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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.

This is an introduction to the special issue, "Animal Models of Neuropsychiatric Disorders and Substance Use Disorders: Progress and Gaps." This issue presents 6 original research reports describing the use of mice and rats to model neurodevelopmental disorders, depressive disorders, anxiety disorders, and substance use disorders. Collectively, these studies demonstrate the progress of the field and the gaps and challenges that remain. They also illustrate the range of conditions that are informed by animal models and identify the clinical populations that stand to benefit from their use in preclinical research. (PsycINFO Database Record

Background The hypocretin/orexin system is involved in regulating arousal, and much recent work demonstrates that decreasing hypocretin receptor-1 (HCRTr1) activity using antagonists decreases appetitive behavior, including stimulant drug self-administration and reinstatement. Methods The present study determined the effects of hypocretin-1 and HCRTr1 antagonists on responding reinforced by intravenous (i.v.) cocaine self-administration (0.0125 – 0.05 mg/kg/infusion) in 5 female rhesus monkeys. Responding was examined using 3 schedules of reinforcement: 1) a Fixed interval 1 min, Fixed ratio 10 Chain schedule [FI 1-min (FR10:S)], 2) a Progressive Ratio (PR) schedule, and 3) a cocaine vs. candy. Results Choice schedule: the HCRTr1 antagonist SB-334867 (8–24 mg/kg, i.m.) decreased cocaine taking under the Chain schedule and PR schedule in all 5 monkeys and in 4 of the 5 monkeys under the Choice schedule. d- Amphetamine (0.06 – 0.25 mg/kg, i.m.), tested as a control manipulation, decreased cocaine taking in all 5 monkeys under the Chain schedule. The peptide hypocretin-1 (0.072 mg/kg, i.v.) increased cocaine taking in the monkeys with low rates of cocaine taking under the Chain (3/4) and Choice (4/5) schedules. Reinstatement of extinguished cocaine responding following response-independent delivery of a large dose of cocaine (0.3 mg/kg) was attenuated in 3 of the 5 monkeys by the HCRTr1 antagonist SB-334867. Conclusions These data expand upon work accomplished in predominantly male rodents suggesting that the hypocretin system modulates the response to appetitive stimuli. A better understanding of this system offers promise as a novel approach in medication development for appetitive disorders.

Many patients with bulimia nervosa (BN) also meet criteria for a lifetime alcohol use disorder (AUD). In order to understand possible mechanisms contributing to the co-occurrence and perpetuation of these disorders, this study investigated the importance of impulsivity and test meal intake among patients with BN by comparing women with BN only (n = 18), BN and current/past AUDs (n = 13), and healthy controls (n = 12). All participants completed assessments of eating disorder symptoms, frequency of alcohol use, binge eating, and purging via questionnaires and semi-structured interviews over two sessions. Measures of impulsivity consisted of computerized and self-report measures, and laboratory test meals. Significant differences between individuals with BN with/without comorbid AUDs were not found for test meal intake, impulsivity measures, or self-reported psychological symptoms. As hypothesized, compared to healthy controls, individuals with BN had significantly higher scores on two subscales and the total score of the Barratt Impulsiveness Scale, a trait measure of impulsivity, and consumed significantly more calories in the binge instruction meal. Total Barratt Impulsiveness Scale scores were also significantly related to kcal consumed during the laboratory test meal when individuals were instructed to binge eat (BN groups). Data from this study add to the existing literature implicating impulsivity in the psychopathology of disorders of binge eating, including BN, and also support the use of laboratory meals as a symptom-specific measure of this trait in eating disorder populations.

