Search

Risky decision-making is characteristic of drug users, but little is known about the effects of circumstances, such as abstinence, on risky choice behavior in human drug users. We hypothesized that cocaine users would make more risky choices for cocaine (defined as taking a chance to receive a large number of cocaine doses as opposed to choosing to receive a fixed amount of cocaine) after 3 or 7 days of cocaine abstinence, compared to 1 day of cocaine abstinence. Six male nontreatment-seeking current cocaine smokers were enrolled in a 21-day inpatient within-subject study. Participants repeatedly smoked six 25 mg doses of cocaine during a training session and were instructed that they would be making decisions about smoking this dose throughout the study. After 1, 3 and 7 days of cocaine abstinence, participants completed a computerized task in which they repeatedly decided between receiving a guaranteed number of cocaine doses (between 1 and 5; fixed option) or receiving a chance (0.13 to 0.75) to smoke a larger number of cocaine doses (probabilistic option). After completing the computerized task, one of the participants' choices was randomly implemented and they smoked either the fixed number of cocaine doses or had the specified chance to smoke the greater number of doses. Contrary to our hypothesis, 5 of the 6 participants made fewer risky choices after 3 and 7 days of cocaine abstinence compared to one day of abstinence suggesting greater risk-aversion. Thus, even during cocaine abstinence cocaine users make rational decisions related to their drug use.

Cannabis and synthetic cannabinoids are abused in spite of possible adverse health consequences. The current study investigated the reinforcing effects of an ecologically relevant mode of administration (inhalation) of delta-9-tetrahydrocannabinol (THC), the primary psychoactive component of cannabis, and three synthetic cannabinoids detected in synthetic cannabinoid products (JWH-018, JWH-073, and HU-210) in non-human primates (NHPs). Male and female (N = 4 each) rhesus macaques were trained to inhale warm air via a metal stem to receive a candy reinforcer, an alcohol aerosol vehicle was then paired with the candy. Dose-dependent responding for inhaled aerosols of THC (2.0-16.0 μg/kg/inhalation), JWH-018 (0.2-1.6 μg/kg/inhalation), JWH-073 (2.0-8.0 μg/kg/inhalation), and HU-210 (1.0-8.0 μg/kg/inhalation) was established using a fixed-ratio five schedule of reinforcement and compared to vehicle (alcohol) self-administration. Dose-dependent responding for inhaled heroin (25.0-100.0 μg/kg/inhalation), a known reinforcer in NHPs, was also established. Responding approximated vehicle levels for many drug doses tested, but at least half of the monkeys responded for ≥ one dose of each cannabinoid and heroin above vehicle, with the exception of THC. Drug deliveries calculated as percent vehicle followed a prototypical inverted-U shaped dose-response curve for cannabinoids and heroin except for THC and JWH-018 (in males). Grouped data according to sex demonstrated that peak percent of vehicle reinforcers earned for THC was greater in males than females, whereas peak percent of vehicle reinforcers earned for JWH-018, HU-210, and heroin were greater in females than males. These findings indicate minimal reinforcing effects of CB1 receptor agonists when self-administered by NHPs via aerosol inhalation. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

The psycholinguistic analysis of client– counselor interactions indicates that how individuals talk about their substance use is associated with treatment outcome. However, the processes by which client speech influences out-of-session behaviors have not been clearly delineated. This study investigated the relationships between deriving relations–a key behavioral process by which language and cognition may come to influence behavior, shifts in the strength of client talk in favor of change, and treatment outcome among 75 cocaine-dependent participants (23% Female). Participants were trained to relate cocaine words, nonsense syllables, and negative-consequence words and were then assessed for a derived relation of equivalence before starting treatment. The DARN-C coding system was used to quantify the strength of participant speech during an early cognitive behavior therapy counseling session. Cocaine use during treatment was the outcome of interest. The analyses (a) characterized the process of deriving relations among individuals seeking help for their misuse of cocaine, (b) tested the relationships between shifts in the strength of participants’ speech in favor of change and treatment outcome, and (c) tested if deriving equivalence relations moderated the relationship between shifts in the strength of in-session speech and treatment response. Results indicated that a minority of participants derived equivalence relations, however increases in the strength of commitment language predicted less cocaine use during treatment only among those who did. The findings suggest deriving relations may be an important process by which changes in the strength of commitment language comes to influence substance use.

Cannabis is the most widely used illicit drugs and the changing legal, political and cultural climate will likely increase cannabis use further. One factor that may underlie the transition from recreational use to problematic use is stress. The hormone oxytocin (OXT) modulates stress and may have therapeutic efficacy for substance use disorders, but few studies have examined OXT in cannabis users. Another factor is sex; although more men smoke cannabis, the transition from recreational to problematic use is faster in women. Using a within-subjects design, the effects of intranasal (i.n.) oxytocin (OXT; 40 IU) administration on stress reactivity (using the Trier Social Stress Test; TSST) and cannabis (5.6% THC) self-administration was assessed in recreational cannabis using men (n = 31) and women (n = 32) relative to i.n. placebo (PBO) and no-stress (NST) conditions. The TSST produced expected subjective and cardiovascular effects compared to the NST. However, in the i.n. OXT-TSST condition, positive subjective effects were lower and negative subjective effects were higher in women compared to PBO administration and compared to men. Further, latency to self-administer cannabis was longer in women than men and women self-administered less cannabis than men regardless of stress condition. There were no differences in cannabis craving as a function of sex, stress, or medication. These results suggest that OXT administration may lead to greater stress reactivity in recreational cannabis users, particularly women, and support growing evidence that sex differences should be carefully considered when examining the therapeutic potential of OXT.

The anorexigenic effects of intramuscular d-amphetamine HCl (0.06-0.50 mg/kg) and dexfenfluramine HCl (0.25-2.0 mg/kg) were determined in experimentally naive baboons. A group of 8 adult male baboons was tested prior to a group of 7 adult female baboons. A 120-min session occurred at 9:00 a.m. during which baboons could respond for food pellets. Drug was given 30 min prior to the 9:00 a.m. morning session. Beginning at 11:00 a.m., baboons had a 6-hr multiple-meal session during which they could have up to 4 food pellet meals. Food was not available overnight, but food was available for 90 min upon awakening such that drug effects were evaluated in non-food-deprived animals. Under baseline conditions baboons earned between 30 and 70 pellets during the morning session and another 175-225 pellets during the remainder of the day. Amphetamine and dexfenfluramine produced dose-dependent decreases in food pellet intake during both the morning food session and the later multiple-meal session. Whereas there were minimal sex differences in the effects of dexfenfluramine, many of the amphetamine doses produced greater decreases in pellet intake in males than females. These results are discordant with much of the rodent literature on abuse-related drug effects that generally reports greater effects of amphetamine in females than males. Additional work is needed to replicate the current findings in nonhuman primates. (PsycINFO Database Record

Human drug use involves repeated choices to take drugs or to engage in alternative behaviors. The purpose of this study was to examine how response cost for cocaine and the value of an alternative reinforcer (opportunity to play a game of chance) and how ‘free’ doses (with minimal response cost) affected cocaine choice. Two laboratory studies of cocaine self-administration were conducted in a group of humans who were habitual cocaine smokers and in a group of rhesus monkeys that intravenously self-administered cocaine. Nine human cocaine smokers who were not seeking treatment for their cocaine were repeatedly presented with the choice to smoke 25 mg cocaine base or play a game of chance for a monetary bonus paid at study completion. The response cost for choosing cocaine varied (up to 4000 responses/dose) and the number of game plays varied (up to 8). In this sample of humans, increasing either the response cost for cocaine or increasing the value of the alternative reinforcer did not significantly affect cocaine choice, while increasing both simultaneously slightly decreased cocaine choice and increased choice of the alternative. In monkeys, the dose–response function for cocaine self-administration (10 choices of 0.0125–0.1 mg/kg/infusion vs. candy coated chocolate) was steep and we failed to achieve a 50/50 cocaine/candy choice even after substantially manipulating cost and number of candies available. Providing a large ‘free’ self-administered cocaine dose to humans did not significantly affect cocaine choice, whereas in monkeys, a large free dose of cocaine decreased cocaine choice when higher doses of cocaine were available for self-administration. The present results demonstrate that in the laboratory, it is difficult to modify on-going cocaine self-administration behavior in both humans and non-human primates.

