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BACKGROUND: Acamprosate (calcium acetyl homotaurinate) reduces alcohol intake in animals and increases abstinence rates in alcohol-dependent persons. Acamprosate's mechanism of action, however, remains poorly understood. In order to examine whether acamprosate/alcohol interactions contribute to acamprosate's efficacy, the present double-blind, placebo-controlled human laboratory study examined effects of acamprosate on the pharmacokinetics and subjective, psychomotor, and physiological effects of alcohol in heavy drinkers. METHODS: In a six-week within-subject design, participants were maintained on acamprosate (0, 2, and 4 g, p.o., double-blind, in counterbalanced order) for 11 days at each dose. Physiological, subjective, and psychomotor measures were collected daily during each dosing cycle. During each acamprosate dose condition, subjects were challenged with 0, 0.5, and 1.0 g/kg ethanol (p.o., counterbalanced order) during three separate laboratory sessions. Subjective, physiological, and psychomotor effects of alcohol, and breath alcohol levels were collected at baseline and at 30-min intervals for a 3-hr post-administration period. RESULTS: Acamprosate alone did not substantially affect subjective, physiological, or psychomotor performance measures. Acamprosate did not alter alcohol pharmacokinetics, or alcohol-induced behavioral impairment or tachycardia, and most subjective alcohol effects were also unaltered by acamprosate as well. Although a trend appeared for acamprosate to increase subjective ratings of intoxication following the lower (0.5 g/kg) alcohol dose, adjustment for individual differences in blood alcohol level eliminated this effect, suggesting the trend was not due to a central effect of acamprosate. CONCLUSIONS: Acamprosate does not alter alcohol pharmacokinetics, acute physiological or psychomotor alcohol effects, or most subjective alcohol effects. [ABSTRACT FROM AUTHOR]

Importance: Novel treatments for opioid use disorder (OUD) are needed to address both the ongoing opioid epidemic and long-standing barriers to existing OUD treatments that target the endogenous μ-opioid receptor (MOR) system. The goal of this review is to highlight unique clinical trial design considerations for the study of emerging treatments for OUD that address targets beyond the MOR system. In November 2019, the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) public-private partnership with the US Food and Drug Administration sponsored a meeting to discuss the current evidence regarding potential treatments for OUD, including cannabinoids, psychedelics, sedative-hypnotics, and immunotherapeutics, such as vaccines., Observations: Consensus recommendations are presented regarding the most critical elements of trial design for the evaluation of novel OUD treatments, such as: (1) stage of treatment that will be targeted (eg, seeking treatment, early abstinence/detoxification, long-term recovery); (2) role of treatment (adjunctive with or independent of existing OUD treatments); (3) primary outcomes informed by patient preferences that assess opioid use (including changes in patterns of use), treatment retention, and/or global functioning and quality of life; and (4) adverse events, including the potential for opioid-related relapse or overdose, especially if the patient is not simultaneously taking maintenance MOR agonist or antagonist medications., Conclusions and Relevance: Applying the recommendations provided here as well as considering input from people with lived experience in the design phase will accelerate the development, translation, and uptake of effective and safe therapeutics for individuals struggling with OUD.

Lapses within the first 2 weeks of a smoking cessation attempt are strongly associated with a return to regular smoking (S. L. Kenford et al., 1994). Unfortunately, little is known about how to prevent an initial lapse from progressing to a full relapse, and presently there are no validated lapse-responsive therapeutic interventions. The present study tested the efficacy and feasibility of rapid smoking plus counseling as a novel lapse-responsive intervention. Sixty-seven participants enrolled in a smoking treatment program involving brief counseling and a 9-week course of bupropion. Beginning on the quit day, participants' smoking behavior was tracked daily for 14 days. Once an early smoking lapse was identified, participants were randomly assigned to receive either 3 sessions of rapid smoking plus counseling or no intervention (usual care). Consistent with previous research, participants who smoked during the first 2 weeks of the quit attempt had significantly poorer 6-month outcomes (3% abstinent) than did those who did not smoke (64% abstinent). Compared with early abstainers, early lapsers were more nicotine dependent and reported greater cravings and lower confidence in their ability to abstain from smoking during the first 48 hours of abstinence. As expected, rapid smoking produced a variety of aversive effects, including increased nausea, dizziness, and vomiting as well as sharply decreased cravings to smoke. However, rapid smoking did not improve abstinence outcomes relative to usual care. Although rapid smoking has been shown to be an effective treatment for initial smoking cessation, in this preliminary study the authors failed to demonstrate its effectiveness as a lapse-responsive treatment.

