CORK Bibliography: Abuse Potential/TITLE> <LINK REL=stylesheet type="text/css" href="http://www.projectcork.org/style.css">  </HEAD> <BODY> <TABLE Width=100% Border=0 bgcolor=white align=center cellspacing=0> <TR> <TD width=15% COLSPAN=2><IMG SRC="http://www.projectcork.org/graphics/project_cork_large.gif" width="315" height="75"> <TD width=*> </TR> <TR bgcolor=#808080> <TD COLSPAN=2> <B> <FONT face=arial color=white size=-2> Serving Substance Abuse Professionals Since 1993 </FONT> </B> <TD align="right"> <B> <font color="white" size="-2" face="arial">Last Update: 26.09.07 </font></B> </TR> <TR> <TD align=top valign="top"> <TABLE Border=0 Width=100% Height=100% Align=top bgcolor=white> <BR> <TR> <TD align=top> <HR NOSHADE SIZE=1 width=55%></TR> <TR> <TD bgcolor= #E3E3E3> <FONT color=white face=arial size=-1> <B> C O R K O N L I N E </B></FONT> </TR> <TR> <TD ALIGN=LEFT VALIGN=TOP WIDTH=10> <A CLASS="small" HREF ="http://www.projectcork.org/powerpoint_presentations/index.html">powerpoint presentations</A><BR> <A CLASS="small" HREF = "http://www.projectcork.org/database_search/index.html">CORK database search</A><BR> <A CLASS="small" HREF = "http://www.projectcork.org/resource_materials/index.html">resource materials</A><BR> <A CLASS="small" HREF = "http://www.projectcork.org/bibliographies/index.html">bibliographies</A><BR> <A CLASS="small" HREF = "http://www.projectcork.org/clinical_tools/index.html">clinical tools</A><BR> <A CLASS="small" HREF = "http://www.projectcork.org/user_services/index.html">user services</A><BR> <A CLASS="small" HREF = "http://www.projectcork.org/newsletters/index.html">newsletters</A><BR> <A CLASS="small" HREF = "http://www.projectcork.org/about_cork/index.html">about cork</A><BR> <A CLASS="small" HREF = "http://www.projectcork.org/index.html">home</A><BR> </TR> </TABLE> <TD width=70%> <BR> <TABLE Border=0 bgcolor=white cellpadding=5 align=top width=100% height=100%> <td> <TABLE Border=0 bgcolor=#0F2480 cellspacing=1 cellpadding=0 align=top width=100% height=100%> <TR> <TD> <TABLE Border=0 Width=100% Height=100% Align=top bgcolor=white cellpadding=3> <TR align=top> <TD> <BR> <CENTER> <H1 CLASS="small">CORK Bibliography: Abuse Potential</H1></Center> <BR> <P><HR></P> <H2 CLASS="small" ALIGN=RIGHT> 112 citations. January 2003 to present</H2> <H2 CLASS="small" ALIGN=RIGHT>Prepared: September 2008</H2> <BR><BR> <H3>Abanades S; Farre M; Barral D; Torrens M; Closas N; Langohr K et al. Relative abuse liability of gamma-hydroxybutyric acid, flunitrazepam, and ethanol in club drug users. <I Class="H3">Journal of Clinical Psychopharmacology</I> 27(6): 625-638, 2007. (62 refs.)</H3>Objectives: Despite the increasing concern about gamma-hydroxybutyric acid (GHB) toxicity, there are few studies examining the clinical pharmacology of GHB and its abuse potential. To evaluate GHB-induced subjective and physiological effects, its relative abuse liability and its impact on psychomotor performance in club drug users. Materials and Methods: Twelve healthy male recreational users of GHB participated in 5 experimental sessions in the framework of a clinical trial. The study was randomized, double-blind, double-dummy, and crossover. Drug conditions were a single oral dose of GHB (40 or 60 mg/kg), ethanol (0.7 g/kg), flunitrazepam (1.25 mg), and placebo. Study variables included vital signs (blood pressure, heart rate, oral temperature, pupil diameter), psychomotor performance (digit symbol substitution test, balance, Maddox-Wing), subjective effects (a set of 13 visual analogue scales, Addiction Research Center Inventory-49 items, and Evaluation of the Subjective Effects of Substanceances with Potential of Abuse questionnaires), and pharmacokinetics. Results: All active conditions induced positive effects related to their abuse potential. The administration of GHB produced euphoria and pleasurable effects with slightly higher ratings than those observed for flunitrazepam and ethanol. gamma-Hydroxybutyric acid induced a biphasic time profile with an initial stimulantlike effect related to the simultaneous rise of plasma concentrations and a latter sedative effect not related to GHB kinetics. gamma-Hydroxybutyric acid increased blood pressure and pupil diameter. Ethanol induced its prototypical effects, and flunitrazepam produced marked sedation. gamma-Hydroxybutyric acid and flunitrazepam impaired psychomotor performance, digit symbol substitution test, and balance task, whereas ethanol, at the dose tested, induced only mild effects exclusively affecting the balance task. Conclusions: Our results suggest a high abuse liability of GHB and flunitrazepam in club drug users. <P CLASS="SMALL">Copyright 2007, Lippincott, Williams & Wilkins</P><BR> <H3>Abanades S; Farre M; Segura M; Pichini S; Barral D; Pacifici R et al. gamma-Hydroxybutyrate (GHB) in humans - Pharmacodynamics and pharmacokinetics. <I Class="H3">Annals of the New York Academy of Sciences. Cellular and molecular mechanisms of drugs of abuse and neurotoxicity.</I> 1074: 559-576, 2006. (40 refs.)</H3>Despite gamma-hydroxybutyrate (GHB) therapeutic uses and the increasing concern about its toxicity, few studies have addressed GHB dose-related effects under controlled administration and their relationship with its pharmacokinetics. The study design was double-blind, randomized, crossover, and controlled. As a pilot pharmacology phase I study, increasing doses of GHB were given. Single oral sodium GHB doses (40, 50, 60, and 72 mg/kg) were administered to eight volunteers. Plasma and urine were analyzed for GHB by gas chromatography-mass spectrometry. Physiological effects, psychomotor performance, and subjective effects were examined simultaneously. GHB produced dose-related changes in subjective effects as measured by questionnaires and VAS. GHB showed a mixed stimulant-sedative pattern, with initially increased scores in subjective feeling of euphoria, high, and liking followed by mild-moderate symptoms of sedation with impairment of performance and balance. Mean peak GHB plasma concentrations were 79.1, 83.1, 113.5, and 130.1 mu g/L for 40, 50, 60, and 72 mg/kg, respectively. GHB-mediated physiological and subjective effects were dose dependent and related to GHB plasma concentrations. GHB urinary excretion was mainly related to administered doses. GHB-mediated subjective and physiological effects seem dose dependent and related to GHB plasma concentrations. Results suggest a high abuse liability of GHB in the range of dose usually consumed. <P CLASS="SMALL">Copyright 2006, New York Academy of Sciences</P><BR> <H3>Adams EH; Breiner S; Cicero TJ; Geller A; Inciardi JA; Schnoll SH et al. A comparison of the abuse liability of tramadol, NSAIDs, and hydrocodone in patients with chronic pain. <I Class="H3">Journal of Pain and Symptom Management</I> 31(5): 465-476, 2006. (57 refs.)</H3>Concern about abuse/dependence in, chronic pain patients taking opioid analgesics may lead to undertreatment of pain, yet little is known about the prevalence of abuse/dependence in these patients and how it differs among analgesic regents. The objective of this study was to assess the prevalence of tramadol abuse compared to nonsteroidal anti-inflammatory drags (NSAIDs) and hydrocodone-containing analgesics in patients with chronic noncancer pain (CNP). The study had three arms. The first arm consisted of subjects prescribed tramadol alone; the second of subjects randomized to either NSAIDs or tramadol; and the third of subjects randomized to hydrocodone or tramadol. Each, investigator received two boxes of prescriptions randomized so that one in every four prescriptions was for tramadol. Upon deciding on the therapeutically appropriate arm, the physician. selected the appropriate box, opened the next envelope and completed the enclosed prescription. After the initial randomization, physicians could prescribe whatever predication. zoos therapeutically appropriate. A total of 11,352 subjects were enrolled. Up to nine interviews using a structured questionnaire were conducted over a 12-month period. An algorithm called the "Abuse Index" zoos developed to identify subjects who were abusing the drug. The primary components of the index were increasing dose without physician, approval, use for purposes other than. intended, inability to stop its use, and withdrawal. The percent of subjects who scored positive for abuse at least once during the 12-month follow-up were 2.5% for NSAIDs, 2.7% for tramadol, and 4.9% for hydrocodone. When more than one hit on the algorithm eras used as a measure of persistence, abuse rates were 0.5% for NSAIDs, 0.7% for tramadol, and 1.2% for hydrocodone. Thus, the results of this study suggest that the prevalence of abuse/dependence over a 12-month period in a chronic noncancer pain population that was primarily female was equivalent for tramadol and NSAIDs, with both significantly less than the rate for hydrocodone. <P CLASS="SMALL">Copyright 2006, U.S. Cancer Pain Relief Committee</P><BR> <H3>Anthierens S; Habraken H; Petrovic M; Christiaens T. The lesser evil? Initiating a benzodiazepine prescription in general practice. <I Class="H3">Scandinavian Journal of Primary Health Care</I> 25(4): 214-219, 2007. (38 refs.)</H3>Objective. Chronic benzodiazepine (BZD) use is widespread and linked with adverse effects. There is consensus concerning the importance of initiating BZD as a crucial moment. Nevertheless specific research in this field is lacking. This paper addresses the views of GPs on why they start prescribing BZDs to first-time users. Design. Qualitative study with five focus groups analysed using a systematic content analysis. Setting. Regions of Ghent and Brussels in Belgium. Subjects. A total of 35 general practitioners. Main outcome measure. The GPs' perspective on their initiating of BZD prescribing. Results. GPs reported that they are cautious in initiating BZD usage. At the same time, GPs feel overwhelmed by the psychosocial problems of their patients. They show empathy by prescribing. They feel in certain situations there are no other solutions and they experience BZDs as the lesser evil. They admit to resorting to BZDs because of time restraint and lack of alternatives. GPs do not perceive the addictive nature of BZD consumption as a problem with first-time users. GPs do not specifically mention patients' demand as an element for starting. Conclusion. The main concern of GPs is to help the patient. GPs should be aware of the addictive nature of BZD even in low doses and a non-pharmacological approach should be seen as the best first approach. If GPs decide to prescribe a BZD they should make plain to the patient that the medication is only a "temporary" solution with clear agreements with regard to medication withdrawal. <P CLASS="SMALL">Copyright 2007, Taylor & Francis</P><BR> <H3>Arfken CL; Cicero TJ. Postmarketing surveillance for drug abuse. <I Class="H3">Drug and Alcohol Dependence</I> 70(3 Supplement 1): S97-S105, 2003. (25 refs.)</H3>Assessing actual abuse of prescribed medications requires post-marketing surveillance. In this article we discuss general systems of postmarketing surveillance that exist as of the end of 2002 in the United States and two medication-specific surveillance systems that were devised and tested. The two specific surveillance systems are compared with limitations highlighted. Postmarketing surveillance is in its infancy and requires more research on ways to improve its validity without inducing illicit experimentation. Information on comparator medications is highly recommended both to validate the system and to place the results in context. <P CLASS="SMALL">Copyright 2003, Elsevier Science</P><BR> <H3>Arfken CL; Schuster CR; Johanson C-E. Postmarketing surveillance of abuse liability of sibutramine. <I Class="H3">Drug and Alcohol Dependence</I> 169(2): 169-173, 2003. (11 refs.)</H3>The abuse liability of medications is a growing concern as the number of newly approved psychoactive medications increases. Postmarketing surveillance can assist in determining abuse liability, but strategies are not well-defined for medications believed to be at low abuse risk. Using a newly approved medication (sibutramine--an anorectic drug), a novel approach to postmarketing abuse surveillance was introduced. A one-page anonymous questionnaire covering sibutramine, a scheduled anorectic drug (phentermine), and a fabricated name was added to the intake process of 58 treatment programs. From the 8780 completed questionnaires, 8.8% had heard of sibutramine and phentermine. For continued use to get high (a proxy for abuse), the rate for sibutramine was lower than for phentermine (0.6 vs. 2.2%, McNemar's small chi, Greek2=110.45, P<0.001) but was higher than for the fabricated name (0.6 vs. 0.3%, McNemar's small chi, Greek2=11.86, P<0.001). These results suggest the risk of abuse associated with sibutramine was lower than that associated with a known abused drug, one that itself is considered low risk despite decades of population exposure. The relatively high rate of hearing of sibutramine may be due to the direct-to-consumer advertisement. This approach is only one indicator in a surveillance framework but appears promising and validates findings from laboratory-based abuse liability studies that also indicate low abuse liability for sibutramine. <P CLASS="SMALL">Copyright 2003, Elsevier Science Ltd</P><BR> <H3>Ator NA; Griffiths RR. Principles of drug abuse liability assessment in laboratory animals. <I Class="H3">Drug and Alcohol Dependence</I> 70(3 Supplement 1): S55-S72, 2003. (125 refs.)</H3>This paper describes the rationale for use of preclinical assessments of abuse liability in laboratory animals, and then discusses `cross-cutting' methodological issues that apply to behavioral evaluations intended to contribute to an abuse liability evaluation package. Issues include use of: (1) positive and negative control conditions; (2) full dose-effect evaluations, (3) multiple dependent measures, (4) pharmacokinetic evaluations to guide choice of dose ranges, (5) a species for which good methodological and comparative data are available to aid interpretation of results, and (6) appropriate methods for the group or single-subject experimental design selected. The remainder of the paper describes basic methodology by which three core pieces of behavioral data required by the Food and Drug Administration for its use in the overall abuse liability analysis can be obtained preclinically. Reinforcing effects are assessed in study of drug self-administration; drug discrimination assesses degree of overlap of interoceptive stimulus effects with relevant comparison drugs; physical dependence potential is determined by assessing whether a withdrawal syndrome occurs after chronic drug administration. Background and methodological issues specific to each procedure are discussed. A key consideration for cross-cutting and specific methodological issues is that choices made enable confident interpretation of both positive and negative results. <P CLASS="SMALL">Copyright 2003, Elsevier Science</P><BR> <H3>Bailey JE; Barton PL; Lezotte D; Lowenstein SR; Dart RC. The effect of FDA approval of a generic competitor to OxyContin((R)) (oxycodone HCl controlled-release) tablets on the abuse of oxycodone. <I Class="H3">Drug and Alcohol Dependence</I> 84(2): 182-187, 2006. (21 refs.)