchers, and moderate switchers did not significantly change their nicotine exposure from what it had been at the end of the initial 12-wk study. Carbon monoxide (CO) in breath showed remarkably little change across the year despite substantial changes in tar and nicotine exposure. To the extent that CO is involved in smoking-related disorders, switchers derived little if any benefit from switching to low-nicotine brands.

Clinical pharmacokinetics of imipramine and desipramine in alcoholics and normal volunteers.

Recently detoxified men with alcohol dependence (n = 15) and healthy volunteers (n = 14) were administered oral and intravenous imipramine and desipramine. Alcoholics had significantly greater total body clearance of imipramine (0.93 vs. 0.48 L/hr/kg; P less than 0.05) and desipramine (1.00 vs. 0.62 L/hr/kg; P less than 0.05) than did control subjects. Intrinsic clearance of unbound imipramine was greater in the alcoholic group (19.80 vs. 6.56 L/hr/kg; P less than 0.05), as was the intrinsic clearance of unbound desipramine (14.52 vs. 9.05 L/hr/kg; P less than 0.05). The mean elimination half-life for imipramine was significantly decreased in alcoholics (8.7 vs. 19.9 hours after intravenous infusion and 10.9 vs. 19.6 hours after oral administration; P less than 0.05). The mean elimination half-life for desipramine was decreased in alcoholics after intravenous infusion (16.5 vs. 22.4 hours; P less than 0.05). Unbound fractions of drug in plasma were decreased in the alcoholic group for both imipramine and desipramine after both routes of administration. alpha 1-Acid glycoprotein levels were elevated in the alcoholic group whereas total protein and albumin levels did not differ between groups. These findings suggest that recently detoxified alcoholics may require higher doses of imipramine than do nonalcoholic subjects. Desipramine clearance was affected to a lesser degree than imipramine, suggesting that from a pharmacokinetic standpoint it may be the preferred drug for the treatment of alcoholics with depression. Periodic monitoring of plasma levels may be required for recently abstinent alcoholics treated with antidepressants.

Use of buprenorphine in the treatment of opioid addiction. II. Physiologic and behavioral effects of daily and alternate-day administration and abrupt withdrawal.

Nineteen heroin-dependent male volunteers were administered buprenorphine sublingually, in ascending daily doses of 2, 4, and 8 mg. They were maintained on 8 mg daily through study day 18. On study days 19 through 36, subjects in group 1 continued to receive burprenorphine daily; subjects in group 2 received buprenorphine or placebo on alternate days. On days 37 through 52, all subjects received placebo. Subjects receiving buprenorphine on alternate days reported significantly greater urge for an opioid, increased dysphoria scores, and pupillary dilation on placebo days. After abrupt termination of buprenorphine, no withdrawal signs were detected with the Himmelsbach scale. However, subjects reported mild-to-moderate opioid withdrawal symptoms, peaking at 3 to 5 and lasting for 8 to 10 days. Daily administration of buprenorphine provided greater control of subtle opioid withdrawal symptoms, but subjects could tolerate a between-dose interval of 48 hours.

Abuse potential of halazepam and of diazepam in patients recently treated for acute alcohol withdrawal.

Thirty men recently treated for alcohol withdrawal were enrolled in a three-way crossover double-blind study with a balanced incomplete block design. Patients received single doses of three of the following: halazepam, 320 mg; halazepam, 160 mg; diazepam, 40 mg; diazepam, 20 mg; and placebo. The doses of the drugs were approximately equivalent in anxiolytic effect. Patients rated themselves at baseline, 30 min after, and 1, 2, 3, 4, 6, and 8 hr after drug on the following: euphoria, sedation, "drug-liking," "feeling the drug," and drug identification. By 30 min both diazepam groups reported increases in euphoria, sedation, and feeling and liking the drug; halazepam groups reported little subjective change at 30 min, and at 1 hr subjective effects did not differ from placebo on any scale. At 2 and 3 hr, both halazepam doses induced subjective effects on several scales, but peak effects were lower than peak effects of high diazepam doses. Unlike diazepam, the higher halazepam dose did not appear to induce greater effects than the lower dose. At peak, more of the diazepam group correctly identified the drug than those in the halazepam groups. More in the halazepam groups identified it as placebo than either diazepam group. To the degree that abuse potential is related to peak intensity and to time of onset of those subjective effects described as pleasant or likable, halazepam should have a lower potential for abuse than diazepam.

Resolution of neuroleptic malignant syndrome with dantrolene sodium: case report.