In this study, the authors prospectively evaluated the impact of a smoking lapse on relapse probability. After 4 days of smoking abstinence, 60 smokers were randomly assigned to smoke 5 nicotine-containing or 5 denicotinized cigarettes, or to remain abstinent (no lapse) during a 4-hr time period. Afterward, smoking abstinence was encouraged with monetary incentives, and smoking behavior was tracked for 6 days. Relative to the no-lapse condition, exposure to either of the cigarette types more than doubled the probability of subsequent smoking. Smoking outcomes did not differ between nicotine-containing and denicotinized cigarettes. The data suggest that stimulus factors may play an important role in lapse to relapse processes., (2006 APA, all rights reserved)

Rationale: Because the dopamine system appears to be involved in both acute and chronic effects of cocaine, medication development efforts for cocaine addiction have focused largely on agents that interact with the dopamine system. Selegiline, a selective monoamine oxidase B inhibitor, indirectly modulates dopamine levels, and research suggests selegiline may modify subjective effects of cocaine., Objectives: To evaluate further the safety and potential of transdermal selegiline as a treatment for cocaine dependence, interactions between transdermal selegiline and intravenous cocaine were studied in cocaine-dependent volunteers., Methods: Pharmacokinetics and subjective, physiological, and endocrinological effects of intravenous cocaine (0,20 and 40 mg) were evaluated both before and during transdermal selegiline treatment (20 mg/day, 10 days) in 12 cocaine-dependent subjects. A transdermal selegiline formulation was used to avoid the risks associated with oral administration of MAO inhibitors., Results: Selegiline attenuated some physiological (systolic blood pressure and heart rate) and subjective (good effects, liking, stimulated, high, desire for cocaine) effects of cocaine. Selegiline did not affect cocaine's pharmacokinetics or cocaine-induced prolactin decrease and growth hormone increase., Conclusions: The combined administration of the transdermal selegiline patch and up to 40 mg cocaine was well tolerated. Selegiline may reduce physiological and subjective effects of cocaine. A randomized trial is needed to evaluate the efficacy of selegiline for cocaine abuse.

Rationale: A nicotine lozenge was developed as a novel smoking cessation aid. Abuse liability, which in this context refers to use by novices not addicted to tobacco, may be expected to be low for the lozenge due to the relatively slow route of nicotine absorption. However, its resemblance to commercially marketed lozenges and its palatability, intended to increase medication compliance, may increase its abuse liability, especially among younger individuals., Objectives: The present study evaluated the abuse liability of the nicotine lozenge. Effects of the lozenge on cigarette craving were also measured., Methods: Subjective and physiological effects of the nicotine lozenge were tested in healthy adult smokers ( n=12, 22-55 years old); a group of younger subjects ( n=12, 18-21 years) was also included to allow for assessment of abuse liability of the lozenge in young adults specifically. Amphetamine and a confectionery lozenge were included in the study conditions as positive controls for abuse liability and palatability, respectively, and nicotine gum was included to allow for comparison with a marketed oral nicotine replacement product with low abuse liability., Results: The nicotine lozenge did not increase ratings of traditional abuse liability predictors (good effect, like effect, MBG scale of the ARCI), while amphetamine significantly increased ratings on these measures. The lozenge dose dependently decreased craving for cigarettes after 70 min of abstinence, but only in the older group. Palatability of the lozenge was rated lower than a confectionery lozenge, but not lower than nicotine mint gum., Conclusions: Results suggest that the nicotine lozenge has low abuse liability, both in adults and young adults. The lozenge reduces craving to smoke, although craving reduction may not apply to young adults (18-21 years). Subjective effects of the lozenge are consistent with utility as a smoking cessation aid and are comparable to those of nicotine gum.