Epidemiological findings suggest that men and women vary in their pattern of cocaine use resulting in differences in cocaine dependence and relapse rates. Preclinical laboratory studies have demonstrated that female rodents are indeed more sensitive to cocaine's reinforcing effects than males, with estrous cycle stage as a key determinant of this effect. The current study sought to extend these findings to normally cycling female rhesus macaques, a species that shares a nearly identical menstrual cycle to humans. Dose-dependent intravenous cocaine self-administration (0.0125, 0.0250, and 0.0500 mg/kg/infusion) using a progressive-ratio schedule of reinforcement was determined across the menstrual cycle. The menstrual cycle was divided into 5 discrete phases – menses, follicular, periovulatory, luteal, and late luteal phases – verified by the onset of menses and plasma levels of estradiol and progesterone. Dependent variables including number of infusions self-administered per session, progressive ratio breakpoint, and cocaine intake were analyzed according to cocaine dose and menstrual cycle phase. Analysis of plasma hormone levels verified phase-dependent fluctuations of estradiol and progesterone, with estrogen levels peaking during the periovulatory phase, and progesterone peaking during the luteal phase. Progressive ratio breakpoint, infusions self-administered, and cocaine intake did not consistently vary based on menstrual cycle phase. These findings demonstrate that under the current experimental parameters, the reinforcing effects of cocaine did not vary across the menstrual cycle in a systematic fashion in normally cycling rhesus macaques.

Heavy drinking has increased in recent years and has been linked to numerous health-related risks, particularly in women. A number of factors may play a role in exacerbating the risks linked to heavy drinking, such as impulsivity, which itself is related to a number of risky behaviors. The present study investigated the effects of alcohol (0, 0.5, 0.75 g/kg) on impulsivity in female heavy drinkers (n = 23) and female light drinkers (n = 23) using a double-blind, placebo-controlled outpatient design; all women were tested during follicular phase of the menstrual cycle. Each session, participants completed a range of tasks including subjective measures of abuse liability, cognitive performance tasks, three behavioral impulsivity tasks, and a risk-taking task. Alcohol increased impulsivity on the Immediate and Delayed Memory Task (IMT and DMT) and Delay Discounting task. Heavy drinkers scored higher on impulsivity self-reports and were more impulsive on the IMT and the GoStop task than light drinkers. The high dose of alcohol further increased impulsive performance on the IMT and DMT in heavy drinkers. There were no group differences or alcohol effects on the Balloon Analogue Risk Task. Alcohol increased sedative-like effects more in light drinkers and increased stimulant-like effects and alcohol liking more in heavy drinkers. In summary, female heavy drinkers are less sensitive to the negative effects of alcohol, report more positive effects of alcohol, and are more impulsive than female light drinkers. Moreover, impulsive responding was exacerbated by alcohol drinking among female heavy drinkers, indicating that women who drink at this level are at increased risk for developing alcohol use disorders and engaging in other risky behaviors, particularly after drinking. (PsycINFO Database Record (c) 2012 APA, all rights reserved). Language: en

The present study determined whether: (1) the response to alcohol varied as a function of menstrual cycle phase and (2) women with a paternal history of alcoholism (FHP) were less sensitive to the effects of alcohol compared to women without a family history of alcoholism (FHN). The behavioral effects of alcohol (0.00, 0.25, and 0.75 g/kg) were evaluated in 21 FHN and 24 FHP women; each dose was tested during both the midfollicular and late luteal phases of the menstrual cycle. Baseline negative mood was increased during the luteal phase compared to the follicular phase (increased Beck Depression scores and decreased Vigor, Arousal, and Friendly scores). Alcohol increased ratings of Drug Liking and Good Drug Effect more in the luteal phase than the follicular phase. FHP women had greater negative mood during the luteal phase and some of these dysphoric effects were increased by alcohol more in FHP women than FHN women. Alcohol impaired performance, with no group or menstrual cycle differences. However, consistent with previous studies, FHP women were less impaired by alcohol than FHN women on the balance task. These data indicate that (1) the differences in response to alcohol across the menstrual cycle are subtle, although alcohol is liked more during the luteal phase; (2) increases in dysphoric mood during the luteal phase are more pronounced in FHP women compared to FHN women, particularly after alcohol; and (3) the differences observed in response to alcohol between FHP and FHN women are less pronounced than previously shown in men.

