Psychostimulant Dependence Research Articles

The new drug phenomenon

The new drug phenomenon

Acceptability of shamanic healing for treating psychostimulant dependence: a pilot survey

Background No therapy has shown robust efficacy for treating psychostimulant dependence. Meanwhile, the feasibility and effectiveness of direct spiritual healing modalities for this disorder are unknown. Objectives To determine the acceptability of participating in research using a spiritual healing approach, namely shamanic healing, among psychostimulant users. Methods Psychostimulant users in central Arkansas, USA, interested in participating in ongoing treatment research, were surveyed to determine willingness to participate in research involving shamanic healing. Results Of the 103 respondents, 74.8% reported being willing to participate in research involving shamanic healing, with women being more likely than men to participate (χ2=4.21, P=0.04). Religious affiliation, age, race, primary drug problem and prior experience with an alternative therapy were not associated with willingness to participate (P>0.1). Respondents stating that participation would be against their religious beliefs always had an evangelical religious affiliation (χ2=6.32, P=0.04). Respondents stating that they needed more information were most likely to have a traditional religious affiliation (χ2=7.54, P=0.02). Those reporting time commitment as the reason for refusal were more likely to have experienced an alternative therapy (χ2=7.88, P=0.005). Conclusions Research involving shamanic healing for treating psychostimulant dependence may be feasible, even in a region with a high prevalence of evangelical affiliations.

Antipsychotics for Cocaine or Psychostimulant Dependence

Since cocaine and psychostimulant dependence are related to increased dopamine release, antipsychotics have been tried to reduce their reinforcing properties. A meta-analysis was undertaken to assess the efficacy and tolerability of antipsychotics in cocaine- or stimulant-dependent patients. We searched PubMed, Cochrane Library databases, and PsycINFO from database inception until June 24, 2013, using the following keywords: (randomized OR random OR randomly) AND (placebo) AND (methylphenidate OR cocaine OR methamphetamine OR amphetamine OR 3,4-methylenedioxymethamphetamine) AND (dependence OR abuse) AND (antipsychotic OR neuroleptic OR 34 specific antipsychotic names). Included were randomized, placebo-controlled trials of antipsychotics lasting at least 2 weeks in patients with primary cocaine or psychostimulant dependence. Of 363 hits, we removed 316 duplicates, 20 references based on abstract/title, and 13 ineligible full-text articles, retaining 14 trials for this meta-analysis. Two authors independently extracted the data. Coprimary outcomes included degree of substance use and lack of abstinence. Risk ratio (RR), 95% CI, and standardized mean difference were calculated. Ten studies in patients with primary cocaine dependence (risperidone = 5, olanzapine = 3, reserpine = 2; n = 562) and 4 in those with amphetamine/methamphetamine dependence (aripiprazole = 4; n = 179) were meta-analyzed (14 studies, total n = 741). When study results were pooled together, antipsychotics did not differ from placebo in regard to cocaine use days and lack of cocaine or amphetamine/methamphetamine abstinence, severity of addiction, cocaine or amphetamine/methamphetamine craving, Clinical Global Impressions-Severity of Illness (CGI-S) scores, depression, anxiety, compliance, all-cause discontinuation, and several side effects. However, antipsychotics caused more intolerability-related discontinuation than placebo (P = .0009). Individually, aripiprazole was superior to placebo in regard to CGI-S (P = .001), while olanzapine was inferior to placebo in regard to cocaine craving (P = .03) and risperidone was inferior to placebo in regard to depression (P = .002). Antipsychotics had no advantages over placebo in regard to cocaine use and cocaine or psychostimulant abstinence or craving, while causing more intolerability-related discontinuations.

