The reinforcing efficacy of vaporized methamphetamine HCl (0.3 mg/kg) was determined in baboons with minimal previous drug exposure. A group of 8 adult male baboons was tested prior to a group of 7 ...adult female baboons. Baboons were initially trained to suck on a brass stem activating a pressure-sensitive relay (i.e., puff), to receive one M&M® candy. Five of the 8 males and 6 of the 7 females learned to activate the relay. 0.05 ml of 95% ethyl alcohol containing 0.3 mg/kg methamphetamine was vaporized and delivered to the mouth of the baboon after he/she completed 2 puffs; a single candy was given after an additional 5 puffs to ensure that baboons continued puffing after the aerosol entered their mouths. Puffing was recorded but not reinforced by candy or drug for 2 min after each aerosol delivery for males and 1 min for females. Males could earn 10 and females could earn 20 aerosol deliveries. Males made between 225 and 650 puffs each session. Females made between 200 and 400 puffs each session. When only candy and placebo aerosol were delivered the number of puffs decreased in all 6 females but increased in all 5 males. When candy was delivered without aerosol, puffing decreased in 4 of 5 males, but this manipulation was not tested in females. Methamphetamine aerosol delivery maintained lower rates of puffing behavior in females than males, but procedural differences weaken interpretation of this sex comparison. Although training non-human primates to inhale drug vapors is time consuming, if successful, their long lifespan could provide years of valuable data justifying further work with non-human primates using models of vaporized drug self-administration.
•Male and female baboons could be trained to inhale aerosolized methamphetamine•Females had lower rates of puffing behavior than males•Rates of puffing methamphetamine were low, but above puffing for vehicle
Rationale
Partial dopamine receptor agonists have been proposed as candidate pharmacotherapies for cocaine dependence.
Objective
This 42-day, within-subject, human laboratory study assessed how ...maintenance on aripiprazole, a partial D
2
receptor agonist, influenced smoked cocaine self-administration, cardiovascular measures, subjective effects, and cocaine craving in nontreatment-seeking, cocaine-dependent volunteers.
Methods
In order to achieve steady-state concentrations, participants (
n
= 8 men) were administered placebo and aripiprazole (15 mg/day) capsules in counter-balanced order for 21 days. A smoked cocaine dose–response curve (0, 12, 25, 50 mg) was determined twice under placebo and aripiprazole maintenance. Sessions comprised a “sample” trial, when participants smoked the cocaine dose available that session, and five choice trials, when they responded on a progressive-ratio schedule of reinforcement to receive the cocaine dose or receive $5.00.
Results
Cocaine’s reinforcing, subjective, and cardiovascular effects were dose-dependent. Aripiprazole significantly increased cocaine (12, 25 mg) self-administration. Following a single administration of cocaine (25 mg), aripiprazole decreased ratings of how much participants would pay for that dose. Following repeated cocaine (50 mg) self-administration, aripiprazole decreased ratings of cocaine quality, craving, and good drug effect as compared to placebo.
Conclusions
These data suggest that aripiprazole may have increased self-administration to compensate for a blunted subjective cocaine effect. Overall, the findings do not suggest aripiprazole would be useful for treating cocaine dependence.
Research has suggested that subanesthetic doses of ketamine may work to improve cocaine-related vulnerabilities and facilitate efforts at behavioral modification. The purpose of this trial was to ...test whether a single ketamine infusion improved treatment outcomes in cocaine-dependent adults engaged in mindfulness-based relapse prevention.
Fifty-five cocaine-dependent individuals were randomly assigned to receive a 40-minute intravenous infusion of ketamine (0.5 mg/kg) or midazolam (the control condition) during a 5-day inpatient stay, during which they also initiated a 5-week course of mindfulness-based relapse prevention. Cocaine use was assessed through self-report and urine toxicology. The primary outcomes were end-of-study abstinence and time to relapse (defined as first use or dropout).