Stimulant abuse continues to be a problem, particularly for women. There is increasing preclinical and clinical evidence showing that the hormone progesterone attenuates the behavioral effects of cocaine, and this effect is primarily observed in females. The purpose of the present study was to determine if progesterone would also alter the behavioral effects of another stimulant, oral d-amphetamine (AMPH) in women. Eighteen normal non-drug abusing women completed eight outpatient sessions over two menstrual cycles. During the follicular phase of each cycle, women were administered AMPH (0, 10, 20 mg); in one cycle they were pretreated with oral micronized progesterone (200 mg) and in another cycle they were pretreated with placebo progesterone. Each session, participants completed a range of tasks including subjective measures of abuse liability, cognitive performance tasks, and behavioral measures of impulsivity and risk-taking. AMPH produced dose-related increases in positive subjective effects and these effects were enhanced by progesterone pretreatment. AMPH alone, or in combination with progesterone, had little effect on performance or behavioral measures of impulsivity. These results are in contrast with previous studies showing that progesterone attenuates the subjective response to cocaine and nicotine. Additional studies are needed to explore the modulatory role of progesterone on the effects of AMPH to determine whether progesterone has any clinical utility for AMPH abuse.

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.

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.

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.

Numerous studies in rodents suggest that there are sex differences in response to cocaine that are related to fluctuations in the ovarian hormones of females. Given that female rhesus monkeys have menstrual cycles that are remarkably similar to those of humans, they provide an ideal laboratory animal model for assessing the effects of cocaine across the menstrual cycle. The present study assessed the effects of 4 injections of intravenous (i.v.) cocaine (0.00, 0.25 or 0.50 mg/kg), spaced 15 min apart, in 4 female rhesus monkeys. Each monkey was tested with each dose during 4 phases of the menstrual cycle: menses, midfollicular, periovulatory and midluteal. Estradiol and progesterone levels were measured each session before cocaine administration to verify phase of the menstrual cycle. Cocaine and cocaine metabolite levels were measured 5 min after each cocaine dose and 5, 15, 30, 45, 60 and 120 min after the last cocaine dose. Similarly, levels of luteinizing hormone (LH) and prolactin levels were measured before, 5, 15, 30, 45, 60 and 120 min after the last cocaine dose. Cocaine and metabolite levels increased as a function of dose, but there were minimal differences across the menstrual cycle following repeated injections of cocaine. With a few exceptions, LH levels decreased as a function of time within the session, with no differences as a function of cocaine dose. Cocaine produced transient increases in LH levels during the luteal phase, with maximal levels occurring after the second cocaine injection. Lastly, cocaine substantially decreased prolactin levels across all menstrual cycle phases. Taken together, these data indicate that any behavioral differences observed either across the menstrual cycle or between males and females, are probably not related to alterations in the pharmacokinetics of cocaine across the menstrual cycle.

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.

Several studies in rodents suggest that there are sex differences in response to cocaine that are related to fluctuations in the ovarian hormones of females. Female rhesus monkeys have menstrual cycles that are remarkably similar to human menstrual cycles in both duration and hormonal variations. Therefore, data obtained in monkeys should be an ideal model for assessing the effects of cocaine across the menstrual cycle in humans. The present study assessed the acute effects of intravenous cocaine (0, 0.25, 0.50, and 1.00 mg/kg) in five female rhesus monkeys during four phases of the menstrual cycle: menses, midfollicular, periovulatory, and midluteal. To reduce the effects of stress that can occur from sedation, all animals were trained to enter primate chairs so that repeated blood samples could be obtained in awake animals. Hormone levels for estradiol and progesterone were measured each session before cocaine administration. Cocaine and cocaine metabolite plasma levels were measured at 5, 15, 30, 45, 60, and 90 min after cocaine administration. Similarly, levels of luteinizing hormone (LH) were measured before, 15, 30, 45, 60, and 90 min after cocaine administration. Within 5 min of cocaine administration, cocaine plasma levels peaked and dose-dependent behavioral changes (ie increased motor activity, mydriasis, and refusal of treats) were observed. These effects typically resolved in 15-30 min. There were few differences in the pharmacokinetic profile of cocaine across the menstrual cycle. However, the cocaine metabolites, BZE and EME, did vary across the menstrual cycle, with both being increased in the luteal phase, particularly following the highest dose of cocaine. In addition, unlike previous studies, cocaine did not produce consistent increases in LH levels. Rather, the change in LH levels depended on menstrual cycle phase and cocaine dose. In summary, there is little evidence that the pharmacokinetics of cocaine vary as a function of menstrual cycle phase.

