Ratings Of Drug Liking Research Articles

Evaluating the Abuse Potential of Lenabasum, a Selective Cannabinoid Receptor 2 Agonist.

Endocannabinoids, which are present throughout the central nervous system (CNS), can activate cannabinoid receptors 1 and 2 (CB1 and CB2). CB1 and CB2 agonists exhibit broad anti-inflammatory properties, suggesting their potential to treat inflammatory diseases. However, careful evaluation of abuse potential is necessary. This study evaluated the abuse potential of lenabasum, a selective CB2 receptor agonist in participants (n = 56) endorsing recreational cannabis use. Three doses of lenabasum (20, 60, and 120 mg) were compared with placebo and nabilone (3 and 6 mg). The primary endpoint was the peak effect (Emax) on a bipolar Drug Liking visual analog scale (VAS). Secondary VAS and pharmacokinetic (PK) endpoints and adverse events were assessed. Lenabasum was safe and well tolerated. Compared with placebo, a 20-mg dose of lenabasum did not increase ratings of Drug Liking and had no distinguishable effect on other VAS endpoints. Dose-dependent increases in ratings of Drug Liking were observed with 60 and 120 mg lenabasum. Drug Liking and all other VAS outcomes were greatest for nabilone 3 mg and 6 mg, a medication currently approved by the US Food and Drug Administration (FDA). At a target therapeutic dose (20 mg), lenabasum did not elicit subjective ratings of Drug Liking. However, supratherapeutic doses of lenabasum (60 and 120 mg) did elicit subjective ratings of Drug Liking compared with placebo. Although both doses of lenabasum were associated with lower ratings of Drug Liking compared with 3 mg and 6 mg nabilone, lenabasum does have abuse potential and should be used cautiously in clinical settings. SIGNIFICANCE STATEMENT: This work provides evidence that in people with a history of recreational cannabis use, lenabasum was safe and well tolerated, although it did demonstrate abuse potential. This work supports further development of lenabasum for potential therapeutic indications.

Clinical Implications of the Relationship Between Naltrexone Plasma Levels and the Subjective Effects of Heroin in Humans.

Extended-release naltrexone (NTX) is an opioid antagonist approved for relapse prevention after medical withdrawal. Its therapeutic effect is dependent on the NTX plasma level, and as it decreases, patients may lack protection against relapse and overdose. Therefore, identifying the minimally effective NTX level needed to block opioid-induced subjective effects has important clinical implications. This secondary, individual-level analysis of data collected in a human laboratory study was conducted to evaluate the relationship between NTX levels and subjective effects of an intravenously administered 25-mg challenge dose of heroin in non-treatment-seeking participants with opioid use disorder (N = 12). Subjective ratings of drug liking using a 100-mm visual analog scale (VAS) and NTX levels were measured across 6 weeks after participants received a single injection of either extended-release NTX 192 mg (N = 6) or 384 mg (N = 6). Cubic spline mixed-effects models were used to provide 95% prediction intervals for individual changes in liking scores as a function of NTX levels. Naltrexone levels above 2 ng/mL blocked nearly all VAS ratings of drug liking after intravenous heroin administration. Participants with NTX levels ≥ 2 ng/mL had minimal (≤20 mm) changes from placebo in VAS ratings of drug liking based on 95% prediction intervals. In contrast, NTX levels < 2 ng/mL were associated with greater variability in individual-level subjective responses. In clinical practice, a plasma level range of 1 to 2 ng/mL is considered to be therapeutic in providing heroin blockade. The current findings suggest that a higher level (>2 ng/mL) may be needed to produce a consistent blockade.

Does childhood adversity alter opioid drug reward? A conceptual replication in outpatients before surgery