A case of neuroleptic malignant syndrome (NMS) with an abrupt onset was terminated quickly with i.v. dantrolene sodium. The prompt and satisfactory outcome after early diagnosis indicates that dantrolene should be considered a useful treatment in NMS.

Effects of nifedipine pretreatment on subjective and cardiovascular responses to intravenous cocaine in humans.

The effects of oral nifedipine pretreatment on subjective and cardiovascular responses to intravenous cocaine infusions were studied in cocaine-using volunteers. Nifedipine, 10 mg or placebo, was administered 20-25 min before placebo, 20 mg, or 40 mg cocaine, using a repeated measures randomized double-blind design. The variables measured were self-reported subjective effects, general behavior rated by two observers, blood pressure and heart rate. Cocaine produced the expected dose-related effects on subjective and cardiovascular measures. Nifedipine pretreatment attenuated some subjective effects of cocaine. Nifedipine directly reduced blood pressure but did not antagonize the effects of cocaine on blood pressure. These findings suggest that dihydropyridine calcium channel modulators may be useful compounds in the clinical management of cocaine users.

Rats self-administer sufentanil in aerosol form.

An ultrasonic nebulizer was used to create a drug vapor to develop an animal model for the self-administration of inhaled nonvolatile psychoactive drugs. An aerosol mist of a sufentanil citrate solution (10, 25, 50, or 75 micrograms/ml) was delivered to rats in response to lever presses on an FR 5 schedule of reinforcement. The speed of acquisition of the operant response and the selectivity of the drug effect were examined. Rats given access to sufentanil vapor (50 or 75 micrograms/ml) in 13-15 h overnight training sessions reached an average of one reinforcement per hour on an FR 5 schedule of reinforcement significantly sooner than did rats given access to water vapor. Responding maintained by sufentanil during 2-h daily testing sessions was dose dependent at 25, 50, and 75 micrograms/ml. Substituting water vapor for each of the four sufentanil concentrations significantly reduced responding within 5-20 sessions. Naloxone (1 mg/kg, IP) decreased responding for sufentanil to the level attained under water vapor. Presentation of drugs in aerosol form thus provides reasonable means of demonstrating in animals the reinforcing properties of non-volatile drugs by the pulmonary or intranasal route.

Discriminative stimulus effects of inhaled cocaine in squirrel monkeys.

Squirrel monkeys (N = 4) were trained with food reinforcement to press one of two levers after administration of IV cocaine (0.3 or 1.0 mg/kg) or the other lever after saline. After training, IV cocaine (0.03-3.0 mg/kg) produced dose-related increases in the percentage of responses on the cocaine lever (ED50 = 0.15 mg/kg). Cocaine delivered IM also produced dose-related increases in cocaine-appropriate responding (ED50 = 0.32 mg/kg), but was approximately half as potent as IV cocaine. Similar relative potency relations were obtained for decreases in response rates produced by cocaine. Prior to some sessions subjects were placed in a Plexiglas chamber and exposed for 60 s to cocaine vapor created with an ultrasonic nebulizer. Exposure to vapor from cocaine solutions (1.0-30.0 mg/ml) produced concentration-dependent increases in cocaine-appropriate responding and decreases in response rates. Exposure to vapor from a 30 mg/ml concentration produced virtually exclusive cocaine-appropriate responding. Concentration-effect curves for inhaled cocaine were similar to dose-effect curves obtained when cocaine was administered by the other routes. The time course of the minimally effective concentration of inhaled cocaine was compared to that of the minimally effective doses of systemically administered cocaine. Inhaled cocaine had a duration of action longer than IV cocaine. The results indicate that inhaled cocaine vapor has effects qualitatively similar to those of IV cocaine, and may have a duration of action longer than that of an IV cocaine dose producing a similar degree of drug-appropriate responding.

Cocaine-induced cocaine craving.

In nine experienced users of cocaine, we examined the urge to use cocaine or other drugs following a 40 mg dose of intravenous (IV) cocaine with and without oral pretreatment with 2.5 mg bromocriptine. The urge to use cocaine was assessed with a questionnaire constructed to assess both "wanting" and "craving" for cocaine or other drugs. Fifteen minutes after the administration of cocaine (but not after placebo), subjects' ratings for both drug "wanting" and drug "craving" were significantly increased. Our results provide a laboratory demonstration of cocaine-induced increases in the urge to use drugs in humans. The findings, stressing the role of internal stimuli associated with drug administration, suggest the possibility of distinguishing among related, but perhaps distinct, components of the fluctuating levels of motivation to reuse drugs.