Individuals who are moderate drinkers are at increased risk to abuse alcohol. Moreover, women are more vulnerable than men to the adverse consequences of alcohol consumption and recent data indicate that the drinking pattern in women is becoming more similar to that of men. However, few studies have determined whether female moderate drinkers (MD) show a differential response to the subjective and performance effects of alcohol, compared to female light drinkers (LD). Fifteen female MD who consumed an average of 34.7 drinks/month were compared to 15 female LD who consumed an average of 6.7 drinks/month. None of the participants had a first-degree family history of alcoholism or substance abuse. The acute effects of alcohol (0, 0.25, 0.50, 0.75 mg/kg) were evaluated using a double-blind, placebo-controlled outpatient design. Drug effects were assessed using a full range of performance measures, subjective-effects questionnaires and observer ratings. Alcohol impaired performance in a dose-related manner on all performance tasks for both groups of females. However, MD were less impaired than LD on balance and Digit Symbol Substitution Test (DSST). This reduced response was also evident from the observer ratings, with MD being viewed as less impaired by alcohol than LD. While ratings of Drug Liking increased in both groups of women on the ascending limb of the breath alcohol curve, alcohol was disliked by LD on the descending limb and LD reported increased ratings of Bad Drug Effects following the high dose of alcohol. The reduced performance impairment, coupled with the positive subjective effects and relative absence of adverse subjective effects, suggestive of behavioral tolerance, could result in a progression towards increased alcohol consumption among moderate female social drinkers.

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.

Several studies have demonstrated that males with a family history of alcoholism (FHP) show less of a response to alcohol (e.g. lower ratings of intoxication) than males without a family history of alcoholism (FHN). The purpose of this pilot study was to determine if FHP females also showed a reduced sensitivity to alcohol compared to FHN females.To determine if FHP females (n=16) were less sensitive to the subjective effects and performance-impairing effects of alcohol compared to FHN females (n=16).The effects of placebo and alcohol (0.25, 0.50, 0.75 g/kg, based on total body water) 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 drug effect.There were no differences in breath alcohol levels between FHN and FHP women. FHP women were less impaired by alcohol than FHN women, as shown by DSST scores and observer-ratings. However, FHP women were more impaired on the Digit Recall task after alcohol than FHN women and they tended to have higher ratings of "Good Drug Effect," "Drug Liking" and "Willingness to Take Again." Of note, FHP women reported more dysphoric mood than FHN women in the absence of alcohol administration.The results of the present study suggest that FHP women may have a reduced response to alcohol on some measures, but FHP women report greater positive effects on other measures. Overall, the differences between FHP and FHN women are subtle compared to the previous studies demonstrating a reduced response to alcohol in FHP men.

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.

There are three purposes for this study: (1) To extend the laboratory study of heavy smoked cocaine use to women, (2) to assess cocaine withdrawal symptoms and (3) to assess the utility of voucher incentives for achieving and maintaining cocaine and other drug abstinence in female cocaine abusers. Methods: Ten non-treatment seeking female cocaine smokers resided inpatient for 4–5 days and could smoke up to 6 doses of cocaine base (50 mg each) twice a day (at 1200 h and again at 1600 h) for 2 consecutive days. During the following 2-week outpatient phase, women were given US$40 in merchandise vouchers if urinalysis indicated lower drug levels from the previous day. Results: Women self-administered 20.4 out of 24 possible doses. Compared to the 1200 session, heart rate and blood pressure, but not subjective effects, were still significantly increased prior to the 1600 session. Nine women completed the outpatient phase, attending 98% of their appointments. Using the One-Half Rule, 56% of urines indicated no new cocaine or other drug use. Implications: Although a US$40 voucher incentive for a “clean” urine was not sufficient to eliminate cocaine use, the possibility of earning the voucher was sufficient to maintain nearly perfect attendance.