Introduction Opioid analgesic treatment during surgery entails the risk of persistent use. Experiences of childhood adversity have been shown to increase opioid reward in preclinical models, a finding recently extended to healthy humans. We tested whether childhood adversity similarly increased opioid reward, operationalized as drug-induced feeling good and drug liking, in outpatients receiving opioids on the operating table. Methods This observational study recruited patients entering a Norwegian hospital for an outpatient surgical procedure. An opioid intravenous opioid analgesic (remifentanil [Minto model, effect-site concentration: 5 ng/ml], or oxycodone [5 mg]) was administered in the minutes before general anesthesia. Verbal numerical ratings of feeling good and anxious were collected 1 min before, and 1–3 min after opioid infusion. Ratings of drug liking, disliking, and feeling high were also collected after infusion. Patients (n = 151) completed measures of childhood adversity at a later date. Results Regression analyses revealed a modest yet significant negative association between childhood adversity and post-opioid liking (b = −0.06, p = 0.046) but no significant effect on feeling good (b = 0.01, p = 0.690) after the pre-operative opioid dose. Exploratory analyses showed that more childhood adversity was significantly associated with higher reports of anxiety, depression, loneliness, and pain catastrophising, however not with alcohol or other drug use, or with any other subjective drug effects. Discussion Ratings of feeling good and drug liking of medically prescribed opioids given before surgery were not higher after childhood adversity, and previous findings were not conceptually replicated. The discrepancy between current and prior results may be due to the context and stress related to the impending surgery, the short duration of drug exposure, and the relatively limited levels of high childhood adversity in the current sample compared to the original study. Exploratory analysis was consistent with the possibility of a nonlinear relationship between positive opioid effects and childhood adversity scores. Future research should assess the link between childhood adversity, subjective effects, and use of the prescribed opioids after surgery.

A nasal abuse potential randomized clinical trial of REMOXY® ER, a high-viscosity extended-release oxycodone formulation.

This study examined the nasal abuse deterrence of REMOXY ER, a novel high-viscosity extended-release oxycodone formulation. An Institutional Review Board-approved, single-center, randomized, double-blind, placebo, and active-controlled, four-way crossover study of intranasal REMOXY ER gel, manipulated or intact, and ground oxycodone immediate-release (IR). An open label extension examined pharmacokinetics of OxyContin® ER in the first 20 subjects. Healthy, adult nondependent recreational opioid users with a history of intranasal abuse. Thirty-eight subjects enrolled; 36 completed. A clinical research in-patient unit. Cross-over arms included nasal self-administration of the entire contents of REMOXY ER 40 mg capsules (manipulated or intact), ground oxycodone IR 40 mg tablets, and placebo. The open-label arm was ground OxyContin ER. The primary endpoint was the maximum effect (Emax) of visual analog scale ratings of Drug Liking. Secondary endpoints included Take Drug Again (12 and 24 hours), Drug High Emax, area under effect curves through 12 hours, pupillometry, peak oxycodone concentrations (Cmax), time to maximum concentration (Tmax), and Abuse Quotient (Cmax/Tmax). Intranasal REMOXY ER (manipulated or intact) elicited lower Drug Liking and Drug High compared to ground oxycodone IR. Secondary endpoints also reflected reduced Abuse Potential. Intranasal REMOXY ER (manipulated or intact) led to fourfold lower Cmax, a 57 to 128 percent longer Tmax, a >10-fold lower Abuse Quotient and lower Take Drug Again scores compared to both OxyContin ER and oxycodone IR. In this study, REMOXY ER demonstrated significantly lower nasal abuse potential compared to oxycodone IR or OxyContin ER. Abuse-deterrent drugs are intended to help fight opioid abuse. Yet the persistence of the opioid epidemic indicates that vast improvements in abuse-deterrent technology are needed. A new, high-viscosity, extended-release oxycodone formulation showed robust abuse-deterrence against the nasal route of abuse in an Food and Drug Administration-advised clinical trial in recreational opioid users.

Relationship between rate of infusion and reinforcing strength of oxycodone in humans

The rate of drug delivery to the central nervous system is believed to be an important predictor of the reinforcing strength of a drug. However, only a few studies have directly examined the relationship between drug-taking behavior and rate of drug administration. The purpose of the present experiment was to determine whether manipulating the infusion rate of a fixed dose of opioid alters its reinforcing effectiveness in humans. Twelve heroin-dependent participants (11 male, one female) completed the 2.5-week inpatient study. During test days, participants received $20 and a dose of drug (0 or 40 mg oxycodone administered intravenously over 2, 15, 30, 60, or 90 minutes) in random order during a morning sample session. Participants then worked for the sampled dose and/or money amount during an afternoon choice session by making finger presses on a computer mouse. Under these conditions, 40 mg oxycodone served as a reinforcer only when it was delivered over 2 and 15 minutes. Subjective ratings of drug liking, good effect, and high were similar to the self-administration results. Peak plasma levels of oxycodone generally occurred at the end of each infusion, eg, 2 minutes for the 2-minute infusion duration. Extended-release opioid medications are commonly prescribed for treating pain. The present results provide empirical support for the development of extended-release opioid medications that are difficult to convert into more rapid-acting forms. Specifically, these "abuse-deterrent formulations" could prevent patients from tampering with their medications to enhance their euphoric and reinforcing effects.

