Christopher L. Wallace

Bupropion Reduces Methamphetamine-Induced Subjective Effects and Cue-Induced Craving

Bupropion is an antidepressant with stimulant properties, which inhibits the reuptake of dopamine (DA) and norepinepherine, and is purported to enhance DA neurotransmission. Bupropion is considered an appealing candidate medication for the treatment of methamphetamine dependence. The current laboratory study was set forth to assess the impact of bupropion treatment on the subjective effects produced by methamphetamine in the laboratory. We also assessed the effects of bupropion treatment on craving elicited by exposure to videotaped methamphetamine cues. A total of 26 participants were enrolled and 20 completed the entire study (n=10 placebo and n=10 bupropion, parallel groups design). Bupropion treatment was associated with reduced ratings of ‘any drug effect’ (p<0.02), and ‘high’ (p<0.02) following methamphetamine administration. There was also a significant bupropion-by-cue exposure interaction on General Craving Scale total score (p<0.002), and on the Behavioral Intention subscale (p<0.001). Overall, the data reveal that bupropion reduced acute methamphetamine-induced subjective effects and reduced cue-induced craving. Importantly, these data provide a rationale for the evaluation of bupropion in the treatment of methamphetamine dependence.

Effects of acute topiramate dosing on methamphetamine-induced subjective mood

Clinical studies have shown that topiramate, a sulphamate-substituted fructopyranose derivative, might be an efficacious treatment for alcohol dependence, smoking cessation within an alcohol-dependent population, and cocaine dependence. Mechanistically, topiramates therapeutic effects have been hypothesized to be due to inhibition of cortico-mesolimbic dopamine function, the primary substrate that governs the acquisition, maintenance, and reinstatement of goal-directed behaviour towards seeking abused drugs. Predicated on this hypothesis, we tested in 10 methamphetamine-dependent individuals (three females) whether low- or high-dose (15 or 30 mg i.v.) methamphetamine-induced positive subjective effects and reinforcement can be antagonized by low- or high-dose (100 or 200 mg orally) topiramate using a placebo-controlled, cross-over, factorial design. Methamphetamine administration was associated with orderly, prototypical, and significant increases on measures of stimulation, euphoria, craving, and reinforcement; however, some dysphoric symptoms also emerged. Topiramate alone showed a non-significant trend towards mild reductions in positive mood and reinforcement; yet topiramate appeared to accentuate the appreciation of methamphetamine-induced stimulation and euphoria significantly, but not craving or reinforcement. The experimental combination of topiramate and methamphetamine appeared to be safe and well tolerated, with few adverse events. Acute dosing with up to 200 mg topiramate appears to enhance, rather than attenuate, the positive subjective effects of methamphetamine. Perhaps this indicates a partial inhibition of methamphetamines reinforcing effects. Thus, testing chronically administered or higher doses, or both, of topiramate would be necessary to determine conclusively whether or not it can attenuate the positive subjective and reinforcing effects of methamphetamine.

Effects of topiramate on methamphetamine-induced changes in attentional and perceptual-motor skills of cognition in recently abstinent methamphetamine-dependent individuals

Methamphetamine-dependent individuals often cite the need to maintain enhanced cognitive performance and attention as a reason for continuing or relapsing to drug-taking. Further, methamphetamine addicts might not comply with taking a potentially therapeutic medication if it had a profound effect on these cognitive processes. Topiramate, a sulfamate-substituted fructopyranose derivative, has been suggested as a putative therapeutic medication for treating methamphetamine dependence. Examination of topiramates effects on cognitive performance and attention is a clinically and scientifically important component of understanding its potential therapeutic profile. In 10 male and female individuals who met DSM-IV criteria for methamphetamine dependence, we examined the effects of low (50 mg b.i.d.)- and high (100 mg b.i.d.)-dose topiramate - in both the presence and absence of low (15 mg)- and high (30 mg)-dose intravenous methamphetamine--on cognitive performance, attention, and concentration on the rapid visual information processing task and the digit symbol substitution test. Intravenous methamphetamine enhanced cognitive performance, attention, and concentration among recently withdrawn methamphetamine addicts--an effect that hitherto had not been well characterized. Topiramates cognitive effects were mixed and rather paradoxical, with a tendency to improve attention and concentration both alone and in the presence of methamphetamine while worsening psychomotor retardation. No deleterious interaction occurred between topiramate and methamphetamine on any of these cognitive processes. While clinical studies with topiramate should prepare participants for possible psychomotor retardation, the cognitive effects profile observed would not likely present an important obstacle to compliance in motivated patients. Topiramates complicated cognitive effects among methamphetamine addicts need more comprehensive examination.

