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Director's Report to the National Advisory Council on Drug Abuse - May, 2008

Research Findings - Research on Pharmacotherapies for Drug Abuse

Cocaine Withdrawal Symptoms Identify "Type B" Cocaine-dependent Patients

Recent studies of substance dependence typologies briefly show that multivariate systems originally developed for identifying subtypes of alcoholics, such as Babor's Type A and B system may also be valid in abusers of other substances, such as cocaine. Type B patients are characterized by an earlier onset of addiction and more severe symptoms of their addiction, psychopathology, and impulsivity. The Type B classification has also been associated with deficits in serotonergic function. The investigators have found that patients who exhibit more severe cocaine withdrawal symptoms, as measured by scores on the Cocaine Selective Severity Assessment (CSSA), have poor treatment outcome and share many characteristics with "Type B" patients. In this paper, the investigators review baseline characteristics of cocaine-dependent patients from several recently completed outpatient cocaine dependence treatment trials to assess the association of cocaine withdrawal symptom severity and the Type B profile. Identifying subtypes of cocaine-dependent patients may improve our ability to treat cocaine dependence by targeting treatments for specific subtypes of patients. The investigators examined the ability of the CSSA scores to capture Type B characteristics in cocaine dependence by analyzing a series of cocaine medication trials that included 255 cocaine-dependent subjects. High CSSA scores at baseline were associated with a history of violent behavior, a family history of substance abuse, antisocial personality disorder, higher addiction severity, and co-morbid psychiatric diseases. Patients with high CSSA scores are also more likely to meet criteria for Type B (Type II) cocaine dependence. Identifying Type B cocaine-dependent patients may help to develop targeted psychosocial or pharmacological treatments for these difficult-to-treat patients. Ahmadi, J., Kampman, K., Dackis, C., Sparkman, T., and Pettinati, H. Cocaine Withdrawal Symptoms Identify "Type B" Cocaine-dependent Patients. Am. J. Addict., 17, pp. 60-64, 2008.

Effects of Co-morbid Major Depressive Disorder (MDD) or Attention-Deficit/Hyperactivity Disorder (ADHD) on the Outcome of Pharmacological Treatment for Cocaine Dependence

Cocaine-dependent patients with MDD (n=66), ADHD (n=53), or those subjects without co-morbid disorders (cocaine-dependent alone, n=48) were treated for 12-weeks with venlafaxine, methylphenidate, or gabapentin, respectively, in concurrent single-blind, placebo-controlled clinical trials. Using logistic-regression modeling techniques, it was found that patients with either MDD or ADHD exhibited an improved outcome over time compared with patients with CD alone - if abstinence was achieved at baseline. However, if subjects remained cocaine-dependent at baseline, patients with either MDD or ADHD were associated with poorer outcome as compared with patients with CD alone. These findings suggest that the diagnosis and treatment of co-occurring disorders such as depression or ADHD may be important aspects of treatment planning for cocaine-dependence and indicate that the baseline level of cocaine use should be included as a covariate in the clinical evaluation of such treatment. Levin, F.R., Bisaga, A., Raby, W., Aharonovich, E., Rubin, E., Mariani, J., Brooks, D.J., Garawi, F., and Nunes, E.V. Effects of Major Depressive Disorder and Attention-Deficit/Hyperactivity Disorder on the Outcome of Treatment for Cocaine Dependence. J. Subst. Abuse Treat. 34(1), pp. 80-89, 2008.

Cocaine Users Differ from Normals on Cognitive Tasks which Show Poorer Performance During Drug Abstinence

In this publication, seventeen non-treatment seeking cocaine-dependent individuals participated in three-week longitudinal inpatient studies of cognitive changes during drug use and abstinence. Protocols included three days drug-free baseline, three days cocaine self-administration, and two weeks complete abstinence. A repeatable cognitive battery showed attention and delayed verbal recognition memory but not working memory to be impaired in cocaine users compared to age- and sex-matched normative values. Attention was significantly poorer during the first and second week of abstinence compared to days on which cocaine was used, suggesting that certain cocaine-induced impairments may be acutely normalized by cocaine use, but may resurface during abstinence. Pace-Schott E.F., Morgan P.T., Malison R.T., Hart C.L., Edgar C., Walker M., and Strickgold R. Cocaine Users Differ from Normals on Cognitive Tasks which Show Poorer Performance During Drug Abstinence. Am. J. of Drug and Alcohol Abuse, 34(1), pp. 109-121, 2008.

A Randomized, Double-Blind, Placebo-Controlled Trial of Long-Acting Risperidone in Cocaine-Dependent Men

There is no approved pharmacotherapy for cocaine dependence. Risperidone is an atypical antipsychotic drug with combined dopamine-2/serotonin-2 (D(2)/5-HT(2)) antagonist activity that has been effective in reducing cocaine use in some animal studies. The investigators tested the efficacy of a long-acting, injectable preparation of risperidone on cocaine use in active cocaine users. Thirty-one cocaine-dependent men who met DSM-IV diagnostic criteria for current cocaine dependence entered a 12-week, randomized, double-blind, placebo-controlled trial of intramuscular risperidone, 25 mg every other week. The primary outcome measure was cocaine use as measured by urinary concentration of cocaine metabolites. Secondary outcomes were self-report of cocaine use and craving, depressive symptoms as measured by the Hamilton Rating Scale for Depression (HAM-D), and adverse events. Participants were recruited during a 12-month period from October 2005 to September 2006. Both groups reduced their cocaine use during the study. There were no between-group differences in the primary measure of cocaine use (urinary metabolites [F = 0.7, p = .41]) or on craving measures. Those assigned to risperidone reported significantly worsened depressive symptoms (mean +/- SD HAM-D change scores: +7.4 +/- 8.8 vs. -2.3 +/- 5.8, respectively, F = 7.5, p = .018) and gained significantly more weight (mean weight change: +6.3 +/- 9.4 lb vs. -4.0 +/- 8.9 lb, respectively, F = 4.65, p = .044) than those assigned to placebo. Treatment with long-acting injectable risperidone in active cocaine users was not associated with reduction in cocaine use or craving and was associated with worsening of depressive symptoms and weight gain. Loebl, T., Angarita, G. A., Pachas, G. N., Huang, K. L., Lee, S. H., Nino, J. et al. A Randomized, Double-Blind, Placebo-Controlled Trial of Long-Acting Risperidone in Cocaine-Dependent Men. J. Clin. Psychiatry, pp. e1-e7, 2008.