Med Check

Back to table of contents Previous article Next article Clinical and Research NewsFull AccessMed CheckNick ZagorskiNick ZagorskiSearch for more papers by this authorPublished Online:31 Aug 2017https://doi.org/10.1176/appi.pn.2017.9a8Injectable Aripiprazole for Bipolar I Disorder The Food and Drug Administration (FDA) has approved Abilify Maintena—a once-monthly injectable formulation of the antipsychotic aripiprazole—for the maintenance of bipolar I disorder in adults. Abilify is manufactured by Otsuka and Lundbeck. This approval was based on a large, year-long phase 3 study in adults aged 18 to 65 with bipolar disorder I. Abilify Maintena significantly delayed time to recurrence of any mood episode during the study compared with placebo. The trial also found significant differences between treatment groups in delaying time to recurrence of both manic and mixed episodes but no substantial difference in depressive mood episodes.“Abilify Maintena provides health care professionals a new treatment option for their patients who have established tolerability with oral aripiprazole,” said Joseph Calabrese, M.D., director of the Mood Disorders Program at University Hospitals Cleveland Medical Center, in a press release from Otsuka. He added that concomitant oral antipsychotic medication must be administered for 14 days after the first injection.New Opioid Agent Cuts Pain Without Euphornia Nektar Therapeutics announced positive results from a Human Abuse Potential (HAP) study of its opioid analgesic NKTR-181—a mu-opioid agonist designed to provide potent pain relief without the euphoria that can lead to opioid abuse and addiction.The NKTR-181 HAP study evaluated the relative oral abuse potential of NKTR-181 at its maximum analgesic or therapeutic dose (400 mg) and at supratherapeutic doses (600 mg and 1,200 mg). The study found that NKTR-181 had significantly lower peak and average ratings of drug liking at 400 mg as well as the supratherapeutic dose of 600 mg compared with common therapeutic doses of oxycodone (40 mg or 60 mg). NKTR-181 1,200 mg had comparable drug liking to 60 mg of oxycodone.Nektar had previously completed a phase 3 efficacy trial in March 2017 demonstrating positive results in 610 opioid-naïve patients with moderate to severe chronic low back pain. That study also demonstrated a favorable safety and tolerability profile.The FDA has granted NKTR-181 a Fast Track designation for the treatment of moderate to severe chronic pain.Insomnia Medication Passes Phase 2 HurdleIdorsia’s experimental insomnia candidate ACT-541468 has met its primary endpoints in a pair of phase 2 trials, setting the stage for a phase 3 study of this dual orexin receptor antagonist (DORA).For the first study, researchers randomly assigned 360 adults aged 18 to 64 to one of three doses of ACT-541468 (5 mg/d, 10 mg/d, or 25 mg/d), zolpidem (10 mg/d), or placebo for four weeks. Participants taking ACT-541468 showed a significant dose-dependent decrease in wake time after sleep onset over zolpidem, with improvements being evident within two days. Participants in the ACT-541468 group also appeared to fall asleep faster. The treatment was generally well tolerated, and there were no reports of serious adverse events.In a separate study of 58 older patients aged 65 and older, ACT-541468 showed similar safety and efficacy.“The positive results of the phase 2 program demonstrate that our DORA can deliver on the potential its mechanism of action offers in insomnia,” Guy Braunstein, M.D., the head of Global Clinical Development at Idorsia, said in a press release. 23andMe Initiates Genetic Study of Depression, Bipolar DisorderThe genetic testing company 23andMe is partnering with the Milken Institute and Lundbeck on a new genetic study of major depressive disorder (MDD) and bipolar disorder (BD).This first-of-its-kind study aims to enroll 25,000 participants (15,000 with MDD and 10,000 with BD) to learn how genes and environment affect brain processes in people with these two conditions. The study will acquire data through genotyping, cognitive assessments, and participant survey responses.The study is open to individuals in the United States aged 18 to 50 who have a diagnosis of MDD or BD and been prescribed medication to treat their condition; they must also have a computer with Internet access. More details can be accessed here. ■ ISSUES NewArchived

Effects of Ibudilast on the Subjective, Reinforcing, and Analgesic Effects of Oxycodone in Recently Detoxified Adults with Opioid Dependence