Sex differences in the analgesic effects of mu-opioid agonists have been documented extensively in rodents and, to a lesser extent, in non-human primates. To date, there have been few experimental studies investigating this effect in humans, and the conclusions have been equivocal. The aims of the present study were to examine potential sex differences in the analgesic, subjective, performance, and physiological effects of morphine in human research volunteers. Using a double-blind outpatient procedure, the present study investigated the effects of intramuscular morphine (0, 5, and 10 mg/70 kg, i.m.) in men (N = 8) and women (N = 10). The primary dependent measure was analgesia, as assessed by the cold pressor and mechanical pressure tests. Secondary dependent measures included subjective, performance, and physiological effects of morphine, as well as plasma levels of morphine. No differences in the analgesic and performance effects of morphine were observed between men and women, but significant differences in morphine’s subjective effects were found. Specifically, men reported greater positive effects, whereas women reported greater negative effects after morphine administration. These data suggest that, in humans, there are sex differences in the subjective mood-altering effects of morphine but, based on this limited sample, there is little evidence for sex differences in its analgesic effects.

Alcoholism is a major public health problem in the United States, such that approximately 15.6 million people meet criteria for alcohol abuse or dependence, and over 800,000 received treatment for alcohol abuse or dependence in 2006 (SAMHSA, 2007). Despite the enormous impact of this disease on society, there are only three medications (disulfiram, naltrexone, and acamprosate) currently approved by the FDA for the treatment of alcohol dependence (e.g., Bouza et al., 2004; Heilig and Egli, 2006; Kiefer and Mann, 2005; Kranzler and Van Kirk, 2001) and given their limited efficacy there is a need for additional pharmacotherapies for alcohol dependence. The interaction of alcohol with the gamma-amino butyric acid (GABA)-ergic neurotransmitter system is well known (Grant and Lovinger, 2005) and targeting GABA-ergic neurotransmission has been considered as a potential treatment strategy for alcohol dependence (Johnson et al., 2005; Heilig and Egli, 2006). Baclofen, a GABA-B receptor agonist, has attracted considerable attention as a potential medication not only for alcoholism (Addolorato et al., 2006a; Colombo et al., 2004; Heilig and Egli, 2006; Johnson et al., 2005; Kranzler, 2000), but also for other addictive disorders (Cousins et al., 2002). There is encouraging preclinical evidence in laboratory rodents that baclofen decreases 1) alcohol withdrawal symptoms (Colombo et al., 2000; Knapp et al., 2007), 2) acquisition and maintenance of voluntary alcohol consumption (Colombo et al., 2000, 2002; Daoust et al., 1987), 3) alcohol consumption associated with alcohol deprivation (Colombo et al., 2003a, 2006), 4) alcohol self-administration (Anstrom et al., 2003; Besheer et al., 2004; Liang et al., 2006; Walker and Koob, 2007), and 5) responding for alcohol during extinction, suggestive of decreased motivation to obtain alcohol (Colombo et al., 2003b; Maccioni et al., 2008). However, not all preclinical studies have reported that baclofen produces a reduction in alcohol consumption or self-administration (e.g., Colombo et al., 2005; Czachowski et al., 2006; Moore et al., 2007; Petry, 1997; Smith et al., 1999; Tomkins and Fletcher, 1996). Nonetheless, the preclinical literature suggests that baclofen may have therapeutic efficacy for alcoholism. Several studies have been conducted in humans to evaluate the efficacy of baclofen for the treatment of patients with alcohol problems. One of the first studies used an open-label design in 10 alcohol-dependent patients (Addolorato et al., 2000) and found that maintenance on 30 mg/day of baclofen for 4 weeks decreased alcohol craving in the 9 patients who completed the study, with 7 patients maintaining total abstinence. Similar positive findings were obtained in two subsequent studies, both of which maintained alcohol-dependent patients on 30 mg/day of baclofen (Addolorato et al., 2002a; Flannery et al., 2004). These findings were recently extended and confirmed in a larger randomized clinical trial among alcohol-dependent patients with liver cirrhosis who were treated with either baclofen (30 mg/day) or placebo for 12 weeks (Addolorato et al., 2007). In all of these studies, side effects of baclofen were minimal and retention was excellent. Further, there have been two case reports showing that high doses of baclofen (100–140 mg/day) were effective in reducing alcohol craving and consumption (Ameisen, 2005; Buckman, 2007). Lastly, several small pilot studies have reported that baclofen (30 mg/day) reduces alcohol withdrawal symptoms in alcohol-dependent patients (Addolorato et al., 2002b, 2003, 2006b). Despite the promising preclinical and clinical findings to date suggesting that baclofen may be effective for treating alcohol dependence, there is a paucity of human laboratory studies assessing the interaction of baclofen and alcohol. Human behavioral laboratory studies can play an important role in the early stages of the medication development process for drug and alcohol abuse (Cousins et al., 2002; O’Brien and Gardner, 2005), particularly for assessing the safety of a candidate medication when administered alone and in combination with alcohol, as well as to elucidate the therapeutic mechanism. Baclofen is a centrally acting muscle relaxant approved by the FDA for the alleviation of signs and symptoms of spasticity; while the usual dose range is between 40–80 mg daily in divided doses, much higher doses have been used for the treatment of spasticity with a good safety profile (Aisen et al., 1992). Baclofen is also known to have anxiolytic effects (Breslow et al., 1989; Drake et al., 2003; Jamous et al., 1994), even among a population of alcoholic patients (Krupitsky et al.,1993), and these anxiolytic effects have been hypothesized to reduce alcohol craving and drinking. In fact, several studies have observed a reduction in anxiety in baclofen-treated alcohol-dependent patients (Addolorato et al., 2002a, 2006b, 2007;Flannery et al., 2004). Alternatively, baclofen may reduce alcohol craving and drinking by reducing the positive effects of alcohol, including the stimulant effects (Cousins et al., 2002), or by enhancing the negative effects of alcohol, including sedation. Despite these potential benefits, the sedative and anxiolytic effects of baclofen also raise concerns about the safety of baclofen in combination with alcohol and its abuse liability (Heilig and Egli, 2006). The purpose of the present study was to comprehensively assess the acute behavioral and physiological effects of baclofen (0, 40, 80 mg) alone, and in combination with an intoxicating dose of alcohol (0.75 g/kg) in non-treatment seeking heavy social drinkers. Specifically, we wanted to address the issues related to the safety profile of baclofen alone and in combination with alcohol, as well as the behavioral effects of baclofen that might elucidate the nature of its putative pharmacotherapeutic effect.

This study examined how response effort (pressing a keyboard button) for cocaine and the value of an alternative reinforcer (opportunity to play a game of chance for money) combined with ‘free’ cocaine (with no response effort) affected cocaine choice when participants were maintained on modafinil or placebo. Nontreatment-seeking current cocaine smokers were enrolled in a placebo-controlled, double-blind, within-subject study comprising both inpatient and outpatient phases. Participants were maintained on placebo capsules (0 mg/day) during one inpatient phase and modafinil (300 mg/day) capsules during another inpatient phase in counter-balanced order. A minimum of 8 medication-free days separated the two 15-day inpatient phases to allow for medication clearance. Under each medication condition participants had the opportunity to self-administer smoked cocaine (25 mg) when the response effort for cocaine was low (500 responses/dose) and had a low value alternative (2 game plays for money) or when the response effort for cocaine was large (2500 responses/dose) and had a more valuable alternative (4 game plays for money). Under both conditions, participants received one free dose of cocaine (0, 12, 25 or 50 mg) prior to making their first choice of the session. Fifteen individuals began the study and 7 completed it. Participants chose fewer cocaine doses when the response effort for cocaine and the alternative value was high (4.4 ± 0.19) compared to when the response effort for cocaine and the alternative value was low (5.3 ± 0.14). Providing individuals a free “priming” dose of cocaine prior to making their cocaine choice did not alter cocaine taking. Modafinil decreased cocaine choice only when the response effort for cocaine and the alternative value was high. These results suggest that modafinil may be most effective when combined with therapy emphasizing the large personal costs of using cocaine.