Levodopa Pharmacotherapy for Cocaine Dependence: Choosing the Optimal Behavioral Therapy Platform

The dopamine precursor levodopa has shown some, albeit relatively weak, promise in treating cocaine dependence. This study sought to identify the most appropriate behavioral therapy platform for levodopa pharmacotherapy by evaluating its effect when administered in combination with behavioral platforms of varying intensities. A total of 161 treatment-seeking cocaine dependent subjects received sustained release levodopa/carbidopa (400/100mg bid, Sinemet) or placebo delivered in combination with Clinical Management (ClinMan); ClinMan+cognitive behavioral therapy (CBT); or ClinMan+CBT+voucher-based reinforcement therapy (VBRT) in a 12-week randomized, placebo-controlled, double-blind (for medication condition) trial. Medication compliance was monitored with riboflavin (100mg/capsule) and the Medication Event Monitoring System. Protocol compliance was addressed in weekly, 10-min nurse-delivered ClinMan sessions. Weekly, 1-h CBT sessions focused on coping skills training. VBRT (with escalating reinforcer value) provided cash-valued vouchers contingent on cocaine-negative urine toxicology results. Urine benzoylecgonine assays collected thrice-weekly were analyzed by intention-to-treat criteria using generalized linear mixed models. Levodopa main effects were found on all outcome measures of cocaine use. Contrasts testing the levodopa-placebo difference within each behavioral platform found reliable effects, favoring levodopa, only in the VBRT platform. Levodopa treatment with vouchers produced higher proportions of cocaine-negative urines and longer periods of consecutive abstinence compared to other treatment combinations. This is the first study to find a significant treatment effect for levodopa and, in doing so, to demonstrate that the magnitude of this effect is dependent upon conditions of the behavioral therapy platform. The data support use of levodopa with abstinence-based reinforcement therapy as one efficacious combination in cocaine dependence disorder treatment. Schmitz, J.M., Mooney, M.E., Moeller, F.G., Stotts, A.L., Green, C., and Grabowski, J. Levodopa Pharmacotherapy for Cocaine Dependence: Choosing the Optimal Behavioral Therapy Platform. Drug Alcohol Depend., 94, pp. 142-150, 2008.

A Double Blind, Placebo-Controlled Trial that Combines Disulfiram and Naltrexone for Treating Co-occurring Cocaine and Alcohol Dependence

This is a double blind, placebo-controlled trial that evaluated the efficacy of disulfiram, naltrexone and their combination in patients with co-occurring cocaine and alcohol dependence. Two-hundred eight patients were randomized to disulfiram (250 mg/day), naltrexone (100 mg/day), the combination, or placebo for 11 weeks. Outcomes were in-trial abstinence from cocaine and/or alcohol. Few safety concerns were reported, although medication adherence was low in a number of patients for both medications, alone or in combination. In the primary analyses (GEE modeling), abstinence from cocaine as measured by cocaine-negative urines and days of self-reported abstinence from cocaine or alcohol did not differ between placebo and any of the medication groups. However, patients taking disulfiram (alone or in combination) were most likely to achieve combined abstinence from cocaine and alcohol. Secondary analyses revealed that patients taking the disulfiram-naltrexone combination were most likely to achieve 3 consecutive weeks of abstinence from cocaine and alcohol. There was an association between disulfiram treatment and abstinence from cocaine and alcohol. More patients taking the disulfiram-naltrexone combination achieved 3 consecutive weeks of abstinence in treatment than placebo-treated patients. Pettinati, H.M., Kampman, K.M., Lynch, K.G., Xie, H., Dackis, C., Rabinowitz, A.R. et al. A Double Blind, Placebo-Controlled Trial that Combines Disulfiram and Naltrexone for Treating Co-occurring Cocaine and Alcohol Dependence. Addict. Behav., 33, pp. 651-667, 2008.

Treatment of Opioid-Dependent Pregnant Women: Clinical and Research Issues

This article addresses common questions that clinicians face when treating pregnant women with opioid dependence. Guidance, based on both research evidence and the collective clinical experience of the authors, which include investigators in the Maternal Opioid Treatment: Human Experimental Research (MOTHER) project, is provided to aid clinical decision making. The MOTHER project is a double-blind, double-dummy, flexible-dosing, parallel-group clinical trial examining the comparative safety and efficacy of methadone and buprenorphine for the treatment of opioid dependence in pregnant women and their neonates. The article begins with a discussion of appropriate assessment during pregnancy and then addresses clinical management stages including maintenance medication selection, induction, and stabilization; opioid agonist medication management before, during, and after delivery; pain management; breast-feeding; and transfer to aftercare. Lastly, other important clinical issues including managing co-occurring psychiatric disorders and medication interactions are discussed. Treatment of Opioid-Dependent Pregnant Women: Clinical and Research Issues. Jones, H.E., Martin, P.R., Heil, S.H., Kaltenbach., Selby, P., Coyle, M.G., Stine, S.M., O'Grady, K.E., Arria, A.M., and Fischer, G. J. Substance Abuse Treat., Jan 11, 2008.