Combined effects of modafinil and d-amphetamine in male Sprague–Dawley rats trained to discriminate d-amphetamine

Modafinil is a novel wake-promoting drug with FDA approval for the treatment of sleep-related disorders that has recently been investigated as a potential agonist replacement therapy for psychostimulant dependence. Previous research in animals and humans indicates modafinil has a lower abuse liability than traditional psychostimulants, although few studies have carefully assessed modafinil's stimulus properties in combination with other psychostimulants. The current study trained male Sprague–Dawley rats to discriminate subcutaneous injections of 0.3mg/kg (n=8) or 1.0mg/kg d-amphetamine (n=8) from saline under an FR 20 schedule of food reinforcement and substitution tests were administered with d-amphetamine (0.03–1.0mg/kg, s.c.), modafinil (32–256mg/kg, i.g.), and a low modafinil dose (32mg/kg, i.g.) in combination with d-amphetamine (0.03–1.0mg/kg, s.c.) to determine if these drugs have additive effects. The selective D2 dopamine agonist, PNU-91356A, was also tested as a positive control and ethanol and morphine were tested as negative controls. Results indicate that modafinil produced dose-dependent and statistically significant d-amphetamine-lever responding in both groups and nearly complete substitution in animals trained to discriminate 1.0mg/kg d-amphetamine. Modafinil pretreatment slightly increased the discrimination of low d-amphetamine doses in animals trained to discriminate 0.3mg/kg d-amphetamine. These results support previous findings that modafinil and d-amphetamine may have additive effects. In consideration of recent interests in modafinil as an agonist treatment for psychostimulant dependence, additional preclinical investigations utilizing other methodologies to examine modafinil in combination with other stimulants, such as behavioral sensitization paradigms or drug self-administration, may be of interest.

Modafinil alone and in combination with low dose amphetamine does not establish conditioned place preference in male sprague-dawley rats.

Modafinil is a novel wake-promoting drug with FDA approval for the treatment of narcolepsy, shift work sleep disorder, and sleep apnea. It is also prescribed for many off-label uses such as ADHD and it is currently being assessed as a treatment for psychostimulant dependence. Previous research assessing the abuse liability of modafinil in animals and humans suggests it is less potent and has a low abuse potential compared to traditional psychomotor stimulants. However, modafinil has not been carefully assessed in combination with other psychostimulant drugs. The current study used an unbiased place conditioning procedure simultaneously with locomotor screening procedures to assess the combined behavioral effects of modafinil and d-amphetamine in adult male Sprague-Dawley rats. Eight 30-min conditioning trials were conducted in a 2 compartment apparatus with distinct visual and tactile cues. Drug and vehicle conditioning trials were alternated with 1 trial per day separated by 24 hr. On drug conditioning trials, rats were administered either modafinil (64 mg/kg, i.g.), d-amphetamine (0.3 or 2.0 mg/kg, s.c.), a combination of modafinil (64 mg/kg) and d-amphetamine (0.3 mg/kg), or vehicle injections. On vehicle conditioning trials, all groups received vehicle injections. Preference for either compartment was assessed by recording time spent in each compartment during a 15-min test conducted 24 hr after the last conditioning trial. Results indicated that this low oral dose of modafinil did not significantly increase locomotor activity or establish conditioned place preference (CPP). Moreover, modafinil did not significantly alter the hyperlocomotor or CPP effects of d-amphetamine. To confirm that modafinil is behaviorally active at this low oral dose, a separate assessment of horizontal and vertical activity was conducted with male Sprague-Dawley rats in an open field apparatus. Results confirmed that modafinil increased locomotor activity relative to vehicle, with increases in vertical activity especially prominent, a measure that was not assessed in place conditioning trials. Although the current results predict a low abuse liability with concurrent use of modafinil and d-amphetamine, additional research with higher dose combinations may be warranted before ruling out the possibility that these drugs could have additive or synergistic effects.