Overall, 48.2% of individuals in the ketamine group maintained abstinence over the last 2 weeks of the trial, compared with 10.7% in the midazolam group (intent-to-treat analysis). The ketamine group was 53% less likely (hazard ratio=0.47; 95% CI=0.24, 0.92) to relapse (dropout or use cocaine) compared with the midazolam group, and craving scores were 58.1% lower in the ketamine group throughout the trial (95% CI=18.6, 78.6); both differences were statistically significant. Infusions were well tolerated, and no participants were removed from the study as a result of adverse events.
A single ketamine infusion improved a range of important treatment outcomes in cocaine-dependent adults engaged in mindfulness-based behavioral modification, including promoting abstinence, diminishing craving, and reducing risk of relapse. Further research is needed to replicate these promising results in a larger sample.
Rationale
Despite their chemical similarities, methamphetamine and 3,4-methylenedioxymethamphetamine (MDMA) produce differing neurochemical and behavioral responses in animals. In humans, individual ...studies of methamphetamine and MDMA indicate that the drugs engender overlapping and divergent effects; there are only limited data comparing the two drugs in the same individuals.
Objectives
This study examined the effects of methamphetamine and MDMA using a within-subject design.
Methods
Eleven adult volunteers completed this 13-day residential laboratory study, which consisted of four 3-day blocks of sessions. On the first day of each block, participants received oral methamphetamine (20, 40 mg), MDMA (100 mg), or placebo. Drug plasma concentrations, cardiovascular, subjective, and cognitive/psychomotor performance effects were assessed before drug administration and after. Food intake and sleep were also assessed. On subsequent days of each block, placebo was administered and residual effects were assessed.
Results
Acutely, both drugs increased cardiovascular measures and “positive” subjective effects and decreased food intake. In addition, when asked to identify each drug, participants had difficulty distinguishing between the amphetamines. The drugs also produced divergent effects: methamphetamine improved performance and disrupted sleep, while MDMA increased “negative” subjective-effect ratings. Few residual drug effects were noted for either drug.
Conclusions
It is possible that the differences observed could explain the differential public perception and abuse potential associated with these amphetamines. Alternatively, the route of administration by which the drugs are used recreationally might account for the many of the effects attributed to these drugs (i.e., MDMA is primarily used orally, whereas methamphetamine is used by routes associated with higher abuse potential).
•Impulsivity domains: delay discounting, delaying gratification, impulsivity and thrill seeking.•Factor analysis yielded 2 factors: Impulsive Action and Thrill-seeking.•Male cocaine users had greater ...Impulsive Action scores than male controls.•Female cocaine users had greater Thrill-seeking scores than female controls.•Impulsivity levels were not predictive of current cocaine use.
Impulsivity has been identified as playing a role in cocaine use. The purpose of this study was to explore self-report measures of impulsivity in large groups of male and female cocaine users and matched controls and to determine if differences in impulsivity measures within a group of cocaine users related to self-reported money spent on cocaine and route of cocaine use.
Eight self-report impulsivity measures yielding 34 subscales were obtained in 230 cocaine users (180 M, 50 F) and a matched group of 119 healthy controls (89 M, 30 F). Correlational analysis of the questionnaires revealed 2 factors: Impulsive Action (Factor 1) consisting of many traditional impulsivity measures and Thrill-seeking (Factor 2) consisting of delay discounting, sensation and thrill seeking.
Sex influenced within group comparisons. Impulsive Action scores did not vary as a function of sex within either group. But, male controls and male cocaine users had greater Thrill-seeking scores than females within the same group. Sex also influenced between group comparisons. Male cocaine users had greater Impulsive Action scores while female cocaine users had greater Thrill-seeking scores than their sex-matched controls. Among cocaine users, individuals who preferred insufflating (“snorting”) cocaine had greater Thrill-seeking scores and lower Impulsive Action scores than individuals who preferred smoking cocaine. Individuals who insufflate cocaine also spent less money on cocaine.
Greater Impulsive Action scores in males and Thrill-seeking scores in females were associated with cocaine use relative to controls.