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.

Previous research suggests that women who report dietary restraint tend to consume alcohol in greater quantities, however most studies use retrospective data collection, which is often unreliable, and no studies have accounted for this relationship with respect to potential changes in alcohol consumption across the menstrual cycle. Therefore, the present study investigated the relationship between prospectively monitored drinking patterns and dietary restraint across the menstrual cycle among females from the general population whose drinking level (7–20 drinks/week) places them at-risk for developing alcohol use disorders. Restrained eaters (RES; N = 51) and unrestrained eaters (UN-RES; N = 55), per the cognitive restraint scale scores from the Three-Factor Eating Questionnaire, provided prospective ratings measuring mood, alcohol consumption, and consequences of alcohol use across one full menstrual cycle. Dysphoric mood increased during the late luteal and menstrual phases in both groups. Although overall the RES group did not drink more than the UN-RES group, the RES group drank less than the UN-RES group during the follicular phase, suggesting that among RES women alcohol consumption may be modulated by hormonal fluctuations across the menstrual cycle. The differences between the present findings and previous research may be due to the cohorts sampled; the majority of previous studies sampled college students, where binge drinking and dietary restraint are more common, whereas this study sampled the general population. Future research should replicate prior studies in a college-aged population using the current design of prospective data collection for greater accuracy of self-reported alcohol consumption.

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.

This paper provides a methodological survey of research of 1253 experiments on the acute effects of drugs used for non-medical purposes on human performance. 305 different tasks were tested, but only 118 tasks were used in more than two experiments. While the majority of experiments did have control conditions and measured drug effects at more than one time point after drug administration, they varied widely on other protocol details: (1) subject populations, (2) training on the tasks prior to drug administration, and (3) number of active test doses that were tested. Administration of stimulants either had no effect, or improved performance. In contrast, administration of marijuana, alcohol, or benzodiazepines had no effect, or impaired performance. In order to maximize comparability and utility, future protocols should use control groups, train subjects prior to participation, test more than one drug dose, and test performance before, and several times after, drug administration. A greater range of subject populations should also be studied. Finally, task standardization including type of instructions to subjects, duration of performance testing, feedback to subjects, motivational conditions, and inclusion of a benchmark task should also be used to enhance comparisons across studies.

There are currently no FDA-approved pharmacotherapies for cocaine abuse. Converging preclinical and clinical evidence indicates that progesterone may have potential as a treatment for cocaine-abusing women, who represent a growing portion of cocaine users. We have previously shown that oral progesterone reduced the positive subjective effects of cocaine in female cocaine users during the follicular phase of the menstrual cycle, when endogenous progesterone levels were low. To extend these findings, the present study assessed the effects of oral progesterone (150 mg BID) administered during the follicular phase on smoked cocaine self-administration in women relative to the normal follicular and luteal phases. Healthy, non-treatment seeking female cocaine smokers (N = 10) underwent three 4-day inpatient stays, during: 1) a normal follicular phase; 2) a normal luteal phase; and 3) a follicular phase when oral progesterone was administered. During each stay, participants completed 4 self-administration sessions in which they first smoked a “sample” dose of cocaine (0, 12, 25 or 50 mg) and then had 5 opportunities at 14-minute intervals to self-administer that dose at a cost of $5 per dose. Expected cocaine dose effects on self-administration, subjective effects, and cardiovascular effects were observed. However, there was no effect of oral progesterone administration or menstrual cycle phase on cocaine self-administration. Thus, oral progesterone was not effective in reducing cocaine use in women under the current conditions. However, based on previous literature, further research assessing the role of oral progesterone for the treatment of cocaine dependence in women is warranted.

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.

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.