Methylphenidate vs. resperidone in treatment of methamphetamine dependence: A clinical trial

Background and aimsCurrently, there is no widely accepted evidence-based pharmacotherapy regime for the treatment of psychostimulant dependence. Yet, different pharmacological approaches have been tried in the treatment of MA addiction. The present study was conducted to compare efficiency of methylphenidate which is relatively easily accessible in our country, with resperidone for this purpose. MethodsEighty-six patients with MA dependence according to criteria defined by DSM IV-TR were divided into two groups. Patients in group R were given oral resperidone 1mg daily for 1week; then 2mg daily in a divided dose for 3weeks. Patients in group M were given oral methylphenidate 10mg daily for 2weeks, 7.5mg daily for 1week, then 5mg daily for 1week. They were evaluated for drug craving, psychological, neurologic and somatic symptoms at the start and end of the study. FindingsBoth drugs were useful for lowering drug craving in patients; however resperidone was more effective (6.31±8.31 vs.19.6±12.45 cravings per week, respectively). The effects of resperidone were more notable in lowering frequency and intensity of psychiatric, neurologic, cardiac and somatic symptoms of the patients after discontinuation of MA abuse; however methylphenidate was effective too; though with a lower potency. ConclusionThe present study confirmed that both methylphenidate and resperidone can successfully be used for treatment of MA dependence, in order to reduce drug craving and psychological, neurologic, and somatic problems in patients. However, the efficacy of methylphenidate was estimated to be less than that of resperidone for this purpose.

Effects of amphetamine on the human brain opioid system – a positron emission tomography study

Studies in rodents have shown that psychostimulant drugs such as cocaine and amphetamine cause endorphin release in the brain reward system. There is also evidence for the involvement of the opioid system in human psychostimulant dependence. The acute effects of an i.v. psychostimulant drug on the brain opioid system, however, have not yet been investigated in humans. We hypothesized that an i.v. dose of amphetamine as compared to placebo would cause an opioid release in the human brain reward system, measurable as a reduction of the binding potential of the μ-opioid receptor radioligand [(11)C]carfentanil. Ten healthy young men were examined using positron emission tomography (PET) and [(11)C]carfentanil in three sessions: at baseline; after placebo; after an i.v. amphetamine dose of 0.3 mg/kg bodyweight. The order of amphetamine and placebo was double-blinded and randomized. PET examinations were performed with a Siemens high resolution research tomograph. Data were analysed with the simplified reference tissue model, applying manually drawn regions of interest for every subject. Using repeated measures analysis of variance, we found no significant differences in [(11)C]carfentanil binding potential between amphetamine and placebo conditions in any of the investigated brain regions. In contrast to data from rodent studies and a recent study of oral amphetamine administration in humans, an i.v. dose of amphetamine does not cause any acute opioid release in healthy human subjects. The postulated role of the opioid system in mediating the effects of amphetamine needs to be further investigated in animal models of the disease as well as in patient populations.

Diversion and misuse of pharmaceutical stimulants among illicit drug users

The study aimed to examine diversion and misuse of pharmaceutical stimulants among illicit psychostimulant users, providing the first data of this type. A total of 269 regular illicit psychostimulant users were administered a structured interview measuring demographics, illicit drug use and treatment history, use and misuse of prescribed pharmaceutical stimulants, illicit use of diverted pharmaceutical stimulants, and illicit psychostimulant dependence. Lifetime use of diverted pharmaceutical stimulants was reported by 31%, with the majority having used on multiple occasions. Use of diverted pharmaceutical stimulants was initiated in adulthood in one out of two cases, at a mean age of 20.4 years, and was significantly and independently associated with being younger (odds ratio [OR] 0.93), having spent more years at school (OR 1.28) and having a more extensive history of polydrug usage (OR 1.58). Though a relatively small proportion (7%) have been prescribed pharmaceutical stimulants in the past, more than two-thirds of those prescribed these medications have misused and/or diverted them to others. Prescribers of pharmaceutical stimulants should be aware that these medications are being diverted not only among adolescents or student peer groups, but via a wider network of adult-illicit drug users.

Attention deficit hyperactivity disorder (ADHD) among illicit psychostimulant users: a hidden disorder?