Effects of isradipine on cocaine-induced changes in cognitive performance in recently abstinent cocaine-dependent individuals.

Recently abstinent cocaine-dependent individuals, compared with healthy controls, appear more likely to exhibit deficits in cognitive performance and attention. Individuals with such cognitive deficits might be less able to avail themselves of rehabilitative or relapse-prevention efforts. Pharmacotherapy that reduces the impairment in cognitive performance among cocaine-dependent individuals would be a useful clinical tool. Preclinical and human studies suggest that the dihydropyridine-class calcium-channel antagonist, isradipine, can enhance neurocognitive function in some neuropsychiatric disorders. Isradipine, presumably by increasing cerebral blood flow and its actions at various neurotransmitter systems, might, therefore, ameliorate the impairment in cognitive performance and attention seen in cocaine addicts and enhance the expected modest improvement in performance during acute cocaine-taking in these same individuals. Among 12 male and female cocaine-dependent individuals, we examined the effects of low and high doses of intravenous cocaine (0, 0.325, and 0.650 mg/kg) on cognitive performance and attention in both the presence and absence of isradipine (0 or 30 mg sustained release each evening prior to testing, plus 0 or 15 mg immediate release each morning 2 h before the cocaine or placebo cocaine infusion and on the day of testing). Intravenous cocaine produced a modest increase in cognitive performance and attention. Isradipine, both with and without cocaine, had no effect on these same parameters. Hence, cocaine-taking by cocaine-dependent individuals produces little improvement in cognitive performance and attention in either the presence or absence of isradipine.

Relative abuse liability of indiplon and triazolam in humans: a comparison of psychomotor, subjective, and cognitive effects.

Indiplon [N-methyl-N-[3-[3-(2-thienylcarbonyl)-pyrazolo[1,5-α]pyrimidin-7-yl]phenyl]acetamide; NBI 34060] is a positive allosteric GABAA receptor modulator that is under development for the treatment of insomnia. This study compared the abuse potential of indiplon, a compound with preferential affinity for GABAA receptors containing an α1 subunit, with triazolam in 21 volunteers with histories of drug abuse. Placebo, triazolam (0.25, 0.5, and 0.75 mg), and indiplon (30, 50, and 80 mg) were studied in counterbalanced order under double-blind conditions at two different residential research facilities. Both drugs impaired psychomotor and cognitive performance and produced similar dose-related increases in participant and observer ratings of drug strength. The onset of action of both drugs was rapid (30 min); however, the duration of action of indiplon (3–4 h) was shorter than that of triazolam (4–6 h). The profiles of subjective effects of triazolam and indiplon were similar; however, a maximum of 52% of participants identified indiplon as a benzodiazepine or barbiturate, compared with 81% of participants after 0.75 mg of triazolam. On participantrated subjective effects relevant to sedation, the slope of the triazolam dose-effect curve was significantly steeper than that of indiplon. Neither the largest doses of indiplon and triazolam nor the slope of the indiplon and triazolam dose-effect curves were significantly different from each other on any of the same-day or next-day measures of positive drug effects or next-day measures of reinforcing effects. Together, these data suggest that although the abuse potential of indiplon is not different from that of triazolam at these doses, psychomotor and cognitive impairment after large doses of indiplon might be less.