Background: There is growing evidence that N-methyl-d-aspartate (NMDA) receptor antagonists may have potential for the treatment of alcohol disorders. Memantine is a selective noncompetitive NMDA receptor antagonist that has been shown to decrease alcohol craving in moderate drinkers. This 16-week double-blind outpatient pilot clinical trial determined if memantine was more effective than placebo at reducing alcohol use in actively drinking alcohol-dependent patients. Methods: Forty-four treatment-seeking alcohol-dependent individuals were enrolled, with 34 patients stratified to either the memantine group (n=19; maximum dose of 40 mg/d) or the placebo (PBO; n=15) group. The primary outcome measures were related to alcohol use (average drinks per day, average drinks per drinking day, percentage of heavy drinking days, and percentage of days abstinent) based on the timeline follow-back (TLFB). Secondary outcome measures included the Obsessive Compulsive Drinking Scale, Clinical Global Impression ratings, and γ-glutamyltransferase (GGT), a biomarker of recent alcohol use. To enhance retention, patients received voucher incentives for clinic attendance. Results: Of those randomized, approximately 80% (27) completed the entire 16-week trial. Longitudinal analysis of drinks per day and drinks per drinking day showed a significant reduction in alcohol use, but no difference between the 2 groups. Further, the percentage of heavy drinking days indicated that both groups showed a significant decrease in drinking behavior, but there was significant treatment effect in favor of the PBO group. Similarly, for the percentage of days abstinent, the PBO group achieved a significantly greater percentage of days abstinent at a faster rate than the memantine group. Lastly, the memantine group reported a greater number of side effects compared with the PBO group, such that 26% of patients had their drug dose decreased or discontinued due to memantine-related side effects. Conclusions: The results of this double-blind placebo-controlled pilot trial do not support the use of memantine for the treatment of actively drinking alcohol-dependent patients. However, voucher incentives did facilitate retention.

The purpose of this double-blind 14-week trial was to compare the efficacy of sustained-release methylphenidate (MPH) to placebo (PBO) in treating adult attention deficit hyperactivity disorder (ADHD) symptoms in current cocaine dependent (CD) treatment seekers. The randomized sample consisted of 106 participants who were predominately male (83%) and 60% Caucasian, 14% Hispanic, 20% African-American and 6% other. All participants met DSM-IV criteria for ADHD and CD. There were no significant demographic differences between the two treatment groups. All participants received weekly individual cognitive behavioral therapy. There was no difference in retention rate based on treatment group (p=.91). The majority of the PBO group and the MPH group reported >30% improvement in their ADHD symptoms (55% versus 47%), with no significant difference between the two groups (p=.44). Using a combined outcome measure (>30% reduction in ADHD symptoms and CGI

Although stimulant abuse is a growing problem among women, few studies have focused on factors that may be implicated in potential sex differences. Numerous preclinical studies have indicated that female rodents are more sensitive than male rodents to the behavioral effects of stimulants and that the hormone estradiol is involved in these sex differences. In humans, the subjective response to stimulants is greater in the follicular phase (characterized by moderate estradiol levels and minimal progesterone levels) than in the luteal phase (characterized by elevated estradiol levels and elevated progesterone levels). Differences between men and women emerge only when men are compared with women in the luteal phase; the subjective response to stimulants is similar in men and women in the follicular phase. In contrast to rodents, there is minimal evidence that estradiol enhances the subjective response to stimulants in humans. Rather, the hormone progesterone has been shown to attenuate the subjective response to stimulants, particularly in women. Recent preclinical data confirm that progesterone reduces the behavioral response to stimulants. In summary, there is converging evidence from studies in humans that (a) men and women do differ in their subjective response to stimulants; (b) these sex differences are evident when women are in the luteal phase, when progesterone levels are elevated; and (c) progesterone administration attenuates the subjective response to stimulants. Therefore, the menstrual cycle should be addressed in mixed-gender studies. Moreover, the modulatory effects of progesterone on reducing the positive effects of cocaine may have some clinical utility in treating stimulant abusers.

Background Effective treatments for cocaine use disorders remain elusive. Two factors that may be related to treatment failures are route of cocaine used and impulsivity. Smoked cocaine users are more likely to have poorer treatment outcomes compared to intranasal cocaine users. Further, cocaine users are impulsive and impulsivity is associated with poor treatment outcomes. While stimulants are used to treat Attention Deficit Hyperactivity Disorder (ADHD) and attenuate certain cocaine-related behaviors, few studies have comprehensively examined whether stimulants can reduce behavioral impulsivity in cocaine users, and none examined route of cocaine use as a factor. Methods The effects of immediate release oral d -amphetamine (AMPH) were examined in 34 cocaine users (13 intranasal, 21 smoked). Participants had three separate sessions where they were administered AMPH (0, 10, or 20 mg) and completed behavioral measures of impulsivity and risk-taking and subjective measures of abuse liability. Results Smoked cocaine users were more impulsive on the Delayed Memory Task, the GoStop task and the Delay Discounting Task than intranasal cocaine users. Smoked cocaine users also reported more cocaine craving and negative mood than intranasal cocaine users. AMPH produced minimal increases on measures of abuse liability (e.g., Drug Liking). Conclusions Smoked cocaine users were more impulsive than intranasal cocaine users on measures of impulsivity that had a delay component. Additionally, although AMPH failed to attenuate impulsive responding, there was minimal evidence of abuse liability in cocaine users. These preliminary findings need to be confirmed in larger samples that control for route and duration of cocaine use.

The purpose of this study was to determine if methadone-maintained patients (MMP) with cocaine dependence (CD) and/or adult Attention Deficit Hyperactivity Disorder (ADHD) exhibited compounded cognitive dysfunction associated with their poly-substance use and/or co-morbid psychiatric diagnoses. The sample consisted of 79 MMP (59% male, 51% Caucasian), maintained on methadone doses ranging from 40-130 mg/day, who were placed into one of four diagnostic categories: (1) a control group (no ADHD, no CD) (n = 24), (2) CD alone (n = 18), (3)ADHDalone (n = 18), and (4)ADHD+ CD(n = 19). The California Computerized Assessment Package (CalCAP) was administered to assess cognitive functioning requiring focused and sustained attention in a standardized fashion. There were no group differences on Simple Reaction tasks. Compared to the control group, the ADHD+ CD group was slower and less accurate on 33% of the Choice Reaction (CR) tasks. Specifically, individuals in the ADHD + CD group and the ADHD alone group performed significantly worse on tasks measuring attention and psychomotor responding. These tasks are associated with broader cognitive skills in working memory, language discrimination and flexibility of cognitive sets that may have implications for treatment outcome. Diagnostic services capable of identifying cognitive deficits among MMP with ADHD and/or CD are needed to maximize the likelihood of treatment success and to serve as an indicator for the efficacy of therapeutic approaches.

Background Alcohol effects in humans involve gamma-amino butyric acid (GABA) neurotransmission. It has been proposed that GABAergic medications may be effective in the treatment of alcohol dependence. This study evaluated the acute effects of gabapentin, an anticonvulsant that increases extracellular GABA, on the subjective, physiological, and performance effects of alcohol in heavy (mean 34 drinks per week) alcohol drinkers. Methods Seventeen volunteers without alcohol dependence were tested using a double-blind design with three 3-day long inpatient phases, each separated by at least a 1-week wash-out period. Each phase, gabapentin (0, 1000, or 2000 mg) was administered 4 h before alcohol (0.75 g/kg), which was given in four divided doses every 20 min. Results Gabapentin impaired the ability to balance without producing changes in subjective, physiological or other performance measures. Pretreatment with gabapentin did not significantly alter subjective and performance effects of alcohol and did not alter alcohol craving. Gabapentin, dose-dependently enhanced alcohol-induced tachycardia. Conclusions Acute gabapentin administration was well tolerated in combination with alcohol, but did not alter the effects of alcohol.