To estimate the prevalence, nature and correlates of symptomatology consistent with adult attention deficit hyperactivity disorder (ADHD) among illicit psychostimulant users. Cross-section survey. Sydney, Australia. 269 regular illicit psychostimulant users. Structured interview assessing demographics, drug use and treatment history, psychostimulant dependence and self-reported symptoms consistent with adult ADHD. Almost half (45%) screened positive for adult ADHD (ADHD+). Symptoms of inattention (90%) were more prevalent than symptoms of hyperactivity/impulsivity (57%). Of those who screened positive for adult ADHD, only 17% had received a prior diagnosis of ADHD. The ADHD+ group differed from other participants in several respects: an earlier initiation of substance use and injecting drug use; more extensive polydrug use; a higher frequency of recent stimulant use and injecting drug use; a greater likelihood of stimulant dependence; and a greater likelihood of having received treatment for drug dependence. After controlling for other factors, screening positive for ADHD was associated independently with fewer years of education, earlier initiation of regular tobacco use and more extensive life-time polydrug use. Clinicians should be aware of the potential for patients of drug and alcohol treatment services to have undiagnosed and/or untreated ADHD that may impact on their compliance with, and retention in, treatment.

Monoamine Transporter Structure, Function, Dynamics, and Drug Discovery: A Computational Perspective

With the breakthrough crystallization of the bacterial leucine transporter protein LeuT, the first available X-ray structure for the neurotransmitter/sodium symporter family, development of 3-D computational models is suddenly essential for structure-function studies on the plasmalemmal monoamine transporters (MATs). LeuT-based MAT models have been used to guide elucidation of substrate and inhibitor binding pockets, and molecular dynamics simulations using these models are providing insight into conformations involved in the substrate translocation cycle. With credible MAT models finally in hand, structure-based virtual screening for novel ligands is yielding lead compounds toward the development of new medications for psychostimulant dependence, attention deficit hyperactivity, depression, anxiety, schizophrenia, and other disorders associated with dopamine, norepinephrine, or serotonin dysregulation.

SB 206553, a putative 5-HT2C inverse agonist, attenuates methamphetamine-seeking in rats

BackgroundMethamphetamine (meth) dependence presents a substantial socioeconomic burden. Despite the need, there is no FDA-approved pharmacotherapy for psychostimulant dependence. We consider 5-HT2C receptors as viable therapeutic targets. We recently revealed that the atypical antidepressant, mirtazapine, attenuates meth-seeking in a rodent model of human substance abuse. Mirtazapine historically has been considered to be an antagonist at 5-HT2C receptors, but more recently shown to exhibit inverse agonism at constitutively active 5-HT2C receptors. To help distinguish the roles for antagonism vs. inverse agonism, here we explored the ability of a more selective 5-HT2C inverse agonist, SB 206553 to attenuate meth-seeking behavior, and compared its effects to those obtained with 5-HT2C antagonists, SDZ Ser 082 and SB 242084. To do so, rats were trained to self-administer meth and tested for seeking-like behavior in cue reactivity sessions consisting of contingently presenting meth-associated cues without meth reinforcement. We also explored motor function to determine the influence of SB 206553 and SDZ Ser 082 on motor activity in the presence and absence of meth.ResultsLike mirtazapine, pretreatment with SB 206553 (1.0, 5.0, and 10.0 mg/kg), attenuated meth-seeking. In contrast, the antagonists, SDZ Ser 082 (0.1, 0.3, and 1.0 mg/kg) and SB 242084 (3.0 mg/kg) had no effect on cue reactivity (CR). SB 242084 (3.0 mg/kg) failed to attenuate the effects of 5.0 and 10 mg/kg SB 206553 on CR. Motor function was largely unaltered by the 5-HT2C ligands; however, SB 206553, at the highest dose tested (10.0 mg/kg), attenuated meth-induced rearing behavior.ConclusionsThe lack of effect by 5-HT2C antagonists suggests that meth-seeking and meth-evoked motor activity are independent of endogenous 5-HT acting at 5-HT2C receptors. While SB 206553 dramatically impacted meth-evoked behaviors it is unclear whether the observed effects were 5-HT2C receptor mediated. Thus, SB 206553 deserves further attention in the study of psychostimulant abuse disorders.