Ibudilast, a nonselective phosphodiesterase inhibitor, is used clinically in Asia for the treatment of asthma and poststroke dizziness. Recent preclinical studies have suggested that it also inhibits glial cell activation in rodents, and may alter opioid-mediated effects, including analgesia and withdrawal symptoms. The effects of ibudilast on the abuse potential of opioids in humans are largely unknown. The present study was designed to examine the influence of ibudilast on subjective (including drug craving), reinforcing, and analgesic effects of oxycodone in human volunteers diagnosed with opioid dependence (equivalent to moderate-severe opioid use disorder). Non-treatment-seeking opioid-dependent male volunteers (n=11) underwent an in-patient detoxification with morphine, followed by maintenance on placebo (0 mg b.i.d.) and active ibudilast (50 mg b.i.d.). Under each maintenance dose, six experimental sample and choice sessions were completed involving oral oxycodone administration (0, 15, and 30 mg/70 kg, p.o.). Subjective effects of oxycodone and drug craving were measured with visual analog scales (VAS) and a Drug Effects Questionnaire. The cold pressor test was used to produce pain, and a modified progressive-ratio choice procedure was used to measure the reinforcing effects of oxycodone. Under the active ibudilast condition compared with the placebo condition, ratings of drug liking following 15 mg of oxycodone were decreased significantly. The mean drug breakpoint value was also significantly lower in the active vs the placebo ibudilast condition under the 15 mg oxycodone condition, but not significantly lower under the 30 mg oxycodone condition. Heroin craving was significantly reduced under active ibudilast vs placebo, and similar effects were observed for tobacco and cocaine craving. Furthermore, mean subjective ratings of pain were lower in the active ibudilast condition. Our data suggest that ibudilast may be useful for treating opioid use disorders and it may enhance the analgesic effects of oxycodone.

Intravenous abuse potential study of oxycodone alone or in combination with naltrexone in nondependent recreational opioid users

ABSTRACTBackground: ALO-02, comprising pellets of extended-release oxycodone surrounding sequestered naltrexone, is intended to deter abuse. Objective: Determine the abuse potential of intravenous oxycodone combined with naltrexone, which represents simulated crushed ALO-02 in solution, compared with intravenous oxycodone in nondependent, recreational opioid users. Methods: A randomized, double-blind, placebo-controlled, three-way crossover study with naloxone challenge, drug discrimination, and treatment phases. Intravenous treatments included oxycodone hydrochloride 20 mg, oxycodone hydrochloride 20 mg plus naltrexone hydrochloride 2.4 mg (simulated crushed ALO-02 20 mg/2.4 mg), or placebo (0.9% sodium chloride for injection). Primary end points were peak effects (Emax) and area under the effects curve within 2 h postdose (AUE0-2h) on drug liking and high visual analog scales. Results: Thirty-three participants were randomized into treatment phase, and 29 completed all treatments. Study validity was confirmed with statistically significant differences in Emax for drug liking and high (p < 0.0001) between intravenous oxycodone and placebo. Intravenous simulated crushed ALO-02 resulted in significantly lower scores than oxycodone on drug liking (Emax: 58.2 vs. 92.4; AUE0-2h: 104.3 vs. 152.4) and high (Emax: 17.2 vs. 93.1; AUE0-2h: 12.0 vs. 133.6), respectively (p < 0.0001, all comparisons). More participants experienced adverse events after intravenous oxycodone (n = 27 [90%]) versus intravenous simulated crushed ALO-02 (n = 4 [12.5%]) or placebo (n = 2 [6.5%]). Conclusion: Intravenous administration of simulated crushed ALO-02 resulted in significantly lower abuse potential, as assessed by subjective ratings of drug liking and high, than intravenous oxycodone in nondependent, recreational opioid users. This suggests that injection of ALO-02 may not be as desirable to recreational opioid users compared with oxycodone taken for nonmedical reasons.