Although most studies show that women have higher subjective pain ratings in response to painful stimuli, there is less consistency across studies with regard to the influence of gonadal hormones on pain responsivity. The present study evaluated sex differences in response to cold pressor pain in normally menstruating women (NMW), women maintained on oral contraceptives (OCW), and men. Testing occurred during 5 phases of the menstrual cycle. All participants completed 10 sessions (2 sessions per phase). During the cold pressor test, participants immersed the forearm into water maintained at 4°C, and pain threshold and tolerance were measured. Subjective ratings of pain, physiologic indices, and plasma levels of estradiol and progesterone were also assessed. Both estradiol and progesterone levels varied as a function of menstrual cycle phase in NMW and were significantly higher in NMW compared with OCW and men. There were no significant differences in pain threshold or tolerance for any of the groups as a function of menstrual cycle phase. There were no significant differences in pain tolerance between groups. However, pain threshold was higher in NMW compared with OCW and men. When the data were reanalyzed across consecutive sessions, a significant sex-by-day interaction was observed for both threshold and tolerance. Specifically, pain threshold and tolerance were similar for NMW, OCW, and men, but these latencies changed at different rates across session days. Pain threshold remained relatively constant for both OCW and men, but it increased across days for NMW. Pain tolerance remained stable across sessions in OCW, a slow consistent increase was observed for men, whereas a sharper increase, followed by an asymptote, was observed for NMW. These results suggest that circulating gonadal hormones might mediate adaptation to cold pressor pain. Perspective The present study supports the notion that differences in pain perception between the sexes and among menstrual cycle phases are subtle. However, normally menstruating women exhibited an increase in pain tolerance and threshold over repeated stimulation, whereas men exhibited a shallow increase in pain threshold only, suggesting a sex difference in the adaptation to painful stimuli in men and women.

Background A decrease in dopamine type 2 receptors (D 2 ) and mesolimbic dopamine transmission predisposes animals to consume alcohol. This study measured D 2 receptors and dopamine transmission in human alcohol-dependent (AD) subjects using positron emission tomography (PET) and [ 11 C]raclopride. Methods Fifteen AD and 15 healthy control (HC) subjects were scanned before and after a psychostimulant challenge (amphetamine .3 mg/kg intravenous). The outcome measures for baseline D 2 receptor availability were binding potential (BP) and the equilibrium partition coefficient (V 3 ″). Amphetamine-induced [ 11 C]raclopride displacement was measured as the difference in V 3 ″ between the two scans. Results [ 11 C]raclopride BP was significantly reduced by 16.6% in the limbic striatum, 19.2% in the associative striatum, and 21.3% in the sensorimotor striatum in AD subjects compared with HC. The alcohol-dependent subjects showed a blunting of amphetamine-induced dopamine release in the limbic striatum: [ 11 C]raclopride displacement was −5.2% ± 3.6% in AD subjects compared with −13.0% ± 8.8% in HC. However, no significant difference in [ 11 C]raclopride displacement was seen in the associative (−4.6% ± 5.8% in AD subjects vs. −6.7 ± 5.4% in HC) and sensorimotor (−12.3% ± 7.3% in AD subjects vs. −13.7 ± 7.5% in HC) subdivisions of the striatum between the two groups. Conclusions Alcohol dependence was associated with a decrease in D 2 receptors in each striatal subdivision, whereas amphetamine-induced dopamine release was reduced in the limbic striatum only.

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.

Alcohol effects in humans involve N-methyl-d-aspartate (NMDA) receptor-mediated glutamatergic neurotransmission. It has been proposed that NMDA receptor antagonists may be effective in the treatment of alcohol dependence. This study evaluated the acute effects of memantine, an NMDA receptor antagonist, on the subjective, physiological, and performance effects of alcohol in moderate (10–30 drinks per week) alcohol drinkers. Eighteen volunteers without alcohol dependence were tested using a double-blind design with three 3-day long inpatient phases separated by at least a 2-week wash-out period. Memantine (0, 15, and 30 mg) was administered 4 h before alcohol (1.5 g/l body water), which was given in four divided doses every 20 min. Pretreatment with memantine attenuated the craving for alcohol before alcohol administration, but not after alcohol was given. Memantine increased the dissociative effects of alcohol, without altering its sedative, stimulant, and overall intoxicating effects. Memantine also did not affect alcohol-induced impairment in performance, physiological changes, or pharmacokinetics. Memantine increased subjective reports of dissociation, confusion, and stimulation, and impaired motor coordination on the balance task. Memantine was well tolerated in combination with alcohol. The findings suggest that NMDA receptor neurotransmission may be involved in alcohol craving and alcohol-induced subjective dissociative effects.

There is a noticeable lack of targeted treatment options for marijuana dependence, in particular pharmacologic approaches. This is the first study evaluating a targeted pharmacologic approach for marijuana dependence. The goals of the study were to determine if such patients would seek pharmacologic treatment, whether these patients could be retained in treatment using a design previously developed for cocaine-dependent patients, and especially whether divalproex sodium showed promise as a treatment agent for marijuana dependence. We found that marijuana-dependent patients will seek treatment, and such patients can be adequately maintained in a pharmacologic trial. Regardless of treatment group, patients reported a significant reduction in their frequency and amount of marijuana use as well as a reduction in irritability. Given the lack of proven effective treatments for marijuana dependence, pharmacotherapies should be sought. The design of a preliminary clinical trial should include a psychosocial/behavioral intervention emphasizing motivation and medication compliance and a placebo control group.

The purpose of the present study was to evaluate the reinforcing effects of smoked heroin in nonopioid-dependent nonhuman primates when an alternative reinforcer, sweetened fluid, was made available. Four adult male rhesus monkeys lived in three chambers, with heroin self-administration (0, 0.3, and 0.6 mg/kg) specific to one end of the chamber, oral sweetened fluid self-administration specific to the other end chamber, and no commodity available in the middle chamber. The length of time monkeys spent in the drug-associated chamber provided one measure of drug seeking (i.e., location preference). During self-administration sessions, a second-order schedule of reinforcement was used, with responding during the first component maintained by a brief presentation of the stimuli associated with reinforcement. Responding during the second component was maintained by a delivery of the reinforcer, and the associated stimuli. Responding during the first component provided a second measure of drug seeking. Monkeys also had choice trials each day, when they could choose to work for either commodity. Choice behavior provided a third measure of drug seeking. Each experimental day consisted of a smoking session (four smoking trials), a sweetened fluid session (four fluid trials), and a choice session (four choice trials). Monkeys typically completed all four smoking trials each day when either of the active heroin doses was available. They chose both heroin doses over fluid on 3.5 of the four choice trials, and they had a location preference for the heroin chamber. Under baseline conditions, the number of acquisition responses and the number of consumption responses (inhalations) were greater for the high dose of heroin compared to the low dose of heroin. Further, it took longer to extinguish the responding for the high dose of heroin compared to the low dose of heroin when a vehicle was substituted. During heroin extinction, acquisition responding for fluid increased, the number of fluid choices increased, and location preference shifted to the fluid chamber. These data suggest that in nondependent rhesus monkeys, measures of heroin seeking decreased when heroin was not available and seeking behavior shifted to the available alternative commodity.

Rationale. Previous studies have shown that buprenorphine differentially suppresses the reinforcing effects of different drugs (cocaine, alfentanil), drug versus nondrug reinforcers (food, drug), and the same reinforcer (food) maintained under different schedules of reinforcement. Objectives. The purpose of the present study was to determine whether buprenorphine (0.03, 0.1, 0.3 mg/kg) differentially affects candy versus sweetened fluid self-administration. The hypotheses were that (1) candy would maintain higher rates of responding and would be chosen on more occasions than sweetened fluid, and (2) buprenorphine would produce smaller disruptions in responding for the more-preferred reinforcer. Methods. During separate sessions, rhesus monkeys self-administered candy alone, sweetened fluid alone, or had the opportunity to choose between candy and sweetened fluid. Monkeys responded under a second order, two-chain schedule of reinforcement. Results. Candy was a more-preferred reinforcer than sweetened fluid. Buprenorphine significantly decreased rates of responding for fluid, but increased rates of responding for candy. Although buprenorphine significantly decreased both candy and fluid intake, it produced a more robust, and longer-lasting suppression of sweetened-fluid intake than candy. Choice to self-administer candy or fluid was not affected by buprenorphine. Conclusions. These results demonstrate that behavior maintained by a less-preferred reinforcer is more easily disrupted by buprenorphine than is behavior maintained by a more-preferred reinforcer.