Duloxetine Inhibits Effects of MDMA (“Ecstasy") In Vitro and in Humans in a Randomized Placebo-Controlled Laboratory Study

This study assessed the effects of the serotonin (5-HT) and norepinephrine (NE) transporter inhibitor duloxetine on the effects of 3,4–methylenedioxy­methamphetamine (MDMA, ecstasy) in vitro and in 16 healthy subjects. The clinical study used a double-blind, randomized, placebo-controlled, four-session, crossover design. In vitro, duloxetine blocked the release of both 5-HT and NE by MDMA or by its metabolite 3,4-methylenedioxyamphetamine from transmitter-loaded human cells expressing the 5-HT or NE transporter. In humans, duloxetine inhibited the effects of MDMA including elevations in circulating NE, increases in blood pressure and heart rate, and the subjective drug effects. Duloxetine inhibited the pharmacodynamic response to MDMA despite an increase in duloxetine-associated elevations in plasma MDMA levels. The findings confirm the important role of MDMA-induced 5-HT and NE release in the psychotropic effects of MDMA. Duloxetine may be useful in the treatment of psychostimulant dependence.Trial RegistrationClinicaltrials.gov NCT00990067

Editorial introductions

Editorial introductions

Involvement of metabotropic glutamate receptor 5 in brain reward deficits associated with cocaine and nicotine withdrawal and somatic signs of nicotine withdrawal

The involvement of metabotropic glutamate 5 (mGlu5) receptors has been suggested in the reinforcing effects of psychostimulants. However, little is known about the role of these receptors in psychostimulant withdrawal. The role of mGlu5 receptors was assessed in the anhedonic and somatic aspects of psychostimulant withdrawal. Anhedonia was assessed with the discrete-trial current-intensity intracranial self-stimulation (ICSS) procedure after the termination of cocaine (180mgkg(-1)day(-1), salt, 3days, i.p.) or nicotine (40mgkg(-1)day(-1), base, 28days, s.c.) administration via osmotic minipumps in mGlu5 receptor knockout (mGluR5(-/-)) and wild-type (mGluR5(+/+)) mice. Somatic signs were assessed during nicotine withdrawal. The effects of the nicotinic acetylcholine receptor antagonist mecamylamine on ICSS thresholds were assessed during chronic nicotine administration. Nicotine-treated mGluR5(+/+) and mGluR5(-/-) mice demonstrated similar threshold elevations during mecamylamine-precipitated withdrawal compared with their saline-treated counterparts. During spontaneous nicotine and cocaine withdrawal, thresholds in drug-withdrawing mGluR5(+/+), but not mGluR5(-/-), mice were elevated up to 72h of nicotine/cocaine withdrawal and then returned to baseline, indicating attenuation of withdrawal-induced anhedonia in mGluR5(-/-) mice. Nicotine-withdrawing mGluR5(+/+), but not mGluR5(-/-), mice showed increases in somatic signs compared with saline-treated counterparts. mGlu5 receptor null mutation attenuates the anhedonic and somatic effects of psychostimulant withdrawal. This attenuated withdrawal in mGluR5(-/-) mice may result from the lack of drug-induced adaptations in mGlu5 receptor function that may occur in mGluR5(+/+) mice with chronic drug administration. Thus, these results suggest the involvement of mGlu5 receptors in psychostimulant dependence and the mediation of the anhedonic and somatic signs of psychostimulant withdrawal.