Opioid Use Disorder in the United States: Insurance Status and Treatment Access

In the United States, insurance status and rates of treatment for individuals with opioid use disorder are unknown. This study employed a cross-sectional survey: 2002-2004 National Survey on Drug Use and Health (NSDUH). Bivariate and multivariate associations between demographics, treatment and insurance status and presence or absence of opioid use disorder were investigated. On unadjusted analysis, young respondents, respondents of Hispanic ethnicity (OR 1.5; 95% CI 1.1-2.2), unemployed respondents (OR 2.6; 95% CI 1.8-3.8) and respondents with Medicaid (OR 4.5; 95% CI 2.5-8.3) or lack of insurance (OR 3.2; 95% CI 1.8-5.9) were more likely to have opioid use disorder. On unadjusted analysis among those with any substance use disorder, 12-16 year olds were more likely to have opioid use disorder (OR 3.4; 95% CI 2.0-5.8) than a non-opioid substance use disorder, as were women (OR for men 0.6; 95% CI 0.5-0.7) and unemployed respondents (OR 1.5; 95% CI 1.02-2.1). Only 15.2% of those with past-year opioid use disorder received treatment in the past year. Respondents treated for opioid use had higher rates of Medicaid (p<0.01), Medicare (p<0.01) and other public assistance (p=0.01) compared with those treated for other substances. Treatments for opioid use were more likely to be hospital (p=0.04) and inpatient rehabilitation (p=0.02) settings compared to treatment for other substance use. Among those with opioid use disorder, not being employed was independently associated with receiving treatment (AOR 3.5; 95% CI 1.4-8.5). The authors conclude that in the U.S., high rates of unemployment, Medicaid and uninsurance among those with opioid use disorder and low rates of treatment suggest that efforts to expand treatment must include policy strategies to help reach a population with significant barriers to treatment access. Becker, W.C., Fiellin, D.A., Merrill, J.O., Schulman, B., Finkelstein, R., Olsen, Y. et al. Opioid Use Disorder in the United States: Insurance Status and Treatment Access. Drug Alcohol Depend., 94, pp. 207-213, 2008.

Office-based Maintenance Treatment of Opioid Dependence: How Does It Compare with Traditional Approaches?

The increasing global public health burden of heroin dependence and prescription opioid dependence warrants further expansion of treatment models. The most effective intervention for opioid dependence remains maintenance with methadone, a full mu-opioid receptor agonist, or buprenorphine, a partial mu-opioid receptor agonist.A growing body of evidence supports the use of opioid receptor agonist maintenance in office-based settings. Office-based opioid treatment (OBOT) can expand treatment access in a less stigmatized environment, which enables integrated care of co-morbid conditions. The current review primarily examines OBOT in the US, although a comparison with the British and French models is provided, given that the public health impact and implementation of OBOT will likely vary between countries because of policy and logistical differences. The comparative effectiveness of maintenance treatment in office-based and traditional programme-based models of care requires further study. Clinical and practical considerations when providing treatment for opioid dependence in traditional versus office-based settings include patient selection and monitoring, health economics, management of co-morbid conditions, and access to ancillary psychosocial treatment. OBOT is not a replacement for more structured, traditional models of care, but provides an additional opportunity to help address the tremendous public health impact of opioid dependence. Gunderson, E.W. and Fiellin, D.A. Office-based Maintenance Treatment of Opioid Dependence: How Does it Compare with Traditional Approaches? CNS Drugs, 22, pp. 99-111, 2008.

Cannabis Reinforcement and Dependence: Role of the Cannabinoid CB1 Receptor

Awareness of cannabis dependence as a clinically relevant issue has grown in recent years. Clinical and laboratory studies demonstrate that chronic marijuana smokers can experience withdrawal symptoms upon cessation of marijuana smoking and have difficulty abstaining from marijuana use. This paper will review data implicating the cannabinoid CB1 receptor in regulating the behavioral effects of Delta(9)-tetrahydrocannabinol (THC), the primary psychoactive component of cannabis, across a range of species. The behavioral effects that will be discussed include those that directly contribute to the maintenance of chronic marijuana smoking, such as reward, subjective effects, and the positive and negative reinforcing effects of marijuana, THC and synthetic cannabinoids. The role of the CB1 receptor in the development of marijuana dependence and expression of withdrawal will also be discussed. Lastly, treatment options that may alleviate withdrawal symptoms and promote marijuana abstinence will be considered. Cooper, Z.D. and Haney, M. Cannabis Reinforcement and Dependence: Role of the Cannabinoid CB1 Receptor. Addict. Biol. Epub ahead of print, 2008.

