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Background: Impulsive choice – the tendency to choose immediate over larger delayed rewards – is associated with both cocaine use and relapse. Little is known about the influence of transient states on impulsive choice in people who use cocaine (PWUC). This study investigated the direct effects of induced boredom on impulsive choice (i.e., temporal discounting) in PWUC relative to well-matched community controls. Methods: In a mixed within-between subject design, 41 PWUC (≥1x cocaine use in past 3 months; 7 females) and 38 demographically-matched controls (5 females) underwent two experimental conditions in counterbalanced order. Temporal discounting was assessed immediately after a standardized boredom induction task (peg-turning) and a self-selected video watched for the same duration (non-boredom). Subjective mood state and perceived task characteristics were assessed at baseline, during experimental manipulations, and after the choice task. Results: PWUC and controls were demographically well-matched and similar in reported drugs use other than cocaine, except for recent cigarette and alcohol use (PWUC>controls). As expected, peg-turning increased boredom in the sample overall, with higher boredom reported during peg-turning than the video (p.05, BF01=2.9). Conclusion: Experimentally-induced boredom increased state impulsivity irrespective of cocaine use status, suggesting a broad link between boredom and impulsive choice. This is the first study to show that transient boredom directly increases impulsive choice. Data support a viable laboratory method to further parse the effects of boredom on impulsive choice.

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).

Women with a history of childhood sexual abuse (CSA) are at greater risk to develop alcohol use disorders. Whereas impulsivity has been postulated as a behavioral mechanism linking childhood trauma and alcohol use, few studies have comprehensively examined impulsivity in women with CSA. We compared women with a history of CSA (n = 21) and control women who did not endorse CSA or other major traumas (CON; n = 21) on self-report measures of impulsivity and risk taking. Additionally, performance on behavioral impulsivity and subjective response to alcohol were examined before and after acute alcohol (0.00, 0.50, 0.75 g/kg) administration. Overall, women with CSA responded more impulsively than CON women on the immediate and delayed-memory tasks (measures of response initiation) and the GoStop task (a measure of response inhibition). Whereas alcohol produced dose-related increases in impulsive responding on the immediate memory task in both groups, alcohol-induced increases in response inhibition on the GoStop task were evident only in the CSA group. In contrast, women with CSA exhibited less risk taking than the CON group on the balloon analogue risk task. Alcohol produced dose-related increases on several subjective response measures (e.g., alcohol liking) in both groups; however, these ratings tended to be greater in women with CSA. These preliminary data suggest that women with CSA may be more impulsive. Importantly, impulsivity can lead to hazardous drinking, and alcohol consumption can further increase impulsivity, putting women with CSA at increased risk for sexual revictimization, particularly in the context of alcohol use. (PsycInfo Database Record (c) 2020 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.

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

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.

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.

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.

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.

Immunopharmacotherapy offers an approach for treating cocaine abuse by specifically targeting the cocaine molecule and preventing its access to the CNS. dAd5GNE is a novel cocaine vaccine that attenuates the stimulant and the reinforcing effects of cocaine in rats. The goal of this study was to extend and validate dAd5GNE vaccine efficacy in non-human primates. Six experimentally naive adult female rhesus monkeys (Macaca mulatta) were trained to self-administer 0.1mg/kg/injection intravenous (i.v.) cocaine or receive candy; then 4 monkeys were administered the vaccine and 2 monkeys were administered vehicle intramuscularly, with additional vaccine boosts throughout the study. The reinforcing effects of cocaine were measured during self-administration, extinction, and reacquisition (relapse) phases. Serum antibody titers in the vaccinated monkeys remained high throughout the study. There was no change in the preference for cocaine over candy over a 20-week period in 5 of the 6 monkeys; only one of the 4 (25%) vaccinated monkeys showed a decrease in cocaine choice. All 6 monkeys extinguished responding for cocaine during saline extinction testing; vaccinated monkeys tended to take longer to extinguish responding than control monkeys (17.5 vs. 7.0 sessions). Vaccination substantially retarded reacquisition of cocaine self-administration; control monkeys resumed cocaine self-administration within 6-41 sessions and 1 vaccinated monkey resumed cocaine self-administration in 19 sessions. The other 3 vaccinated monkeys required between 57 and 94 sessions to resume cocaine self-administration even in the context of employing several manipulations to encourage cocaine reacquisition. These data suggest that the dAdGNE vaccine may have therapeutic potential for humans who achieve cocaine abstinence as part of a relapse prevention strategy.

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.

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 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.

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.

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.