The first purpose of this study was to compare the effects of D-amphetamine (AMPH) on operant responding reinforced under fixed ratio (FR) or progressive ratio (PR) schedules of reinforcement, testing the hypothesis that responding reinforced under a PR operant schedule would be disrupted by lower doses of AMPH than responding reinforced under a FR operant schedule. The second purpose of this study was to test the generalizability of the first hypothesis by comparing the effects of AMPH on responding reinforced by two different reinforcers under both FR and PR operant schedules. Rhesus monkeys had five to six candy and five to six fruit drink sessions per day, and could receive two reinforcers per session. Responding was initially reinforced under a PR procedure, such that the ratio size increased with each subsequent session. The parameters of the PR schedule were individually selected so that monkeys consumed a similar number of candy and fruit-drink reinforcers each day. The effects of oral AMPH (0.5, 0.75, 1.0 mg/kg) on responding were assessed. Responding was then stabilized using a FR schedule with parameters individually selected so that monkeys consumed a similar number of candy and fruit-drink reinforcers each day, and the effects of oral AMPH were again assessed. The PR breakpoint was significantly greater for candy than fruit-drink. AMPH produced dose-related decreases in both candy and fruit-drink intake, but each AMPH dose decreased the number of fruit-drink deliveries to a greater extent than the number of candy deliveries. The results failed to support the hypothesis that responding under PR schedules of reinforcement would be disrupted by lower doses of AMPH.

Using a laboratory animal procedure designed to measure two aspects of reinforcement (self-administration and location preference), five adult rhesus monkeys each lived in three chambers: oral cocaine self-administration (0.26 mg/kg/delivery cocaine hydrochloride in a sweet fluid) was specific to one end chamber, food self-administration was specific to the other end chamber, and no food cues or fluid cues were available in the middle chamber. Throughout the 10-h experimental day monkeys experienced multiple food, cocaine, and choice (food vs. sweet cocaine fluid), sessions. Oral d -amphetamine (AMPH; 0.5–1.5 mg/kg) or placebo was administered before the sessions to determine if this anorectic drug would differentially alter food and sweet cocaine fluid self-administration. Further, the effects of AMPH on the length of time a monkey spent in each chamber, when the stimulus cues indicating commodity availability were not present (location preference) were determined. AMPH produced dose-dependent decreases in both food and cocaine self-administration without affecting choice behavior. AMPH also increased the length of time monkeys spent in the food chamber, even when no stimuli indicating food availability were present. These results indicate that the relationship between self-administration and location preference measures of reinforcement is not completely concordant. The current procedure may prove useful in studying these two measures of reinforcement.

A small, controlled study was conducted to assess whether pergolide mesylate has clinical promise as a treatment for cocaine abuse prior to embarking on a larger, randomized, double-blind, controlled trial. Fourteen individuals were placed on placebo for 2 weeks, followed by a 24-week single-blind study in which they were placed on pergolide for 12 weeks, followed by placebo for 12 weeks. Another 14 patients received single-blind placebo for two weeks and then were randomized into a 24-week double-blind, placebo-controlled, multiple baseline design. Initially, patients enrolled in the study were placed on risperidone (n = 9) or placebo (n = 5). During the first 12 weeks, retention was worse for those receiving pergolide compared to risperidone or placebo. Neither risperidone nor pergolide were more efficacious in reducing cocaine use than placebo. Although earlier open studies found pergolide to show promise as a treatment for cocaine abuse, this study did not support these earlier findings. Comparing an agent to both an active control and placebo group may better predict whether a promising new agent will have clinical utility compared to the standard open trial.

Objective: To compare caffeine and theobromine absorption after oral administration of capsules, cola beverage and chocolate candy. Methods: Three males and four females who abstained from methylxanthines received five methylxanthine-containing treatments: caffeine in capsules (72 mg), administered twice; theobromine in capsules (370 mg); cola beverage (72 mg caffeine) and chocolate candy (72 mg caffeine and 370 mg theobromine). Plasma methylxanthine levels were assayed from samples collected before and 0.25, 0.50, 0.75, 1.0, 1.5, 2.0, and 3.0 h after caffeine capsule and cola treatments and, additionally, at 4.0 and 6.0 h after theobromine capsule and chocolate treatments. Results: Caffeine plasma concentrations increased rapidly and peaked at approximately 30 min following both capsule treatments 1 (Cmax: 1.93 μg ⋅ ml−1); and 2 (Cmax: 2.05 μg ⋅ ml−1). Relative to capsules, caffeine absorption from cola and chocolate was delayed and produced lower maximum caffeine plasma concentrations which peaked 1.5–2.0 h after treatment (For cola, Cmax: 1.57 μg ⋅ ml−1); and for chocolate, Cmax: 1.50 μg ⋅ ml−1. Theobromine plasma concentrations peaked approximately 3 h after capsule administration (Cmax: 6.72 μg ⋅ ml−1). Relative to capsules, theobromine absorption from chocolate was more rapid and produced higher maximum theobromine plasma concentrations which peaked approximately 2 h after treatment (Cmax: 8.05 μg ⋅ ml−1). Conclusions: The results suggest that a usual dietary portion of the cola or chocolate used in this study would produce behaviorally discriminable plasma levels of caffeine in most subjects and of theobromine in at least one subject.

Twenty volunteers were trained to discriminate between 75 mg tripelennamine (TP) and placebo. During the first four sessions, the drugs were identified prior to ingestion by letter code. During the next six sessions, the procedure was the same except the capsules were not identified. At the end of the 3-h session, participants indicated which capsule they believed they received using the letter codes. When correct, they received a monetary bonus. If they were correct on five sessions, they entered the third phase which had ten additional training and 12 test sessions. During tests, participants received capsules that contained other drugs, including diphenhydramine (50 and 75 mg), chlorpheniramine (4 and 6 mg), diazepam (5 and 10 mg), d-amphetamine (5 and 10 mg), as well as tripelennamine (25, 50 and 75 mg) and placebo. Thirteen participants learned the discrimination and nine entered the third phase. Except for placebo, most participants identified the test compounds as TP and labeled them as sedatives. TP produced significant changes on several subjective and physiological measures. The test compounds produced varied effects which were neither clearly dose-related nor related to the identification as TP or placebo. These results indicate that tripelennamine can function as a discriminative stimulus, but with little evidence of pharmacological specificity.

Objective To evaluate the behavioral, subjective, and reinforcing effects of immediate-release (IR) alprazolam and extended-release (XR) alprazolam to assess the effect of release rate on laboratory measures of abuse liability. Methods Fourteen healthy men with histories of sedative abuse participated as subjects in a double-blind crossover study. All subjects received placebo, 1 and 2 mg immediate-release alprazolam, and 2 and 3 mg extended-release alprazolam in random order. Behavioral performance, subjective effects, and alprazolam plasma concentrations were assessed repeatedly ½ hour before and ½, 1, 3, 5, 7, 9, 12, and 24 hours after drug administration. Results Mean peak alprazolam plasma concentrations occurred 1.7 and 9.2 hours after immediate-release alprazolam and extended-release alprazolam, respectively. Compared to placebo, 2 mg immediate-release alprazolam impaired all measures of psychomotor and cognitive performance (Digit Symbol Substitution Test), motor coordination (circular lights and balance), and memory (digit entry and recall); 2 mg extended-release alprazolam did not affect any of these measures and 3 mg extended-release alprazolam impaired circular lights only. Immediate-release alprazolam, 2 mg, increased all six measures of positive drug effects (e.g., ratings of liking or good effects); none of these measures were increased by 2 mg extended-release alprazolam and only three of the six measures were increased by 3 mg extended-release alprazolam. A drug versus money multiple-choice procedure designed to assess the relative reinforcing effects of each condition was administered 24 hour after the drug. The amount of money subjects were willing to “pay” to take the drug was significantly greater than placebo for both doses of immediate-release alprazolam but for neither dose of extended-release alprazolam. Conclusions These data indicate that extended-release alprazolam has less potential for abuse than immediate-release alprazolam. Clinical Pharmacology & Therapeutics (1995) 57, 356–365; doi

Little is known about whether the duration of cocaine use or an individual's age may influence the acute effects of cocaine, patterns of use, and specific treatment needs.This post hoc analysis determined whether the duration of cocaine use or current age influenced the acute subjective response to cocaine. Data from four smoked cocaine self-administration laboratory studies were combined and analyzed to determine whether the subjective effects of a 25-mg smoked cocaine dose varied as a function of years of cocaine use or current age.Thirty-six nontreatment-seeking healthy cocaine users (ages 32-49) were admitted to studies lasting from 12 to 105 days. Participants rated the subjective effects of each cocaine dose from 0 to 100 by completing a computerized self-report visual analogue scale (VAS). The main outcome measures were the change in VAS ratings between a baseline placebo dose and the first 25-mg dose of smoked cocaine.No significant relationship was found between the subjective effects of cocaine and years of cocaine use (mean 20.9, range 5-30) or current age (mean 41.1, range 32-49).Among long-term cocaine users between the ages of 32 and 49, the acute subjective effects of cocaine did not vary as a function of years of cocaine use or current age.These data fail to support the incentive sensitization theory for addiction by Robinson and Berridge, as cocaine "liking" and "wanting" remained the same regardless of age or years of cocaine use.