Effects of the α2-Adrenergic Agonist Clonidine on the Pharmacodynamics and Pharmacokinetics of 3,4-Methylenedioxymethamphetamine in Healthy Volunteers

The mechanism of action of 3,4-methylenedioxymethamphetamine (MDMA; ecstasy) involves the carrier-mediated and potentially vesicular release of monoamines. We assessed the effects of the sympatholytic α₂-adrenergic receptor agonist clonidine (150 μg p.o.), which inhibits the neuronal vesicular release of norepinephrine, on the cardiovascular and psychotropic response to MDMA (125 mg p.o.) in 16 healthy subjects. The study used a randomized, double-blind, placebo-controlled crossover design with four experimental sessions. The administration of clonidine 1 h before MDMA reduced the MDMA-induced increases in plasma norepinephrine concentrations and blood pressure but only to the extent that clonidine lowered norepinephrine levels and blood pressure compared with placebo. Thus, no interaction was found between the cardiovascular effects of the two drugs. Clonidine did not affect the psychotropic effects or pharmacokinetics of MDMA. The lack of an interaction of the effects of clonidine and MDMA indicates that vesicular release of norepinephrine, which is inhibited by clonidine, does not critically contribute to the effects of MDMA in humans. Although clonidine may be used in the treatment of stimulant-induced hypertensive reactions, the present findings do not support a role for α₂-adrenergic receptor agonists in the prevention of psychostimulant dependence.

Neuropsychological profiling of impulsivity and compulsivity in cocaine dependent individuals

Research on the relative impact of trait impulsivity vs. drug exposure on neuropsychological probes of response inhibition vs. response perseveration has been posited as a valid pathway to explore the transition between impulsivity and compulsivity on psychostimulant dependence. The objectives of this study are to examine performance differences between cocaine-dependent individuals (CDI) and healthy comparison individuals (HCI) on neuropsychological probes of inhibition and perseveration and to examine the predictive impact of trait impulsivity-a proxy of premorbid vulnerability, and severity of cocaine use-a proxy of drug exposure, on CDI's performance. Forty-two CDI and 65 HCI were assessed using the UPPS-P Scale (trait impulsivity), the Stroop and go/no-go (inhibition) and revised-strategy application and probabilistic reversal tests (perseveration). CDI, compared to HCI, have elevated scores on trait impulsivity and perform significantly poorer on inhibition and perseveration, with specific detrimental effects of duration of cocaine use on perseveration. CDI have both inhibition and perseveration deficits; both patterns were broadly indicative of orbitofrontal dysfunction in the context of reinforcement learning. Impulsive personality and cocaine exposure jointly contribute to deficits in response perseveration or compulsivity.

Unidirectional relationship between heroin self-administration and impulsive decision-making in rats

RationaleThere is growing clinical evidence for a strong relationship between drug addiction and impulsivity. However, it is not fully clear whether impulsivity is a pre-existing trait or a consequence of drug abuse. Recent observations in the animal models show that pre-existing levels of impulsivity predict cocaine and nicotine seeking. Whether such relationships also exist with respect to non-stimulant drugs is largely unknown.ObjectiveWe studied the relationship between impulsive choice and vulnerability to heroin taking and seeking.Materials and methodsRats were selected in the delayed reward task based on individual differences in impulsive choice. Subsequently, heroin intravenous self-administration behaviour was analysed, including acquisition of heroin intake, motivation, extinction and drug- and cue-induced reinstatement. Throughout the entire experiment, changes in impulsive choice were monitored weekly.Results and discussionHigh impulsivity did not predict measures of heroin taking. Moreover, high impulsive rats did not differ from low impulsive rats in extinction rates or heroin- and cue-induced reinstatement. However, both groups became more impulsive as heroin self-administration continued. During abstinence, impulsivity levels returned towards baseline (pre-heroin) levels. Our results indicate that, in contrast to psychostimulants, impulsive choice does not predict vulnerability to heroin seeking and taking.ConclusionThese data implicate that different neural mechanisms may underlie the vulnerability to opiate and psychostimulant dependence. Moreover, our data suggest that elevated impulsivity levels as observed in heroin-dependent subjects are a consequence of heroin intake rather than a pre-existing vulnerability trait.

Is serum brain-derived neurotrophic factor related to craving for or use of alcohol, cocaine, or methamphetamine?

