Psychostimulant-like discriminative stimulus and locomotor sensitization properties of the wake-promoting agent modafinil in rodents

The present studies assessed the potential abuse liability and likely mechanism(s) of action of the wake-promoting agent modafinil.

Methods

Experiments assessed the locomotor sensitization (LS) and discriminative stimulus (DS) properties of modafinil in mouse and rat, respectively. Comparative data were generated with a range of psychostimulants and monoamine reuptake inhibitors.

Results

Repeated administration of d-amphetamine and cocaine, psychostimulants with high abuse liability, resulted in the induction and expression of LS in mice. Bupropion and caffeine, two psychostimulants not abused in humans, were not associated with LS. GBR12909 induced LS during repeated exposure, but there was no evidence of expression of LS after acute challenge following withdrawal. In contrast, repeated administration of modafinil resulted in the expression, but not induction, of LS. d-amphetamine, but not the μ-opioid agonist morphine or the nAChR agonist nicotine, fully substituted for the cocaine DS in rats. The selective dopamine transporter (DAT) inhibitor GBR12909 fully substituted, the preferential norepinephrine transporter (NET) inhibitor desipramine partially substituted, and the selective serotonin reuptake inhibitor citalopram failed to substitute for cocaine. Modafinil fully substituted for cocaine, similar to the mixed DAT/NET inhibitor bupropion.

Conclusions

Two preclinical assays indicated potential abuse liability of modafinil; drug discrimination studies suggest DAT blockade by modafinil is a likely mechanism of action in vivo.     

Exposure to alcohol during adolescence alters the aversive and locomotor-activating effects of cocaine in adult rats

Objectives

The present study assessed the effect of adolescent alcohol exposure on the later aversive and locomotor-activating effects of cocaine.

Methods

Male rats were exposed to alcohol or vehicle for 10 days [postnatal day (PND) 30-39; 2 g/kg IP]. Taste aversion conditioning began on PND 65. During aversion conditioning, subjects were presented with saccharin followed by cocaine (32 mg/kg; 15, 180 or 300 min post saccharin) or saline. Following each injection, animals were placed in locomotor chambers for 1 h. To determine if any effects seen were specific to the adolescent developmental period, the procedure was replicated in adult animals.

Results

Animals exposed to vehicle during adolescence showed significant aversions at all time delays. Animals exposed to ethanol during adolescence showed a decrease in consumption only at the 15 and 180 min delays. Groups exposed to alcohol during adolescence showed a decrease in gross, and an increase in fine, motor activity in response to cocaine. Animals exposed to alcohol during adulthood also showed attenuated taste aversions.

Conclusions

Exposure to ethanol during adolescence attenuated the aversive effects of cocaine and altered its locomotor-activating effects. Although this effect is not specific to adolescence, this is the time when alcohol use is typically initiated so that such exposure may enhance later abuse liability of cocaine.     

5-HT induces temporomandibular joint nociception in rats through the local release of inflammatory mediators and activation of local β adrenoceptors

Objectives

The present studies assessed the effects of adolescent and adult ethanol exposure on the rewarding effects of cocaine as measured with the conditioned place preference procedure.

Methods

Male rats were exposed to intraperitoneal (IP) injections of ethanol or vehicle for 10 days [postnatal days (PNDs) 30-39 or PNDs 70-79; 2 mg/kg]. Place preference conditioning began on PND 65 or PND 105, respectively, and consisted of a baseline test followed by four conditioning cycles with either 0, 5, 10 or 20 mg/kg cocaine. Following the fourth conditioning cycle a final preference test was performed. Changes in time on the drug-paired side between the baseline and final test were analyzed.

Results

Animals exposed to vehicle (during adolescence or adulthood) showed a significant place preference at 20 mg/kg cocaine. Animals exposed to ethanol (during adolescence or adulthood) showed a significant place preference at 10 mg/kg cocaine.

Conclusions

Exposure to ethanol (adolescents or adults) sensitized the rewarding effects of cocaine. This may indicate an increase in the abuse liability of cocaine following a history of ethanol exposure.     

A single-day paradigm of self-regulated human cocaine administration

Prior work by our group has shown the feasibility, safety, and validity of a multi-day, multi-dose paradigm of self-regulated cocaine administration in humans. The current work sought to consolidate these methods in a single-day design focused on reducing logistical complexity, decreasing research burden to human subjects, and increasing suitability for medication development designs.