Tolerance to the analgesic effects of opioids has been demonstrated in laboratory animals after repeated drug administration; yet, this effect has been studied less frequently under controlled laboratory conditions in humans. This within-subject, double-blind, placebo-controlled study was designed to determine whether tolerance developed to the analgesic, subjective, and physiological effects of the commonly prescribed opioid oxycodone when it was administered daily for 5 days. The effects of oxycodone (0, 5, and 20 mg/70 kg, orally) were compared, using a within-session cumulative dosing procedure, on the first and fifth days of the 'daily' dosing phase to assess for tolerance; active oxycodone was administered on the second and fourth days of the daily dosing phase. Changes in the effects of oxycodone were also compared when the medication was only administered on the first and the fifth day of a 5-day 'intermittent' dosing phase; placebo medication was administered on the second and fourth days of the intermittent dosing phase. A 9-day 'washout' period occurred between phases during which no medication was administered. Healthy volunteers (N=10) with no history of drug dependence or current drug use participated in this outpatient study. Analgesia was assessed using the cold pressor test, pain and drug effects were measured using a variety of questionnaires, and pupil diameter was monitored as an index of physiological effects. When administered daily, no differences were observed in oxycodone-induced analgesia between the first and the fifth days, but tolerance did develop to some of the positive subjective effects of oxycodone. In contrast, oxycodone-induced analgesia and participant ratings of some positive subjective drug effects were greater on the fifth compared with the first day of the intermittent dosing phase. No differences in the miotic effects of oxycodone between the first and the fifth days of either dosing phase were detected. Although obtained under limited experimental conditions, these findings suggest that tolerance may not develop to the analgesic effects of therapeutic doses of oxycodone under short-term daily dosing conditions, even though some of its subjective effects may decrease. These data also suggest that intermittent administration may enhance the analgesic effects of oxycodone, while also increasing some of the drug's positive subjective effects related to abuse liability.

Theobromine versus placebo discrimination and caffeine versus placebo discrimination were studied in two consecutive experiments in seven volunteers who abstained from methylxanthines. Daily sessions involved PO double-blind ingestion of two sets of capsules sequentially, one of which contained drug and the other placebo. Subjects attempted to identify, and were later informed, which set of capsules contained the drug. In each experiment subjects were exposed to progressively lower doses. Five subjects acquired the theobromine discrimination; the lowest dose discriminated ranged from 100 to 560 mg. All seven subjects acquired the caffeine discrimination; the lowest dose discriminated ranged from 1.8 to 178 mg. A final experiment evaluated subjective effect ratings following 560 mg theobromine, 178 mg caffeine and placebo, which were administered double-blind in capsules once daily, five times each in mixed sequence. Caffeine produced changes in both group and individual ratings (e.g. increased well-being, energy, social disposition and alert). Theobromine did not produce changes in group ratings but changed ratings in some subjects. Across subjects, sensitivity to caffeine discriminative effects in the discrimination experiment correlated significantly with the number and magnitude of caffeine subjective effects in the final experiment. This study documents modest discriminative effects of theobromine in humans, but the basis of the discrimination is unclear. This study suggests that commonly consumed cocoa products contain behaviorally active doses of caffeine and possibly theobromine.

Laboratory studies in which drugs of abuse are self- or experimenter-administered to non-treatment-seeking research volunteers provide valuable data about new pharmacotherapies for substance use disorders, as well as behavioral and performance data for understanding the neurobiology of drug abuse. This paper analyzed follow-up data from six smoked cocaine self-administration laboratory studies, in order to determine whether changes in substance use occurred 1 and 3 months after study participation compared to pre-study baseline.Ninety-eight healthy, non-treatment-seeking cocaine users were admitted to inpatient and combined inpatient/outpatient studies lasting from 12 to 105 days. The studies allowed participants to self-administer repeated doses of smoked cocaine (0, 6, 12, 25, and/or 50mg per dose) on multiple occasions. Participants returned for follow-up at 1 and 3 months, at which time self-reported consumption of cocaine, alcohol, marijuana, and nicotine was assessed.Compared to baseline ($374.04/week, S.D. $350.09), cocaine use significantly decreased at 1 month ($165.13/week, S.D. $165.56) and 3 months ($118.59/week, S.D. $110.48) after study participation (p0.001; results based on the 39 participants who completed all 3 time points). This decrease was not accompanied by a change in other drug use, e.g., a compensatory increase in alcohol, marijuana or nicotine use.Study participation was not associated with increased post-study cocaine, alcohol, marijuana, or nicotine use. Thus, human laboratory models of cocaine self-administration, conducted in non-treatment-seeking research volunteers, are relatively safe, and study participation does not exacerbate ongoing drug use.

People who stop consuming caffeine may have symptoms, but the incidence and severity of caffeine withdrawal are not known. This study was performed to determine the effects in the general population of ending one's dietary intake of caffeine.We studied 62 normal adults whose intake of caffeine was low to moderate (mean amount, 235 mg--the equivalent of 2.5 cups of coffee--per day). They completed questionnaires about symptoms and tests of their mood and performance when consuming their normal diets (base-line period) and at the end of each of two two-day periods during which they consumed caffeine-free diets and under double-blind conditions received capsules containing placebo (placebo period) or caffeine (caffeine period) in amounts equal to their daily caffeine consumption.More subjects had abnormally high Beck Depression Inventory scores (11 percent), high scores on the trait scale of the State-Trait Anxiety Inventory (8 percent), low vigor scores (11 percent) and high fatigue scores (8 percent) on the Profile of Mood States, and moderate or severe headache (52 percent) during the placebo period than during either the base-line period (2, 0, 0, 0, and 2 percent, respectively; P less than 0.05) or the caffeine period (3, 2, 2, 0, and 6 percent; P less than 0.05). More subjects reported unauthorized use of medications during the placebo period (13 percent) than during the caffeine period (2 percent, P = 0.017). Performance of a tapping task was slower during the placebo period than during the base-line and caffeine periods (P less than 0.01).Persons who consume low or moderate amounts of caffeine may have a withdrawal syndrome after their daily consumption of caffeine ceases.

Thirty-two healthy subjects with histories of moderate caffeine consumption abstained from dietary caffeine throughout the study. Subjects were stratified into two groups based on several factors including caffeine preference, which was assessed using a caffeine versus placebo choice procedure. Subsequently, subjects received either caffeine (300 mg t.i.d.) or placebo (placebo t.i.d.) for 18 consecutive days, and thereafter were exposed again to a caffeine versus placebo choice procedure. The study documented tolerance development to the subjective effects of caffeine: after chronic dosing, administration of caffeine produced significant subjective effects in the chronic placebo group but not in the chronic caffeine group. The study also provided indirect evidence for tolerance development: during chronic dosing, the chronic caffeine and placebo groups did not differ meaningfully on ratings of mood and subjective effect. When subjects were categorized into caffeine choosers or nonchoosers, caffeine choosers tended to report positive subjective effects of caffeine and negative subjective effects of placebo. Nonchoosers, in contrast, tended to report negative subjective effects of caffeine. Chronic caffeine did not alter the reinforcing effects of caffeine as assessed by caffeine versus placebo choice, possibly because the relatively short duration of caffeine abstinence in the placebo condition was not sufficient to result in maximal withdrawal effects after termination of the relatively high caffeine dose. This study provides the clearest evidence to date of complete tolerance development to a CNS effect of caffeine in humans.