Stimulant abuse continues to be a growing problem among women. Over the last 10-15 years, an increasing number of studies have focused on factors that may be implicated in stimulant abuse in women as compared to men, including the role of hormonal fluctuations across the menstrual cycle. Numerous preclinical studies have documented that female rodents are more sensitive than male rodents to the behavioral effects of stimulant administration and the hormone estradiol is involved in the enhanced response to stimulants observed in females. In contrast, fewer studies have been conducted in humans and non-human primates addressing the role of sex and gonadal hormones on the effects of cocaine. This review paper presents a recent update on data collected in our Human Cocaine Challenge Laboratory and our Non-human Primate Laboratory, including analysis of cocaine pharmacokinetics, sex differences, the menstrual cycle, and the role of progesterone in modulating the response to cocaine. Our studies indicate that there is minimal evidence that the response to intranasal cocaine varies across the menstrual cycle or between men and women. In contrast, the response to smoked cocaine is greater in the follicular phase than the luteal phase and differences between men and women generally only emerge when men are compared to women in the luteal phase. In terms of potential hormonal mechanisms for these differences, the hormone progesterone attenuates the subjective response to cocaine. With respect to cocaine self-administration, there are minimal changes across the menstrual cycle in both humans and non-human primates. Thus, there is converging evidence across a range of species that the behavioral effects of cocaine (1) differ between males and females, (2) differ in relation to hormonal fluctuations, (3) can be attenuated by progesterone (at least in females), and (4) do not appear to be related to differences in cocaine pharmacokinetics.

This paper describes the rationale, practical details, and laboratory lore relevant to conducting an acute dose-effect crossover evaluation for abuse liability of a novel anxiolytic/hypnotic compound relative to a standard compound. Basic principles underlying meaningful abuse liability assessments are presented and illustrated with examples from a comparative evaluation of the hypnotics zolpidem and triazolam. These principles include using a double-blind placebo-controlled design, selecting an appropriate comparison compound, evaluating a wide range of doses including supratherapeutic doses, using subjects with histories of sedative drug abuse, and using a range of dependent measures. The dose-effect crossover evaluation is proposed as a crucial first step in any rigorous drug abuse liability evaluation of a novel anxiolytic or hypnotic drug. Such a study can be expected to generate a broad data base which not only provides a prediction about the likelihood of abuse of the novel compound, but provides an assessment of some of the adverse consequences of recreational abuse. The crossover study also establishes parameters for subsequent studies such as direct assessment of reinforcing effects with drug self-administration testing.

With the greater acceptance of adult attention-deficit hyperactivity disorder (ADHD) as a valid clinical diagnosis, this disorder has been increasingly recognized among substance abusers seeking treatment. Because adult ADHD occurs in a substantial minority of substance abusers—from 10 to 30 percent—the question arises of whether individuals identified as having adult ADHD and substance abuse would benefit from targeted treatment interventions. Cocaine abusers with childhood histories of ADHD are more likely to use cocaine at an earlier age and to have more exposure to treatment, but they do less well in treatment (1). Furthermore, Dansereau and associates (2) have found that methadone maintenance patients with “poor attention” do less well in treatment. Thus it seems reasonable to conclude that improving an individual’s difficulties with inattention, hyperactivity, or impulsivity will increase that person’s likelihood of succeeding in substance abuse treatment.

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.