</H3>Controversy exists concerning whether abuse of oxycodone will increase after the introduction of generic controlled-release (CR) oxycodone. We evaluated the effect of FDA approval of generic CR oxycodone on the misuse/abuse of oxycodone, hydrocodone, methadone and morphine utilizing data from eight poison control centers (PCC). PCC intentional exposure (IE) reason codes were used as measures of abuse. Opioid-specific quarterly IE rates (per 100,000 population and per 10,000 patients) were calculated for 1 year before and after approval (March 24, 2004). Changes in regression slopes (1 year before to 1 year after) and in IE rates (1 quarter before to 1 quarter after) were analyzed using Poisson regression. The regression slopes for oxycodone, methadone and morphine did not change after approval but decreased significantly for hydrocodone. None of the prescription opioids' IE rates significantly increased after approval. When changes in oxycodone's IE rates were compared to the other opioids, no statistically significant differences were found, indicating a lack of time-opioid interaction. These results did not vary when population rates or patient rates were used. PCC data indicate that approval of generic CR oxycodone was not followed by an immediate unfavorable effect on the misuse/abuse of oxycodone. <P CLASS="SMALL">Copyright 2006, Elsevier Science</P><BR> <H3>Bain JN; Prendergast MA; Terry AV; Arneric SP; Smith MA; Buccafusco JJ. Enhanced attention in rhesus monkeys as a common factor for the cognitive effects of drugs with abuse potential. <I Class="H3">Psychopharmacology</I> 169(2): 150-160, 2003. (41 refs.)</H3>Rationale. One of the common neurochemical features of many drugs of abuse is their ability to directly or indirectly enhance dopaminergic activity in the brain, particularly within the ventral tegmental-nucleus accumbens pathway. Dopaminergic pathways in the frontal and limbic cortex also may be targets for these agents, where pharmacological effects could result in heightened attention and/or support self-administration behavior. Objectives. The purpose of this study was to determine whether drugs from differing pharmacological classes that exhibit abuse potential would share the ability to counter distractability in the delayed matching task. Methods. Well trained mature macaques performed a computer-assisted delayed matching-to-sample task which included trials associated with three delay intervals and randomly interspersed task-relevant distractors. Drug regimens included four to five doses and subjects were tested no more than twice per week. Results. All but one of the six compounds (tomoxetine), on average, increased task accuracy for either non-distractor or distractor trials. It was evident that for several compounds, doses required to improve accuracy for non-distractor trials were routinely greater than the doses required to improve accuracy for distractor trials. Data for the individualized Best dose (based upon the subject's optimal level of accuracy during distractor trials) revealed statistically significant distractor-related improvements in task accuracy for the same five compounds. The relative efficacy for reversing distractor-induced decrements in task accuracy was estimated by the level of improvement with respect to baseline: nomifensine (31%)>nicotine (22%)approximate tomorphine (19%)approximate tocaffeine (19%)approximate tomethylphenidate (22%) >tomoxetine (9%). Tomoxetine (noradrenergic preferring) was the only compound that did not produce a significant improvement in accuracy. Conclusions. These results provide pharmacological support for the concept that attentional mechanisms may play an important role in the 'environmental' associative aspects of drug seeking behavior, and as such they may provide the basis for treatment strategies aimed at preventing relapse in detoxified addicts. <P CLASS="SMALL">Copyright 2003, Springer-Verlag</P><BR> <H3>Balster RL; Bigelow GE. Guidelines and methodological reviews concerning drug abuse liability assessment. <I Class="H3">Drug and Alcohol Dependence</I> 70(3 Supplement 1): S13-S40, 2003. (136 refs.)</H3>Regulatory control of drugs with abuse liability is an important component of drug control policy and is believed to help prevent nonmedical use. To be maximally effective, this requires a scientific assessment of abuse liability of drugs considered for regulatory control. These assessments have relied extensively on laboratory-based animal and human testing, but also utilize information from clinical trials, actual abuse and other sources. Here, we discuss recommendations and guidelines that have been proposed for abuse liability assessment and describe important review papers and conference proceedings that have addressed this matter, focusing primarily on drugs with medical usefulness. Historically, there is substantial consensus about how to approach abuse liability evaluation of drugs with actions similar to those of abused opiates, stimulants, depressants, and to a somewhat lesser extent, cannabinoids and hallucinogens, and much of what has been recommended for abuse potential assessment in the past remains valid and useful. On the other hand, novel CNS-active medications which cannot be readily classified with these traditional drugs of abuse are increasingly under development. In addition, advances in the science of abuse liability assessment need to be incorporated into future guidelines and recommendations on this subject. Developers of new medications need guidance on how to utilize scientific research to maximize therapeutic benefit while minimizing risk for abuse. Thus, another goal of this review has been to identify areas where critical thinking and new guideline development are needed <P CLASS="SMALL">Copyright 2003, Elsevier Science</P><BR> <H3>Barbera J; Shaprio C. Benefit-risk assessment of zaleplon in the treatment of insomnia. <I Class="H3">Drug Safety</I> 28(4): 301-318, 2005. (67 refs.)</H3>Insomnia is a heterogeneous, highly prevalent condition that is associated with a high level of psychiatric, physical, social and economic morbidity. The treatment of insomnia involves pharmacological and non-pharmacological interventions. The mainstay of pharmacological treatment of insomnia has been the benzodiazepines, the introduction of which represented a significant improvement over the barbiturates and chloral hydrate. Although benzodiazepines have been shown to be efficacious in treating insomnia, they have also been associated with a number of adverse effects including tolerance, dependence, withdrawal and abuse potential, impairment in daytime cognitive and psychomotor performance (including an increased risk of accidents and falls), adverse effects on respiration and the disruption of normal sleep architecture with reduction in both slow wave sleep and rapid eye movement. In the last decade, the treatment of insomnia has been supplemented by the introduction of a number of non-benzodiazepine hypnotics including zolpidem, zopiclone and, most recently, zaleplon. Zaleplon possesses a unique pharmacological profile, with an ultra-short half-life of about 1 hour, and selective binding to the BZ(1)(omega(1)) receptor subtypes of the GABA(A) receptor. This unique pharmacological profile predicts a number of pharmacodynamic properties that account for a unique benefit-risk profile. Consistent with these predictions, zaleplon has been shown in a number of studies to be efficacious in promoting sleep initiation, but less so in promoting sleep maintenance. The adverse effects associated with zaleplon have been shown to be more rapidly resolved and/or lesser in magnitude than those associated with benzodiazepines (including triazolam) and the longer acting non-benzodiazepine hypnotics (zolpidem and zopiclone). This improved risk profile includes: the effects of zaleplon on psychomotor and cognitive performance; tolerance, withdrawal and rebound; respiratory depression; sleep architecture; and other treatment-emergent adverse effects. The unique benefit-risk profile of this agent may be particularly suitable for certain patients with insomnia and provides yet another option in the management of this impairing condition. <P CLASS="SMALL">Copyright 2005, Adis International</P><BR> <H3>Baruch E; Vernon LF; Hasbun RJ. Intractable nausea caused by Zolpidem withdrawal: A case report. <I Class="H3">Journal of Addiction Medicine</I> 1(1): 48-50, 2007. (27 refs.)</H3>First launched in France in 1988, zolpidem (Ambien(R)) is a short-acting hypnotic agent. Early studies reported that that the development of physical dependence and tolerance to sedative-hypnotic drugs, such as the depressant and anticonvulsant effects evidenced with benzodiazepines, is not found with zolpidem. Direct to consumer advertising by the manufacturer continues to state that the risk for dependency is low; however, recent publications seem to contradict this. Additionally, adverse drug reactions affecting the central nervous system, gastrointestinal tract, and respiratory system have been reported. Other studies have examined the interactions of selective serotonin reuptake inhibitors and zolpidem as a possible cause of hallucinations. With continued physician marketing efforts touting the safety and efficacy of zolpidem, there is a high likelihood to overlook the risk of dependency and the symptoms related to zolpidem withdrawal. We report a case of a 41-year-old female who developed a dependency to zolpidem, who on her own decided to decrease her dosage, resulting in intractable nausea requiring hospitalization. Reported cases of zolpidem withdrawal have occurred with doses in excess of 160 mg per day, none of these have reported with intractable nausea as the sole symptom. In our reported case, although exceeding recommended dosage withdrawal phenomenon seemed to be severe after withdrawal from a comparatively low dose of zolpidem. Before zolpidem is prescribed, patient education should include warnings about the potential problems associated with dependency and abrupt discontinuation. Education about this common and likely underrecognized clinical phenomenon will help prevent future episodes and minimize the risk of misdiagnosis. <P CLASS="SMALL">Copyright 2007, American Society of Addiction Medicine</P><BR> <H3>Bergman J; Paronis CA. Measuring the reinforcing strength of abused drugs. (review). <I Class="H3">Molecular Interventions</I> 6(5): 273-+, 2006. (65 refs.)</H3>The abuse liability of a drug is closely related to its ability to maintain self-administration behavior in laboratory subjects. But how do researchers gauge the reinforcing value of a self-administered drug in the preclinical laboratory? One approach is to determine the "preference" for that drug, that is, the allocation of behavior to drug taking, when alternative reinforcers are concurrently available. Careful analyses of such "choice" behavior in laboratory subjects can lead to a scientific understanding of the pharmacological and behavioral determinants of the reinforcing strength of a drug and, ultimately, to a more useful preclinical evaluation of abuse liability. <P CLASS="SMALL">Copyright 2006, American Society for Pharmacology and Experimental Therapeutics</P><BR> <H3>Bobo WV; Miller SC; Martin BD. The abuse liability of dextromethorphan among adolescents: A review. (review). <I Class="H3">Journal of Child & Adolescent Substance Abuse</I> 14(4): 55-75, 2005. (108 refs.)</H3>Dextromethorphan (DM) is a popular over-the-counter antitussive medication. Although adverse effects from appropriate use are rare, a specific toxidrome with significant psychomimetic effects occurs with ingestions in excess of those recommended. Both DM and its active metabolite, dextrorphan (DOR), share pharmacologic and neurobehavioral properties similar to opiates and phencyclidine (PCP). As Such, cases of recreational DM abuse and, rarely, dependence, have been reported, and some data Suggest that Such abuse is on the rise. DM may be considered by substance abusers, especially adolescents, to be a dissociative agent devoid of financial concerns, legal limitations, negative stigma, problems with access or adverse health consequences. However, DM's popularity among adolescent substance abusers is generally not matched by adequate health care provider awareness, pharmacological understanding or epidemiological characterization. In this review, we summarize the current understanding of DM's addiction medicine-based neuropharmacology and epidemiology, describe social characteristics more unique to DM as in agent of abuse, review treatment and prevention issues, and identify areas in need of further research. <P CLASS="SMALL">Copyright 2005, Haworth Press, Inc.</P><BR> <H3>Brady KT; Lydiard RB; Brady JV. Assessing abuse liability in clinical trials. <I Class="H3">Drug and Alcohol Dependence</I> 70(3 Supplement 1): S87-S95, 2003. (18 refs.)</H3>In this article, the use of data collected in registration-focused clinical trials to provide information concerning abuse liability of compounds under development is discussed. Registration-focused trials are limited by the small and select sample chosen for study participation and design constraints. However, most compounds under development are first administered to humans during the conduct of registration-focused trials, so this presents an opportunity to collect potentially important information about the effects of drugs in humans. At present, information concerning subjective effects and symptoms associated with drug discontinuation are not collected systematically. Reports are generally considered as adverse events (AEs) and are recorded on the case report forms (CRFs) in the investigators own language. There is generally no rating of drug "liking". The authors suggest strategies that could be implemented in registration-focused clinical trials to improve the information gathered with regard to subjective effects, abuse liability and discontinuation-emergent symptoms. Importantly, there remains much groundwork to be done in developing and validating appropriate assessment instruments and determining "threshold" levels for concern. Under the best of circumstances, registration-focused clinical trials have limited potential to detect abuse liability because of the small number of patients seen and the exclusion of many subjects who might be particularly vulnerable to the abuse of marketed compounds (i.e. individuals with substance use disorders). In cases where there are reasons to suspect that a drug under development has abuse potential, systematic exploration with a series of studies specifically designed to assess abuse potential must be conducted. <P CLASS="SMALL">Copyright 2003, Elsevier Science</P><BR> <H3>Bramness JG; Furu K; Engeland A; Skurtveit S. Carisoprodol use and abuse in Norway. A pharmacoepidemiological study. <I Class="H3">British Journal of Clinical Pharmacology</I> 64(2): 210-218, 2007. (34 refs.)