Rationale: The relative contribution of sensory and pharmacological variables in regulating craving and smoking remains unclear. Rapid smoking procedures and denicotinized cigarettes can be used to further disentangle these factors, and to explore the relationship between craving and smoking., Objective: The present study examined the role of nicotine and sensory cues in mediating craving and smoking, and the relationship between craving and smoking., Methods: Participants ( n=15) engaged in one session each of rapid smoking (up to nine cigarettes with puffs taken every 6 s) and normal paced smoking with nicotinized and denicotinized cigarettes (total of four sessions). During the next 3 h, craving and withdrawal assessments and smoking opportunities were scheduled every 15 min. Plasma nicotine levels were measured at baseline, immediately and 15 min after the smoking interventions, and subsequently at the time when the participant first chose to smoke., Results: Craving ratings were equally suppressed immediately after all conditions. After self-paced conditions, both types of cigarettes produced equivalent effects on latency to smoke. Latency to smoke was significantly longer after rapid smoking of nicotinized cigarettes compared to all other conditions. Finally, changes in craving were associated with choices to smoke., Conclusions: The sensory cues associated with smoking suppressed craving ratings regardless of the smoking pace or nicotine content. Only at high doses did nicotine levels play an additional role in acutely suppressing smoking behavior. Small elevations in craving ratings were associated with choices to smoke.

Rationale: Changes in dopamine level are thought to play an important role in both smoking reward and withdrawal symptoms during abstinence. Medications that modulate dopamine levels may have beneficial effects on both withdrawal symptom levels and on response to smoking lapses during abstinence., Objectives: To examine the effects of the selective MAO-B inhibitor selegiline on withdrawal symptoms, smoking behavior and smoking satisfaction ratings., Methods: Fifteen smokers received selegiline (10 mg/day) and placebo (in counterbalanced order) on Monday through Thursday of 2 study weeks, separated by a 2-week washout. During each study week, ad lib smoking sessions were scheduled to assess smoking behavior both before and after a brief period of abstinence. Subjective withdrawal symptoms and mood were measured daily, and a modified Stroop test sensitive to withdrawal was scheduled during the period of abstinence., Results: Selegiline decreased craving, especially during abstinence, and impaired performance on the modified Stroop test during subjects' attempts to abstain. Medication also reduced number of cigarettes smoked and smoking satisfaction ratings during the smoking sessions both before and after the brief abstinence attempt., Conclusion: These results are consistent with an important role of dopamine in smoking behavior and abstinence. They suggest that pharmacological reduction of MAO-B levels during the early part of a quit attempt may aid in smoking cessation.

Because the taste of nicotine gum has impeded compliance with dosing recommendations, nicotine gum with improved taste (mint, orange) was developed and marketed. Prior to marketing, the Food and Drug Administration (FDA) required a rigorous abuse liability assessment to examine whether enhanced palatability of nicotine gum would increase its abuse liability. Subjective, physiological, and psychomotor effects of mint flavor and original nicotine gum were tested in adult smokers (22-55 years old); a group of younger subjects (18-21 years old) was also included to allow for assessment of abuse liability in young adults specifically. Amphetamine and confectionery gum served as positive controls for abuse liability and palatability. Subjects rated palatability of mint gum higher than original nicotine gum, but substantially lower than confectionery gum. Palatability decreased with increasing dose of nicotine. Neither original nor mint gum increased ratings of traditional abuse liability predictors [Good Effect, Like Effect, Morphine-Benzedrine Group (MBG) scales of Addiction Research Center Inventory (ARCI)], while amphetamine increased ratings of all these measures. Both flavors of nicotine gum decreased craving during 2 h of abstinence. These effects were more pronounced in the adult group and mint gum was more effective than original gum. Younger subjects reported fewer withdrawal symptoms and lower ratings for drug effects and flavor. Improved flavor of nicotine gum does not increase abuse liability, but may be associated with enhanced craving reduction.