Methods

Eleven experienced cocaine users participated in a 6-hour, single-day design, consisting of one safety/eligibility and three experimental cocaine periods (during which subjects were allowed to self-administer 8, 16, and 32 mg/70 kg cocaine doses under a fixed-ratio 1:5 minute timeout schedule). Changes in cocaine-induced cardiovascular response, self-administration behavior, and subjective effects were assessed.

Results

Procedures were well tolerated by participants, and no significant adverse events were noted. Significant (p < 0.05), changes in measures of cocaine self-administration (e.g., responses, infusions, interinfusion intervals, consumption, and plasma levels), cardiovascular response (HR), and subjective effects (“high”) were observed. In contrast, cocaine-induced increases in other vital signs (e.g., SBP, DBP) and subjective effect measures (e.g., paranoia) did not differ between doses.

Conclusions

These data support the safety, tolerability and validity of our single-day design. Depending on the application, such methods may afford advantages for assessing the self-regulation of cocaine administration behavior in humans (e.g., including medication development designs).     

Sleep disturbance and the effects of extended-release zolpidem during cannabis withdrawal

Background

Sleep difficulty is a common symptom of cannabis withdrawal, but little research has objectively measured sleep or explored the effects of hypnotic medication on sleep during cannabis withdrawal.

Methods

Twenty daily cannabis users completed a within-subject crossover study. Participants alternated between periods of ad libitum cannabis use and short-term cannabis abstinence (3 days). Placebo was administered at bedtime during one abstinence period (withdrawal test) and extended-release zolpidem, a non-benzodiazepine GABA_A receptor agonist, was administered during the other. Polysomnographic (PSG) sleep architecture measures, subjective ratings, and cognitive performance effects were assessed each day.

Results

During the placebo-abstinence period, participants had decreased sleep efficiency, total sleep time, percent time spent in Stage 1 and Stage 2 sleep, REM latency and subjective sleep quality, as well as increased sleep latency and time spent in REM sleep compared with when they were using cannabis. Zolpidem attenuated the effects of abstinence on sleep architecture and normalized sleep efficiency scores, but had no effect on sleep latency. Zolpidem was not associated with any significant side effects or next-day cognitive performance impairments.

Conclusions

These data extend prior research that indicates abrupt abstinence from cannabis can lead to clinically significant sleep disruption in daily users. The findings also indicate that sleep disruption associated with cannabis withdrawal can be attenuated by zolpidem, suggesting that hypnotic medications might be useful adjunct pharmacotherapies in the treatment of cannabis use disorders.     

Effects of topiramate on ethanol-cocaine interactions and DNA methyltransferase gene expression in the rat prefrontal cortex

BACKGROUND AND PURPOSE

Recent and ongoing clinical studies have indicated that topiramate (Topamax®) could be effective in treating ethanol or cocaine abuse. However, the effects of topiramate on the co-administration of ethanol and cocaine remain largely unknown.

EXPERIMENTAL APPROACH

We studied the effects of topiramate, in Wistar rats, on operant ethanol self-administration with the co-administration of cocaine (i.p.). The psychomotor effects of topiramate were examined before ethanol self-administration and cocaine exposure. Blood samples were collected to analyse ethanol and cocaine metabolism (blood ethanol levels and benzoylecgonine). Quantitative real-time PCR was used to characterize the gene expression in the prefrontal cortex.

KEY RESULTS

Topiramate prevented the cocaine-induced increased response to ethanol in a dose-dependent manner without causing any motor impairment by itself. This effect was observed when topiramate was administered before ethanol access, but not when topiramate was administered before the cocaine injection. Topiramate did not block cocaine-induced psychomotor stimulation. Topiramate reduced blood ethanol levels but did not affect cocaine metabolism. Ethanol increased the gene expression of DNA methyltransferases (Dnmt1 and Dnmt3a), the corepressor Dnmt1-associated protein 1 (Dmap1), and the RNA methyltransferase Trdmt1. These effects were prevented by topiramate or cocaine. Gene expression of histone deacetylase-2 and glutamate receptor kainate-1 were only increased by cocaine treatment. Topiramate and cocaine co-administration caused an up-regulation of dopamine (Drd1, Th) and opioid (Oprm1) receptor genes. Topiramate showed a tendency to alter episodic-like memory.