This is an introduction to the special issue "50th Anniversary of APA Division 28: The Past, Present, and Future of Psychopharmacology and Substance Abuse." Taken together, the scholarly contributions included in this special issue serve as a testament to the important work conducted by our colleagues over the past five decades. Division 28 and its members have advanced and disseminated knowledge on the behavioral effects of drugs, informed efforts to prevent and treat substance abuse, and influenced education and policy issues more generally. As past and current leaders of the division, we are excited to celebrate 50 years of Division 28 and look forward to many more successful decades for our division and its members. (PsycINFO Database Record

Cocaine use disorders are mediated by the cocaine blockade of the dopamine transporter in the central nervous system (CNS). On the basis of the concept that these effects could be obviated if cocaine were prevented from reaching its cognate receptors in the CNS, we have developed an anticocaine vaccine, dAd5GNE, based on a cocaine analog covalently linked to capsid proteins of an E1(-)E3(-) serotype 5 adenovirus. While the vaccine effectively blocks systemically administered cocaine from reaching the brain by mediating sequestration of the cocaine in the blood, the fact that cocaine also has significant peripheral effects raises concerns that vaccination-mediated redistribution could lead to adverse effects in the visceral organs. The distribution of systemically administered cocaine at a weight-adjusted typical human dose was evaluated along with cocaine metabolites in both dAd5GNE-vaccinated and control nonhuman primates. dAd5GNE sequestration of cocaine to the blood not only prevented cocaine access to the CNS, but also limited access of both the drug and its metabolites to other cocaine-sensitive organs. The levels of cocaine in the blood of vaccinated animals rapidly decreased, suggesting that while the antibody limits access of the drug and its active metabolites to the brain and sensitive organs of the periphery, it does not prolong drug levels in the blood compartment. Gross and histopathology of major organs found no vaccine-mediated untoward effects. These results build on our earlier measures of efficacy and demonstrate that the dAd5GNE vaccine-mediated redistribution of administered cocaine is not likely to impact the vaccine safety profile.

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.

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.

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.

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.

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.

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.

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.

Objective: The purpose of this study was to demonstrate the utility of food-reinforced operant task performance in modeling binge-eating disorder (BED). We hypothesized that food reinforcement after a caloric preload would be related to BED status, but not hunger. Methods and Procedures: We investigated the association between reports of hunger, binge tendency, and food reinforcement in a sample of 18 women (12 non-BED, 7 lean, 5 obese, and 6 obese BED). Participants completed two sessions of operant task performance after consuming 600 ml of flavored water or 600 ml of a 1 kcal/ml liquid meal. Results: Under the water condition, food reinforcement did not differ between the non-BED and BED groups, and was positively correlated with hunger ratings across all participants (r = 0.55, P = 0.023). Under the liquid meal condition, food reinforcement was significantly decreased compared with the water condition in the non-BED group (t = −2.6, P = 0.026). There was also a significant difference between the non-BED and BED groups in the fed condition (41 ± 40, 117 ± 60, F = 10.3, P = 0.005, non-BED vs. BED, respectively, mean ± s.d.). The correlation between food reinforcement and hunger remained significant only in the non-BED group (r = 0.69, P = 0.011). Discussion: Our results support the hypothesis that food reinforcement measured after a caloric preload is related to BED status but not hunger in those subjects with BED. The data also suggest that operant task performance can be useful in modeling BED criteria such as “eating when not physically hungry.”

Although it's been reported that women with premenstrual dysphoric disorder (PMDD) have increased negative mood, appetite (food cravings and food intake), alcohol intake and cognitive deficits premenstrually, few studies have examined these changes concurrently within the same group of women or compared to women without PMDD. Thus, to date, there is not a clear understanding of the full range of PMDD symptoms. The present study concurrently assessed mood and performance tasks in 29 normally cycling women (14 women who met DSM-IV criteria for PMDD and 15 women without PMDD). Women had a total of ten sessions: two practice sessions, 4 sessions during the follicular phase and 4 sessions during the late luteal phase of the menstrual cycle. Each session, participants completed mood and food-related questionnaires, a motor coordination task, performed various cognitive tasks and ate lunch. There was a significant increase in dysphoric mood during the luteal phase in women with PMDD compared to their follicular phase and compared to Control women. Further, during the luteal phase, women with PMDD showed impaired performance on the Immediate and Delayed Word Recall Task, the Immediate and Delayed Digit Recall Task and the Digit Symbol Substitution Test compared to Control women. Women with PMDD, but not Control women, also showed increased desire for food items high in fat during the luteal phase compared to the follicular phase and correspondingly, women with PMDD consumed more calories during the luteal phase (mostly derived from fat) compared to the follicular phase. In summary, women with PMDD experience dysphoric mood, a greater desire and actual intake of certain foods and show impaired cognitive performance during the luteal phase. An altered serotonergic system in women with PMDD may be the underlying mechanism for the observed symptoms; correspondingly, treatment with specific serotonin reuptake inhibitors (SSRIs) remains the preferred treatment at this time.

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.

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.

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.