</H3>What is already known about this subject: Carisoprodol was developed to create a drug with less abuse potential than meprobamate. Case reports have established carisoprodol as a drug of abuse, but no systematic studies have been published about the extent of abuse. What this study adds: A large number of patients used more carisoprodol than recommended. High use of carisoprodol was associated with high use of benzodiazepines and opiates. Compared with other medicinal drugs, carisoprodol showed many prescription database signals of being a potential drug of abuse. Carisoprodol was developed to create a drug with less potential for abuse than meprobamate. However, case reports have established carisoprodol as a drug of abuse. This paper explores the extent of potential abuse of this drug in Norway. The Norwegian Prescription Database contains information on prescription drugs dispensed to individuals in Norway. Patients can be followed over time. High levels of carisoprodol use could indicate use for pleasurable effects or development of tolerance. Concomitant use of other potential drugs of abuse was also studied. We studied drug-seeking behaviour by looking at patients who received carisoprodol from many different pharmacies and doctors or from high-prescribing doctors. Carisoprodol was compared with a series of other medicinal drugs with or without known potential for abuse. Some 53 889 Norwegian women (2.4%) and 29 824 men (1.3%) >= 18 years old received carisoprodol at least once in 2004. Prescribing of carisoprodol was skewed. As many as 32% of the patients received more than 15 defined daily doses (DDDs) of carisoprodol and > 11 000 patients (15%) received >= 75 DDDs in 2004. High users of carisoprodol also received more benzodiazepines and opioids. Few patients used three or more doctors for prescriptions, but carisoprodol-abusing patients more often received their prescription from high-prescribing doctors. Carisoprodol was widely used and the skewedness in use indicated that it is a potential drug of abuse. A large number of patients used more carisoprodol than recommended in the guidelines. The high level of use and abuse of carisoprodol should be of concern in Norway. <P CLASS="SMALL">Copyright 2007, Blackwell Publishing</P><BR> <H3>Butler S; Benoit C; Budman S; Fernandez K; McCormick C et al. Development and validation of an Opioid Attractiveness Scale: A novel measure of the attractiveness of opioid products to potential abusers. <I Class="H3">Harm Reduction Journal</I> 3(article 5), 2006. (23 refs.)</H3>BACKGROUND: Assessment of the abuse liability of prescription opioid products and growing efforts by the pharmaceutical industry to develop 'abuse-resistant' formulations highlight a need to understand the features that make one product more 'attractive' than another to potential abusers. We developed a scale to measure the 'attractiveness' of prescription opioids to potential abusers, and used the scale to measure the relative attractiveness of 14 opioid analgesic products. METHODS: First, the concept of attractiveness was empirically defined with a group of prescription opioid abusers and experts in opioid abuse using a process called Concept Mapping. Abuse liability consisted of two components: factors intrinsic to the drug formulation (e.g., speed of onset, duration) and factors extrinsic to drug formulation (e.g., availability, availability of alternatives, cost). A 17-item Opioid Attractiveness Scale (OAS) was constructed, focusing on factors intrinsic to the drug product. RESULTS: A total of 144 individuals participated in tests of validity and reliability. Internal consistency was excellent (Cronbach's a=0.85-0.94). Drug rankings based on OAS scores achieved good inter-rater agreement (Kendall's W 0.37, p<0.001). Agreement on drug OAS scores between the developmental sample and a confirmation sample was good (IntraClass Correlations [ICC] of 0.65-0.69). Global ratings of overall attractiveness of the 14 selected opioid products by substance abuse counselors corresponded with the rankings based on OAS ratings of the abuser group. Finally, substance abuse counselors completed the OAS, yielding a high level of correspondence with ratings by the abuser group (ICC=0.83, p=0.002). The OAS differentiated attractiveness among 14 selected pharmaceutical opioid products. OxyContin, Dilaudid, and Percocet were ranked highest (most attractive); Talwin NX and Duragesic were ranked lowest (least attractive). CONCLUSIONS: The OAS appears to be a valid and reliable scale capable of providing important guidance on product features that may be attractive to potential abusers. <P CLASS="SMALL">Copyright 2006, BioMed Central</P><BR> <H3>Cardinal RN; Everitt BJ. Neural and psychological mechanisms underlying appetitive learning: Links to drug addiction. (review). <I Class="H3">Current Opinion in Neurobiology</I> 14(2): 156-162, 2004. (87 refs.)</H3>The complexity of drug addiction mirrors the complexity of the psychological processes that motivate animals to work for any reinforcer, be it a natural reward or a drug. Here, we review the role of the nucleus accumbens, together with its dopaminergic and cortical innervation, in responding to reinforcement. One important contribution made by the nucleus accumbens is to the process through which neutral stimuli, once paired with a reinforcer such as a drug, have the capacity to motivate behaviour. This process may be one of several contributing to addiction, and it may be amenable to pharmacological intervention. <P CLASS="SMALL">Copyright 2004, Current Biology Ltd</P><BR> <H3>Carter LP; Richards BD; Mintzer MZ; Griffiths RR. Relative abuse liability of GHB in humans: A comparison of psychomotor, subjective, and cognitive effects of supratherapeutic doses of triazolam, pentobarbital, and GHB. <I Class="H3">Neuropsychopharmacology</I> 31(11): 2537-2551, 2006. (57 refs.)</H3>Although preclinical studies suggest that GHB has low likelihood for abuse, case reports indicate that GHB is abused. This study evaluated the relative abuse liability of GHB in 14 volunteers with histories of drug abuse. Psychomotor, subjective, and cognitive effects of a broad range of GHB doses ( 2-18 g/70 kg), up to a dose that produced severe behavioral impairment in each participant, were compared to placebo and two abused sedative/hypnotic drugs, triazolam ( 0.5 and 1 mg/70 kg) and pentobarbital ( 200 and 400 mg/70 kg), under double-blind, double-dummy conditions at a residential research facility. In general, GHB produced effects similar to triazolam and pentobarbital, although GHB was not identified as a benzodiazepine or barbiturate by participants that correctly identified triazolam and pentobarbital as such. On most measures of likelihood of abuse ( eg ratings of liking, reinforcing effects), effects of pentobarbital were significantly greater than those of triazolam, with GHB being intermediate. GHB produced significantly greater negative subjective effects, including nausea, than the other drugs. Memory impairment after GHB was less than that after triazolam and pentobarbital. Within participants, the dose-effect function for sedation was steeper for GHB than for triazolam and pentobarbital. Also, at higher doses, GHB was associated with greater sedation and more variability across participants in sedation. Taken together, these data suggest that the profile of effects of GHB only partially overlaps with that of triazolam and pentobarbital. Although the likelihood for GHB to be abused is intermediate to triazolam and pentobarbital, the possibility of accidental overdose (i.e. greater sedation than intended) with GHB appears to be greater. <P CLASS="SMALL">Copyright 2006, Nature Publishing Group</P><BR> <H3>Chen CY; Anthony JC. Epidemiological estimates of risk in the process of becoming dependent upon cocaine: Cocaine hydrochloride powder versus crack cocaine. <I Class="H3">Psychopharmacology</I> 172(1): 78-86, 2004. (38 refs.)</H3>Rationale. To estimate the risk of experiencing clinical features of cocaine dependence within 1-2 years of starting cocaine use, and to examine whether crack smoking might increase this risk. Methods. A national sample of recent-onset cocaine users was identified within public data files of the National Household Surveys on Drug Abuse (NHSDA) for the years 1995 through 1998. The sample included 572 recent-onset users of cocaine HCl powder but not crack, and 190 recent-onset users of crack, some of whom had also started use of cocaine powder no more than 23 months prior to assessment. A separate group of 93 recent-onset crack users was identified; this comparison group had started using cocaine HCl powder 2+ years before assessment. Cocaine dependence was assessed via seven standardized questions about clinical features experienced within 12 months of assessment, such as feeling unable to cut down. Multivariate response regressions were used to evaluate crack-associated excess risk and clinical profiles of cocaine dependence. Results. Among persons who had recently started to use cocaine HCl powder but not crack cocaine, about 5-12% experienced clinical features of cocaine dependence. Most clinical features occurred 2-3 times more often among crack smoking users as compared to those using powder only, even with statistical adjustment for frequency of cocaine use (P<0.01). This crack-associated excess risk is more prominent for several clinical features of cocaine dependence, including tolerance associated with cocaine use and narrowed behavioral repertoire attributed to cocaine use. Conclusions. This new epidemiological evidence suggests that crack-smoking may increase risk of cocaine dependence once cocaine use starts, but we cannot rule out the possibility that crack users start out with a greater susceptibility to become cocaine dependent. <P CLASS="SMALL">Copyright 2004, Springer-Verlag</P><BR> <H3>Chen L; Tsong Y. Design and analysis for drug abuse potential studies: Issues and strategies for implementing a crossover design. <I Class="H3">Drug Information Journal</I> 41(4): 481-489, 2007. (10 refs.)</H3>It is important to conduct a drug abuse potential study for a new drug that may have potential to be abused. The acute dose-effect comparisons of the test, positive control, and placebo treatments are often performed on healthy volunteers with histories of drug abuse in drug abuse clinical trials. Because of large between-subject variability in the endpoint measurements based on self-evaluated responses and the difficulty in recruiting appropriate study subjects; the designs for such studies are typically crossover, with self-control. In this article, design issues and statistical analysis issues are presented. The advantages and disadvantages of currently used study designs are discussed. Some new ideas for improving existing designs are proposed. <P CLASS="SMALL">Copyright 2007, Drug Information Association</P><BR> <H3>Cho HS; D'Souza DC; Gueorguieva R; Perry EB; Madonick S; Karper LP. Absence of behavioral sensitization in healthy human subjects following repeated exposure to ketamine. <I Class="H3">Psychopharmacology</I> 179(1): 136-143, 2005. (78 refs.)</H3>Rationale: Sensitization to the effects of N-methyl-D-aspartate (NMDA) glutamate receptor antagonists is robust in animals. However, the applicability of this model to humans is unclear because it currently rests on highly confounded retrospective studies of individuals who experienced protracted psychoses following repeated binges with NMDA receptor antagonists. Objectives: The purpose of the current study was to determine whether there was evidence of sensitization to the behavioral effects of ketamine in healthy human subjects with repeated exposure to this drug. Methods: Data were studied from 295 healthy human subjects who participated in one or more of 11 separate studies that involved ketamine administration over 14 years. Positive and negative symptoms (Brief Psychiatric Rating Scale: BPRS), perceptual alterations (Clinician-Administered Dissociative States Scale: CADSS), and "high" and "anxiety" states (Visual Analog Scale: VAS) that were measured in all studies were included as outcome measures. Results: After including the number of previous exposures, number of previous studies, and time since first exposure as variables, repeated exposure to ketamine did not result in increased behavioral responses, suggestive of behavioral sensitization. Conclusion: The current data do not provide evidence that repeated exposure to ketamine, albeit limited, is associated with sensitization to the behavioral effects of ketamine. <P CLASS="SMALL">Copyright 2005, Springer Verlag</P><BR> <H3>Cimolai N. Zopiclone - Is it a pharmacologic agent for abuse? (review). <I Class="H3">Canadian Family Physician</I> 53: 2124-2129, 2007. (56 refs.)</H3>OBJECTIVE: To determine whether the hypnosedative drug zopiclone could be an agent for abuse. SOURCES OF INFORMATION: Using MEDLINE and PubMed, English-language medical literature was systematically reviewed for reports of direct drug abuse and addiction. A review was also conducted for clinical trials or patient series that discussed issues of addiction or rebound effects. MAIn MESSAGE Evidence of drug abuse and dependency was found in case reports and small patient series. Dependency symptoms of severe rebound, severe anxiety, tremor, palpitations, tachycardia, and seizures were observed in some patients after withdrawal. Abuse occurred more commonly among patients with previous drug abuse or psychiatric illnesses. Many clinical trials have found evidence of rebound insomnia after recommended dosages were stopped, albeit for a minority of patients. Comparative studies of zopiclone and benzodiazepines or other "Z" drugs are conflicting. CONCLUSION Zopiclone has the potential for being an agent of abuse and addiction. While many have suggested that the addictive potential for this and other "Z" drugs is less than for most benzodiazepines, caution should be taken when prescribing this agent for insomnia. ideally, prescriptions should be given for a short period of time and within the recommended dosage guidelines. <P CLASS="SMALL">Copyright 2007, College of Family Physicians of Canada</P><BR> <H3>Coleman JJ; Bensinger PB; Gold MS; Smith DE; Bianchi RP; DuPont RL. Can drug design inhibit abuse? <I Class="H3">Journal of Psychoactive Drugs</I> 37(4): 343-362, 2005. (89 refs.)</H3>A recent federal report indicates that prescription drug abuse is now the second leading category of illicit drug use, following marijuana use. Control strategies typically focus on reducing the diversion of prescription drugs from legitimate sources. The proliferation of unregulated Internet sources, however, has rendered control strategies less effective. This study examines a new approach that focuses on reducing abusability through the use of abuse-resistant drug designs. Drugs with and without such designs are compared and abuse levels assessed using multiple sources. In every instance, drugs employing abuse-resistant designs were found to have significantly lower levels of abuse than comparator drugs without such designs. <P CLASS="SMALL">Copyright 2005, Haight-Ashbury Publications</P><BR> <H3>Comer SD; Ashworth JB; Foltin RW; Johanson CE; Zacny JP; Walsh SL. The role of human drug self-administration procedures in the development of medications. <I Class="H3">Drug and Alcohol Dependence</I> 96(1-2): 1-15, 2008. (116 refs.)</H3>The purpose of this review is to illustrate the utility and value of employing human self-administration procedures in medication development, including abuse liability assessments of novel medications and evaluation of potential pharmacotherapies for substance use disorders. Traditionally, human abuse liability testing has relied primarily on subjective reports describing drug action by use of questionnaires; similarly, drug interactions between putative treatment agents and the drugs of abuse have relied on these measures. Subjective reports are highly valued because they provide qualitative and quantitative information about the characteristics of central and peripheral pharmacodynamic effects as well as safety and tolerability. However, self-administration procedures directly examine the behavior of interest-that is, drug taking. The present paper (1) reviews the most commonly used human self-administration procedures, (2) discusses the concordance of subjective reports and self-administration within the context of medications development for substance use disorders, focusing primarily on illustrative examples from development efforts with opioid and cocaine dependence, and (3) explores the utility of applying self-administration procedures to assess the abuse liability of novel compounds, including "abuse-deterrent" formulations (ADFs). The review will focus on opioid and cocaine dependence because a rich database from both clinical laboratory and clinical trial research exists for these two drug classes. The data reviewed suggest that drug-induced changes in self-administration and subjective effects are not always concordant. Therefore, assessment of self-administration in combination with subjective effects provides a more comprehensive picture that may have improved predictive validity for translating to the clinical setting. <P CLASS="SMALL">Copyright 2008, Elsevier Science</P><BR> <H3>Comer SD; Sullivan MA; Walker EA. Comparison of intravenous buprenorphine and methadone self-administration by recently detoxified heroin-dependent individuals. <I Class="H3">Journal of Pharmacology and Experimental Therapeutics</I> 315(3): 1320-1330, 2005. (37 refs.)