CONCLUSIONS AND IMPLICATIONS

Topiramate is an effective inhibitor of the cocaine-induced increase in operant ethanol self-administration.     

A randomized controlled trial of Structural Ecosystems Therapy for HIV medication adherence and substance abuse relapse prevention

Background

Substance abuse in women with HIV/AIDS overshadows other priorities, including health care. Substance abuse may cause women to avoid health care systems and not adhere to their medication regimen.

Methods

A randomized controlled trial tested the efficacy of Structural Ecosystems Therapy (SET) relative to a psychoeducational Health Group (HG) in 126 HIV+ women in recovery. SET, a 4-month intervention, focused on building family support for relapse prevention and HIV medication adherence. Over 12-month follow-up, women were assessed for drug use and medication adherence every 2 months; CD4 T-cell count and HIV viral load were assessed every 4 months.

Results

Levels of drug use did not differ by condition. There was a significant difference in curvature of the rates of change in drug use with SET increasing and then decreasing and HG decreasing and then increasing. Women in SET were more likely to increase substance abuse services in response to relapse and separate from drug using household members than were women in HG. These two changes explained the decline in drug use observed within SET between 6 and 12 months. SET showed declines in medication adherence but increases in CD4 T-cell count relative to HG. The increase in CD4 T-cell count in SET was related to increasing proportions of women in SET taking antiretroviral medications.

Conclusion

The results of the trial were mixed. Women in SET did not show better drug use or medication adherence outcomes, but did show improvement in CD4 T-cell count and theoretical mechanisms of action on drug relapse.     

Prenatal cocaine exposure and small-for-gestational-age status: effects on growth at 6 years of age

Objective

To evaluate the impact of prenatal cocaine exposure and small-for-gestational-age (SGA) status on childhood growth.

Study design

Cocaine exposure was defined by history or meconium metabolites. Hierarchical linear modeling was used to examine cocaine exposure and SGA status on growth, while controlling for exposure to other drugs and alcohol use.

Results

At birth cocaine-exposed infants (n = 364) had significantly lower growth parameters compared to non-exposed children (n = 771). At 6 years, weight was similar between exposed and unexposed children. SGA infants continued to be growth impaired. There was a significant interaction between prenatal cocaine exposure and SGA status at 6 years. The negative effects of cocaine on weight and height were greater among non-SGA than SGA children (432 vs. 280 gm, and 0.7 and 0.5 cm, respectively) while negative effects of SGA status on weight and height were larger in non-cocaine exposed compared to the exposed children (2.3 kg vs.1.6 kg and 2.2 and 1.0 cm).

Conclusions

Children exposed to prenatal cocaine were similar in weight to non-exposed children at 6 years of age. Cocaine had an unexplained greater detrimental effect on non-SGA than SGA children. SGA status at birth has an independent detrimental effect on childhood growth.     

Psychosocial treatments for cocaine dependence: the role of depressive symptoms

Background

The association between cocaine use and depression has been frequently observed. However, less is known about the significance of depression in the treatment of cocaine use disorders. This study examined possible interrelations between drug use and depression severity among cocaine-dependent patients in psychosocial treatments for cocaine dependence.

Methods

Monthly assessed drug use and depression severity scores of N = 487 patients during 6-month psychosocial treatments for cocaine dependence were analyzed using hybrid latent growth models.

Results

Results indicated a moderate but statistically significant (z = 3.13, p < .01) influence of depression severity on increased drug use in the upcoming month, whereas drug use did not affect future depression severity.

Conclusions

Findings suggest that depression symptoms are an important predictor of drug use outcomes during psychosocial treatments for cocaine dependence and, hence, underline the importance of adequately addressing depression symptoms to improve treatment outcomes.     

Regulation of cocaine self-administration in humans: Lack of evidence for loading and maintenance phases

Background

In rodents, cocaine self-administration under a fixed-ratio schedule and with timeout intervals limited to the duration of the infusions is characterized by an initial burst of drug intake (loading) followed by more stable infusion rates (maintenance). We sought to examine whether similar phases might characterize self-regulated cocaine use in humans.