Cannabis Withdrawal is Common Among Treatment-Seeking Adolescents with Cannabis Dependence and Major Depression, and is Associated with Rapid Relapse to Dependence

Recently, reports have suggested that cannabis withdrawal occurs commonly in adults with cannabis dependence, though it is unclear whether this extends to those with comorbid depression or to comorbid adolescents. The investigators hypothesized that cannabis withdrawal would be common among our sample of comorbid adolescents and young adults, and that the presence of cannabis withdrawal symptoms would be associated with a self-reported past history of rapid reinstatement of cannabis dependence symptoms (rapid relapse). The participants in this study included 170 adolescents and young adults, including 104 with cannabis dependence, 32 with cannabis abuse, and 34 with cannabis use without dependence or abuse. All of these subjects demonstrated current depressive symptoms and cannabis use, and most demonstrated current DSM-IV major depressive disorder and current comorbid cannabis dependence. These subjects had presented for treatment for either of two double-blind, placebo-controlled trials involving fluoxetine. Cannabis withdrawal was the most commonly reported cannabis dependence criterion among the 104 subjects in our sample with cannabis dependence, being noted in 92% of subjects, using a two-symptom cutoff for determination of cannabis withdrawal. The most common withdrawal symptoms among those with cannabis dependence were craving (82%), irritability (76%), restlessness (58%), anxiety (55%), and depression (52%). Cannabis withdrawal symptoms (in the N=170 sample) were reported to have been associated with rapid reinstatement of cannabis dependence symptoms (rapid relapse). These findings suggest that cannabis withdrawal should be included as a diagnosis in the upcoming DSM-V, and should be listed in the upcoming criteria list for the DSM-V diagnostic category of cannabis dependence. Cornelius, J.R., Chung, T., Martin, C., Wood, D.S., and Clark, D.B. Cannabis Withdrawal is Common Among Treatment-seeking Adolescents with Cannabis Dependence and Major Depression, and is Associated with Rapid Relapse to Dependence. Addict. Behav., Epub ahead of print, 2008.

Effects of THC and Lofexidine in a Human Laboratory Model of Marijuana Withdrawal and Relapse

Individuals seeking treatment for their marijuana use rarely achieve sustained abstinence. The objectives of the study are to determine if THC, a cannabinoid agonist, and lofexidine, an alpha(2)-adrenergic receptor agonist, given alone and in combination, decreased symptoms of marijuana withdrawal and relapse, defined as a return to marijuana use after a period of abstinence. Nontreatment-seeking, male volunteers (n = 8), averaging 12 marijuana cigarettes/day, were maintained on each of four medication conditions for 7 days: placebo, tetrahydrocannabinol (THC) (60 mg/day), lofexidine (2.4 mg/day), and THC (60 mg/day) combined with lofexidine (2.4 mg/day); each inpatient phase was separated by an outpatient washout phase. During the first three inpatient days, placebo marijuana was available for self-administration (withdrawal). For the next 4 days, active marijuana was available for self-administration (relapse). Participants paid for self-administered marijuana using study earnings. Self-administration, mood, task performance, food intake, and sleep were measured. THC reversed the anorexia and weight loss associated with marijuana withdrawal, and decreased a subset of withdrawal symptoms, but increased sleep onset latency, and did not decrease marijuana relapse. Lofexidine was sedating, worsened abstinence-related anorexia, and did not robustly attenuate withdrawal, but improved sleep and decreased marijuana relapse. The combination of lofexidine and THC produced the most robust improvements in sleep and decreased marijuana withdrawal, craving, and relapse in daily marijuana smokers relative to either medication alone. These data suggest the combination of lofexidine and THC warrant further testing as a potential treatment for marijuana dependence. Haney, M., Hart, C.L., Vosburg, S.K., Comer, S.D., Reed, S.C., and Foltin, R.W. Effects of THC and Lofexidine in a Human Laboratory Model of Marijuana Withdrawal and Relapse. Psychopharmacology (Berl), 197, pp. 157-168, 2008.

The Acetylcholinesterase Inhibitor Rivastigmine Does Not Alter Total Choices for Methamphetamine, but May Reduce Positive Subjective Effects, in a Laboratory Model of Intravenous Self-administration in Human Volunteers

A human laboratory model of intravenous methamphetamine self-administration may facilitate study of putative treatments for methamphetamine addiction. The investigators conducted a double-blind, placebo-controlled, between groups investigation of the acetylcholinesterase (AChE) inhibitor rivastigmine in non-treatment-seeking volunteers who met criteria for methamphetamine abuse or dependence. Safety and subjective effects data derived from days 1-10 of this protocol are described in a separate publication. In this report, the investigators describe self-administration outcomes in participants randomized to treatment with rivastigmine (0 mg, N=7; 1.5 mg, N=6; 3 mg, N=9); data that were collected on days 11-15 of the inpatient protocol. On day 11, participants sampled two infusions of methamphetamine (0 and 30 mg, IV). On days 12-15, participants made ten choices each day to receive an infusion of either methamphetamine (3 mg, IV) or saline or a monetary alternative ($0.05-$16). The study design allowed for evaluation of differences in behavior on days in which infusions were performed by the physician (experimenter-administered) versus by the participant using a PCA pump (self-administered), and when monetary alternatives were presented in either ascending or descending sequence. The data show that rivastigmine (1.5 and 3 mg), as compared to placebo, did not significantly alter total choices for methamphetamine (p=0.150). Importantly, the number of infusion choices was greater when methamphetamine was available then when saline was available (p<0.0001), and the number of money choices was greater when saline was available then when methamphetamine was available (p<0.0001). The total number of choices for methamphetamine was not altered as a function of a participant's preferred route of methamphetamine use (p=0.57), and did not differ significantly whether they were experimenter-administered or self-administered (p=0.30). In addition, total choices for methamphetamine were similar when money was available in an ascending versus descending sequence (p=0.49). The participants' years of methamphetamine use, recent use of methamphetamine (in the past 30 days), or baseline craving (indexed here as "Desire") on the day of the self-administration task were not predictive of number of choices for methamphetamine. In a subset of participants (N=8) for which data was available, individual dose of methamphetamine (3x3 mg, IV) produced significant increases in positive subjective effects, and a preliminary analysis revealed that 3 mg rivastigmine was associated with reductions in these responses, as compared to placebo. In summary, the current report indicates that there were no effects of rivastigmine on total choices for methamphetamine, that there were low levels of methamphetamine self-administration but these were 8 times greater than saline, and that choice behavior was insensitive to alternative reinforcers. In addition, the investigators showed that rivastigmine may reduce the positive subjective effects produced by methamphetamine during self-administration. De La, G.R., Mahoney, J.J., III, Culbertson, C., Shoptaw, S., and Newton, T.F. The Acetylcholinesterase Inhibitor Rivastigmine Does Not Alter Total Choices for Methamphetamine, but May Reduce Positive Subjective Effects, in a Laboratory Model of Intravenous Self-administration in Human volunteers. Pharmacol. Biochem. Behav., 89, pp. 200-208, 2008.