</H3>Although buprenorphine is used worldwide as a safe and effective maintenance medication for opioid dependence, some countries have reported a growing incidence of abuse of this medication. Buprenorphine is considered to have lower abuse potential because of its partial agonist profile, but no studies have directly compared the reinforcing effects of buprenorphine with those of full mu opioid agonists in humans. The present double-blind, placebo-controlled inpatient study compared the reinforcing and subjective effects of intravenously administered buprenorphine (0.5, 2, and 8 mg) and methadone (5, 10, and 20 mg). Participants (n = 6) were detoxified from heroin during the first 1 to 2 weeks after admission. During subsequent weeks, participants received a sample drug dose and $20 on Monday, and they could self-administer either the sampled dose or $20 during one choice session per day on Thursday and Friday. Participants responded under a modified progressive ratio schedule during each choice session. All active doses maintained higher progressive ratio break points (largest completed ratio) than placebo. There were no significant differences in break point values between buprenorphine and methadone or among the different doses of drug. However, several subjective ratings, including "good drug effect", "high", and "liking" dose-dependently increased after administration of buprenorphine and methadone. The peak ratings for these effects did not significantly differ for the two drugs. These results demonstrate that under these experimental conditions, buprenorphine and methadone were equally effective in producing reinforcing and subjective effects. <P CLASS="SMALL">Copyright 2005, American Society of Pharmacology and Experimental Therapeutics</P><BR> <H3>Compton WA; Volkow ND. Abuse of prescription drugs and the risk of addiction. <I Class="H3">Drug and Alcohol Dependence</I> 83(Supplement 1): S4-S7, 2006. (28 refs.)</H3>Abuse of several categories of prescription drugs has increased markedly in the United States in the past decade and is now at alarming levels for certain agents, especially opioid analgesics and stimulants. Prescription drugs of abuse fit into the same pharmacological classes as their non-prescription counterparts. Thus, the potential factors associated with abuse or addiction versus safe therapeutic use of these agents relates to the expected variables: dose, route of administration, co-administration with other drugs, context of use, and expectations. Future scientific work on prescription drug abuse will include identification of clinical practices that minimize the risks of addiction, the development of guidelines for early detection and management of addiction, and the development of clinically effective agents that minimize the risks for abuse. With the high rates of prescription drug abuse among teenagers in the United States, a particularly urgent priority is the investigation of best practices for effective prevention and treatment for adolescents, as well as the development of strategies to reduce diversion and abuse of medications intended for medical use. <P CLASS="SMALL">Copyright 2006, Elsevier Science</P><BR> <H3>Compton WM; Volkow ND. Major increases in opioid analgesic abuse in the United States: Concerns and strategies. <I Class="H3">Drug and Alcohol Dependence</I> 81(2): 103-107, 2006. (28 refs.)</H3>The problem of abuse of and addiction to opioid analgesics has emerged as a major issue for the United States in the past decade and has worsened over the past few years. The increases in abuse of these opioids appear to reflect, in part, changes in medication prescribing practices, changes in drug formulations as well as relatively easy access via the internet. Though the use of opioid analgesics for the treatment of acute pain appears to be generally benign, long-term administration of opioids has been associated with clinically meaningful rates of abuse or addiction. Important areas of research to help with the problem of opioid analgesic abuse include the identification of clinical practices that minimize the risks of addiction, the development of guidelines for early detection and management of addiction, the development of opioid analgesics that minimize the risks for abuse, and the development of safe and effective non-opioid analgesics. With high rates of abuse of opiate analgesics among teenagers in the United States, a particularly urgent priority is the investigation of best practices for treating pain in adolescents as well as the development of prevention strategies to reduce diversion and abuse. <P CLASS="SMALL">Copyright 2006, Elsevier Scientific Publishers Ireland, Ltd.</P><BR> <H3>Darke S; Kaye S; McKetin R; Duflou J. Major physical and psychological harms of methamphetamine use. (review). <I Class="H3">Drug and Alcohol Review</I> 27(3): 253-262, 2008. (112 refs.)</H3>Issues. The major physical and psychological health effects of methamphetamine use, and the factors associated with such harms. Approach. Comprehensive review. Key Findings. Physical harms reviewed included toxicity and mortality, cardiovascular/cerebrovascular pathology, dependence and blood-borne virus transmission. Psychological harms include methamphetamine psychosis, depression, suicide, anxiety and violent behaviours. Implications. While high-profile health consequences, such as psychosis, are given prominence in the public debate, the negative sequelae extend far beyond this. This is a drug class that causes serious heart disease, has serious dependence liability and high rates of suicidal behaviours. Conclusion. The current public image of methamphetamine does not portray adequately the extensive, and in many cases insidious, harms caused. <P CLASS="SMALL">Copyright 2008, Taylor & Francis</P><BR> <H3>Donny EC; Bigelow GE; Walsh SL. Assessing the initiation of cocaine self-administration in humans during abstinence: Effects of dose, alternative reinforcement, and priming. <I Class="H3">Psychopharmacology</I> 172(3): 316-323, 2004. (25 refs.)</H3>Rationale. Impaired ability to refrain from initiating cocaine-taking is a central feature of cocaine dependence and an important target for behavioral and pharmacological interventions. One potential trigger of cocaine-taking is exposure to cocaine (i.e. priming). Objective. Here, we report a model of human cocaine self-administration that quantifies the ability to refrain from initiating cocaine self-administration during abstinence and after cocaine administration. Methods. In a double-blind, within-subject, residential laboratory study, we assessed cocaine-taking as a function of the choice dose, priming dose, and the magnitude of alternative reinforcement. During each of 3 weeks, cocaine-dependent volunteers participated in one sample and three choice sessions. During sample sessions, participants were administered the dose of cocaine (0, 15 or 30 mg/70 kg IV) available during subsequent choice sessions that week. During choice sessions, participants chose between cocaine and decreasing amounts of money ($19, $16, $13, $10, $7, $4, $1). A priming dose of cocaine (0, 15 or 30 mg/70 kg) was administered 30 min prior to the first choice trial during each of three choice sessions each week. Results. Cocaine-taking was moderate, dose-dependent, and negatively related to the monetary alternative. An active priming injection of cocaine compared to placebo shifted choice to cocaine over money earlier in the session. Conclusions. A descending schedule of alternative reinforcement provided a measure of cocaine-taking during abstinence that was sensitive to cocaine choice dose, magnitude of alternative reinforcement, and priming. This procedure may be a useful tool for assessing potential therapies for cocaine dependence. <P CLASS="SMALL">Copyright 2004, Springer-Verlag</P><BR> <H3>Donny EC; Bigelow GE; Walsh SL. Choosing to take cocaine in the human laboratory: Effects of cocaine dose, inter-choice interval, and magnitude of alternative reinforcement. <I Class="H3">Drug and Alcohol Dependence</I> 69(3): 289-301, 2003. (41 refs.)</H3>Cocaine abuse involves a variety of behaviors including the initiation of cocaine-seeking, the self-selected patterning of cocaine administrations, and the cessation of cocaine-taking. To date, most human laboratory models of cocaine self-administration have only assessed the amount of cocaine consumed under a fixed set of conditions. This double-blind, randomized, within-subject, inpatient study evaluated a novel model of human cocaine self-administration that aimed to quantify the reinforcing value of cocaine after cocaine-taking was initiated. Cocaine-dependent volunteers (n=8) sampled cocaine (12.5, 25 or 50 mg per 70 kg i.v.) or placebo and were subsequently allowed to choose between another injection of the same dose or money over six trials during 12 experimental sessions. The value of the monetary alternative increased with each trial from $1 to $16. Each cocaine dose was assessed under three inter-choice intervals: 15 min, 30 min, and an interval selected by the volunteer. Injection choices increased dose dependently; however, there was little relationship between the value of the alternative reinforcer and the choice to take cocaine. Most volunteers exclusively chose injections when active cocaine was available and money when placebo was available. Inter-choice interval did not affect cocaine choices. These results illustrate the persistence of cocaine self-administration once cocaine-taking has been initiated. <P CLASS="SMALL">Copyright 2003, Elsevier Science Ltd</P><BR> <H3>DuPont RL; Bensinger PB. Abuse-resistant drug delivery. <I Class="H3">Pediatric Annals</I> 35(8): 587-+, 2006. (5 refs.)</H3>This article considers the difference between two groups of stimulants, the levels of abuse and the factors which may account for this. The nonmedical use of prescription stimulants, particularly dextroamphetamine and methylphenidate, is compared to the patterns of use for cocaine and methamphetamine. The latter, when used on campus, commonly are used to enhance academic performance not to alter mood. Historically there have been efforts to improve on opiate analgesics, by retaining therapeutic benefits while discouraging nonmedical use. The clear distinction in the patterns of use are seen as confirmation of this approach. The difference between these two groups of drugs suggests a difference that is not simply a matter of availability, but having a biological basis. With these two prescription drugs, there is not the rapid onset and rapid decline in blood levels that are common to cocaine and methamphetamine. <P CLASS="SMALL">Copyright 2006, Slacks Inc.</P><BR> <H3>Earleywine M, ed. <I Class="H3">Mind-Altering Drugs: The Science of Subjective Experience</I>. New York: Oxford University Press, 2005. (Chapter refs.)</H3>This edited volume in organized into 13 chapters and 20 contributors. The goal is to explore the subjective experience associated with substance use, the biological basis, and the implications for abuse potential. What is the nature of intoxication? This question is addressed in respect to hallucinogens, alcohol, opioids, marijuana, methylphenidate, and nitrous oxide. In addition there is examination of the relationship of ethnicity and acute effects for alcohol, the relationship of personality and the response to stimulant drugs, and interrelationship between sex and drugs. <P CLASS="SMALL">Copyright 2006, Project Cork</P><BR> <H3>Esch T; Stefano GB. The neurobiology of pleasure, reward processes, addiction and their health implications. (review). <I Class="H3">Neuroendocrinology</I> 25(4): 235-251, 2004. (138 refs.)</H3>Modern science begins to understand pleasure as a potential component of salutogenesis. Thereby, pleasure is described as a state or feeling of happiness and satisfaction resulting from an experience that one enjoys. We examine the neurobiological factors underlying reward processes and pleasure phenomena. Further, health implications related to pleasurable activities are analyzed. With regard to possible negative effects of pleasure, we focus on addiction and motivational toxicity. Pleasure can serve cognition, productivity and health, but simultaneously promotes addiction and other negative behaviors, i.e., motivational toxicity. It is a complex neurobiological phenomenon, relying on reward circuitry or limbic activity. These processes involve dopaminergic signaling. Moreover, endorphin and endogenous morphinergic mechanisms may play a role. Natural rewarding activities are necessary for survival and appetitive motivation, usually governing beneficial biological behaviors like eating, sex and reproduction. Social contacts can further facilitate the positive effects exerted by pleasurable experiences. However, artificial stimulants can be detrimental, since flexibility and normal control of behavior are deteriorated. Additionally, addictive drugs are capable of directly acting on reward pathways. Thus, the concrete outcome of pleasant experiences may be a question of dose. Moderate pleasurable experiences are able to enhance biological flexibility and health. Hence, pleasure can be a resistance resource or may serve salutogenesis. Natural rewards are mediated by sensory organ stimulation, thereby exhibiting a potential association with complementary medical approaches. Trust and belief can be part of a self-healing potential connected with rewarding stimuli. Further, the placebo response physiologically resembles pleasure phenomena, since both involve brain's reward circuitry stimulation and subjective feelings of well-being. Pleasurable activities can stimulate personal growth and may help to induce healthy behavioral changes, including stress management. However, more research is needed to better understand the nature, neurobiology and maybe dangerous aspects of pleasure. Also, a possible involvement of endogenous morphinergic signaling has to be studied further. <P CLASS="SMALL">Copyright 2004, Maghira & Mass Publications</P><BR> <H3>Expert Panel; Sellars EM; Chilcoat HD; Gorodetzky SW; Reidenberg MM; Strain EC et al. Abuse liability assessment of CNS drugs: conclusions, recommendations, and research priorities. <I Class="H3">Drug and Alcohol Dependence</I> 70(3 Supplement 1): S107-S114, 2003. (9 refs.)