Background Cocaine dependence involves problematic neuroadaptations that might be responsive to modulation of glutamatergic circuits. This investigation examined the effects of subanesthetic ketamine ...infusions on motivation for quitting cocaine and on cue-induced craving in cocaine-dependent participants, 24 hours postinfusion. Methods Eight volunteers with active DSM-IV cocaine dependence not seeking treatment or abstinence were entered into this crossover, double-blind trial. Three 52-min intravenous infusions were administered: ketamine (.41 mg/kg or .71 mg/kg) or lorazepam 2 mg, counterbalanced into three orderings in which ketamine .41 mg/kg always preceded the .71 mg/kg dose. Infusions were separated by 48 hours, and assessments occurred at baseline and at 24 hours postinfusion. Outcomes were change between postinfusion and preinfusion values for: 1) motivation to quit cocaine scores with the University of Rhode Island Change Assessment; and 2) sums of visual analogue scale craving ratings administered during cue exposure. Results Compared with the active control lorazepam, a single ketamine infusion (.41 mg/kg) led to a mean 3.9-point gain in University of Rhode Island Change Assessment ( p = .012), which corresponds to an approximately 60% increase over preceding values. There was a reduction of comparable magnitude in cue-induced craving ( p = .012). A subsequent ketamine infusion (.71 mg/kg) led to further reductions in cue-induced craving compared with the control. Infusions were well-tolerated. Conclusions Subanesthetic ketamine demonstrated promising effects on motivation to quit cocaine and on cue-induced craving, 24 hours postinfusion. Research is needed to expand on these preliminary results and to evaluate the efficacy of this intervention in clinical settings.
Few individuals seeking treatment for marijuana use achieve sustained abstinence. The cannabinoid receptor agonist, Δ(9)-tetrahydrocannabinol (THC; dronabinol), decreases marijuana withdrawal ...symptoms, yet does not decrease marijuana use in the laboratory or clinic. Dronabinol has poor bioavailability, which may contribute to its poor efficacy. The FDA-approved synthetic analog of THC, nabilone, has higher bioavailability and clearer dose-linearity than dronabinol. This study tested whether nabilone administration would decrease marijuana withdrawal symptoms and a laboratory measure of marijuana relapse relative to placebo. Daily, nontreatment-seeking marijuana smokers (8 men and 3 women), who reported smoking 8.3±3.1 marijuana cigarettes/day completed this within-subject study comprising three, 8-day inpatient phases; each phase tested a different nabilone dose (0, 6, 8 mg/day, administered in counter-balanced order on days 2-8). On the first inpatient day, participants took placebo capsules and smoked active marijuana (5.6% THC) at six timepoints. For the next 3 days, they had the opportunity to self-administer placebo marijuana (0.0% THC; withdrawal), followed by 4 days in which active marijuana was available for self-administration (5.6% THC; relapse). Both nabilone dose conditions decreased marijuana relapse and reversed withdrawal-related irritability and disruptions in sleep and food intake (p<0.05). Nabilone (8 mg/day) modestly worsened psychomotor task performance. Neither dose condition increased ratings of capsule 'liking' or desire to take the capsules relative to placebo. Thus, nabilone maintenance produced a robust attenuation of marijuana withdrawal symptoms and a laboratory measure of relapse even with once per day dosing. These data support testing of nabilone for patients seeking marijuana treatment.
Impulsive choice is associated with both cocaine use and relapse. Little is known about the influence of transient states on impulsive choice in people who use cocaine (PWUC).
This study investigated ...the direct effects of induced boredom on impulsive choice (i.e., temporal discounting) in PWUC relative to well-matched community controls.
Forty-one PWUC (≥1× cocaine use in past 3 months; 7 females) and 38 demographically matched controls (5 females) underwent two experimental conditions in counterbalanced order. Temporal discounting was assessed immediately after a standardized boredom induction task (peg-turning) and a self-selected video watched for the same duration (non-boredom). Subjective mood state and perceived task characteristics were assessed at baseline, during experimental manipulations, and after the choice task.
