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Director's Report to the National Advisory Council on Drug Abuse - September, 2007

Research Findings - Research on Pharmacotherapies for Drug Abuse

Smoked Cocaine Self-administration is Decreased by Modafinil

This study investigated the effects of modafinil maintenance on cocaine self-administration by frequent users (4 days/week) under controlled laboratory conditions. In this 48-day double-blind, crossover design study, the effects of modafinil maintenance (0, 200, and 400 mg/day) on response to smoked cocaine (0, 12, 25, and 50 mg) were examined in 8 nontreatment-seeking cocaine dependent individuals. Cocaine significantly increased self-administration, subjective-effect ratings, and cardiovascular measures. Modafinil at both doses (200 and 400 mg/day) markedly attenuated these effects. This data supports the potential of modafinil as a pharmacotherapy for cocaine dependence. Hart, C.L., Haney, M., Vosburg, S.K., Rubin, E., and Foltin, R. Smoked Cocaine Self-administration is Decreased by Modafinil. Neuropsychopharmacology, pp. 1-8, 2007.

Gabapentin Shows Poor Treatment Retention and Ineffectiveness in Reducing Cocaine Use Versus Tiagabine which Significantly Reduced Cocaine taking Behavior Compared to Placebo or Gabapentin among methadone-stabilized cocaine abusers

In this study, 76 treatment seeking, cocaine dependent, methadone-maintained subjects were randomly assigned to tiagabine 24 mg/day, gabapentin 2400 mg/day, or placebo in a 10-week double-blind placebo-controlled trial. The primary outcome measure was thrice-weekly drug free urine samples. All subjects were required to participate in a 1-h weekly manual driven individual CBT psychotherapy session. Treatment retention was significantly less for the gabapentin group relative to the other groups. The proportion of cocaine-free urine samples during weeks 6 - 10 was significantly larger in the tiagabine treated group. The longitudinal data showed significant change in thrice-weekly cocaine free urines that reached a greater abstinence rate for the tiagabine treated group (22%) compared to gabapentin (5%) or placebo (13%) treated groups. The study results showed that gabapentin resulted in poor treatment retention and ineffectiveness in reducing cocaine use. Tiagabine significantly reduced cocaine taking behavior compared to placebo or gabapentin among methadone-stabilized cocaine abusers. Gonzalez, G., Desai, R., Sofuoglu, M., Poling, J., Oliveto, A., Gonsai, K. and Kosten, T. Clinical Efficacy of Gabapentin Versus Tiagabine for Reducing Cocaine Use Among Cocaine Dependent Methadone-treated Patients. Drug and Alcohol Dep, 87, pp. 1-9, 2007.

N-acetylcysteine May Reduce Desire to Use Cocaine

Animal models suggest that N-acetylcysteine inhibits cocaine-seeking. The present pilot study evaluated whether N-acetylcysteine would suppress reactivity to cocaine-related cues in cocaine-dependent humans. In this double-blind, placebo-controlled trial, 15 participants received N-acetylcysteine or placebo during a 3-day hospitalization. Participants were crossed over to receive the opposite condition on a second, identical 3-day stay occurring 4 days later. During each hospital stay, participants completed a cue-reactivity procedure that involved collecting psychophysical and subjective data in response to slides depicting cocaine and cocaine use. Results suggest that while taking N-acetylcysteine, participants reported less desire to use and less interest in response to cocaine slides and watched cocaine slides for less time. The inhibition of cocaine cue reactivity is consistent with existing preclinical data and supports the use of N-acetylcysteine as a treatment for cocaine dependence. In sum, the reduced subjective reports of desire to use and interest in cocaine indicate that N-acetylcysteine may be a promising new treatment and that cysteine-glutamate exchange may be a potential pharmacotherapeutic target for treating cocaine dependence. LaRowe, S.D., Myrick, H., Hedden, S., Mardikian, P., Saladin, M., McRae, A., Brady, K., Kalivas, P.W., and Malcolm, R. Is Cocaine Desire Reduced by N-acetylcysteine? Am J Psychiatry. 164(7), pp. 1115-1117, 2007.

Subjective and Cardiovascular Effects of Cocaine During Treatment with Amantadine and Baclofen in Combination

This study assessed the subjective and cardiovascular effects of relevant doses of cocaine administration during steady-state treatment of the combination of amantadine and baclofen compared to placebo in 8 healthy, male, cocaine-dependent, non-treatment-seeking individuals. Data were collected prior to and following double-blind iv administration of cocaine (0, 20, and 40 mg). Data were collected at baseline, following 5 days of treatment with placebo, and again following 5 days of treatment with a combination of amantadine 100 mg. t.i.d. and baclofen 30 mg t.i.d. counterbalanced for order of medication and placebo in a cross-over design. Results showed no significant alterations to cardiovascular variables from treatment using combination medication or placebo in the presence of cocaine. Self-rated 'desire' for cocaine was significantly lower during cocaine administrations while participants were receiving treatment with amantadine-baclofen compared to infusions while taking placebo medication, although there was no difference in the intensity of cocaine-induced euphoria, or reduction in the likelihood to use cocaine if given access. Study findings support the safety of the amantadine-baclofen combination treatment for cocaine dependence. Rotheram-Fuller, E., De La Garza II, R., Mahoney III, J.J., Shoptaw, S., and Newton, T.F. Subjective and Cardiovascular Effects of Cocaine during Treatment with Amantadine and Baclofen in Combination. Psychiatry Res., 2007 (e-publication ahead of print).