Methods

31 Non-treatment seeking, cocaine dependent subjects participated in three (8, 16, and 32 mg/70 kg/infusion), self-regulated, 2-h cocaine self-administration sessions under a fixed-ratio 1, 5-min timeout schedule. Data were assessed for visual (e.g., by graphs of cumulative numbers of infusions) and statistical evidence of change in phase (by step-function analyses of individual infusion rates).

Results

Graphs of cumulative infusions over time suggested a single, linear rate of self-administration over 2 h at each cocaine dose. Statistical analyses of infusion data by generalized estimating equation (GEE) models also failed to support a loading/maintenance pattern (suggesting, if anything, the possibility of increasing infusion rates over time).

Conclusions

Our findings fail to support the existence of distinct loading and maintenance phases of self-regulated cocaine administration in humans at behaviorally relevant doses. Several factors may account for these observations including differences between humans and rodents in self-regulated drug intake.     

Topiramate increases the rewarding properties of cocaine in young-adult mice limiting its clinical usefulness

Rationale

Topiramate is an anticonvulsant drug which has been evaluated as a therapeutic option for the treatment of cocaine addiction during the last decade.

Objectives

The purpose of this study was to evaluate the effects of topiramate on the reinforcing actions of cocaine. To this aim, the topiramate-mediated regulation of acquisition and extinction phases of the cocaine conditioned place preference (CPP) was assessed in young-adult mice using three experimental designs.

Methods

Topiramate (50 mg/kg, p.o.) was given as follows: (1) during cocaine (1 and 25 mg/kg, i.p.) conditioning sessions (4 days) and cocaine (25 mg/kg) post-conditioning session; (2) 2 weeks before and during cocaine conditioning (25 mg/kg); and (3) during extinction of CPP induced by cocaine (25 mg/kg). In the first experimental design, changes in tyrosine hydroxylase (TH) and dopamine transporter (DAT) gene expressions were measured in the ventral tegmental area (VTA).

Results

Topiramate significantly increased cocaine-induced CPP and delayed or failed to produce extinction after the first cocaine reinstatement extinction in the first and second experiments. Furthermore, treatment with topiramate after place conditioning blocked the extinction of cocaine-induced CPP. TH and DAT gene expression in the VTA was significantly lower both with topiramate alone and in combination with cocaine compared with animals receiving only cocaine.

Conclusions

These findings suggest that topiramate increases the rewarding properties of cocaine, at least in part, by regulating dopaminergic signaling in the mesolimbic circuit. Consequently, the results of this study do not support the use of topiramate for the treatment of problems related to cocaine dependence.

Highlights

? Topiramate increases the rewarding properties of cocaine in CPP? Topiramate alters dopaminergic signaling in the mesolimbic circuit? Topiramate delays the extinction of cocaine-induced CPP? TH and DAT gene expression in the VTA decreases with topiramate and/or with cocaine? Results show that it should limit the use of topiramate in cocaine-dependent subjects

     

Evaluation of the hydrolytic activity of a long-acting mutant bacterial cocaine in the presence of commonly co-administered drugs

Background

Cocaine toxicity is a prevalent problem in the Unites States for which there is currently no FDA-approved pharmacotherapy. We have developed a bacterial cocaine esterase (CocE) towards this indication. A thermostabilized mutant of CocE (DM-CocE) retains the hydrolytic activity of the wild-type esterase, rapidly hydrolyzing cocaine into the inactive metabolites ecgonine methyl ester and benzoic acid, and can prevent cocaine toxicities in rodent and non-human primate models. To advance DM-CocE towards clinical use, we examine here how the hydrolytic activity of DM-CocE is altered by some drugs commonly co-administered with cocaine.

Methods

We employed a spectrophotometric cocaine hydrolysis assay to evaluate whether pharmacologically relevant doses of alcohol, nicotine, morphine, phencyclidine, ketamine, methamphetamine, naltrexone, naloxone, or midazolam would alter the Michaelis-Menten kinetics of DM-CocE for cocaine. Mass spectrometry was used to evaluate interaction with diazepam as this drug interferes with the absorbance spectra of cocaine critical for the spectrophotometric assay.

Results

Alcohol, nicotine, morphine, phencyclidine, ketamine, methamphetamine, naltrexone, naloxone, and midazolam did not alter cocaine hydrolysis by DM-CocE. However, diazepam significantly slowed DM-CocE cocaine hydrolysis at very high concentrations, most likely through interaction of the phenyl ring of the benzodiazepine with the active site of DM-CocE.