Evaluation of the Cardiovascular and Subjective Effects of Rivastigmine in Combination with Methamphetamine in Methamphetamine-Dependent Human Volunteers

Acetylcholine (ACh) has been implicated in the reinforcing and locomotor-activating effects produced by methamphetamine (Meth). Of interest, recent data suggest that acetylcholinesterase (AChE) inhibitors attenuate Meth-seeking behaviour in rats. The investigators conducted this study in order to determine the safety (adverse events, mood changes, cardiovascular effects) and preliminary efficacy (subjective effects) of the AChE inhibitor rivastigmine (Riv) when tested in combination with Meth. Twenty-three non-treatment-seeking Meth-dependent participants resided in an in-patient unit at UCLA for 2 wk, and completed this double-blind, between-subjects, placebo-controlled study. Prior to randomization to study drug, infusions of saline (day 4, 0 mg i.v.) and Meth (day 5, 30 mg i.v.) were given to all participants at 11:30 hours in single-blinded fashion. On day 7 and continuing to day 11, participants were randomized to receive oral placebo (0 mg, n=7) or Riv (1.5 mg, n=7; 3 mg, n=9). On day 11, the subjects received saline and Meth infusions again (randomized to either 11:30 or 14:30 hours), under double-blind conditions. The data analyses compared across-study measures of adverse events and mood, and a post-randomization analysis of cardiovascular and subjective effects (on day 11). The data reveal that rivastigmine was not associated with increased adverse events or alterations in mood. As expected, acute Meth exposure (30 mg i.v.) increased heart rate and blood pressure, as well as several positive subjective effects, Addiction Research Center Inventory (ARCI) ratings, and reported monetary value (p<0.05). The data indicated that Riv, at 3 mg, significantly attenuated Meth-induced increases in diastolic blood pressure, and self-reports of 'anxious' and 'desire' (p<0.05). Taken together, the findings in the current report suggest that pharmacological manipulations that enhance brain ACh warrant continued investigation as potential treatments for Meth addiction. De La, G.R., Shoptaw, S., and Newton, T.F. Evaluation of the Cardiovascular and Subjective Effects of Rivastigmine in Combination with Methamphetamine in Methamphetamine-Dependent Human Volunteers. Int. J. Neuropsychopharmacol., pp. 1-13, 2008.

Residual Effects of Intranasal Methamphetamine on Sleep, Mood, and Performance

Although intranasal methamphetamine abuse has increased, there are no published data investigating the residual effects of the drug under controlled conditions. Thus, the current study examined the residual effects of single-dose intranasal methamphetamine administration on a broad range of behavioral and physiological measures. Non-treatment seeking methamphetamine abusers (n=11) completed this two-week, in patient, within-participant, double-blind study. The study consisted of four two-day blocks of sessions; each block was separated by at least 48h. At approximately 10:00h, on the first day of each block, participants received one of four intranasal methamphetamine doses (0, 12, 25, 50mg/70kg). Lights were turned out at 23:00h that evening and sleep measures were assessed. On the morning of the second day of each block, methamphetamine plasma levels, cardiovascular measures, mood, subjective reports of the previous evening's sleep, and psychomotor performance were assessed to determine residual drug effects. The larger methamphetamine doses (25 and 50mg) markedly disrupted subjective measures of that night's sleep and some indices of next-day mood, but only the largest dose (50mg) decreased objective measures of that night's sleep and increased next-day physiological measures. Methamphetamine did not produce any negative residual effects on early next-day performance. Future studies should assess methamphetamine-related residual effects following repeated doses administered over consecutive days. Perez, A.Y., Kirkpatrick, M.G., Gunderson, E.W., Marrone, G., Silver, R., Foltin, R.W. et al. Residual Effects of Intranasal Methamphetamine on Sleep, Mood, and Performance. Drug Alcohol Depend., 94, pp. 258-262, 2008.