Randomized, Double-Blind, Placebo-Controlled Study of the Abuse Potential of Different Formulations of Oral Oxycodone

The objective of this study was to evaluate the pharmacokinetics and abuse potential of different formulations of oxycodone. The participants completed an 8-day, placebo-controlled trial with four phases: naloxone challenge, double-blind drug discrimination, double-blind abuse liability, and discontinuation. Nineteen healthy, male, recreational drug abusers participated in this study. The participants were administered different doses and formulations of oxycodone (40 mg immediate release [IR], 40 mg controlled release [CR], crushed 40 mg CR, and 80 mg CR) to evaluate pharmacokinetic parameters and ratings of drug liking and high. Pharmacokinetic parameters were determined over a 12-hour dosing interval. The primary pharmacodynamic endpoints were two questions from the Drug Effects Questionnaire ("Do you like the drug?" and "How high are you now?"). Maximal plasma concentrations and area under the curve determinations were similar for 40 mg IR, crushed 40 mg CR, and 80 mg CR, which were all greater than 40 mg CR. For drug liking and high, the maximal effect and area under the effect curve were similar for the three formulations, which were all greater than 40 mg CR. The dose required to produce comparable reports of drug liking and high was approximately twofold greater for the CR vs IR formulation. When the 40 mg CR tablet was crushed, the pharmacokinetic and pharmacodynamic profile was similar to the 40 mg IR formulation. Adverse events were consistent with opioid administration. Intact, orally administered oxycodone CR produced less drug liking and high than IR oxycodone, and required approximately twofold greater doses to produce subjective effects comparable to IR oxycodone.

Subjective, psychomotor, and physiological effects of pregabalin alone and in combination with oxycodone in healthy volunteers

Pregabalin is an anticonvulsant drug indicated for neuropathic disorders and fibromyalgia. Some chronic pain patients suffering from these disorders take both this drug and an opioid for pain relief. Pregabalin is a scheduled drug under the Controlled Substances Act. The subjective effects of this drug have not been well-characterized, and the extent to which it alters the subjective effects of opioids has not been studied to the best of our knowledge. Using a double-blind, randomized, crossover design, 16 healthy volunteers were administered (in separate sessions) capsules containing placebo, 75mg pregabalin, 150mg pregabalin, 10mg oxycodone, and 75mg pregabalin combined with 10mg oxycodone. Subjective, psychomotor, and physiological measures were assessed during each of the five sessions. Pregabalin produced dose-related increases in some subjective effects and decreased respiration rate, but did not impact on psychomotor performance. Abuse liability-related subjective effects such as drug liking and desire to take the drug again were not increased by either pregabalin dose. Oxycodone produced increases in several subjective effects, including ratings of drug liking. When 75mg pregabalin was combined with oxycodone some subjective effects were altered relative to placebo, in contrast to when each drug was tested alone. Liking of oxycodone was not increased by 75mg pregabalin. However, recent studies have suggested that this drug is abused, and we would recommend that further psychopharmacological studies with pregabalin are warranted, including a study assessing its abuse liability across a range of doses in sedative abusers.

Psychopharmacological effects of oxycodone in volunteers with and without generalized anxiety disorder.

A number of studies have documented a relationship between anxiety disorders and opioid misuse and abuse, and there is some data to suggest that some people use opioids in an attempt to reduce their anxiety. We tested the hypothesis that volunteers with an anxiety disorder would report a more positive spectrum of subjective effects (i.e., greater ratings of drug liking and wanting to take the drug again) from oxycodone, a mu opioid agonist, than would volunteers without the disorder, and that oxycodone would have greater reinforcing efficacy in volunteers with the anxiety disorder. In addition to subjective and reinforcing effects, the psychomotor and physiological effects of oxycodone also were assessed. Individuals with generalized anxiety disorder (GAD, n = 8) and nonanxious controls (CTL, n = 8) were administered 0, 10, and 20 mg oxycodone (per os) in 3 separate sessions. Oxycodone produced a number of effects in a dose-related fashion in both groups. However, on several subjective effects measures, only CTL participants reported effects of oxycodone (e.g., high, lightheaded). Neither group had statistically significant increases in peak liking or "take drug again" ratings in the oxycodone conditions relative to the placebo condition, and in neither group did the drug function as a reinforcer, as measured by the Multiple-Choice Procedure (Griffiths, Troisi, Silverman, & Mumford, 1993). Anxiety ratings were low in the GAD group (in the absence of drug), and this may have lessened the possibility of detecting a more positive spectrum of oxycodone effects in this group than in the CTL group.

Response to alcohol in women: Role of the menstrual cycle and a family history of alcoholism

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 0.75g/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.