Previous studies have demonstrated that sex differences in pain responsivity can be detected using various models of experimentally induced pain. The present study employed the mechanical pressure test in order to examine potential differences in pain report among men, normally menstruating women (NMW), and women taking monophasic oral contraceptives (OCW). Testing occurred during 5 phases of the menstrual cycle (menstrual, follicular, ovulatory, luteal, and late luteal) and all participants completed 10 sessions (2 sessions per phase). Menstrual-cycle phase was estimated for OCW based on their first day of menses. Men were tested at time points that roughly corresponded to the intervals during which the different phases occurred in NMW. During the mechanical pressure test, 4 different weights were placed on the fingers, one at a time, and ratings of pain were recorded for 30 seconds. The statistical decision-making model and a forced-choice procedure were used to analyze the response data. Two variables, based on signal detection theory, were thus generated: P(A), a measure of sensory pain, and B, a measure of response bias. P(A) is believed to be a measure of pain sensitivity while B measures stoicism. NMW tended to report lower P(A) values, indicating reduced ability to discriminate among different stimulus intensities, during the menstrual and late luteal phases compared to the luteal phase. OCW reported lower B values, indicating less stoicism, during the menstrual compared to the follicular and ovulatory phases. Men tended to have significantly lower B values than OCW, but not NMW. These results demonstrate subtle menstrual-cycle effects in NMW and OCW. Sex differences were few, with more group differences and trends emerging between OCW and men, as opposed to men and NMW. Perspective The lack of consistent differences between men and NMW underscores the subtle impact of sex and hormonal changes in pain report. In addition, the data obtained in NMW support the notion that changes in hormone levels during the menstrual cycle can lead to changes in pain responsivity as NMW had trends for better discrimination in menstrual phases when estradiol levels were highest.

Studies using rodents have shown that behavioral responses to a stimulant are enhanced when the stimulant is given within the same context as previous stimulant administrations; this increase in effect related to context is often referred to as sensitization. We examined the role of environmental stimuli in modulating the subjective and cardiovascular effects of cocaine in humans (1) within a daily “binge” and (2) after cocaine abstinence. Ten non-treatment seeking users of smoked cocaine were admitted to the hospital for 17 consecutive days. Participants smoked cocaine (25 mg/dose) under two counterbalanced conditions: paired stimuli (same stimuli presented each session) and unpaired stimuli (varied stimuli presented each session). Under each stimulus condition, participants had cocaine test sessions for three consecutive days, no sessions for the next 3 days, then another cocaine test session on the following day, for a total of eight test days. Stimulus condition had no effect on cardiovascular or subjective effects so data were analyzed as a function of repeated cocaine administration over 2 weeks. Maximal ratings on “good drug” and “drug rating” subjective effects clusters decreased over days of repeated cocaine exposure. In contrast, baseline and peak heart rate and systolic pressure increased over days of repeated cocaine administration. Thus, repeated administration of smoked cocaine to experienced cocaine users resulted in increases in baseline blood pressure and heart rate and modest decreases in positive subjective effects. These data indicate modest tolerance rather than sensitization to the positive subjective effects of cocaine with repeated exposure.

Studies have shown that smoked and intravenous cocaine’s effects differ in cocaine-dependent women compared to men and across the menstrual cycle. However, this has not been systematically investigated with intranasal cocaine. Thus, a range of intranasal cocaine doses was examined in cocaine-dependent women across the menstrual cycle. Female cocaine users were admitted to the hospital once during the luteal phase and once during the follicular phase of their menstrual cycle; menstrual cycle phase during admissions was counterbalanced. During each admission, an intranasal cocaine dose–response curve (0.06, 0.34, 0.69 and 1.37 mg/kg) was determined during four laboratory sessions. Cocaine produced similar dose-related increases in ratings of ‘‘positive’’ subjective effects, cardiovascular effects and cocaine plasma levels in women in both menstrual cycle phases. To assess sex differences in the effects of intranasal cocaine, the current data were compared to published data collected in men using an identical procedure. Cocaine produced similar dose-related increases in ratings of positive subjective effects, cardiovascular effects and cocaine plasma levels in men and women. Thus, in contrast to studies examining smoked or intravenous cocaine administration, there were no sex differences or menstrual cycle effects on the subjective or cardiovascular response to intranasal cocaine, suggesting that the influence of sex and menstrual cycle on cocaine’s effects vary as a function of route of administration.

Although there are some data suggesting that individuals with depressive disorders may be more likely to remain in treatment than those without depressive disorders, it is less clear how well other psychiatric subgroups compare to those without psychiatric comorbidity. This sample is a follow-up study of 135 individuals who were admitted into a therapeutic community. Individuals with attention-deficit hyperactivity disorder (ADHD), other Axis I disorders (no ADHD), and no Axis I disorders were compared. Although individuals with other Axis I disorders had a strikingly low early drop-out rate, after a prolonged time in treatment, the drop-out rate increased substantially, such that these individuals were found to complete treatment at a lower rate (17%) than those with no Axis I disorders (29%). Furthermore, individuals with ADHD were less likely to graduate treatment than those with other Axis I or no Axis I disorders (0%, 9%, and 19%, respectively). Future investigations may be useful to determine whether pharmacologic or nonpharmacologic interventions might improve treatment outcome.

The purpose of this double-blind, three-arm, 12-week trial was to compare the efficacy of sustained-release methylphenidate or sustained-release bupropion to placebo in treating adult attention deficit hyperactivity disorder (ADHD) symptoms. The randomized sample consisted of 98 methadone-maintained patients who were predominately male (57%) and 40% Caucasian, 40% Hispanic and 20% African American. All participants met DSM-IV criteria for adult ADHD, with 53% meeting DSM-IV criteria for cocaine dependence/abuse. In addition to medication and treatment as usual at a methadone program, individuals received weekly individual cognitive behavioral treatment. Other than current employment status, there were no significant demographic differences across the three treatment groups. Seventy percent completed the 12-week trial. There were no differences in retention rate based on treatment group. A reduction in ADHD symptoms using the adult ADHD rating scale was observed in all three groups, but there were no significant differences in outcome between treatments. The placebo response rate was high, with 46% of the placebo group self-reporting substantial improvement in their ADHD symptoms (>30% reduction in adult ADHD rating scale). Using other ADHD outcome measures, the placebo response and medication response rates were substantially lower. There was no evidence of misuse of medication or worsening of cocaine use among those randomized to methylphenidate. Taken together, sustained-release methylphenidate or sustained-release bupropion did not provide a clear advantage over placebo in reducing ADHD symptoms or additional cocaine use in methadone-maintained patients.

Ingestive behavior consists of appetitive or foraging behavior, i.e., “acquisition,” followed by consummatory behavior. Responding of six adult rhesus monkeys, living in three-chambered enclosures, was studied under an operant chain schedule that simulated commodity acquisition and commodity consumption. Responding during the initial acquisition component was reinforced by stimuli paired with that commodity, while responding during the following consumption component was reinforced with that commodity. Throughout the 10-h experimental day, monkeys experienced multiple candy (plain M & Ms) and fruit-drink (Kool-Aid) sessions in different end chambers. The effects of response-independent candy reinforcement, in the context of extinction, were examined when monkeys received a daily food ration of 8 or 20 chow. Response-independent candy increased responding during the acquisition components of candy sessions when monkeys received a daily food ration of 8 chow but not when the food ration was 20 chow. Furthermore, response-independent candy increased candy choice over fruit-drink during choice opportunities and increased the length of time spent in the candy chamber when the candy stimulus lights were illuminated under both food ration conditions, i.e., location preference. The present procedure, which combines operant and place preference measures of commodity acquisition, when used in combination with methods of studying reinstatement of responding, may prove useful in analyzing factors affecting relapse.

There are few published studies assessing the efficacy of pharmacologic treatments for attention-deficit hyperactivity disorder (ADHD) among substance abusers seeking treatment. Eleven patients who met DSM-IV diagnostic criteria for cocaine dependence and adult ADHD were entered into a 12-week single-blind trial of divided daily doses of bupropion (BPR). All patients received weekly individual standardized relapse prevention therapy. Treatment compliance and retention were good. Patients reported significant reductions in attention difficulties, hyperactivity and impulsivity. Self-reported cocaine use, cocaine craving, and cocaine positive toxicologies, also decreased significantly. In a previously published trial, 12 patients who met similar diagnostic criteria for adult ADHD and cocaine dependence were entered into a 12-week trial of divided daily doses of sustained-release methylphenidate (MPH). Improvements observed on BPR were similar to, and did not differ from those previously observed with MPH. These preliminary data suggest that BPR may be as effective as sustained-release MPH, when combined with relapse prevention therapy, for cocaine abusers with adult ADHD. However, a future study directly comparing BPR to MPH in a double-blind placebo-controlled trial is needed.