This review outlines the development and use of placebo cigarettes in smoking research. Research on effects of smoking has been disadvantaged by the lack of an adequate placebo condition. Recently, tobacco-based denicotinized cigarettes have been used in smoking research to distinguish effects of smoking due to the delivery of nicotine, other components of tobacco smoke, and the sensory process of smoking. Placebo cigarettes do not increase heart rate and blood pressure or produce electroencephalogram changes ordinarily associated with nicotine. However, placebo cigarettes reduce subjective measures of tobacco craving, desire to smoke, and tobacco withdrawal. These findings indicate that the effects of cigarette smoking are dependent on the delivery of nicotine, tar, other compounds of tobacco smoke, and the sensory stimuli. The next generation of research may begin to investigate the mechanisms that modulate these placebo effects.

Craving is thought to play an important role in maintaining regular smoking patterns in current smokers, and in leading to relapse in smokers attempting to quit. Within the scientific community however, the concept is surrounded by controversy. In an effort to 1) identify interventions that can reliably influence cigarette cravings, and 2) assess the relationship between cigarette craving and smoking behavior, effects of aversive rapid smoking (up to nine cigarettes with puffs taken every 6 s) on self-reported craving and subsequent smoking behavior were compared to effects of self-paced smoking or no smoking. Subjects (n = 14) engaged in a rapid, self-paced or no smoking procedure at the start of three separate sessions. Craving levels, measured repeatedly during the next 3 h of no smoking, were significantly lower after rapid smoking than after either self-paced or no smoking. Measures of subsequent smoking behavior (latency to first cigarette, number of cigarettes, number of puffs) did not differ systematically across conditions. Thus, craving was reliably suppressed by aversive rapid smoking, but craving scores did not predict actual smoking behavior.

Studies investigating the effect of 8-OH-DPAT (DPAT) on male sexual response have typically used subjects having variable sexual experience and levels of testosterone, factors known to independently influence male sexual behavior. This experiment examined the role of these two variables in the mediation of DPAT effects on sexual behavior. One hundred and six castrated males, half of whom received sexual experience, were tested with an effective dose of 8-OH-DPAT (0.1 mg/kg) or saline. In addition, males were tested under one of three regimens of testosterone. Results indicated that DPAT and testosterone exerted independent effects on ejaculatory measures, and along with sexual experience, showed interactive effects as well. When testosterone (T) levels were substantially below normal, DPAT showed no effect. When T reached threshold levels, the DPAT effect was limited to sexually experienced males. At high T levels, both experienced and naive males exhibited strong effects from DPAT. In contrast with ejaculatory measures, mounting and intromitting behaviors were relatively unaffected by DPAT. These results emphasize the importance of specifying both the animal's sexual history and its testosterone profile in studies investigating pharmacological effects on sexual response.

Levo-alpha-acetylmethadol (LAAM) currently is approved as an opioid maintenance treatment. This double-blind study was designed to characterize withdrawal suppression and opioid blockade produced by two different LAAM maintenance doses. Outpatient opioid-dependent volunteers were stabilized (5-7 weeks) on 25 (n = 8) or 75 mg (n = 8) LAAM administered every-other-day with placebo administered on intervening days. After stabilization, four inpatient, randomly ordered experimental sessions were conducted at 24, 48, 72 and 96 hr after LAAM dosing; the timing of these sessions corresponds to intervals that occur during typical thrice-weekly treatment and after a missed dose. During each session, after baseline assessments, ascending doses of hydromorphone (0, 6 and 12 mg i.m.) were administered 45 min apart; physiological, subjective and observer-rated effects were recorded throughout the session. Physiological and subjective indices of opioid withdrawal measured at session base lines increased with time since the last LAAM dose, but did not depend on the maintenance dose. Withdrawal symptoms were mild in both groups, even at 96 hr after LAAM dosing. Hydromorphone produced dose-related opioid agonist effects at all intervals in the 25 mg LAAM group; these effects were attenuated substantially in the 75 mg LAAM group. Time since last LAAM dose had little influence on hydromorphone effects in either group. Thus, 75 mg LAAM provides opioid blockade and withdrawal suppression for up to 96 hr, whereas 25 mg LAAM is relatively ineffective at producing significant opioid blockade.