Stress-induced changes in mood and cortisol release predict mood effects of amphetamine

Background Stress is thought to contribute to both initiation and relapse to drug abuse. However, the mechanisms by which stress influences drug use are unclear. Interestingly, responses to acute administration of stimulant drugs resemble certain neuronal and hormonal responses to acute stress, and there is accumulating evidence that individual variation in the positive reinforcing or euphorigenic effects of a drug is related to individual differences in responsivity to acute stress. Methods In this study we evaluated relationships between physiological and subjective responses to a stressful task and to an oral dose of d-amphetamine in healthy adult volunteers ( N = 34). Individuals participated in four experimental sessions; two behavioral sessions involving a stressful task (i.e., public speech) or a non-stressful control task, and two drug sessions involving oral administration of d-amphetamine (20 mg) or a placebo. The dependent measures included salivary cortisol, heart rate, mean arterial pressure, and subjective ratings of mood. Results As expected, both stress and d-amphetamine increased cortisol, heart rate and blood pressure. Stress increased negative mood, whereas d-amphetamine induced prototypic stimulant effects and increased ratings of drug liking. Analyses revealed that increased negative mood states after stress were correlated with positive mood after amphetamine. In addition, increased cortisol after stress was correlated with positive mood responses to amphetamine. Finally, there were modest positive correlations between cortisol and heart rate increases after stress and mean arterial pressure after amphetamine. Conclusions These results support and extend previous observations that responses to acute stress are correlated with certain subjective, hormonal and cardiovascular effects of a stimulant drug.

Amphetamine-Induced Place Preference in Humans

The conditioned place preference procedure is a widely used animal model of rewarding drug effects that, to date, has not been tested in humans. In this study, we sought to demonstrate that humans, like nonhumans, would exhibit a preference for a place previously associated with amphetamine. Further, we investigated the relationship between conditioned place preference and the mood-altering effects of the drug. Thirty-one healthy individuals participated in a five-session procedure during which they experienced the effects of d-amphetamine (20 mg) or placebo on two occasions in two distinctive environments (sessions 1-4). One group of subjects (paired group, n = 19) received amphetamine consistently in one room and placebo in another room, whereas a second group (unpaired group, n = 12) received amphetamine and placebo without regard to room. During the sessions, participants completed questionnaires to rate their mood. On the fifth session, they rated their preference for the two rooms. Individuals in the paired group rated their liking of the amphetamine-paired room significantly higher than the placebo-associated room, whereas there was no difference between ratings of the two rooms for individuals in the unpaired group. In the paired group, drug-liking ratings during the conditioning sessions positively predicted preference for the drug-associated room, whereas reports of amphetamine-induced anxiety and dysphoria negatively predicted room-liking scores. This study demonstrates that humans, like nonhumans, prefer a place associated with amphetamine administration. These findings support the idea that subjective responses to a drug contribute to its ability to establish place conditioning.

A therapeutic dose of zolpidem has limited abuse-like effects in drug-naïve females: A pilot study

Zolpidem has abuse potential, particularly among individuals with histories of drug abuse. This double-blind, placebo-controlled, cross over pilot study investigated the subjective effects of zolpidem (10 mg) in drug-naïve females. Over the course of a 5-h period vital signs were monitored and a series of computerized questionnaires was administered. Results indicate that zolpidem engendered subjective effects characteristic of hypnotic drugs, but reduced ratings of drug liking, willing to take again, and willing to pay for, relative to placebo. Thus, a therapeutic dose of zolpidem may have limited potential for misuse among females who have no experience with drugs of abuse.

Self-Administration of Intravenous Nicotine in Male and Female Cigarette Smokers

Although nicotine is the main addictive chemical in tobacco, there have been few studies of pure nicotine self-administration in humans. The goal of this study was to test the parameters of an intravenous (IV) nicotine self-administration model using nicotine doses presumed to be within the range of those of average intake from cigarette smoking. Six male and four female smokers participated in a double-blind, placebo-controlled, crossover study, which consisted of one adaptation and three experimental sessions. In each experimental session, subjects were randomly assigned to one of the three doses of nicotine (0.1, 0.4, or 0.7 mg). The lowest nicotine dose, 0.1 mg, was chosen to be approximately half the amount of nicotine inhaled from one puff of a cigarette. During each experimental session, subjects first sampled the assigned nicotine dose and placebo and then had the opportunity to choose between nicotine and placebo for a total of six choices over a 90-min period. Out of six options, the average (SEM) number of nicotine choices were 3.0 (0.48) for 0.1 mg, 4.7 (0.48) for 0.4 mg and 4.5 (0.46) for 0.7 mg, indicating a significant effect of nicotine dose on nicotine choice. Both the 0.4 and 0.7, but not the 0.1 mg, nicotine doses were preferred to placebo. These higher doses also produced increases in heart rate, blood pressure, and ratings of drug liking and high. Overall, these findings indicate that smokers chose both the 0.4 and the 0.7 mg nicotine doses over placebo. Our model may be useful in the evaluation of the effects of both behavioral and pharmacological manipulations on nicotine self-administration in humans.