Riluzole and D-amphetamine Interactions in Humans

In preclinical studies, medications which decrease glutamate release have been shown to block some of the effects of psychostimulants. One such medication is riluzole, marketed for the treatment of Amyotrophic Lateral Sclerosis (ALS). The goal of this study was to determine riluzole's effects on acute physiological and subjective responses to d-amphetamine in healthy volunteers. Seven male and 5 female subjects participated in an outpatient double-blind, placebo-controlled, crossover study. Across 4 sessions, subjects were randomly assigned to a sequence of 4 oral treatments: placebo, 20 mg D-amphetamine alone, 100 mg riluzole alone, or d-amphetamine plus riluzole. Outcome measures included heart rate, blood pressure, plasma cortisol, performance on the Sustained Attention to Response Test (SART), and subjective measures. D-amphetamine increased heart rate, blood pressure and plasma cortisol levels while inducing psychostimulant-type subjective effects. On the SART, d-amphetamine enhanced the speed of correct responses but also significantly increased the number of errors of commission. Riluzole at 100 mg did not block the typical subjective and physiological responses to 20 mg D-amphetamine. Riluzole alone induced amphetamine-like subjective responses. On the SART test, riluzole increased the number errors of commission, but unlike d-amphetamine, did not speed reaction time. The mechanism accounting for these findings is unclear, but may involve processes other than decreased glutamate release by riluzole. The effects of glutamate medications on psychostimulant responses need to be further examined. Sofuoglu, M., Waters, A.J., Mooney, M., and Kosten, T. Riluzole and D-amphetamine Interactions in Humans. Prog. Neuropsychopharmacol. Biol. Psychiatry, 32, pp. 16-22, 2008.

Profile of Lifetime Methamphetamine Use Among Homeless Adults in Los Angeles

Although the dramatic rise of methamphetamine use in the general population has been well-documented, little is known about methamphetamine use in the homeless population. This study examines self-reported methamphetamine use and its correlates among a sample of 664 urban homeless adults in Los Angeles. Over one-quarter of the overall sample, and 60% of whites, disclosed lifetime methamphetamine use. Less than 10% of African-Americans reported ever using methamphetamine. Approximately one-tenth of respondents reported current methamphetamine use; almost 90% of current users shared straws to snort methamphetamine and half used it daily. Logistic regression analysis in younger (18-39) and older (40+) respondents revealed that white ethnicity, polydrug use and binge drinking were independently associated with lifetime methamphetamine use, regardless of age. Injection drug use (IDU) was also an important correlate of methamphetamine use for older African-Americans. IDU was not important for the younger group. Findings suggest that there is need for greater surveillance of methamphetamine use among homeless whites and Hispanics, and methamphetamine-use prevention and reduction targeted to younger, polydrug-using, alcohol-binging homeless adults. Nyamathi, A., Dixon, E.L., Shoptaw, S., Marfisee, M., Gelberg, L., Williams, S. et al. Profile of Lifetime Methamphetamine Use Among Homeless Adults in Los Angeles. Drug Alcohol Depend., 92, pp. 277-281, 2008.

Substance Abuse and Schizophrenia: Pharmacotherapeutic Intervention

Substance use disorder is common in patients with schizophrenia and dramatically worsens their outcome. The typical antipsychotic medications, introduced more than 50 years ago, are effective for the treatment of psychosis but may have only limited efficacy in patients with these co-occurring disorders because patients continue to use substances while taking them. In preliminary studies, however, several of the atypical antipsychotic medications have shown promise for reducing alcohol and drug use in patients with schizophrenia. A neurobiological formulation is discussed, suggesting that the use of substances in patients with schizophrenia may be based on a dysfunction within the dopamine-mediated brain reward circuitry and that clozapine, in particular, may potentially ameliorate this dysfunction and lessen the desire for substance use. Medications for the treatment of alcohol use disorders, such as disulfiram, naltrexone, and acamprosate, as well as other adjunctive medications, may also be useful. Further studies are required to establish a solid evidence base of best practices for the use of medications in these patients. Green, A.I., Noordsy, D.L., Brunette, M.F., and O'Keefe, C. Substance Abuse and Schizophrenia: Pharmacotherapeutic Intervention. J. Subst. Abuse Treat., 34, pp. 61-71, 2008.

Controversies in Translational Research: Drug Self-Administration

Laboratory animal and human models of drug self-administration are used to evaluate potential pharmacotherapies for drug abuse, yet the utility of these models in predicting clinically useful medications is variable. The objective of this study was to track how antagonist, agonist, and partial agonist medication approaches influence heroin and cocaine self-administration by rodents, non-human primates, and humans and to compare these results to clinical outcomes. Across species, heroin self-administration was decreased by all three medication approaches, paralleling their demonstrated clinical utility. The heroin data emphasize the importance of assessing a medication's abuse liability preclinically to predict medication abuse and compliance and of considering subject characteristics (e.g., opioid dependence) when interpreting medication effects. For cocaine, the effects of ecopipam, modafinil, and aripiprazole were consistent in the laboratory and clinic, provided that the medications were administered repeatedly before self-administration sessions. Modafinil attenuated cocaine's reinforcing effects in the human laboratory and improved treatment outcome, while ecopipam and aripiprazole increased the reinforcing effects of cocaine and do not appear promising in the clinic. The self-administration model has reliably identified medications to treat opioid dependence, and the recent data with modafinil suggest that the human laboratory model also identifies medications to treat cocaine dependence. There have been numerous false positives when subjective effects are the primary outcome measure, but not when self-administration is the outcome. Factors relevant to the predictive validity of self-administration procedures include medication maintenance and the concurrent assessment of a range of behaviors to determine abuse liability and the specificity of effect. Haney, M. and Spealman, R. Controversies in Translational Research: Drug Self-Administration. Psychopharmacology (Berl). Epub ahead of print, 2008.