In an earlier article an enlarged subpopulation of vasopressin containing neurons was found in the suprachiasmatic nucleus (SCN) of homosexual men as compared to heterosexuals. The present study investigates the possibility that the number of vasopressin neurons in the SCN and sexual partner preference behavior in male rats are both influenced by sex hormones during brain development. For this purpose, we studied groups of adult male rats that had been treated either prenatally or pre- and postnatally with the aromatase inhibitor ATD (1,4,6-androstatriene-3,17-dione) which blocks the aromatization of testosterone to estradiol. Rats treated with ATD in both pre- and postnatal periods showed 'bisexual' partner preference behavior and appeared to have 59% more vasopressin-expressing neurons in the SCN than the controls. The prenatally treated rats did not differ from the controls. This observation supports the hypothesis that the increased number of vasopressin neurons found earlier in the SCN of adult homosexual men might reflect differences that took place in the interaction between sex hormones and the brain early in development.

Plasma testosterone levels were higher in pooled samples from male fetuses than from female fetuses on day 19 of pregnancy. Plasma testosterone from female fetuses with males located caudally in the uterus was higher than from females that lacked such males. Testosterone level of both male and female fetuses was correlated with maternal testosterone. No correlation was found between maternal testosterone and number of males in the litter, male-to-female ratio, or litter size. These results corroborate earlier findings of a sex difference in plasma testosterone levels on fetal day 19 in rats, and provide support for the hypothesis that female rats receive androgens from males located caudally in the uterus. No evidence was found that testosterone of pregnant females is affected by the sex ratio or size of her litter.

The present study investigated 1) the importance of the aromatization process during the perinatal period for the development of the sexually dimorphic nucleus in the preoptic area of the hypothalamus (SDN-POA) of male rats, and 2) the relationship between SDN-POA volume and parameters of masculinization in male rats that were treated perinatally with the aromatase-inhibitor ATD. Males were treated with ATD either prenatally or pre- and neonatally, or with the vehicle. Masculine sexual behavior and partner preference were investigated in adulthood. Thereafter, animals were sacrificed and SDN-POA volume was measured. The SDN-POA volume was reduced in both the prenatally and the pre- and neonatally treated group, with a larger reduction in the latter than in the former group. Combined pre- and neonatal ATD treatment resulted in reduced frequency of mounts, intromissions, and ejaculations, as well as a reduced preference for a female over a male. The SDN-POA size was significantly and positively correlated with frequency of masculine sexual behavior, as well as preference for a female over a male.

It has been suggested that the sexual differentiation of female rats is affected by androgens from male fetuses in the uterine horn (intra-uterine position phenomenon). Effects of adjacent males, as well as of males located caudally in the uterus have been reported. The present study investigated whether male rats, like females, are affected by the presence of either caudal or adjacent male littermates. When tested in adulthood for sexual behavior, males that had male fetuses located caudally in the uterine horn showed shorter latencies to the first mount or intromission and shorter latencies to ejaculation, and exhibited more mounts and intromissions per minute than males that lacked caudal male siblings in the uterus. The presence of adjacent males did not significantly affect the parameters studied in this experiment.

It is assumed that female rats are masculinized by the presence of males in the same uterine horn. Two hypotheses regarding the mechanism have been proposed: 1) interamniotic diffusion of androgens (contiguity hypothesis) and 2) transport of androgens via the bloodflow (caudal male hypothesis). This study was designed to test these hypotheses while taking into account two previously uncontrolled factors: hemihysterectomy of the mother during pregnancy and birth by caesarean section. Pregnant females were hemihysterectomized during pregnancy or left intact; pups were born naturally or through caesarean section. Position in utero was determined. In adulthood all females were ovariectomized and tested for mounting behavior before and during testosterone treatment and lordosis behavior during estradiol treatment. It was found that females with males located caudally in the same uterine horn were more masculinized and defeminized than females without such males. Adjacent males had no influence on the behavioral sexual differentiation of females. These results confirm the "caudal male hypothesis" rather than the "contiguity hypothesis." Hemihysterectomy during pregnancy prevented the "caudal male effect." Birth through caesarean section did not interfere with the caudal male effect.