Conclusions

DM-CocE does not display significant drug interactions, with the exception of diazepam, which may warrant further study as DM-CocE progresses towards a clinically used pharmacotherapy for cocaine toxicity. Alternate benzodiazepines, e.g., midazolam could be used to avoid this potential interaction.     

Genetic moderators and psychiatric mediators of the link between sexual abuse and alcohol dependence

Background/objective

This study used a case-control female sample to test psychiatric mediators and genetic moderators of the effect of sexual abuse on later alcohol dependence. The study also tested differences between alcohol dependent women with or without a history of sexual abuse on variables that might affect treatment planning.

Methods

A case-control design compared 192 treatment-seeking alcohol dependent women with 177 healthy population controls. All participants were assessed for alcohol-related behaviors, sexual abuse history, psychiatric problems, and personality functioning. Markers were genotyped in the CRHR1, MAO-A and OPRM1 genes.

Results

The association of sexual abuse with alcohol dependence was limited to the most severe category of sexual abuse involving anal or vaginal penetration. Of the five psychiatric disorders tested, anxiety, anorexia nervosa, and bulimia met criteria as potential mediators of the abuse-alcohol dependence association. Severe sexual abuse continued to have an independent effect on alcohol dependence status even after accounting for these potential mediators. None of the candidate genetic markers moderated the association between sexual abuse and alcohol dependence. Of alcohol dependent participants, those with a history of severe abuse rated higher on alcoholism severity, and psychiatric comorbidities.

Conclusion

Sexual abuse is associated with later alcohol problems directly as well as through its effect on psychiatric problems. Treatment-seeking alcohol dependent women with a history of abuse have distinct features as compared to other alcohol dependent women.     

Markers of abuse liability of short- vs long-acting opioids in chronic pain patients: A randomized cross-over trial

Background

Abuse liability is thought to possibly be lower in long- than in short-acting opioids because lower peak serum levels may be less likely to induce psychoactive effects.

Methods

We compared patient responses to extended-release morphine, hydrocodone plus acetaminophen, and placebo in a randomized, double-blind crossover study using markers of abuse liability. Patients indicated their craving for drugs on 5 visual analog scales (VASs), completed the Addiction Research Center Inventory, and underwent cue reactivity testing. To perform the latter, subjects watched a video intended to produce a positive or a negative affect, after which a vial of medication was or was not presented (the cue) and then indicated their craving for drugs on 5 different VASs (the reactivity).

Results

Differences in Addiction Research Inventory scores were statistically significant but clinically unimportant. Neuropsychological test results were mixed and unrelated to the medications studied. Cue reactivity did not differ among conditions but was uniformly high.

Conclusions

Using several markers of abuse liability, long-acting opioids do not have lower abuse potential than do short-acting opioids or placebo. Although cue reactivity did not differ among the conditions, uniformly high results in these patients suggest that it may have some value as a component of abuse liability testing.     

An allosteric enhancer of M4 muscarinic acetylcholine receptor function inhibits behavioral and neurochemical effects of cocaine

Rationale

The mesostriatal dopamine system plays a key role in mediating the reinforcing effects of psychostimulant drugs like cocaine. The muscarinic M₄ acetylcholine receptor subtype is centrally involved in the regulation of dopamine release in striatal areas. Consequently, striatal M₄ receptors could be a novel target for modulating psychostimulant effects of cocaine.

Objectives

For the first time, we here addressed this issue by investigating the effects of a novel selective positive allosteric modulator of M₄ receptors, VU0152100, on cocaine-induced behavioral and neurochemical effects in mice.

Methods

To investigate the effect of VU0152100 on the acute reinforcing effects of cocaine, we use an acute cocaine self-administration model. We used in vivo microdialysis to investigate whether the effects of VU0152100 in the behavioral studies were mediated via effects on dopaminergic neurotransmission. In addition, the effect of VU0152100 on cocaine-induced hyperactivity and rotarod performance was evaluated.