ADHD, Substance Use Disorders, and Psychostimulant Treatment: Current Literature and Treatment Guidelines

This review explores the relationship between ADHD and substance use disorder (SUD), factors that determine the abuse potential of psychostimulants, and strategies for identifying and treating at-risk ADHD patients. This study uses a Medline review of literature. Results show that psychostimulants, such as methylphenidate and amphetamines, are effective first-line pharmacotherapy for ADHD and when used appropriately in individuals with ADHD do not appear to be frequently abused by patients. Diversion and misuse of prescription stimulants are growing concerns, especially among young adults and college students. Short-acting psychostimulant formulations may have higher potential for abuse, misuse, and diversion, but more data are needed to substantiate this observation. Nonstimulant treatments for ADHD may be considered for patients at particularly high risk for substance use, misuse, or diversion of stimulants. The authors conclude that in treating patients with ADHD and comorbid substance use, psychostimulants may be a useful pharmacologic alternative. However, the risks of such treatment with high-risk populations must be considered alongside potential benefits. Kollins, S.H., J. Atten. Disord. Jan 11, Epublication ahead of print, 2008.

Cigarette Reduction: An Intervention for Adolescent Smokers

This observational study examined whether adolescents who were not interested in quitting could reduce cigarette smoking and if cigarette reduction led to a corresponding and significant reduction in biomarkers of exposure. The study design was a randomized, open-label trial of nicotine patch and nicotine gum with an added placebo control. Participants (n=103) attended 4 treatment visits over 4 weeks and follow-up visits at 3- and 6-months. Participants were told to reduce their smoking by 25% of baseline smoking during the 1st week and by 50% of baseline smoking during the subsequent 3 weeks. Of consented participants, 91.3% (n=94/103) completed the study until the end-of-treatment, 85.1% (n=80/94) completed the 3-month follow-up visit and 71.3% (n=67/94) completed the 6-month follow-up visit. Participants had a very high prevalence of co-morbidity. With regard to the percentage of participants who achieved a 50% reduction of baseline smoking, there were no significant differences among treatment groups (p=.89). At the end-of-treatment, 49.4% of participants (n=41) had reduced smoking by at least 50%. Additionally, there was no significant group, visit or interaction effect of a biomarker measure for carcinogen exposure (p>.05). The results suggest that reduction may be a potential aid to engage adolescents who are unable or unwilling to quit, but should not be an end goal. The effect of treatment methods on outcome measures did not differ significantly. Hanson, K., Zylla, E., Allen, S., Li, Z., and Hatsukami, D.K. Cigarette Reduction: An Intervention for Adolescent Smokers. Drug Alcohol Depend., 95, pp. 164-168, 2008.

Smokeless Tobacco Reduction: Preliminary Study of Tobacco-Free Snuff Versus No Snuff

This preliminary study examined the effects of tobacco-free snuff (intervention, n = 52) compared with no snuff (control, n = 54) for reducing tobacco use among smokeless tobacco (ST) users not interested in quitting. Both groups received behavioral instructions, and intervention subjects received tobacco-free snuff for 8 weeks. Participants were required to reduce their intake by 50% during the first 4 weeks and by 75% during the subsequent 4 weeks. Follow-up occurred at 12 weeks. Significant reductions were observed from baseline to week 8 (end of treatment) for both treatment groups in the amount of ST use (tins/week and dips/day, p<.001); mean urinary cotinine (p<.001); and mean urinary total NNAL, a carcinogen biomarker (p<.001). At week 8 the intervention resulted in a lower mean total NNAL (p = .048). Compared with the control condition, the intervention resulted in a higher percentage of subjects achieving at least a 50% reduction in cotinine (p = .046) and total NNAL (p = .002) at the end of treatment, more quit attempts (p = .030), and a longer mean duration of abstinence (p = .013) through follow-up. An ST reduction intervention incorporating tobacco-free snuff could potentially reduce risk for ST-related disease beyond that achieved with no snuff by increasing the number of patients who achieve significant reductions in carcinogen exposure and, more important, by facilitating tobacco abstinence by increasing quit attempts and abstinence duration. Hatsukami, D.K., Ebbert, J.O., Edmonds, A., Li, C., Lin, H., Le, C. et al. Smokeless Tobacco Reduction: Preliminary Study of Tobacco-free Snuff Versus No Snuff. Nicotine. Tob. Res., 10, pp. 77-85, 2008.

Smoking Reduction Fails to Improve Clinical and Biological Markers of Cardiac Disease: A Randomized Controlled Trial

Cigarette reduction has been proposed as a treatment goal for smokers who are not interested in stopping completely. This randomized controlled trial was designed to determine the effect of a smoking reduction intervention on smoking behavior, symptoms of heart disease, and biomarkers of tobacco exposure. It included 152 patients with heart disease who did not intend to stop smoking in the next 30 days. Participants were randomly assigned to smoking reduction (SR) or usual care (UC). SR subjects received counseling and nicotine replacement therapy to encourage >/=50% reduction in cigarettes per day (CPD). They were followed at 1, 3, 6, 12 and 18 months to assess smoking, heart disease symptoms, quality of life and nicotine, cotinine, carbon monoxide (CO), white blood cell (WBC) count, fibrinogen, hs-C-reactive protein (hs-CRP), F(2)-isoprostane, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol and its glucuronides (total NNAL), and 1-hydroxypyrene (1-HOP). At 6 months SR participants reduced by 10.9 CPD, compared with 7.4 CPD in UC (difference NS). At 18 months, 9/78 SR vs. 9/74 UC participants quit smoking. There were no significant differences between treatment groups in angina, quality of life or adverse events, nicotine, cotinine, CO, WBC count, fibrinogen, hs-CRP, F(2)-isoprostane, total NNAL or 1-HOP levels at any time point. To determine if smoking reduction, regardless of treatment condition, was associated with improved outcomes, the investigators compared all subjects at 6 months to baseline (mean reduction in CPD from 27.4 to 18.1, p<.01). There were no significant changes in outcome variables except CO, which decreased by 5.5 ppm (p<.01). There were also no significant improvements considering only subjects who reduced by >/=50%, or those who had no history of reduction prior to enrollment in the study. The SR intervention did not significantly reduce CPD or toxin exposure, or improve smoking cessation or clinical outcomes compared to UC. These results emphasize the importance of abstinence for smokers with heart disease to minimize health risks from tobacco. Joseph, A.M., Hecht, S.S., Murphy, S.E., Lando, H., Carmella, S.G., Gross, M. et al. Smoking Reduction Fails to Improve Clinical and Biological Markers of Cardiac Disease: A Randomized Controlled Trial. Nicotine. Tob. Res., 10, pp. 471-481, 2008.