PWUC and controls were well matched on sex, age, and socioeconomic status. Groups were also similar in reported use of drugs other than cocaine, except for recent cigarette and alcohol use (PWUC > controls). As expected, peg-turning increased boredom in the sample overall, with higher boredom reported during peg-turning than the video (
< .001, η
= .20). Participants overall exhibited greater impulsive choice after boredom than non-boredom (
= .028, η
= .07), with no preferential effects in PWUC (
> .05, BF
= 2.9).
Experimentally induced boredom increased state impulsivity irrespective of cocaine use status - in PWUC and carefully matched controls - suggesting a broad link between boredom and impulsive choice. This is the first study to show that transient boredom directly increases impulsive choice. Data support a viable laboratory method to further parse the effects of boredom on impulsive choice.
Despite the high prevalence of polysubstance use, outcomes and potential risks associated with common drug combinations are not well characterized. Many individuals who use cocaine also use cannabis, ...yet little is known about how interactions between the two drugs might contribute to continued co-use.
The aim of this double-blind, placebo-controlled study was to determine the physiological and subjective effects of smoked cannabis with smoked cocaine, to identify variables that may contribute to the continued use of this drug combination. Healthy, non-treatment seeking volunteers who reported smoking both cocaine and cannabis (N = 9, all males) completed a 13-day inpatient protocol. On session days, cannabis 0.0 or 5.6 % tetrahydrocannabinol (THC) was administered 28 min prior to cocaine (0, 12, or 25 mg). Dependent measures included pharmacokinetic assessment of THC and cocaine and their respective metabolites, in addition to subjective and cardiovascular effects.
Active cannabis (5.6 % THC) increased plasma levels of THC and the metabolite 11-nor-9-carboxy-Δ9-THC (THCCOOH), as well as subjective ratings of cannabis effects and heart rate relative to inactive cannabis. Cocaine dose-dependently increased plasma cocaine and metabolites and subjective ratings of cocaine effects. Active cannabis pre-treatment decreased plasma levels of cocaine and metabolites. Furthermore, active cannabis attenuated cocaine-related reductions in ‘Hunger’ and ‘Calm.’
Cannabis pre-treatment altered the subjective experience of smoked cocaine and reduced peak plasma levels of cocaine. Future studies should explore additional doses of each drug and whether these changes also impact cocaine’s reinforcing effects.
•Cannabis, smoked prior to cocaine, decreases plasma cocaine and metabolite levels.•Cannabis pretreatment did not enhance cocaine-related effects on heart rate or mood.•Cannabis attenuated some of cocaine’s subjective effects, such as Hunger and Calm.
In a previous study, we showed that the positive subjective effects of cocaine were higher during the follicular phase compared to the luteal phase of the menstrual cycle. The purpose of the present ...study was to determine if exogenously administered progesterone during the follicular phase in females would attenuate the response to cocaine compared to the normal follicular phase, thus making the response to cocaine similar to the luteal phase. To address the role of sex differences, males were also administered exogenous progesterone during one inpatient stay. In all, 11 female and 10 male non-treatment-seeking cocaine smokers participated. Females had three inpatient stays: one during a normal follicular phase, one during a normal luteal phase, and one during a follicular phase when exogenous progesterone was administered. Males had two inpatient stays: one when exogenous progesterone was administered and the other when placebo was administered. During each inpatient admission, there were four smoked cocaine administration sessions: participants were administered six doses of cocaine (0, 6, 12, or 25 mg cocaine base) at 14 min intervals. Smoked cocaine increased heart rate, blood pressure and several subjective effects such as 'good drug effect' and 'drug quality' cluster scores. Administration of progesterone during the follicular phase in women attenuated the positive subjective effects of cocaine, whereas only minimal changes were observed in men. These results indicate that progesterone modulates the response to cocaine in women and suggests that fluctuations in endogenous progesterone levels account for some of the sex differences observed in humans.
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