BackgroundData suggests that brain-derived neurotropic factor (BDNF) plays a neuroadaptive role in addiction. Whether serum BDNF levels are different in alcohol or psychostimulants as a function of craving is unknown. Here, we examined craving and serum BDNF levels in persons with alcohol versus psychostimulant dependence. Our goals were to explore BDNF as an objective biomarker for 1) craving 2) abstinence, and 3) years of chronic substance use.MethodsAn exploratory, cross-sectional study was designed. Men and women between 20–65 years old with alcohol, cocaine, or methamphetamine dependence were eligible. A craving questionnaire was used to measure alcohol, cocaine and methamphetamine cravings. Serum levels of BDNF were measured using enzyme linked immunoassay. Analysis of variance, chi-square, and correlations were performed using a 95% confidence interval and a significance level of P < 0.05.ResultsWe found a significant difference in the mean craving score among alcohol, cocaine and methamphetamine dependent subjects. There were no significant influences of race, gender, psychiatric disorder or psychotropic medication on serum BDNF levels. We found that among psychostimulant users BDNF levels were significantly higher in men than in women when the number of abstinent days was statistically controlled. Further, a significant correlation between serum BDNF levels and the number of abstinent days since last psychostimulant use was found.ConclusionThese data suggest that BDNF may be a biomarker of abstinence in psychostimulant dependent subjects and inform clinicians about treatment initiatives. The results are interpreted with caution due to small sample size and lack of a control group.

Neuroendocrine and behavioral response to amphetamine challenge after exposure to an organophosphorus pesticide

Exposure to various stressors is known to result in sensitization to psychostimulants, a state related to the psychostimulant dependence and addiction. It has been shown in some studies that the rise in corticosterone (CORT) concentration is indispensable for both the induction and the expression of behavioral sensitization. Therefore, it might be suspected that behavioral hyposensitivity to amphetamine (AMPH) is somehow related to a reduced CORT response to the psychostimulant subsequent to the chlorphenvinphos (CVP) intoxication. The male adult Wistar rats received single i.p. injections of CVP at the doses 0.5, 1.0 or 3.0 mg/kg b.w., or pure corn oil. CORT concentration was determined in samples of blood drawn from the tail vein before and then 30, 60, 180 min and 24 h after injection. The other rats were divided into two groups and tested, three weeks after the CVP injection for the effect of AMPH (0.5 mg/kg b.w. i.p.) on the serum CORT concentration. In addition, behavioral sensitivity to AMPH was assessed by measuring locomotor activity of the animals in an open-field. 1) The stressor property of CVP was confirmed. The injection resulted in up to tenfold increase in the serum CORT concentration. The magnitude and duration of this response were dose-related. 2) Three weeks after the CVP exposure, the CORT response to AMPH was significantly increased. 3) The behavioral response to the psychostimulant, i.e. augmented locomotion, was significantly reduced compared to the control. The results confirm that CVP exposure causes behavioral hyposensitivity to AMPH. This effect, however, could not be ascribed to a diminished CORT response.

Efficacy of indirect dopamine agonists for psychostimulant dependence: A systematic review and meta-analysis of randomized controlled trials

Psychostimulant dependence is characterized by dopamine deficit, which could be reversed with indirect dopamine agonists (IDAs). A systematic review and meta-analysis of randomized, parallel-group, placebo-controlled clinical trials assessing the efficacy of IDAs in psychostimulant-dependent individuals were conducted. The study outcomes were psychostimulant abstinence, assessed by means of urinalysis, and retention in treatment. Risk of bias was determined using a Cochrane Collaboration instrument. Twenty-nine studies fulfilled the inclusion criteria, involving 2,467 participants. Compared with placebo, IDAs increased psychostimulant abstinence (standardized mean difference = 0.20; 95% confidence interval, 0.06–0.35; p = .005) but did not increase retention in treatment. Efficacy was larger in comorbid heroin-dependent individuals and was positively related with treatment length. No study was considered fully free of bias. IDAs appear to be efficacious for reducing psychostimulant use but did not improve retention. Efforts should be undertaken to reduce the risk of bias of clinical trials with psychostimulant-dependent individuals.