Effects of isradipine, a dihydropyridine-class calcium-channel antagonist, on d-methamphetamine's subjective and reinforcing effects

In healthy human volunteers, we have previously shown that isradipine, a dihydropyridine-class calcium-channel antagonist, reduces some methamphetamine-induced positive subjective effects associated with its abuse liability, presumably by antagonizing cortico-mesolimbic dopamine pathways. In the present study, we combined acute immediate-release (IR) isradipine with repeated sustained-release (SR) isradipine pretreatment to determine whether isradipine could antagonize methamphetamines positive subjective and reinforcing effects in methamphetamine-dependent research subjects. We included 18 non-treatment-seeking, methamphetamine-dependent subjects aged between 18 and 51 years in this double-blind, within-subject, cross-over study, which was done in a human laboratory. Intravenous methamphetamine (0, 15 and 30 mg) was administered on three different days after 5 days of double-blind cross-over treatment with either isradipine or matching placebo. Subjects received oral isradipine 30 mg SR at bedtime, plus 15 mg IR administered 2 h before methamphetamine infusion. Self-report questionnaires measured drug liking, euphoria, craving, stimulation, and methamphetamine preference. Methamphetamine reinforcement was measured by a behavioural procedure involving choices between methamphetamine and money. For those who received isradipine second and placebo first as the pretreatment paradigm but not vice versa, methamphetamine-induced drug liking, elation, and preference were reduced significantly by isradipine. Depending upon conditioning status, isradipine can reduce some methamphetamine-induced positive subjective and reinforcing effects associated with its abuse liability in methamphetamine addicts.

A double-blind, placebo-controlled assessment of the safety of potential interactions between intravenous cocaine, ethanol, and oral disulfiram

BACKGROUND A majority of cocaine addicts have a comorbid alcohol use disorder. Previous studies demonstrated efficacy of disulfiram in the treatment of cocaine dependence among patients with comorbid alcohol use disorder or opioid dependence. However, the cardiac risks of a disulfiram-ethanol reaction (DER) in individuals who drink, when coupled with the cardiac effects of cocaine, could result in significant toxicity or lethality due to the 3-way drug interaction. AIMS This study examined the safety of combining cocaine (30 mg i.v.) and ethanol (0.4 g/kg i.v.) in disulfiram-treated (0, 250, and 500 mg/d, p.o.) cocaine-dependent research volunteers. RESULTS The results showed that disulfiram did not enhance the cardiovascular effects of cocaine and may have reduced the subjective high from cocaine. In contrast, ethanol produced adverse ECG changes including QTc prolongation and a DER consisting of hypotension, tachycardia, nausea, and flushing in disulfiram-treated subjects. The severity of the DER was related to disulfiram dose and the trial with 500 mg/d was stopped prematurely due to safety concerns. The DER-related hypotension and tachycardia seen with ethanol infusion alone in disulfiram-treated subjects, was not exacerbated when combined with cocaine. In fact, cocaine tended to counteract the ethanol-related hypotension though it did exacerbate the tachycardia in two of seven subjects. CONCLUSIONS Though conclusions are limited by the moderate doses of cocaine, ethanol, and disulfiram tested, the data do suggest that the risks of the moderate use of cocaine and ethanol in individuals treated with moderate doses of disulfiram (≤ 250 mg/d) may not be as problematic as some may assume.

Kinetic and cardiovascular effects of acute topiramate dosing among non-treatment-seeking, methamphetamine-dependent individuals

Previously, we have shown that orally administered topiramate, a sulfamate-substituted fructopyranose derivative, appears to accentuate rather than diminish some aspects of methamphetamine-induced positive subjective mood and cognitive performance. One possible mechanism by which this might occur would be for topiramate to increase plasma methamphetamine level. Such an effect also would be expected to enhance methamphetamine-induced hemodynamic response. We, therefore, studied -- in the same experiment from which the previous findings originated -- the effects of topiramate on the kinetic profile and hemodynamic response to methamphetamine. In a 27-day inpatient study, 10 methamphetamine-dependent individuals participated in a double-blind, placebo-controlled, cross-over design, with oral doses of topiramate (0, 100, and 200 mg) administered as a pretreatment before intravenous doses of methamphetamine (0, 15, and 30 mg). The 3x3 factorial combination of topiramate and methamphetamine resulted in a sequence of the nine treatments administered to each subject in an order determined by a 9x9 Latin Square design. Methamphetamine alone was associated with prototypical increases in hemodynamic response that were not altered in the presence of topiramate. While there was no significant kinetic interaction between topiramate and methamphetamine, there was a non-significant trend for topiramate to increase plasma methamphetamine level. No significant adverse events were reported. The combination of topiramate and methamphetamine at pharmacologically relevant doses appears to be safe. Larger laboratory studies with chronic dosing regimens are needed to establish whether or not there is a kinetic interaction between topiramate and methamphetamine.