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Abstract: The primary objective of this study was to determine the safety of lofexidine, an α2 receptor agonist, alone and concurrent with cocaine in non-treatment seeking cocaine-dependent or cocaine-abusing participants. After screening, eligible participants received double-blind, randomized infusions of saline and 20mg of cocaine on Day 1, and saline and 40mg of cocaine on Day 2. Subjects were randomized and started receiving daily administration of placebo (N=4) or lofexidine on Day 3 and continued on this schedule until Day 7. Two dosing regimens for lofexedine were investigated: 0.8 QID (N=3) and 0.2mg QID (N=11). On Days 6 and 7, subjects received double-blind infusions of saline and 20mg of cocaine on Day 6, and saline and 40mg of cocaine on Day 7. The data reveal a notable incidence of hemodynamic-related AEs over the course of the study. Two of the three participants at the 0.8mg dose level discontinued, and five of 11 participants at the 0.2mg dose level were withdrawn (or voluntarily discontinued) after hemodynamic AEs. Subjective effects and cardiovascular data were derived from all participants who were eligible to receive infusions (i.e., did not meet stopping criteria) on Days 6 and 7 (6 received lofexidine 0.2mg, QID and 4 received placebo, QID). As expected, cocaine significantly increased heart rate and blood pressure, as well as several positive subjective effects. There was a trend for lofexidine to decrease cocaine-induced cardiovascular changes and cocaine-induced ratings for “any drug effect”, “good effects”, and “desire cocaine”, but sample size issues limit the conclusions that can be drawn. Despite the trends to reduce cocaine-induced subjective effects, cardiovascular AEs may limit future utility of lofexidine as a treatment for this population. [Copyright &y& Elsevier]

Abstract: We previously reported that treatment with the cholinesterase inhibitor rivastigmine (3mg, PO for 5days) significantly attenuated “Desire for METH”. Given that higher dosages of rivastigmine produce greater increases in synaptic ACh, we predicted that 6mg should have more pronounced effects on craving and other subjective measures. In the current study, we sought to characterize the effects of short-term exposure to rivastigmine (0, 3 or 6mg) on the subjective and reinforcing effects produced by administration of methamphetamine (METH) in non-treatment-seeking, METH-dependent volunteers. This was a double-blind, placebo-controlled, crossover study. Participants received METH on day 1, and were then randomized to placebo or rivastigmine on day 2 in the morning and treatment continued through day 8. METH dosing was repeated on day 6. The data indicate that METH (15 and 30mg), but not saline, increased several positive subjective effects, including “Any Drug Effect”, “High”, “Stimulated”, “Desire METH”, and “Likely to Use METH” (all p''s <0.0001). In addition, during self-administration sessions, participants were significantly more likely to choose METH over saline (p <0.0001). Evaluating outcomes as peak effects, there was a trend for rivastigmine to reduce “Desire METH” (p =0.27), and rivastigmine significantly attenuated “Likely to Use METH” (p =0.01). These effects were most prominent for rivastigmine 6mg when participants were exposed to the low dose (15mg, IV), but not high dose (30mg, IV), of METH. The self-administration data reveal that rivastigmine did not alter total choices for METH (5mg, IV/choice). Overall, the results indicate some efficacy for rivastigmine in attenuating key subjective effects produced by METH, though additional research using higher doses and longer treatment periods is likely needed. These data extend previous findings and indicate that cholinesterase inhibitors, and other drugs that target acetylcholine systems, warrant continued consideration as treatments for METH dependence. [Copyright &y& Elsevier]

Abstract: Compared to smokers alone, smokers with co-morbid substance use disorders are at greater risk of suffering from smoking-related death. Despite this, relatively few studies have examined smoking cessation treatments for those with stimulant dependence. In the current study, we sought to evaluate the effects produced by short-term exposure to the cholinesterase inhibitor rivastigmine (0, 3 or 6mg) on cigarette smoking in non-treatment-seeking, methamphetamine-dependent volunteers. This was a double-blind, placebo-controlled, crossover study that took place over 9days. The data indicate that rivastigmine treatment did not alter Fagerström Test for Nicotine Dependence scores, carbon monoxide readings, or cigarettes smoked per day, but a trend toward reduced urges to smoke (p <0.09) was detected during treatment with rivastigmine 3mg. These data, while preliminary, indicate that cholinesterase inhibitors warrant consideration as treatments for nicotine dependence, including use in stimulant-dependent individuals who exhibit significantly higher rates of smoking than the general population. [Copyright &y& Elsevier]