</H3>The specific charge to the expert panel by the conference conveners was to develop conclusions and recommendations on the state of the science of Abuse Liability Assessment, to provide a framework drug developers, drug regulators, and research centers. The conclusions and recommendations were developed according to a protocol developed prior to the meeting. The conclusions and recommendations are not implied to constitute a consensus of all conference participants; however, the intent of the panel was that its product would be a credible representation of the workshop and that it would provide a framework to serve regulatory agencies, drug developers, research institutions, and public health. Among the conclusions are (1) ALA has served to protect public health in the United States and globally by producing information useful to drug regulatory agencies in their control of CNS drugs. (2) There is a broad range of drugs that potentially warrant ALA. (3) An ALA provides a framework for determining whether or not a drug should be placed under the CSA and, if so, the level of control. (4) In the process of developing a new medication, preclinical data regarding abuse liability are critical for early decision making. (5) Confidence in predictions is increased when data are considered across a range of control conditions and drug doses. Decisions, instead, should be based upon a broad spectrum of evaluations from both preclinical and clinical studies. (6) Pharmacologic profiles are relatively well characterized for opioids, stimulants and sedative-hypnotics. These profiles provide a general framework for evaluation of new compounds. (7) Models for the assessment of abuse liability in humans have been established and these models have been useful for assessing the risk of abuse of new drugs and drug formulations. (8) Drug abusers are an appropriate population in which to study abuse liability. Studies with drug abusers can be ethically conducted as long as procedures are in place for adequate human subjects review and monitoring. (9) Failure to detect a signal of abuse liability in a drug abusing population is good evidence of lack of abuse liability in less vulnerable populations. However, a positive signal in this population is not sufficient to conclude that there is risk of abuse to a wider population. (10) Testing a range of doses is important, especially with novel compounds, although the use of high doses can raise safety and ethical questions. Therefore, ALA should include the widest range of doses that can safely and ethically be administered. <P CLASS="SMALL">Copyright 2003, Elsevier Science</P><BR> <H3>Fredericks EM; Kollins SH. A pilot study of methylphenidate preference assessment in children diagnosed with attention-deficit/hyperactivity disorder. <I Class="H3">Journal of Child & Adolescent Psychopharmacology</I> 15(5): 729-741, 2005. (62 refs.)</H3>Objective: The use of methylphenidate (MPH) in the treatment of attention-deficit/hyperactivity disorder (ADHD) is widely accepted; however, there is increased concern regarding its abuse potential. Few studies have examined the reinforcing effects of drugs in individuals receiving them for clinical purposes. This study attempts to assess MPH preference in children with ADHD using a choice procedure in order to explore the relationship among drug preference, clinical efficacy, and abuse potential. Methods: Participants were 5 children (10-14 years of age) receiving MPH for the treatment of ADHD. Reinforcing effects were assessed using a double-blind choice procedure, with six sampling sessions and six choice sessions. Participant-rated effects were measured using self-report questionnaires. Clinical effects were measured using direct observations and behavior ratings. Results: Differences between the number of MPH, Placebo, and Neither choices across participants were significant (chi(2) = 9.6; p < 0.01). Three of five participants reliably chose MPH more often than placebo. MPH produced idiosyncratic patterns of participant-rated effects but failed to produce significant clinical effects. Conclusions: These findings add to the literature on the reinforcing effects of MPH and are the first reported in a clinical sample of children. Further research exploring the role of clinical efficacy in MPH preference is warranted. <P CLASS="SMALL">Copyright 2005, Mary Ann Liebert Inc.</P><BR> <H3>Fredericks EM; Kollins SH. Assessing methylphenidate preference in ADHD patients using a choice procedure. <I Class="H3">Psychopharmacology</I> 175(4): 391-398, 2004. (66 refs.)</H3>Rationale: Methylphenidate (MPH) is widely used in the treatment of attention deficit hyperactivity disorder (ADHD) and is associated with positive clinical effects across a wide range of domains. Despite the clinical effectiveness of MPH, concern has arisen with respect to its abuse potential. Objectives: To assess MPH preference in adults diagnosed with ADHD using a choice procedure and to evaluate the relationship among drug preference, therapeutic efficacy, and abuse potential in a clinical sample. Methods: Participants were ten volunteers (ages 18-22 years) with ADHD who were receiving MPH treatment. Preference was assessed using a double-blind choice procedure with four sampling sessions wherein subjects received either placebo or MPH and eight choice sessions when they chose either capsule or no capsules. Results: Overall, MPH was chosen significantly more often than placebo (chi(2)=52.5; P<0.001) and participants were equally separated into groups of those who chose MPH reliably (MPH choosers) and those who did not (MPH non-choosers). MPH decreased ADHD symptoms and resulted in lower ratings of stimulant effects among MPH choosers. MPH choosers also reported higher levels of baseline ADHD symptoms. Conclusions: Despite higher preference of MPH than placebo in this clinical sample, other measures of abuse potential were not elevated, and MPH choosers were more symptomatic than non-choosers. As such, MPH preference in ADHD populations likely reflects therapeutic efficacy rather than abuse potential. Future work should examine MPH choice in diagnosed and non-diagnosed populations to further explore the role of clinical efficacy in the preference of this stimulant drug. <P CLASS="SMALL">Copyright 2004, Springer</P><BR> <H3>Fu SS; Okuyemi KS; Partin MR; Ahluwalia JS; Nelson DB; Clothier BA et al. Menthol cigarettes and smoking cessation during an aided quit attempt. <I Class="H3">Nicotine & Tobacco Research</I> 10(3): 457-462, 2008. (20 refs.)</H3>Menthol may make cigarettes more addictive and rates of menthol cigarette smoking are disproportionately higher among Black. However, few studies have examined the association between menthol cigarette smoking and cessation, and the studies to date have produced conflicting findings. The present study examines the effect of menthol cigarette smoking on cessation among a multi-ethnic sample of smokers making a pharmacotherapy-aided quit attempt. We hypothesized that menthol cigarette smoking would be associated with lower smoking abstinence rates and conducted a secondary analysis of data from a multi-site randomized controlled trial of an intervention designed to facilitate repeat tobacco cessation treatment (N=1,343). The intervention consisted of a patient phone call and a computerized provider prompt. The primary outcome for this analysis was 7-day point prevalence smoking abstinence. The average age of the sample was 56 years old. Overall, 25% of the sample smoked menthol cigarettes: 19% of Whites, 62% of Blacks, and 25% of other ethnicity (p<.001). We observed no significant effects for menthol cigarette smoking or ethnicity on smoking abstinence rates. In conclusion, combined with findings from previous research, this study suggests that smoking menthol cigarettes does not decrease smoking cessation among older smokers during a quit attempt aided with pharmacotherapy. <P CLASS="SMALL">Copyright 2008, Taylor & Francis</P><BR> <H3>Fudala PJ; Johnson RE. Development of opioid formulations with limited diversion and abuse potential. <I Class="H3">Drug and Alcohol Dependence</I> 83(Supplement 1): s40-s47, 2006. (58 refs.)</H3>Non-medical abuse of prescription opioid medications is not a new phenomenon, but such use has been increasing in recent years. Various methods have been used and continue to be developed in an effort to limit diversion and abuse of opioid medications. A number of these methods will be described for opioid analgesic and addiction treatment formulations using relevant historical examples (e.g. propoxyphene, pentazocine, buprenorphine) as well as examples of formulations currently being considered or under development (e.g. oxycodone plus naltrexone, sustained-release buprenorphine). The focus, though not exclusively, will be on those formulations that represent a combination of an opioid agonist with an antagonist. These methods must take into consideration the pharmacokinetic profile of the agonist and antagonist, the expected primary route of abuse of the medication and the medication combination, the dose of medication that is likely to be abused, the availability of alternative drugs of abuse, and the population of potential abusers that is being targeted with the revised formulation. <P CLASS="SMALL">Copyright 2006, Elsevier Science</P><BR> <H3>Gable RS. Risk assessment of ritual use of oral dimethyltryptamine (DMT) and harmala alkaloids. (review). <I Class="H3">Addiction</I> 102(1): 24-34, 2007. (76 refs.)</H3>To extend previous reviews by assessing the acute systemic toxicity and psychological hazards of a dimethyltryptamine and beta-carboline brew (ayahuasca/hoasca) used in religious ceremonies. A systematic literature search, supplemented by interviews with ceremony participants. No laboratory animal models were located that tested the acute toxicity or the abuse potential of ayahuasca. Separate animal studies of the median lethal dose of dimethyltryptamine (DMT) and of several harmala alkaloids indicated that a lethal dose of these substances in humans is probably greater than 20 times the typical ceremonial dose. Adverse health effects may occur from casual use of ayahuasca, particularly when serotonergic substances are used in conjunction. DMT is capable of inducing aversive psychological reactions or transient psychotic episodes that resolve spontaneously in a few hours. There was no evidence that ayahuasca has substantial or persistent abuse potential. Long-term psychological benefits have been documented when ayahuasca is used in a well-established social context. A decoction of DMT and harmala alkaloids used in religious ceremonies has a safety margin comparable to codeine, mescaline or methadone. The dependence potential of oral DMT and the risk of sustained psychological disturbance are minimal. <P CLASS="SMALL">Copyright 2007, Society for the Study of Addiction to Alcohol and Other Drugs</P><BR> <H3>Greenwald MK. Behavioral economic analysis of drug preference using multiple choice procedure data. <I Class="H3">Drug and Alcohol Dependence</I> 93(1/2): 103-110, 2008. (31 refs.)</H3>The multiple choice procedure has been used to evaluate preference for psychoactive drugs, relative to money amounts (price), in human subjects. The present re-analysis shows that MCP data are compatible with behavioral economic analysis of drug choices. Demand curves were constructed from studies with intravenous fentanyl, intramuscular hydromorphone and oral methadone in opioid-dependent individuals; oral d-amphetamine, oral MDMA alone and during fluoxetine treatment, and smoked marijuana alone or following naltrexone pretreatment in recreational drug users. For each participant and dose, the MCP crossover point was converted into unit price (UP) by dividing the money value ($) by the drug dose (mg/70 kg). At the crossover value, the dose ceases to function as a reinforcer, so "0" was entered for this and higher UPs to reflect lack of drug choice. At lower UPs, the dose functions as a reinforcer and "1" was entered to reflect drug choice. Data for UP vs. average percent choice were plotted in log-log space to generate demand functions. Rank of order of opioid inelasticity (slope of non-linear regression) was: fentanyl > hydromorphone (continuing heroin users) > methadone > hydromorphone (heroin abstainers). Rank order of psychostimulant inelasticity was d-amphetamine > MDMA > MDMA + fluoxetine. Smoked marijuana was more inelastic with high-dose naltrexone. These findings show this method translates individuals' drug preferences into estimates of population demand, which has the potential to yield insights into pharmacotherapy efficacy, abuse liability assessment, and individual differences in susceptibility to drug abuse. <P CLASS="SMALL">Copyright 2008, Elsevier Science</P><BR> <H3>Griffiths RR; Bigelow GE; Ator NA. Principles of initial experimental drug abuse liability assessment in humans. <I Class="H3">Drug and Alcohol Dependence</I> 70(3 Supplement 1): S41-S54, 2003. (67 refs.)</H3>This paper describes the rationale and procedures for conducting what is considered by many to be the current "gold standard" for initial abuse liability testing of a novel compound: the classic acute dose-effect comparison study in volunteers with histories of drug abuse. Such a trial is most appropriate for predicting the likelihood of abuse by drug abusers and, in turn, the extent of drug diversion and illicit street sales if the novel compound became available in the community. The dose-effect abuse liability trial typically involves a double-blind complete crossover design in 10-14 subjects with histories of polydrug abuse in a controlled clinical pharmacology laboratory setting. Drug conditions usually involve placebo, three doses of the novel compound and three doses of an appropriate reference compound of known abuse liability. In each session, the time-course of effects of a single drug dose are evaluated. Intervals between experimental sessions are typically 1 to several days. The importance of testing high supra-therapeutic doses of the novel drug for the validity of the trial is emphasized, and the use of a dose run-up pilot study for selecting maximal doses and matching doses between the novel and comparison compound is explained. The rationale and description of outcome measures is discussed, including measures that reflect likelihood of abuse (e.g. drug vs. money choice and subject ratings of liking, good effects, estimated monetary street value), secondary measures that should be considered in interpreting likelihood of abuse (e.g. drug identification, subject-rated side effects and mood changes), and additional concurrent measures to establish equivalence of the novel and comparison compound (e.g. behavioral performance, observer-rated assessments, physiological measures). <P CLASS="SMALL">Copyright 2003, Elsevier Science</P><BR> <H3>Grudzinskas C; Balster RL; Gorodetzky CW; Griffiths RR; Henningfield JE; Johanson CE et al. Impact of formulation on the abuse liability, safety and regulation of medications: The expert panel report. <I Class="H3">Drug and Alcohol Dependence</I> 83(Supplement 1): s77-s82, 2006. (7 refs.)</H3>A scientific meeting was held in April 2005 to consider how the formulation of medications might impact on their potential for abuse. The background papers prepared for this meeting, as well as abstracts of volunteered presentations, are published in this supplemental issue of Drug and Alcohol Dependence. This paper is the Expert Panel Report summarizing the discussions held following the formal presentations and including the suggested recommendations for additional research that emerged from these discussions. There was overwhelming consensus that formulation does play a role in prescription drug abuse, i.e., a formulation of an abused substance can be developed that will decrease its abuse potential, and several examples were cited. Nevertheless, it is imperative that new formulations have similar efficacy and in no way compromise medication access to doctors and patients. However, there was also consensus that a great deal of research and discussion was needed to fully implement a program of risk management through reformulation of existing products or tailoring the formulation of new products to retain clinical efficacy and safety while minimizing potential for abuse. Those who need to take part in this discussion include scientific groups, pharmaceutical companies, as well as governmental and regulatory agencies. The areas where more research is needed include development of standards for assessing tamper-resistance, improved animal models that can address formulation-related variables (e.g., onset, duration), the redesign of human laboratory studies providing appropriate models for comparing formulations, and improved post-marketing surveillance. Finally, knowledge and experience are needed to translate scientific work into a predictable, transparent and reliable regulatory process. <P CLASS="SMALL">Copyright 2006, Elsevier Science</P><BR> <H3>Hajak G; Muller WE; Wittchen HU; Pittrow D; Kirch W. Abuse and dependence potential for the non-benzodiazepine hypnotics zolpidem and zopiclone: A review of case reports and epidemiological data. (review). <I Class="H3">Addiction</I> 98(10): 1371-1378, 2003. (74 refs.)