An abuse liability comparison of flunitrazepam and triazolam in sedative drug abusers

The present double-blind, placebo-controlled study compared the acute effects of oral administration of the benzodiazepine hypnotics flunitrazepam (6 mg/70 kg) and triazolam (1 and 2 mg/70 kg) on measures relevant to abuse liability as well as on psychomotor performance and observer- and participant-rated measures of drug effects in nine sedative drug abusers. Analysis of participant-rated measures collected 24 h after drug administration (next-day; assessing the overall effects of the drug received 24 h earlier) indicated that flunitrazepam, but neither triazolam dose, produced significant increases relative to placebo in next-day ratings of drug liking, the amount of money the drug would be worth on the street, and the amount of money the participant would be willing to pay for the drug on the street. Importantly, these abuse liability differences between flunitrazepam and triazolam were present at a dose of flunitrazepam (6 mg/70 kg) that produced overall drug effects that were comparable to, or significantly less than, those of a high triazolam dose (2 mg/70 kg). Consistent with results of a previous study in our laboratory, these results suggest that flunitrazepam may have a greater abuse liability than triazolam, and that this abuse liability difference emerges on measures taken 24 h after drug administration but not on same-day measures.

Profiling the subjective, psychomotor, and physiological effects of tramadol in recreational drug users

Tramadol is a mu opioid agonist that also inhibits the reuptake of norepinephrine and serotonin. Because non-medical use of prescription opioids, including tramadol, has increased in the U.S. over the last several years, we sought to profile its subjective, psychomotor, and physiological effects in recreational drug users. Twenty-two subjects received placebo, 50 or 100 mg tramadol, morphine, or 2 mg lorazepam in a randomized, crossover, double-blind design. The last 12 subjects in the study received 25 mg morphine, a dose that is putatively equianalgesic to 100 mg tramadol. In these subjects, morphine induced miosis and several other mu agonist subjective effects; 100 mg tramadol increased “feel drug effect” and drug liking ratings, and decreased pupil size, but the miotic effect was not statistically significant. Lorazepam, but neither tramadol nor morphine, impaired psychomotor performance. When the placebo, tramadol, and lorazepam data from all 22 subjects were analyzed, 100 mg tramadol induced miosis, and several subjective effects were increased significantly, including ratings of drug liking and “want to take again.” The present results indicating that a clinically-prescribed dose of oral tramadol has abuse liability-related effects in recreational drug users suggest the need for further abuse liability testing of the oral formulation in opioid abusers.

Reinforcing and subjective effects of the volatile anesthetic, sevoflurane

Sevoflurane is a volatile anesthetic that is chemically similar to volatile substances of abuse and can be safely administered to humans in laboratory research. In this study, the reinforcing and subjective effects of five concentrations of sevoflurane (0, 0.2, 0.4, 0.6, 0.8% sevoflurane in O 2) were studied in 20 non-drug-abusers. During each of five sessions, subjects sampled a concentration of sevoflurane and 100% O 2 (placebo) for 10 min each. Later, within the session, they chose nine times, once every 5 min, among sevoflurane (e.g. “Agent A”), placebo (e.g. “Agent B”), or neither (and were administered 100% O 2, identified as “drug-free air”). Although “neither” was selected most frequently, mean preference ratios (sevoflurane choices/[sevoflurane choices + placebo choices]) and total sevoflurane choice peaked at the 0.4% concentration. Choice patterns varied across subjects, with some subjects never choosing sevoflurane and other subjects showing monotonic increasing or bitonic concentration–choice functions. Concentration-related increases in subjective effects were observed, including effects that are putatively associated with abuse liability. Ratings of drug liking and of wanting to inhale the drug again were positively correlated with sevoflurane choice. This study shows that sevoflurane can function as a reinforcer and produce abuse liability-related subjective effects in some healthy volunteers.

Differential response to alcohol in light and moderate female social drinkers

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