Abstract: A human laboratory model of intravenous methamphetamine self-administration may facilitate study of putative treatments for methamphetamine addiction. We conducted a double-blind, placebo-controlled, between groups investigation of the acetylcholinesterase (AChE) inhibitor rivastigmine in non-treatment-seeking volunteers who met criteria for methamphetamine abuse or dependence. Safety and subjective effects data derived from days 1–10 of this protocol are described in a separate publication. In this report, we describe self-administration outcomes in participants randomized to treatment with rivastigmine (0 mg, N =7; 1.5 mg, N =6; 3 mg, N =9); data that were collected on days 11–15 of the inpatient protocol. On day 11, participants sampled two infusions of methamphetamine (0 and 30 mg, IV). On days 12–15, participants made ten choices each day to receive an infusion of either methamphetamine (3 mg, IV) or saline or a monetary alternative ($0.05–$16). The study design allowed for evaluation of differences in behavior on days in which infusions were performed by the physician (experimenter-administered) versus by the participant using a PCA pump (self-administered), and when monetary alternatives were presented in either ascending or descending sequence. The data show that rivastigmine (1.5 and 3 mg), as compared to placebo, did not significantly alter total choices for methamphetamine (p =0.150). Importantly, the number of infusion choices was greater when methamphetamine was available then when saline was available (p <0.0001), and the number of money choices was greater when saline was available then when methamphetamine was available (p <0.0001). The total number of choices for methamphetamine was not altered as a function of a participant''s preferred route of methamphetamine use (p =0.57), and did not differ significantly whether they were experimenter-administered or self-administered (p =0.30). In addition, total choices for methamphetamine were similar made when money was available in an ascending versus descending sequence (p =0.49). The participants'' years of methamphetamine use, recent use of methamphetamine (in the past 30 days), or baseline craving (indexed here as “Desire”) on the day of the self-administration task were not predictive of number of choices for methamphetamine. In a subset of participants (N =8) for which data was available, individual dose of methamphetamine (3×3 mg, IV) produced significant increases in positive subjective effects, and a preliminary analysis revealed that 3 mg rivastigmine was associated with reductions in these responses, as compared to placebo. In summary, the current report indicates that there were no effects of rivastigmine on total choices for methamphetamine, that there were low levels of methamphetamine self-administration but these were 8 times greater than saline, and that choice behavior was insensitive to alternative reinforcers. In addition, we showed that rivastigmine may reduce the positive subjective effects produced by methamphetamine during self-administration. [Copyright &y& Elsevier]

Abstract: Objective: The purpose of the present study was to determine the effects of modafinil, escitalopram, and modafinil + escitalopram administration on neurocognition in a sample of long-term, high-dose cocaine users. Method: Sixty-one cocaine-dependent individuals were randomly assigned to receive placebo (n = 14), modafinil, 200 mg, once daily (n = 16), escitalopram, 20 mg, once daily (n = 16), or modafinil and escitalopram, once daily (n = 15), for five days on an inpatient basis. Urinanalysis was used to confirm abstinence from cocaine on the day of admission and the next five days. Baseline neurocognitive assessment, which included measures of attention/information processing, episodic memory, and working memory, was conducted immediately after the washout phase and prior to the administration of modafinil. The follow-up assessment was conducted after participants had received modafinil or placebo for five days. Results: Repeated-measures, mixed model analysis of variance showed that modafinil administration was associated with significantly improved performance on two measures of working memory span (mean n-back span, maximum n-back span) and a trend toward significant improvement on a measure of visual working memory (visual accuracy) and two measures of sustained attention, consistency of response time (Variability) and reduced impulsivity (Perseveration). Modafinil administration did not modulate performance on measures of information processing speed or episodic memory. Escitalopram did not modulate performance on measures of cognition, either alone or in combination with modafinil. Conclusions: This study provides initial data showing that, in a sample of long-term, high-dose cocaine users, administration of psychotropic medications, such as modafinil, can improve performance on measures of working memory. Moreover, it confirms the utility of studying the interactive effects of psychotropic medications to confirm the manner in which the candidate medications independently and interactively affect neurocognition. These effects are likely relevant in the treatment of cocaine dependence, in which the remediation of impaired working memory may be associated with improved treatment outcomes. This article is part of a Special Issue entitled ‘Cognitive Enhancers’. [Copyright &y& Elsevier]

Abstract: Neurocognitive impairment is a well‐documented consequence of long‐term, repeated cocaine exposure and has been identified as an important target of treatment. Thus, this study sought to determine whether the N-methyl-d-aspartate (NMDA) partial agonist, d‐cycloserine could improve neurocognitive performance in a sample of 27 long‐term, high dose cocaine dependent individuals who were not seeking treatment at the time of enrollment in the study. This double-blind, placebo-controlled study evaluated whether a single dose of 0 or 50mg of d‐cycloserine would enhance performance on measures of attention/information processing speed, episodic memory, and executive/frontal lobe functioning relative to test performance at baseline. The results revealed that d‐cycloserine did not modulate neurocognition in this cohort, though there are a number of factors that may have mitigated the effects of d‐cycloserine in this particular study. The negative findings notwithstanding, the current study serves as a springboard for future investigations that will examine whether other medications that can modulate neurocognition in cocaine-dependent study participants. [Copyright &y& Elsevier]

Abstract: 3,4-Methylenedioxymethamphetamine (MDMA) and methamphetamine (METH) are amphetamine analogues with similar persistent neurochemical effects in the mouse which some have described as neurotoxicity. We attempted to identify dose regimens of MDMA and METH with similar effects on behavioral and physiological variables in the mouse, then quantified the effects of these dose regimens on neurochemistry and microglial markers. Four discrete injections of saline, MDMA (10, 20, or 30 mg/kg), or METH (5 or 10 mg/kg) were administered to mice at 2 h intervals. Body weight was quantified immediately before each injection, and 2 h after the last injection, while core temperature and locomotor activity were continuously monitored via radiotelemetry. Mice were killed 72 h after the final injection and brains were rapidly dissected on ice. Dopamine content in various brain regions was quantified via high pressure liquid chromatography (HPLC), and microglial activation was assessed by saturation binding of the peripheral benzodiazepine receptor (PBR) ligand 1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinoline carboxamide ([3H]PK11195). Specific dose regimens of MDMA and METH induced similar reductions in body weight, depletions of dopamine and its metabolites, and similar hyperthermic and locomotor stimulant effects, but only METH activated microglia in striatum. These results suggest that repeated high doses of MDMA and METH that produce hyperthermia, locomotor stereotypy, weight loss and neurochemical depletion are not consistently accompanied by microglial activation. The finding that METH, but not MDMA, induces microglial effects in the striatum consistent with neurotoxicity might imply different mechanisms of toxic action for these two psychostimulants. [Copyright &y& Elsevier]