Attention deficit hyperactivity disorder (ADHD) is prevalent in adult cocaine abusers. Yet, it remains to be determined how the response to cocaine differs in cocaine abusers with ADHD compared to cocaine abusers without ADHD. Further, since ADHD is commonly treated with stimulants, such as methylphenidate (MPH), it is important to examine whether MPH maintenance alters the response to cocaine in cocaine abusers with ADHD. Thus, the first phase of this study compared the response to cocaine in adult cocaine abusers with ADHD to those without ADHD. The second phase assessed the effects of oral sustained-release methylphenidate (MPH-SR) maintenance (40 and 60 mg) on the response to cocaine only in those with ADHD. Cocaine abusers with ADHD (N=7) and without ADHD (N=7) who were not seeking treatment remained inpatient initially for 1 week, when the effects of cocaine alone were tested (Phase 1). Cocaine abusers with ADHD remained inpatient for an additional 3 weeks, during which the effects of cocaine during oral MPH-SR maintenance were tested (Phase 2). During cocaine fixed dosing sessions, participants received four injections of i.v. cocaine (0, 16 or 48 mg/70 kg), spaced 14 min apart. During cocaine choice sessions, participants had a choice between receiving i.v. cocaine (16 or 48 mg/70 kg) or two tokens, each exchangeable for 2 US dollars. Subjective effects related to ADHD symptoms (e.g. ratings of "Able to Concentrate") were significantly lower in cocaine abusers with ADHD compared to those without ADHD when placebo cocaine was administered. Active cocaine produced similar increases in cardiovascular and positive subjective effects in both groups and there was no difference in cocaine choice between the two groups. These data suggest that the response to cocaine is not different between cocaine abusers with ADHD compared to those without ADHD. When the cocaine abusers with ADHD were maintained on MPH-SR, cardiovascular effects were increased, however, this did not warrant termination of any test session. Maintenance on MPH-SR decreased some of the positive subjective effects of cocaine. Further, maintenance on a high dose of MPH-SR decreased cocaine choice. Thus, oral MPH-SR is safe in combination with repeated cocaine doses and decreases some of the positive and reinforcing effects of cocaine in cocaine abusers with ADHD.

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.

Studies have shown that alcohol expectancies are positively associated with drinking and alcohol abuse and dependence symptoms among alcohol users. This study looked at the relationship of alcohol expectancies, family history of alcoholism, menstrual cycle and drinking behavior. The present study compared alcohol expectancies using the Alcohol Expectancy Questionnaire (AEQ) in 85 women ranging from 18 to 35 years of age. Forty-one women had a confirmed parental history of alcoholism (family history positive, FHP) and 44 women had no parental history of alcoholism (family history negative, FHN). Participants' mood, alcohol consumption, and daily consequences of alcohol use were prospectively tracked across one menstrual cycle. Alcohol expectancies at screening were significantly greater in FHP women in four of the six AEQ subscales, as well as the composite score. Alcohol expectancies correlated significantly with drinking behavior among FHN women. In FHP women, alcohol expectancies were elevated regardless of their drinking level. Alcohol expectancies decreased among FHP women, but not FHN women, after prospectively tracking their drinking behavior and consequences of drinking. Negative outcomes of drinking were increased among the FHP women who were heavy drinkers. Irrespective of family history status, alcohol use in moderate drinkers increased significantly during menses compared to the follicular and luteal phases of the menstrual cycle. These findings suggest that menstrual cycle may also play a role in alcohol consumption. Thus, the results of the present study indicate that issues related to the level of alcohol consumption, menstrual cycle phase and family history of alcoholism should be considered when addressing alcohol abuse in women.

Individuals who are moderate/heavy drinkers are at increased risk to abuse benzodiazepines and this risk is increased in women compared to men. However, no studies have determined whether female moderate drinkers (MD) show a differential response to the subjective and performance effects of benzodiazepines compared to female light drinkers (LD). Fourteen female MD who consumed an average of 36 drinks/month were compared to 14 female LD who consumed an average of 4.2 drinks/month. None of the participants had either a first- or second-degree family history of alcoholism. 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 a full range of performance measures and subjective-effects questionnaires. Alprazolam impaired performance in a dose-related manner on all performance tasks for both groups of females, whereas buspirone had minimal effects on performance. There were few differences between LD and MD with respect to subjective response or performance impairment following either alprazolam or buspirone. Although MD reported greater ratings of Good Drug Effect and Drug Liking than LD, this was neither dose-related, nor specific to alprazolam. The results of the present study suggest that female MD without a family history of alcoholism experience the same level of performance impairment as female LD, although they tend to report greater positive subjective effects from alprazolam.

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.