</H3>Aims: The non-benzodiazepine hypnotics zolpidem and zopiclone, which are indicated for short-term treatment of insomnia, were considered originally by physicians as almost devoid of abuse and dependence potential. Several recent publications, however, have suggested that both agents carry a significant risk of abuse. To substantiate and re-evaluate this situation, the world literature was reviewed for cases of dependence of both agents; these cases were analysed in order to identify certain underlying patterns, if evident. Methods A systematic review based on a Medline literature search was conducted including the years 1966-2002 to assemble all available clinical case reports that were analysed for typical features of abuse and dependence according to prespecified criteria. Only case reports were of interest, and clinical studies were excluded. No limitations as to language or publication year were applied. The terms 'zolpidem', 'zopiclone' and 'abuse', 'dependence', 'addiction', 'with-drawal' and 'intoxication' were used to identify relevant publications. Potentially relevant citations were retrieved and assessed for inclusion independently by two authors. Results A total of 3 6 cases for zolpidem were identified, most of them reported in recent years, and 22 cases for zopiclone. Both sexes were involved to a similar extent; and cases were reported in all age groups. In extreme cases, dose increases reached a factor of 30-120 above the recommended doses. The majority of patients had a history of former drug or alcohol abuse and/or other psychiatric conditions. Conclusion On the basis of world-wide prescription numbers, which are approximately twofold higher for zolpidem (1 338 774 000 tablets from June 2001 to June 2002 in Europe, Japan and United States) than for zopiclone (664 897 000 tablets during the same period in Europe and Japan), the relative incidence of reported dependence similar for both drugs and remarkably lower than that of benzodiazepines used for the treatment of disturbed sleep. The findings offer the conclusion that zolpidem and zopiclone are relatively safe drugs. However, as both drugs are psychotropic drugs, patients with a history of abuse or dependence and those with psychiatric diseases seem to be at increased risk of abuse of these agents. <P CLASS="SMALL">Copyright 2003, Society for the Study of Addiction to Alcohol and Other Drugs</P><BR> <H3>Harris LS. Exempt preparations: Historical perspectives. <I Class="H3">Drug and Alcohol Dependence</I> 83(Supplement 1): s48-s51, 2006. (27 refs.)</H3>This article is part of a supplemental issue of the journal devoted entirely to papers on how abuse liability of medications is affected by their formulation for medical use. This article reviews the history of the development of the concept of "exempt preparations" from its first use internationally to its current use, both nationally and internationally. The role of the WHO Expert Committee on Drug Dependence (ECDD) and the College on Problems of Drug Dependence (CDPP) is presented. Examples of exempt preparations are given and the use of the concept to permit useful therapeutic agents to be marketed with reduced regulatory control is discussed. <P CLASS="SMALL">Copyright 2006, Elsevier Science</P><BR> <H3>Hart CL; Haney M; Vosburg SK; Comer SD; Foltin RW. Reinforcing effects of oral Delta(9)-THC in male marijuana smokers in a laboratory choice procedure. <I Class="H3">Psychopharmacology</I> 181(2): 237-243, 2005. (28 refs.)</H3>Rationale: Oral Delta-9-tetrahydrocannabinol (Delta(9)-THC; Marinol) is medically available for the treatment of nausea associated with cancer chemotherapy and for wasting syndromes related to HIV/AIDS. Little is known about its reinforcing effects. Objective: This study was conducted to characterize the reinforcing effects of oral Delta(9)-THC in experienced marijuana smokers under controlled laboratory conditions. Methods: Ten healthy male marijuana users completed this 17-day residential study. On days 2, 6, 10, and 14, at 0900 h, participants received a "sample" oral dose of Delta(9)-THC (0, 10, 20 mg) and an alternative reinforcer, a $2 voucher (redeemable for cash at study's end). Over the next 3 days, they had 11 opportunities to self-administer either the sampled dose of Delta(9)-THC or to receive a $2 voucher. Results: Participants chose active A(9)-THC (10 and 20 mg) more often than placebo (< two selections vs -four selections, respectively). However, they chose active Delta(9)-THC on less than 50% of choice opportunities. Both active A9-THC doses produced significant increases in "positive" subjective effects, impaired psychomotor performance, and increased heart rate, relative to the placebo conditions. Conclusion: These data indicate that oral A9-THC may have modest abuse liability in experienced marijuana smokers. <P CLASS="SMALL">Copyright 2005, Springer</P><BR> <H3>Hillemacher T; Bleich S; Demling J; Kornhuber J. Ketamine for the treatment of depression: What about the addictive potential? <I Class="H3">Australian and New Zealand Journal of Psychiatry</I> 41(9): 772-773, 2007. (5 refs.)</H3></P><BR> <H3>Holzbach R. Practice to research: Use of benzodiazepines as adjunctive medications. <I Class="H3">Current Opinion in Psychiatry</I> 17(6): 519-522, 2004. (14 refs.)</H3>Purpose of review:Benzodiazepines are among the most frequently used psychoactive drugs; their effectiveness has been proved in clinical practice and the literature on benzodiazepines is extensive. Nevertheless, some core issues have hardly been investigated. Is it useful, as often recommended, to use benzodiazepines in cases of severe mental illness until treatment with other drugs, for instance with an antidepressant, is effective? Are there any criteria to decide when long-term treatment is appropriate and when it is not? What is the probability of becoming addicted in case of long-term treatment and how is addiction defined in the case of a low-dose dependency? What is the best withdrawal strategy and why do benzodiazepines lead to dependence? Recent findings The paper presents the main studies, carried out in the last 2 years, which focus on basic research, on indications in everyday life, on the importance of benzodiazepines in the treatment of depression and anxiety, on withdrawal symptoms and on success of withdrawal treatment. For some of these topics, only a few studies were available. This is the more regrettable as benzodiazepine dependence presents an ideal model for the investigation of addictions. Most of the great number of benzodiazepine addicts in industrial nations are not treated in specialized addiction wards or outpatient clinics. Neither are specialized treatment concepts available. Summary If addictive patients are the 'forgotten children of psychiatry' then benzodiazepine dependent patients are the 'forgotten children of addiction medicine'. During the last few years, basic research on benzodiazepine dependence delivered exciting insights into the mode of action. This progress has not been matched by progress in clinical research. <P CLASS="SMALL">Copyright 2004, Lippincott, Williams & Wilkins</P><BR> <H3>Houtsmuller EJ; Henningfield JE; Stitzer ML. Subjective effects of the nicotine lozenge: Assessment of abuse liability. <I Class="H3">Psychopharmacology</I> 167(1): 20-27, 2003. (44 refs.)</H3>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. <P CLASS="SMALL">Copyright 2003, Springer-Verlag</P><BR> <H3>Hruby VJ; Porreca F; Yamamura HI; Tollin G; Agnes RS; Lee YS et al. New paradigms and tools in drug design for pain and addiction. (review). <I Class="H3">AAPS Journal</I> 8(3): E450-E460, 2006. (29 refs.)</H3>New modalities providing safe and effective treatment of pain, especially prolonged pathological pain, have not appeared despite much effort. In this mini-review/overview we suggest that new paradigms of drug design are required to counter the underlying changes that occur in the nervous system that may elicit chronic pain states. We illustrate this approach with the example of designing, in a single ligand, molecules that have agonist activity at mu and delta opioid receptors and antagonist activities at cholecystokinin (CCK) receptors. Our findings thus far provide evidence in support of this new approach to drug design. We also report on a new biophysical method, plasmon waveguide resonance (PWR) spectroscopy, which can provide new insights into information transduction in G-protein coupled receptors (GPCRs) as illustrated by the d opioid receptor. <P CLASS="SMALL">Copyright 2006, American Association of Pharmaceutical Scientists</P><BR> <H3>Huang BJ; Dawson DA; Stinson FS; Hasin DS; Ruan WJ; Saha TD et al. Prevalence, correlates, and comorbidity of nonmedical prescription drug use and drug use disorders in the United States: Results of the National Epidemiology Survey on Alcohol and Related Conditions. <I Class="H3">Journal of Clinical Psychiatry</I> 67(7): 1062-1073, 2006. (58 refs.)</H3>Objective: To present national data on the prevalence, correlates, and comorbidity of nonmedical prescription drug use and drug use disorders for sedatives, tranquilizers, opioids, and amphetamines. Method: Data were derived from the National Epidemiologyogic Survey on Alcohol and Related Conditions (NESARC), a face-to-face nationally representative survey of 43,093 adults conducted during 2001 and 2002. Results: Lifetime prevalences of nonmedical use of sedatives, tranquilizers, opioids, and amphetamines were 4.1%, 3.4%, 4.7%, and 4.7%, respectively. Corresponding rates of abuse and/or dependence on these substances were 1.1%, 1.0%, 1.4%, and 2.0%. The odds of nonmedical prescription drug use and drug use disorders were generally greater among men, Native Americans, young and middle-aged, those who were widowed/separated/divorced or never married, and those residing in the West. Abuse/dependence liability was greatest for amphetamines, and nonmedical prescription drug use disorders were highly comorbid with other Axis I and II disorders. The majority of individuals with nonmedical prescription drug use disorders never received treatment. Conclusions: Nonmedical prescription drug use and disorders are pervasive in the U.S. population and highly comorbid with other psychiatric disorders. Native Americans had significantly greater rates of nonmedical prescription drug use and drug use disorders, highlighting the need for culturally-sensitive prevention and intervention programs. Unprecedented comorbidity between nonmedical prescription drug use disorders and between nonmedical prescription drug use disorders and illicit drug use disorders suggests that the typical individual abusing or dependent on these drugs obtained them illegally, rather than through a physician. Amphetamines had the greatest abuse/dependence liability, and recent increases in the potency of illegally manufactured amphetamines may portend an epidemic in the youngest NESARC cohort. <P CLASS="SMALL">Copyright 2006, Physicians Postgraduate Press</P><BR> <H3>Iversen L. GABA pharmacology: What prospects for the future? <I Class="H3">Biochemical Pharmacology</I> 68(8): 1537-1540, 2004. (35 refs.)</H3>Following the recognition of GABA as an inhibitory neurotransmitter, the discovery of high affinity GABA uptake, and the characterisation of GABA receptors great progress has been made in developing GABA pharmacology. Tiagabide, the first marketed GABA uptake inhibitor may, be followed by new and more selective uptake inhibitors. Knowledge of the molecular pharmacology of GABA-A receptors, both synaptic and non-synaptic, may lead to improved anti - anxiety/anticonvulsant agents devoid of the sedative and dependence liabilities of earlier compounds and new hypnotics. Gaboxadol (THIP) is an example of a novel hypnotic that acts on GABAA receptors by a non-benzodiazepine mechanism. Exploiting neurosteroid interactions with GABAergic mechanisms also holds much future promise. <P CLASS="SMALL">Copyright 2004, Elsevier Science Ltd.</P><BR> <H3>Jaffe JH; Bloor R; Crome I; Carr M; Alam F; Simmons A; Meyer RE. A postmarketing study of relative abuse liability of hypnotic sedative drugs. <I Class="H3">Addiction</I> 99(2): 165-173, 2004. (25 refs.)</H3>Aims: To demonstrate the utility of postmarketing studies using in-treatment drug and alcohol abusers as informants for assessing the relative abuse liability of sedative-hypnotic drugs. Design: A survey was conducted that ascertained exposure to a variety of drugs with hypnotic/sedative properties and elicited subjective evaluations indicative of abuse liability. Methods: Complete data were obtained from 297 admissions (78% male) to three addiction treatment sites in the United Kingdom. Subjects were asked 15 questions about 12 different drugs, including five benzodiazepines, three antidepressants, two non-benzodiazepine hypnotics and two antihistamines (plus one fictitious drug). Three of the benzodiazepines (diazepam, nitrazipam, temazepam) emerged as having substantially more abuse liability than any of the other drugs tested, as revealed by higher scores on abuse liability items (purchased on street, taken to get high, like drug, potential for addiction to drug). The antihistamines (chlorpheniramine, diphenhydramine) had lowest abuse liability profiles, while the antidepressants (amitriptyline, fluoxetine, trazadone) and non-benzodiazepine hypnotics (zolpidem, zopiclone) had similar profiles. Conclusion This pilot study suggests that postmarketing information on hypnotic drug use obtained from drug addicts entering treatment produces data consistent with other measures of abuse liability. The data suggest that the risk of misuse of newer non-benzodiazepine hypnotics may be less than that of benzodiazepine drugs, and similar to that of sedating antidepressants. The new methodology may serve to clarify or validate premarketing abuse liability data, and may help to inform the regulatory process and physician practice. <P CLASS="SMALL">Copyright 2004, Society for the Study of Addiction to Alcohol and Other Drugs</P><BR> <H3>Johnson RE; Fudala PJ; Payne R. Buprenorphine: Considerations for pain management. (review). <I Class="H3">Journal of Pain and Symptom Management</I> 29(3): 297-326, 2005. (269 refs.)