Therapeutic Drug Monitoring of Nortriptyline in Smoking Cessation: A Multistudy Analysis

Multiple, controlled clinical trials support the efficacy of nortriptyline as a smoking cessation agent. Although therapeutic plasma nortriptyline concentrations (PNCs) are known for the treatment of depression, little is known about PNCs in smoking cessation treatment. PNCs from three randomized, placebo-controlled smoking cessation trials (N=244) were analyzed both separately and pooled. PNCs normalized for dose and weight were associated with cigarettes per day and race, but not with sex or age. Greater smoking was associated with decreased normalized PNCs. In addition, both Asian and black populations had significantly higher normalized PNCs than the white populations. Weak and inconsistent associations between PNCs and self-reported side effects were observed. PNCs were linearly related to end of treatment and long-term biochemically verified smoking abstinence. Maximum therapeutic effects were observed over a range of plasma concentrations somewhat lower than those found effective for the treatment of depression. Mooney, M.E., Reus, V.I., Gorecki, J., Hall, S.M., Humfleet, G.L., Munoz, R.F. et al. Therapeutic Drug Monitoring of Nortriptyline in Smoking Cessation: A Multistudy Analysis. Clin. Pharmacol. Ther., 83, pp. 436-442, 2008.

Uses of Coercion in Addiction Treatment: Clinical Aspects

Coerced or involuntary treatment comprises an integral, often positive component of treatment for addictive disorders. By the same token, coercion in health care raises numerous ethical, clinical, legal, political, cultural, and philosophical issues. In order to apply coerced care effectively, health care professionals should appreciate the indications, methods, advantages, and liabilities associated with this important clinical modality. An expert panel, consisting of the Addiction Committee of the Group for the Advancement of Psychiatry, listed the issues to be considered by clinicians in considering coerced treatment. In undertaking this task, they searched the literature using Pubmed from 1985 to 2005 using the following search terms: addiction, alcohol, coercion, compulsory, involuntary, substance, and treatment. In addition, they utilized relevant literature from published reports. In the treatment of addictions, coercive techniques can be effective and may be warranted in some circumstances. Various dimensions of coercive treatment are reviewed, including interventions to initiate treatment; contingency contracting and urine testing in the context of psychotherapy; and pharmacological methods of coercion such as disulfiram, naltrexone, and the use of a cocaine vaccine. The philosophical, historical, and societal aspects of coerced treatment are considered. Sullivan, M.A., Birkmayer, F., Boyarsky, B.K., Frances, R.J., Fromson, J.A., Galanter, M. et al. Uses of Coercion in Addiction Treatment: Clinical Aspects. Am. J. Addict., 17, pp. 36-47, 2008.

Imputation-Based Strategies for Clinical Trial Longitudinal Data with Nonignorable Missing Values

Biomedical research is plagued with problems of missing data, especially in clinical trials of medical and behavioral therapies adopting longitudinal design. After a literature review on modeling incomplete longitudinal data based on full-likelihood functions, this paper proposes a set of imputation-based strategies for implementing selection, pattern-mixture, and shared-parameter models for handling intermittent missing values and dropouts that are potentially nonignorable according to various criteria. Within the framework of multiple partial imputation, intermittent missing values are first imputed several times; then, each partially imputed data set is analyzed to deal with dropouts with or without further imputation. Depending on the choice of imputation model or measurement model, there exist various strategies that can be jointly applied to the same set of data to study the effect of treatment or intervention from multi-faceted perspectives. For illustration, the strategies were applied to a data set with continuous repeated measures from a smoking cessation clinical trial.. Yang, X., Li, J., and Shoptaw, S. Imputation-Based Strategies for Clinical Trial Longitudinal Data with Nonignorable Missing Values. Stat. Med., Epub ahead of print, 2008.

Role of CYP2B6 in Stereoselective Human Methadone Metabolism

Metabolism and clearance of racemic methadone are stereoselective and highly variable, yet the mechanism remains largely unknown. CYP3A4 was assumed responsible for methadone clearance in vivo. Nevertheless, recent clinical data do not support a primary role for CYP3A4 and suggest that CYP2B6 may mediate methadone clearance. A crossover clinical investigation (control, CYP2B6 and CYP3A4 induction by rifampin, CYP3A inhibition by troleandomycin and grapefruit juice) evaluated stereoselective methadone disposition. Rifampin diminished both R- and S-methadone plasma concentrations, but troleandomycin and grapefruit juice altered neither R- nor S-methadone concentrations. Plasma R/S-methadone ratios were increased by rifampin but unchanged by CYP3A inhibition. These results suggest a significant role for CYP2B6, but not CYP3A, in stereoselective human methadone metabolism and disposition. Totah, R.A., Sheffels, P., Roberts, T., Whittington, D., Thummel, K., and Kharasch, E.D. Anesthesiology. 108(3), pp. 351-352, 2008.


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