Results

We found that VU0152100 caused a prominent reduction in cocaine self-administration, cocaine-induced hyperlocomotion, and cocaine-induced striatal dopamine increase, without affecting motor performance. Consistent with these effects of VU0152100 being mediated via M₄ receptors, its inhibitory effects on cocaine-induced increases in striatal dopamine were abolished in M₄ receptor knockout mice. Furthermore, selective deletion of the M₄ receptor gene in dopamine D₁ receptor-expressing neurons resulted in a partial reduction of the VU0152100 effect, indicating that VU0152100 partly regulates dopaminergic neurotransmission via M₄ receptors co-localized with D₁ receptors.

Conclusions

These results show that positive allosteric modulators of the M₄ receptor deserve attention as agents in the future treatment of cocaine abuse.     

A Single Brain-Derived Neurotrophic Factor Infusion into the Dorsomedial Prefrontal Cortex Attenuates Cocaine Self-Administration-Induced Phosphorylation of Synapsin in the Nucleus Accumbens during Early Withdrawal

Background:

Dysregulation in the prefrontal cortex-nucleus accumbens pathway has been implicated in cocaine addiction. We have previously demonstrated that one intra-dorsomedial prefrontal cortex brain-derived neurotrophic factor (BDNF) infusion immediately following the last cocaine self-administration session caused a long-lasting inhibition of cocaine-seeking and normalized the cocaine-induced disturbance of glutamate transmission in the nucleus accumbens after extinction and a cocaine prime. However, the molecular mechanism mediating the brain-derived neurotrophic factor effect on cocaine-induced alterations in extracellular glutamate levels is unknown.

Methods:

In the present study, we determined the effects of brain-derived neurotrophic factor on cocaine-induced changes in the phosphorylation of synapsin (p-synapsin), a family of presynaptic proteins that mediate synaptic vesicle mobilization, in the nucleus accumbens during early withdrawal.

Results:

Two hours after cocaine self-administration, p-synapsin Ser9 and p-synapsin Ser62/67, but not p-synapsin Ser603, were increased in the nucleus accumbens. At 22 hours, only p-synapsin Ser9 was still elevated. Elevations at both time points were attenuated by an intra-dorsomedial prefrontal cortex brain-derived neurotrophic factor infusion immediately after the end of cocaine self-administration. Brain-derived neurotrophic factor also reduced cocaine self-administration withdrawal-induced phosphorylation of the protein phosphatase 2A C-subunit, suggesting that brain-derived neurotrophic factor disinhibits protein phosphatase 2A C-subunit, consistent with p-synapsin Ser9 dephosphorylation. Further, co-immunoprecipitation demonstrated that protein phosphatase 2A C-subunit and synapsin are associated in a protein-protein complex that was reduced after 2 hours of withdrawal from cocaine self-administration and reversed by brain-derived neurotrophic factor.

Conclusions:

Taken together, these findings demonstrate that brain-derived neurotrophic factor normalizes the cocaine self-administration–induced elevation of p-synapsin in nucleus accumbens that may underlie a disturbance in the probability of neurotransmitter release or represent a compensatory neuroadaptation in response to the hypofunction within the prefrontal cortex-nucleus accumbens pathway during cocaine withdrawal.     

The association between frontal-striatal connectivity and sensorimotor control in cocaine users

Background

In addition to cognitive and emotional processing dysfunction, chronic cocaine users are also impaired at simple sensorimotor tasks. Many diseases characterized by compulsive movements, repetitive actions, impaired attention and planning are associated with dysfunction in frontal-striatal circuits. The aim of this study was to determine whether cocaine users had impaired frontal-striatal connectivity during a simple movement task and whether this was associated with sensorimotor impairment.

Methods

Functional MRI data were collected from 14 non-treatment seeking cocaine users and 15 healthy controls as they performed a finger-tapping task. Functional coupling was quantified by correlating the timecourses of each pair of anatomically connected regions of interest. Behavioral performance was correlated with all functional coupling coefficients.

Results

In controls there was a significant relationship between the primary motor cortex and the supplementary motor area (SMA), as well as the SMA and the dorsal striatum during ongoing movement. Cocaine users exhibited weaker fronto-striatal coupling than controls, while the cortical-cortical coupling was intact. Coupling strength between the SMA and the caudate was negatively correlated with reaction time in the users.

Conclusions

The observation that cocaine users have impaired cortical-striatal connectivity during simple motor performance, suggests that these individuals may have a fundamental deficit in information processing that influences more complex cognitive processes.     