Rationale: Although common in humans, little is known about the reinforcing efficacy of smoked heroin in laboratory animals. Objectives: To evaluate the reinforcing efficacy of smoked heroin in non-opioid dependent, non-human primates. Methods: Self-administration and location-preference measures were obtained by having monkeys live in two chambers with heroin self-administration (0, 0.3, 0.6 mg/kg; eight dosings available per day) specific to one chamber and no commodity available in the other chamber. Operant responding reinforced by smoked heroin provided a self-administration measure of reinforcement, and the length of time monkeys spent in the heroin-associated chamber provided a location preference estimate of reinforcing efficacy. Results: Four of six monkeys acquired heroin self-administration: these monkeys completed six to eight smoking trials each day when either of the active heroin doses was available. Urine toxicology confirmed that monkeys were absorbing the smoked heroin. The number of completed smoking trials rapidly decreased under extinction conditions, indicating that smoked heroin was an efficacious reinforcer using the self-administration measure. Monkeys developed a location preference for the chamber where heroin was self-administered, indicating that smoked heroin was an efficacious reinforcer using the location-preference measure. Conclusions: Smoked heroin is an efficacious reinforcer in non-opioid dependent rhesus monkeys as measured using a self-administration procedure and estimated using a location-preference procedure.

Rationale: Few studies have directly examined the effects of benzodiazepines in individuals with a family history of alcoholism, particularly women, to determine whether they are differentially sensitive to their effects. Objectives: To determine whether females with a confirmed paternal history of alcoholism (FHP; n=14) were differentially sensitive to the mood and performance effects of alprazolam and buspirone compared with females without a first-degree family history of alcoholism (FHN; n=14). Methods: The acute effects of placebo, alprazolam (0.25, 0.50, 0.75 mg), and buspirone (5, 10, 15 mg) were evaluated using a double-blind, placebo-controlled outpatient design. Drug effects were assessed using performance tasks, observer ratings of drug effect, and subjective ratings of mood, drug strength, and drug liking. Results: Alprazolam impaired performance in a dose-related manner on all performance tasks for both groups of females, whereas buspirone had minimal effects on performance. The highest dose of alprazolam impaired the response to the digit symbol substitution test (DSST), digit recall, and word memory more in FHP females than in FHN females. Further, performance on the DSST and immediate word recall was able to accurately predict family history status. Correspondingly, FHP women reported greater increases in "difficulty concentrating" and "unmotivated" and greater decreases in items such as positive mood following alprazolam than FHN women. In contrast, alprazolam produced similar dose-related increases in subject-rated and observer-rated drug strength ratings in both groups of females. Lastly, there was no evidence of an increase in ratings of drug liking in either group following alprazolam. Conclusions: In contrast to many previous findings with FHP males, these results suggest that FHP females may be more sensitive to the performance-impairing effects and negative subjective effects of alprazolam.

The subjective and physiological effects of repeated smoked cocaine self-administration were compared in 11 men and 9 women. Twice a day, on 2 consecutive days, participants smoked up to six 50-mg doses of cocaine base, at 14 min intervals. Men and women self-administered a similar number of cocaine doses (21.7 and 21.6, respectively). The most striking sex difference was that women had higher cocaine plasma concentrations than men (632.7 ng/ml vs. 376.7 mg/ml) after the sixth cocaine dose of the first session. After the first cocaine dose, women reported that they would spend significantly less for the dose than men ($1.58 vs. $3.15). Although cocaine produced similar effects in men and women 4 min after each dose, 15 min after the last dose of the session, heart rate and blood pressure remained elevated in women, but ratings of “I want cocaine” were lower in women as compared to men. Thus, smoking cocaine produced similar acute subjective effects in men and women, but prolonged cardiovascular effects and higher cocaine plasma concentrations in women.

In this study, 281 cocaine abusers seeking treatment were assessed for adult attention-deficit hyperactivity disorder (ADHD). Structured assessments included the SCID for DSM-IV, a SCID-like module for ADHD, and a pattern of drug use questionnaire. The sample consisted of 82% men, 67% African-Americans, 19% Hispanics, and 14% Caucasians identified at several treatment sites. Average age was 33.7±.4 years. Twelve percent (n=34) of the sample met DSM-IV criteria for childhood ADHD. Of the entire sample, 10% (n=27), or 79% of the patients diagnosed with childhood ADHD, had adult ADHD. A history of conduct disorder and antisocial personality disorder were prevalent among those with adult ADHD (63% and 52%, respectively). This subpopulation of cocaine abusers may be one of the most difficult-to-treat cocaine-abusing groups, particularly if the ADHD remains undetected. To provide effective treatment for cocaine abusers, clinicians may need to identify subpopulations of patients, such as those with ADHD, and target both pharmacologic and nonpharmacologic interventions for these groups.

The purpose of this study was to determine if multiple aspects of drug and food-reinforced behavior could be measured in a single study. Drug or food seeking can be observed under four conditions: 1) internal drug or food cues and external stimulus cues present; self-administration, 2) only internal cues present; priming, 3) no internal or external stimulus cues present; abstinence, and 4) no internal cues, but external stimulus cues present; extinction. Six adult rhesus monkeys lived in three-chambered enclosures: fluid (0.26, 0.52 mg/kg per delivery cocaine hydrochloride, sweetened-vehicle, or water)- related cues and oral fluid self-administration were specific to one end chamber, food pellet-related cues and food self-administration were specific to the other end chamber, and no food cues or fluid cues were available in the middle chamber. Throughout the 10-h experimental day, monkeys experienced multiple food, fluid, and stimulus-cue test sessions. Adding cocaine to the vehicle initially increased fluid intake during training (condition 1), but vehicle intake did not return to baseline levels after cocaine was later removed (condition 4). Monkeys developed a location preference for the fluid chamber, even when fluid was not available, when responding was reinforced by cocaine, but not when responding was reinforced by vehicle (condition 3). Non-contingent food or fluid delivery did not increase responding in non-deprived animals (condition 2). The current protocol provides both self-administration and place-preference measures of the motivational effects of drugs. Given that human drug abusers spend much time thinking about and seeking drugs prior to actual self-administration, an animal model that uses multiple measures of drug seeking may be useful in the preclinical testing of pharmacological adjuncts for the treatment of drug abuse.

The purpose of the present study was to determine the preference for buspirone, an anxiolytic predicted to have minimal abuse potential, in comparison with diazepam in moderate drinkers. Preference for diazepam and buspirone was assessed in 55 moderate drinkers using a seven-session procedure consisting of four sampling sessions followed by three choice sessions. On each sampling session subjects ingested five capsules, one every 30 min. Color-coded capsules contained placebo on two sessions and drug on two sessions. Each drug capsule contained diazepam (4 mg) for 30 subjects and buspirone (5 mg) for 25 subjects. On choice sessions subjects chose whichever of the two color-coded capsules, i.e., drug or placebo, they wished to take. After ingesting one capsule, every 30 min they had the option of ingesting another capsule of the same color and content, for a maximum of seven capsules over the session (maximum of 28 mg diazepam or 35 mg buspirone). In the diazepam group 70% of subjects chose diazepam over placebo on at least two of the three choice sessions, whereas in the buspirone group only 24% of subjects chose buspirone over placebo on at least two sessions. Both diazepam and buspirone increased measures of sedation. Only diazepam increased ratings of liking and impaired performance, whereas only buspirone decreased ratings of feeling Friendly. These results replicate previous findings indicating that diazepam has reinforcing effects in moderate drinkers. Further, these results demonstrate the pharmacological specificity of this effect by showing that buspirone did not function as a reinforcer under these same conditions.

The discriminative stimulus (DS) effects of smoked marijuana were studied by training marijuana smokers to discriminate between the effects of marijuana containing 2.7% delta 9-THC (M) and marijuana containing 0.0% delta 9-THC (P). In addition to measures of discrimination responding, subjective effects were assessed with standardized mood questionnaires. The post-smoking increase in expired air carbon monoxide (CO) level was used as an index of smoke inhalation. Relative to P cigarettes, M cigarettes increased heart rate and produced changes on eight mood scales. M cigarettes were rated as harsher and more potent than P cigarettes, and produced lower levels of CO than P cigarettes. The P--M discrimination was readily acquired by most subjects. The DS effects of marijuana showed a rapid onset, appearing within 90 s from the beginning of smoking. The DS effects were dose dependent, with 0.9% delta 9-THC marijuana producing primarily placebo-appropriate discrimination responding, and 1.4% delta 9-THC marijuana producing 100% drug-appropriate responding. This experimental paradigm could be used to determine whether the DS effects of smoked marijuana would generalize to those of other psychoactive drugs.