</H3>New effective analgesics are needed for the treatment of pain. Buprenorphine, a partial muopioid agonist which has been in clinical use for over 25 years, has been found to be amenable to new formulation technology based on its physiochemical and pharmacological profile. Buprenorphine is marketed as parenteral, sublingual, and transdermal formulations. Unlike full mu-opioid agonists, at higher doses, buprenorphine's physiological and subjective effects, including euphoria, reach a plateau. This ceiling may limit the abuse potential and may result in a wider safety margin. Buprenorphine has been used for the treatment of acute and chronic pain, as a supplement to anesthesia, and for behavioral and psychiatric disorders including treatment for opioid addiction. Prolonged use of buprenorphine can result in physical dependence. However, withdrawal symptoms appear to be mild to moderate in intensity compared with those of full mu agonists. Overdoses have primarily involved buprenorphine taken in combination with other central nervous system depressants. <P CLASS="SMALL">Copyright 2005, U.S. Cancer Pain Relief Committee</P><BR> <H3>Kollins SH. Comparing the abuse potential of methylphenidate versus other stimulants: A review of available evidence and relevance to the ADHD patient. <I Class="H3">Journal of Clinical Psychiatry</I> 64(Supplement): 14-18, 2003. (18 refs.)</H3>The use of psychostimulants to treat attention-deficit/hyperactivity disorder (ADHD) has been controversial for a number of reasons. In an effort to clarify the extent to which the psychostimulant methylphenidate has abuse potential, the existing published evidence has been reviewed and is summarized here, with an emphasis on delineating a number of related but independent issues that are often confused. Methylphenidate produces behavioral effects associated with abuse potential as assessed by traditional assays, but the relevance of this literature to the clinical use of the drug in the treatment of ADHD is ambiguous at best. Existing neuropharmacologic data suggest that methylphenidate has pharmacokinetic properties that reduce its abuse potential as compared with other stimulant drugs of abuse, such as cocaine. <P CLASS="SMALL">Copyright 2003, Physicians Postgraduate Press, Inc. Used with permission</P><BR> <H3>Lile JA; Ross JT; Nader M. A comparison of the reinforcing efficacy of 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy") with cocaine in rhesus monkeys. <I Class="H3">Drug and Alcohol Dependence</I> 78(2): 135-140, 2005. (44 refs.)</H3>The purpose of the present study was to compare the reinforcing efficacy of 3,4-methylenedioxymethamphetamine (MDMA, 'ecstasy') to cocaine. Rhesus monkeys (n = 4) responded under a within-session, exponentially increasing, progressive-ratio (PR) schedule of cocaine reinforcement. Breaking point (BP) for the PR schedule was defined as the final response requirement completed before 2 h had elapsed without an injection delivered. Saline and doses of cocaine (0.003-0.3 mg/kg/injection) and MDMA (0.01-0.56 mg/kg/injection) were substituted for the training dose of cocaine for at least five consecutive sessions. Both cocaine and MDMA functioned as reinforcers, but self-administration of MDMA occurred at fewer doses and a significantly lower peak BP was obtained for MDMA. These data demonstrate that MDMA functions as a reinforcer, although its reinforcing efficacy appears to be less than that of cocaine. <P CLASS="SMALL">Copyright 2005, Elsevier Science</P><BR> <H3>Liu ZM; Lu XX; Lian Z; Mu Y; Guo P; An X. Evaluation on drug dependence of buprenorphine. <I Class="H3">Acta Pharmacologica Sinica</I> 24(5): 448-452, 2003. (18 refs.)</H3>Aim: To survey and assess the drug dependence and abuse potential liability of buprenorphine among opiate abusers. Methods: Subjects of opiate dependence with history of buprenorphine use for 3 d at least were surveyed by interview. Physical dependence of buprenorphine was assessed using 30 items opiate withdrawal scale (OWS), which composed of 30 symptoms/signs. A 4-point scale was used to rate each symptoms/signs: zero (0), mild (1), moderate (2), and severe (3). Subjects were asked to rate their symptoms according to severity of previous experienced buprenorphine withdrawal. The estimate of the degree of subjective euphoria for buprenorphine was assessed using visual analogue scale (VAS). Results: Subjects 1235 who met the research criteria cases completed this survey in multi-detoxification treatment centers. The main initial purposes of buprenorphine use were detoxification (77.4%) and protracted abstinence treated (26.6%) respectively. The scores of OWS of buprenorphine were between 0.2 to 1.3. The mean scores of OWS in 3 different categories of frequency of buprenorphine use on "continuous use", "un-continuous use", and "sometimes continuous, sometimes un-continuous" were 0.9+/-0.9, 0.4+/-0.5, and 0.7+/-0.4, respectively (F=70.846, P<0.05). The degree of subjective euphoria for buprenorphine was slight to sub-moderate (mean score of VAS was 27 mm &PLUSMN; 24 mm). The mean scores of VAS in different routes of buprenorphine administration of sublingual and injection were (24&PLUSMN;23) mm. and (27&PLUSMN;24) mm, respectively. No significant difference was found between sublingual and injection use of buprenorphine (u=1.516, P>0.05). Conclusion: Both physical and psychic, dependence of buprenorphine were low. <P CLASS="SMALL">Copyright 2003, Acta Pharmacologica Sinica Inc.</P><BR> <H3>MacKillop J; Murphy JG; Ray LA; Eisenberg DTA; Lisman SA; Lum JK et al. Further validation of a cigarette purchase task for assessing the relative reinforcing efficacy of nicotine in college smokers. <I Class="H3">Experimental and Clinical Psychopharmacology</I> 16(1): 57-65, 2008. (30 refs.)</H3>The authors sought to further validate a cigarette purchase task (CPT), a self-report analogue of a progressive-ratio operant schedule, for the assessment of the relative reinforcing efficacy (RRE) of nicotine in smokers. The measure was assessed in terms of its correspondence to typically observed operant behavior, convergent validity, and divergent validity. Participants were 33 individuals (58% male, age M = 19.30 years) who smoked at least weekly (M = 5.31 cigarettes/day) and underwent a single assessment session. Data from the CPT exhibited the predicted inverse relationship between consumption and price, the predicted relationship between consumption and expenditure, and a heterogeneous pattern of interrelationships among the indices of reinforcement. In addition, 2 indices from the measure, intensity of demand and maximum expenditure for cigarettes, exhibited robust convergent and divergent validity. Although this is an incipient research area and the current study used a relatively small sample, these findings support the validity of a CPT as a time- and cost-efficient method for assessing nicotine reinforcement. Theoretical implications of the findings, limitations, and future directions are also discussed. <P CLASS="SMALL">Copyright 2008, American Psychological Association</P><BR> <H3>Mansbach RS; Feltner DE; Gold LH; Schnoll SH. Incorporating the assessment of abuse liability into the drug discovery and development process. <I Class="H3">Drug and Alcohol Dependence</I> 70(3 Supplement 1): S73-S85, 2003. (55 refs.)</H3>Evaluation of abuse liability is one of many obligations incurred by industrial sponsors in the development of medications acting on substrates in the central nervous system. In addition to providing the information necessary for a scheduling recommendation in the marketing application, the abuse liability assessment allows sponsors to estimate safety and commercial risks associated with scheduling, as well as to tailor their pre- and post-approval programs to collect information relevant to product misuse, illicit diversion and physical dependence. There are several important factors to consider before embarking on an abuse liability assessment, including the compound's primary and secondary biochemical activities, its absorption and metabolism, its final formulation, and its intended clinical population. Each of these factors will temper the timing and extent of the abuse liability program in animals and humans. Although every drug development program is unique in some way, a decision-making process may be applied to abuse liability assessment that will serve to better utilize limited resources and inform decisions regarding subsequent steps in the process. The emerging properties of the product will define the unique procedures best applied to assess it. <P CLASS="SMALL">Copyright 2003, Elsevier Science</P><BR> <H3>Mansbach RS; Moore RA. Formulation considerations for the development of medications with abuse potential. <I Class="H3">Drug and Alcohol Dependence</I> 83(Supplement 1): s15-s22, 2006. (22 refs.)</H3>The availability of increasingly sophisticated drug formulations and delivery devices has created new opportunities in drug development. These newer approaches can result in improved drug bioavailability, or they can alter key pharmacokinetic parameters in such a way as to decrease dosing interval, decrease variability, or blunt maximal concentrations that are associated with adverse events of particular concern. Special formulations or devices can also provide for easier or more convenient dosing in subpopulations of interest, such as children or the elderly. Although the key principles of abuse potential assessment and the underlying neurochemistry and pharmacology are relatively well understood, evaluation of the influences of drug formulation have received much less study. Because dose and formulation - and even the therapeutic indication - are refined over the course of development, it is usually difficult to conduct more than a cursory evaluation of the influence of formulation on the underlying abuse potential of the active pharmaceutical ingredient. Industrial sponsors would benefit from further research in areas of formulation science and pharmacokinetics that would improve the predictability of prescription drug abuse. In particular, validation of new pharmacokinetic parameters and standardization of methods to understand the consequences of product tampering could assist in gaining a better assessment of risk for controlled release formulations. Such methods could apply not only to innovator products, but also to those wishing to develop generic versions with similar pharmaceutical performance. This article proposes several factors that may be of use to industrial sponsors in making formulation choices for drugs with the potential for abuse. <P CLASS="SMALL">Copyright 2006, Elsevier Science</P><BR> <H3>Martins SS; Copersino ML; Soderstrom CA; Smith GS; Dischinger PC; McDuff DR et al. Risk of psychoactive substance dependence among substance users in a trauma inpatient population. <I Class="H3">Journal of Addictive Diseases</I> 26(1): 71-77, 2007. (27 refs.)</H3>One measure of a substance's addictive risk is the proportion of users who become dependent. This study evaluates the lifetime and current risk of substance dependence among lifetime substance users among trauma inpatients and provides a relative ranking of addictive risk among the substances. Data on use of 8 substance groups (alcohol, opiates, cannabis, cocaine, other stimulants, sedative-hypnotics, hallucinogens, other drugs) were obtained by interview (Structured Clinical Interview for the DSM-III-R) from 1,118 adult trauma inpatients. Prevalence of lifetime dependence among lifetime users ranged from 80.7% for opiates and 70.9% for cocaine to 33.3% for hallucinogens and 26.6% for sedative-hypnotics. The rank order of addictive risk was similar to that found in the general population. Trauma inpatients had a higher absolute addictive risk than the general population, comparable to the risk found in patients in treatment for substance use disorders, suggesting the importance of screening trauma inpatients for substance dependence. <P CLASS="SMALL">Copyright 2007, Haworth Press</P><BR> <H3>McColl S; Sellers EM. Research design strategies to evaluate the impact of formulations on abuse liability. <I Class="H3">Drug and Alcohol Dependence</I> 83(Supplement 1): S52-S62, 2006. (64 refs.)</H3>Scheduling of a chemical drug substance under the Controlled Substances Act (CSA) includes an evaluation of preclinical and clinical safety, and experimental abuse liability studies, as well as information on diversion and overdose. Formulations that mitigate abuse liability, dependence potential and public health risks (e.g., altered absorption rate and tamperability, long half-life, pro-drugs and combination products) are amenable to preclinical and clinical studies to compare their abuse potential to reference compounds. For new formulations (NF) as marketed agents, direct comparison to the immediate release (IR) formulation of the reference compound is typically needed across the full range of potential studies. While the public health advantage of formulation changes in the marketplace can be conceptualized in behavioral economic terms, generating persuasive data is challenging. Study complexity increases because of additional conditions (e.g., placebo, 2-3 doses of the IR formulation, 2-3 doses of the new formulation, and 2-3 doses of the unscheduled or negative control drug), larger sample sizes (study power driven by the comparison of the new formulation versus the IR or placebo), and associated increases in study duration. However, the use of single maximal doses of well-characterized controls can reduce the number of study arms, and using incomplete block designs can reduce study duration. Less typical experimental approaches may also be useful, such as human choice or discrimination procedures, or pre-marketing consumer studies among experienced drug tamperers. New formulations that demonstrate a substantial difference from marketed or reference products have a potential marketing advantage and should require less onerous risk management. Post-marketing epidemiological data demonstrating the lack of abuse will carry the most weight from a public health and physician perspective. <P CLASS="SMALL">Copyright 2006, Elsevier Science</P><BR> <H3>McColl SL; Burstein AH; Reeves KR; Billing CB; Stolar M; Sellers EM. Human abuse liability of the smoking cessation drug varenicline in smokers and nonsmokers. <I Class="H3">Clinical Pharmacology and Therapeutics</I> 83(4): 607-614, 2008. (39 refs.)</H3>Varenicline is an alpha(4)beta(2) nicotinic acetylcholine receptor partial agonist developed as an aid for smoking cessation. This study evaluated varenicline's potential for abuse by smokers (n = 23) and nonsmokers (n = 22). The study used a randomized, double-blind, placebo-controlled, double-dummy crossover design with five treatment periods: 15 and 30 mg amphetamine, 1 and 3 mg varenicline, and placebo. Following each treatment, the participants were assessed on aspects relating to potential abuse of the drug (e. g., drug liking, drug high, and drug monetary value). The positive effects measured for 3 mg varenicline were similar to those for the placebo, and significantly lower than those for amphetamine in both smokers and nonsmokers. unpleasant effects were reported for 3 mg varenicline in both participant groups. For 1 mg varenicline, the overall patterns were similar, with the exception that the nonsmokers group showed some small positive effects balanced by some negative effects when compared with the effects of placebo. These findings lead to the conclusion that varenicline is unlikely to be abused. <P CLASS="SMALL">Copyright 2008, Nature Publishing</P><BR> <H3>McCormick CG. Regulatory challenges for new formulations of controlled substances in today's environment. <I Class="H3">Drug and Alcohol Dependence</I> 83(Supplement 1): s63-s76, 2006. (50 refs.)