Aims: This study evaluated the efficacy of oral micronized progesterone (PROG) for reducing cocaine use in women. Methods: A 10-week double-blind treatment trial compared PROG (up to 400mg/day, b.i.d.) to placebo (PBO) in cocaine-dependent women who were cocaine abstinent before randomization. Voucher incentives for attendance were used to enhance retention. Primary outcome measures included time to relapse, days of consecutive cocaine abstinence and retention. Response to a laboratory stressor, the Trier Social Stress Test (TSST) and treatment outcome was also explored. Results: Out of 227 women assessed, 25 women entered the trial, with 10 stratified to the PBOGroup and 11 to the PROGGroup. Thirteen women (62%) completed the entire 10-week trial. Five patients (2 in the PROG group and 3 in the PBO group) did not relapse, i.e., remained cocaine abstinent, during the trial. Two other women, one in each group, also did not relapse, but did not complete the trial. For the remainingwomen, themean number of days to relapse was 2.0 for the PROG group and 2.3 for the PBO group (p>0.05). Themean number of consecutive days of abstinence was 7.5 for the PROG group and 9.0 days for the PBO group (p>0.05). Among the 14 women who completed the TSST before randomization, increases in heart rate (r=−.33), anxiety scores (r=−.37) and cocaine craving (r=−.34) in response to stress were negatively correlated with the percentage of cocaine negative urines. Conclusions: PROG was well tolerated, but due to the small sample size it was not possible to adequately determine if PROG may be an effective treatment for cocaine-dependent women. Although cocaine-abstinence rates were low, they could be potentially improved using voucher incentives contingent on cocaine abstinence. Lastly, the preliminary findings showing that increased stress reactivity was related to low rates of cocaine abstinence suggest that stress-reduction techniques could improve treatment outcome. Financial support: NIDA grants RO1 DA022218 (SME), K24 DA029647 (FRL) and KO1 DA022282 (SCR). Medication was provided by the Women’s International Pharmacy.

Rationale: Few studies have systematically determined whether the response to cocaine in human females is related to hormonal fluctuations at different phases of the menstrual cycle. Objectives: To investigate the responses to repeated doses of smoked cocaine in women during two phases of the menstrual cycle using a within-subject design. Methods: Eleven non-treatment seeking female cocaine smokers were administered smoked cocaine during the follicular and mid-luteal phases of the menstrual cycle. The order of menstrual cycle phase was counterbalanced across women and the order of cocaine doses was randomized. During each phase, there were four cocaine administration sessions. During each session, participants could smoke up to six doses of cocaine (either 0, 6, 12, or 25 mg cocaine base, depending on the session) at 14-min intervals. Results: The number of cocaine doses administered did not vary between the follicular and luteal phases. After cocaine administration, heart rate and several ratings – such as "good drug effect", "high", "stimulated", and "drug quality ratings" – were increased more during the follicular phase than the luteal phase, although, for some measures, these effects varied based on the cocaine dose. Further, dysphoric mood during the luteal phase was improved after cocaine administration. Conclusions: These results indicate that the cardiovascular and subjective effects of repeated doses of smoked cocaine are complex and vary as a function of menstrual cycle phase and cocaine dose.

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.

This study determined if women with premenstrual dysphoric disorder (PMS) showed impaired mood and performance when they were experiencing their premenstrual symptoms, and if the effects of alprazolam varied as a function of menstrual cycle phase. Under double-blind conditions, the acute effects of placebo and alprazolam (0.25, 0.50, 0.75 mg) were tested during both luteal and follicular phases. Women with confirmed PMS experienced substantial changes in mood as a function of menstrual cycle phase. However, under controlled laboratory conditions, acute doses of alprazolam did not improve negative premenstrual mood, but rather increased negative mood in the follicular phase. Alprazolam impaired task performance, although this impairment was generally similar in both phases when baseline phase differences were taken into consideration. Consistent with the failure of alprazolam to improve mood premenstrually, subjective measures indicative of abuse liability were not increased following alprazolam. Taken together, these data suggest that acute administration of alprazolam doses are not clinically useful for the treatment of PMS.

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.