Treatment of substance abusing patients with comorbid psychiatric disorders

Objective

To update clinicians on the latest in evidence-based treatments for substance use disorders (SUD) and non-substance use disorders among adults and suggest how these treatments can be combined into an evidence-based process that enhances treatment effectiveness in comorbid patients.

Method

Articles were extracted from Pubmed using the search terms “dual diagnosis,” “comorbidity” and “co-occurring” and were reviewed for evidence of effectiveness for pharmacologic and psychotherapeutic treatments of comorbidity.

Results

Twenty-four research reviews and 43 research trials were reviewed. The preponderance of the evidence suggests that antidepressants prescribed to improve substance-related symptoms among patients with mood and anxiety disorders are either not highly effective or involve risk due to high side-effect profiles or toxicity. Second generation antipsychotics are more effective for treatment of schizophrenia and comorbid substance abuse and current evidence suggests clozapine, olanzapine and risperidone are among the best. Clozapine appears to be the most effective of the antipsychotics for reducing alcohol, cocaine and cannabis abuse among patients with schizophrenia. Motivational interviewing has robust support as a highly effective psychotherapy for establishing a therapeutic alliance. This finding is critical since retention in treatment is essential for maintaining effectiveness. Highly structured therapy programs that integrate intensive outpatient treatments, case management services and behavioral therapies such as Contingency Management (CM) are most effective for treatment of severe comorbid conditions.

Conclusions

Creative combinations of psychotherapies, behavioral and pharmacological interventions offer the most effective treatment for comorbidity. Intensity of treatment must be increased for severe comorbid conditions such as the schizophrenia/cannabis dependence comorbidity due to the limitations of pharmacological treatments.     

Lack of sex differences to the subjective effects of nitrous oxide in healthy volunteers

Background

Although numerous studies have assessed subjective effects of nitrous oxide, few studies have analyzed for sex differences. Since sex differences have been reported in subjective effects of several drugs such as opioids, nicotine and alcohol, we sought to determine if sex modulates the subjective effects of the inhalant, nitrous oxide, in healthy volunteers.

Methods

Thirty-eight females and seventy-two males from nine studies that were conducted in our laboratory were included in this retrospective analysis. All experimental studies utilized randomized, placebo-controlled, repeated measures designs in which subjects inhaled 30% nitrous oxide in oxygen and 100% oxygen (placebo). Dependent measures in this analysis were subjective effects measured at baseline and 15 min into the inhalation period.

Results

Nitrous oxide produced a number of subjective effects, including those that could be considered abuse liability-related (“elated,” “having pleasant thoughts,” drug liking), but sex did not modulate these effects.

Conclusions

Females and males showed similar subjective responses to 30% nitrous oxide. Future prospective studies might assess other concentrations, other measures (choice, analgesic response), and other inhaled general anesthetics to more comprehensively characterize the role of sex in response to inhalants.     

Gender, race, and group behavior in group drug treatment

Background

Group drug counseling is the primary treatment modality used to treat drug dependence in community settings in the United States. Findings from the social psychology literature suggest that gender may influence how individuals participate in groups, and that race may moderate the effects of gender on group behavior. This study examined gender, race, and their interaction as predictors of alliance, participation, self-disclosure, and receipt of advice and feedback in drug counseling groups, and explored how gender and racial differences in drug counseling group behavior related to outcome of cocaine dependence treatment.

Method

Ratings of group behavior were made from videotaped sessions of group drug counseling drawn from a randomized trial of treatment for cocaine-dependent individuals (n = 438). Analyses examined the effects of race (African American or non-Hispanic White), gender, and the race by gender interaction on group behavior. Additional analyses examined race, gender, and group behavior, and interactions among these variables in predicting monthly cocaine use.

Results

Race and the race by gender interaction, but not gender alone, predicted many group behaviors. Non-Hispanic White women had the highest rates of self-disclosure and receipt of advice and non-positive feedback, followed by men of both races, with African American women having the lowest levels. These differences were unrelated to cross-sectional cocaine outcome.

Conclusions

Women, but not men, of different races acted differently in mixed-race, mixed-gender cocaine treatment groups, with African American women exhibiting less of several behaviors. Additional research on causes and consequences of these differences could inform interventions for drug-dependent women.