</H3>The pharmaceutical industry has made substantial innovations in the area of targeted drug delivery and optimization of pharmacokinetics for existing drugs to try to maximize therapeutic effect while simultaneously minimizing adverse consequences of medication abuse. These innovations, however, have not come without a price. Designer drugs and high content modified release formulations have been exploited both in casual recreational drug abuse as well as, on a much larger scale, by the criminal diversion of these products for profit. In this paper we will consider the challenges before manufacturers and regulators as they approach the problem of abuse potential of these new drug products and some of the solutions specifically designed to counteract abuse. <P CLASS="SMALL">Copyright 2006, Elsevier Science</P><BR> <H3>Mendelson J; Jones RT. Clinical and pharmacological evaluation of buprenorphine and naloxone combinations: Why the 4:1 ratio for treatment? (review). <I Class="H3">Drug and Alcohol Dependence</I> 70(2, Supplement 1): S29 - S37, 2003. (55 refs.)</H3>Although only a partial small mu, Greek-opiate agonist, buprenorphine can be abused and diverted from medical therapy to the illicit drug market. A combination of buprenorphine and naloxone for sublingual administration may discourage diversion and abuse by precipitating opiate withdrawal when taken parenterally. Because opiate-abusing populations are not homogeneous and have varying levels of opiate dependence, the efficacy of buprenorphine and naloxone in precipitating opiate withdrawal or in attenuating the pleasurable effects of buprenorphine may vary. This chapter describes the effects of sublingual and parenteral buprenorphine and naloxone combinations in several populations of opiate-dependent people. We conclude that buprenorphine and naloxone combinations should not diminish the efficacy of sublingual buprenorphine, but should have lower abuse liability than buprenorphine alone. <P CLASS="SMALL">Copyright 2003, Elsevier Science</P><BR> <H3>Miller SC. Dextromethorphan psychosis, dependence and physical withdrawal. <I Class="H3">Addiction Biology</I> 10(4): 325-327, 2005. (13 refs.)</H3>As part of a synthesis of evidence regarding the abuse and addiction liability of dextromethorphan (DM), an over-the-counter cough medicine available in over 140 preparations, all uncommonly published case of dextromethorphan dependence (addiction) is described, with specific, rarely published complications. The individual was interviewed and several medical databases were also reviewed (Medline, 1966 -present; PubMed) for all content relating to the Keywords: dextromethorphan, abuse, dependence, cough medicine, addiction, withdrawal, psychosis. The patient evidenced history suggesting substance dependence, substance-induced psychosis and substance withdrawal in relation to DM. A literature review revealed that DM has specific serotonergic and sigma-1 opioidergic properties. Dextrolphan (DOR), the active metabolite of DM, has similar properties; however, DOR is a weaker sigma opioid receptor agonist, and a stronger NMDA receptor antagonist. DM and DOR display specific biological features of addiction, and are capable of inducing specific psychiatric sequelae. A specific, reproducible toxidropne with significant psychiatric effects occurred, when DM was abused at greater than indicated doses, with more profound and potentially life-threatening effects at even higher doses. DM withdrawal appears evident. DMs active metabolite, DOR, has pharmacodynamic properties and intoxication effects similar to dissociatives, and may be more responsible for the dissociative effect that this DM abuser sought. However, it is this same metabolite that may be fraught with the potentially life-threatening psychoses and dissociative-induced accidents, as well as addiction. While DM has been hypothesized as the most commonly abused dissociative, health-care providers seem largely unaware of its toxidrome and addiction liability. <P CLASS="SMALL">Copyright 2005, Taylor and Francis Ltd.</P><BR> <H3>Miller SC. Treatment of dextromethorphan dependence with naltrexone. <I Class="H3">Addictive Disorders & Their Treatment</I> 4(4): 145-148, 2005. (22 refs.)</H3>Dextromethorphan has been described as one of the most abused dissociative drugs of abuse in America, yet many clinicians are unaware of its potential for abuse and addiction. A case is presented herein supporting the syndrome of dextromethorphan dependence (addiction), describing this drug's unique pharmacological profile, summarizing what little is known about its associated use, and providing the first known description in the peer-reviewed medical literature of the use of an established anti-relapse medication to treat this medical disease. <P CLASS="SMALL">Copyright 2005, Lippincott, Williams & Wilkins</P><BR> <H3>Mintzer MZ; Griffiths RR. An abuse liability comparison of flunitrazepam and triazolam in sedative drug abusers. <I Class="H3">Behavioural Pharmacology</I> 16(7): 579-584, 2005. (20 refs.)</H3>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 psychornotor 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. <P CLASS="SMALL">Copyright 2005, Lippincott, Williams & Wilkins</P><BR> <H3>Munro CA; McCaul ME; Wong DF; Oswald LM; Zhou Y; Brasic J et al. Sex differences in striatal dopamine release in healthy adults. <I Class="H3">Biological Psychiatry</I> 59(10): 966-974, 2006. (67 refs.)</H3>Background: Sex differences in addictive disorders have been described. Preclinical studies have implicated the striatal dopamine system in these differences, but human studies have yet to substantiate these findings. Methods: Using positron emission tomography (PET) scans with high-specific-activity [C-11] raclopride and a reference tissue approach, we compared baseline striatal dopamine binding potential (BP) and dopamine release in men and women following amphetamine and placebo challenges. Subjective drug effects and plasma cortisol and growth hormone responses were also examined. Results: Although there was no sex difference in baseline BP, men had markedly greater dopamine release than women in the ventral striatum. Secondary analyses indicated that men also had greater dopamine release in three of four additional striatal regions. Paralleling the PET findings, men's ratings of the positive effects of amphetamine were greater than women's. We found no sex difference in neuroendocrine hormone responses. Conclusions: We report for the first time a sex difference in dopamine release in humans. The robust dopamine release in men could account for increased vulnerability to stimulant use disorders and methamphetamine toxicity. Our findings indicated that future studies should control for sex and may have implications for the interpretation of sex differences in other illnesses involving the striatum. <P CLASS="SMALL">Copyright 2006, Elsevier Science</P><BR> <H3>O'Brien MS; Anthony JC. Risk of becoming cocaine dependent: Epidemiology estimates for the United States, 2000-2001. <I Class="H3">Neuropsychopharmacology</I> 30(5): 1006-1018, 2005. (33 refs.)</H3>In this paper, we present new estimates for the risk of becoming cocaine dependent within 24 months after first use of the drug, and study subgroup variation in this risk. The study estimates are based on the National Household Survey on Drug Abuse conducted during 2000-2001, with a representative sample of US residents aged 12 years and older (n = 114 241). A total of 1081 respondents were found to have used cocaine for the first time within 24 months prior to assessment. Between 5 and 6% of these recent-onset users had become cocaine dependent since onset of use. Excess risk of recent cocaine dependence soon after onset of cocaine use was found for female subjects, young adults aged 21-25 years, and non-Hispanic Black/African-Americans. Use of crack-cocaine and taking cocaine by injection were associated with having become cocaine dependent soon after onset of use. These epidemiologic findings help to quantify the continuing public health burden associated with new onsets of cocaine use in the 21st century. <P CLASS="SMALL">Copyright 2005, American College of Neuropsychopharmacology</P><BR> <H3>Owens C; Pugmire B; Salness T; Culbertson V; Force R; Cady P et al. Abuse potential of carisoprodol: A retrospective review of Idaho medicaid pharmacy and medical claims data. <I Class="H3">Clinical Therapeutics</I> 29(10): 2222-2225, 2007. (17 refs.)</H3>Background: Carisoprodol is a muscle relaxant indicated as adjunctive therapy in acute, painful musculoskeletal conditions. Case reports of drug-seeking behavior and utilization of carisoprodol in combination with opioids have suggested abuse potential. Objectives: We undertook a retrospective review of claims data to identify and characterize potential indicators of abuse in long-term users of carisoprodol and to determine any continued use of the drug by former long-term users following prior authorization implementation. Methods: The Idaho Medicaid pharmacy and medical claims database was queried from January 1 to December 31, 2005, to identify long-term users of muscle relaxants. Use of concomitant opiolds and coded diagnoses relating to past drug abuse were analyzed,zed and compared between patients who used carisoprodol and patients who used other muscle relaxants. Data from 11 of 30 surveys mailed to pharmacies filling prescriptions for long-term users of carisoprodol were also collected to determine the frequency of self-pay-continued use after Medicaid coverage of the drug was discontinued. Results: Long-term users of carisoprodol (n = 340) and other skeletal muscle relaxants (SMRs) (n = 453) were identified from among 130,000 individuals in the Idaho Medicaid pharmacy and medical claims database in calendar year 2005. Patients in both groups were similar in terms of mean age (-47 years) and sex (71.5% female). Patients using carisoprodol used concomitant oploids more frequently (81.5% vs 59.8%; P < 0.01), more commonly had past diagnoses indicating other drug abuse (34.1% vs 21.4%; P < 0.01), and in 80% of reported cases, continued to pay out of pocket for carlsoprodol when third-party coverage was discontinued. Taken together, these findings are consistent with published case reports suggesting the abuse potential of carlsoprodol. Conclusions: The results from this review suggest that, compared with long-term users of other SMRs, carisoprodol patients utilized concomitant opioids more frequently and concomitant NSAIDs less frequently, more commonly had past diagnoses indicating other drug dependence or abuse, and continued to pay out of pocket for carisoprodol when third-party coverage was discontinued. While none of these issues alone may be direct indicators of abuse, collectively they suggest that patients who used carisoprodol long term displayed abuse potential characteristics more frequently than long-term users of other agents. <P CLASS="SMALL">Copyright 2007, Elsevier Science</P><BR> <H3>Parasrampuria DA; Schoedel KA; Schuller R; Silber SA; Ciccone PE; Gu J et al. Do formulation differences alter abuse liability of methylphenidate? - A placebo-controlled, randomized, double-blind, crossover study in recreational drug users. <I Class="H3">Journal of Clinical Psychopharmacology</I> 27(5): 459-467, 2007. (35 refs.)</H3>The primary objective of this study was to determine if the abuse liability of methylphenidate is governed by formulation differences that affect rates of drug delivery. In this double-blind, placebo-controlled, randomized, crossover study, subjects with a history of recreational drug use received single oral doses of placebo, 60 mg of immediate-release methylphenidate (IR) and 108 mg of extended-release methylphenidate (osmotic release oral system [OROS]). Over 24 hours after dosing, blood was collected to determine plasma concentrations of methylphenidate, and subjects completed subjective assessments of abuse liability (Addiction Research Center Inventory, Drug Rating Questionnaire-Subject, and Subjective Drug Value). The abuse-related subjective effects of IR and OROS methylphenidate were statistically significantly different from placebo, confirming the overall validity of the study. Although a higher dose of OROS methylphenidate was used compared with IR methylphenidate (108 mg vs 60 mg), subjective effects were consistently lower for OROS compared with IR methylphenidate (statistically significant for 3 of 6 measures of positive effects), particularly at early time points. In general, pharmacokinetic-pharmacodynamic parameters were correlated from a poor to modest degree, with greater correlations observed for IR methylphenidate. In addition,, a post hoc "qualification" method was developed, which demonstrated that pharmacological qualification might improve the assessment of subjective effects. Although requiring epidemiological confirmation, the results suggest that OROS methylphenidate, with its characteristic slow ascending plasma concentration profile, may have lower abuse potential. This conclusion is reflected by lower subjective responses during early hours as compared with the IR formulation with its rapid drug delivery and accompanying greater subjective effects. <P CLASS="SMALL">Copyright 2007, Lippincott, Williams & Wilkins</P><BR> <H3>Pragst F; Herre S; Bakdash A. Poisonings with diphenhydramine: A survey of 68 clinical and 55 death cases. <I Class="H3">Forensic Science International</I> 161(2-3): 189-197, 2006. (30 refs.)</H3>The antihistaminic drug diphenhydramine (DPH) is mainly used as a sedative, hypnotic and antiemetic. In many countries it is over-the-counter available, very common, and generally regarded as a harmless drug. Sixty-eight non-fatal and 55 fatal poisonings with DPH alone or in combination with other drugs were investigated in the Institute of Legal Medicine of the University Hospital Charite between 1992 and 2004. The analytical investigations were performed by HPLC with photodiode array detector (HPLC-DAD). The DPH concentrations ranged from 0.5 to 8.9 mu g/mL in the non-fatal cases and from 0.3 to 119 mu g/mL in fatal cases. The intoxication symptoms stated during emergency admission were inconsistent, with somnolence, sedation and retardation on one hand and tachycardia, anticholinergic syndrome, agitation, hallucinations, confusion, tremor, convulsions, delirium and coma on the other. In three cases rhabdomyolysis occurred. A concentration above 5 mu g/mL can be regarded as potentially lethal. In many of the survivors the time course of the concentrations of DPH and the metabolites desmethyldiphenhydramine (DM-DPH) and diphenylmethoxyacetic acid (DPMA) were investigated. Whereas DM-DPH is present in blood from the very beginning because of the high first pass metabolism, DPMA is slowly formed over several metabolic steps. For this reason, the concentration ratio DPMA/DPH can be used for an approximate estimation of the time between drug intake and sampling in clinical cases or of the survival time after drug ingestion in death cases. In some of the deaths the concentrations in heart blood were much higher than in venous blood. This is explained mainly by agonal aspiration of the vomited gastric content. Besides the majority of suicidal cases also a case of child maltreatment and a case, in which the drug was forcibly administrated in a drug facilitated crime, were investigated. From the results it follows that diphenhydramine is not less poisonous than other prescribed hypnotics. However, despite the hallucinogenic effects, an abuse for recreational purposes was not observed until now. <P CLASS="SMALL">Copyright 2006, Elsevier Science</P><BR> <H3>Rasu RS; Shenolikar RA; Nahata MC; Balkrishnan R. Physician and patient factors associated with the prescribing of medications for sleep difficulties that are associated with high abuse potential or are expensive: An analysis of data from the National Ambulatory Medical Care Survey for 1996-2001. <I Class="H3">Clinical Therapeutics</I> 27(12): 1970-1979, 2005. (47 refs.)</H3>Objective: This study evaluated the association betwee