Effects of Major Depressive Disorder and Attention-Deficit/Hyperactivity Disorder on the Outcome of Treatment for Cocaine Dependence

Co-occurring psychiatric disorders have been associated with poor prognosis among substance-dependent patients, but few studies have examined this association among patients with cocaine dependence (CD). This study compared baseline characteristics and treatment outcome between cocaine-dependent patients with major depressive disorder (MDD, n=66), attention-deficit/hyperactivity disorder (ADHD, n=53), and those with CD without comorbid disorders (CD alone, n=48), who had been randomized to the placebo arms of clinical trials with Venlafaxine, methylphenidate, and gabapentin, respectively. The three groups differed in racial makeup, with more Caucasians and Hispanics among patients with MDD and with ADHD, but more African Americans among those with CD alone. The groups did not differ significantly in treatment retention, with retention rates ranging from 42% to 47%, neither did they differ in the rates of achieving 2 consecutive weeks of urinalysis-confirmed abstinence (40% to 50%). Among cocaine-dependent patients who achieved abstinence at baseline, those with MDD alone and those with ADHD had better outcome over time as compared to patients with CD alone. Among patients with cocaine-positive urine specimens at baseline, those with MDD and those with ADHD were associated with poor outcome as compared with patients with CD alone. The findings suggest that diagnosis and treatment of co-occurring disorders such as depression and ADHD may be important components of treatment planning for CD and that the baseline level of cocaine use should be included as a covariate in studies evaluating the impact 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. Substance Abuse Treatment, 2007 (e-publication ahead of print).

Neither Citalopram nor Citalopram Augmented with Bupropion are more Effective than Placebo in the Treatment of Opioid Abuse

This study evaluated the efficacy of citalopram (an SSRI) augmented with bupropion in the treatment of illicit opiate use in 60 methadone-stabilized subjects. In this 12-week randomized, double-blind, outpatient clinical trial, subjects were randomly assigned to placebo, citalopram (40 mg/day) plus placebo, or citalopram (40 mg/day) plus bupropion (50 mg/day). The primary outcome was opioid use, as measured by thrice-weekly urine toxicology results for opiates. A secondary analysis was illicit cocaine urine toxicology. Study results did not find any impact of either citalopram alone or in combination with bupropion, either for opioid abuse or for cocaine abuse (although the level of cocaine use in the study was low). These results suggest that an antidepressant intervention alone may not be sufficient to treat opiate or cocaine abuse. Previous studies using desipramine or bupropion and contingency management (CM) have demonstrated that a combination of medication and CM can reduce illicit drug use. Antidepressants could still continue to be investigated in combination with an effective behavioral intervention, as this combination may produce a synergistic treatment effect greater than either treatment alone. Poling, J., Pruzinsky, R., Kosten, T.R., Gonsai, K., Sofuoglu, M., Gonzalez, G., and Oliveto, A. Clinical Efficacy of Citalopram Alone or Augmented with Bupropion in Methadone-Stabilized Patients. Am. J. on Addictions, 16, pp. 187-194, 2007.

Modest Opioid Withdrawal Suppression Efficacy of Oral Tramadol in Humans

Tramadol is in an unscheduled atypical analgesic with low rates of diversion and abuse and mixed pharmacologic actions, including modest opioid agonist activity. The purpose of the current study was to characterize the opioid withdrawal suppression efficacy of oral tramadol. Residential, opioid-dependent adults (n = 10) were maintained on morphine (15 mg subcutaneously, quad in diem) for approximately 6 weeks. Spontaneous opioid withdrawal was produced by substituting placebo for scheduled morphine doses 17.5 h before experimental sessions that occurred twice weekly. The acute effects of placebo, tramadol (50, 100, 200, and 400 mg orally), naloxone (0.1 and 0.2 mg intramuscularly [IM]), and morphine (15 and 30 mg IM) were tested under double-blind, double-dummy, randomized conditions. Results indicated that Naloxone and morphine produced prototypic opioid antagonist and agonist effects, respectively. Tramadol 50 and 100 mg produced effects most similar to placebo. Tramadol 200 and 400 mg initially produced significant dose-related increases in ratings of "bad effects" and "feel sick," followed by evidence of opioid withdrawal suppression. Tramadol did not produce significant increases on measures of positive drug effects nor any clinically significant physiologic changes. Tramadol 200 and 400 mg show evidence of opioid withdrawal suppression without significant observer- and subject-rated opioid agonist effects. The profile of action did not suggest a high risk for tramadol abuse in opioid dependent individuals. Tramadol may be a useful medication for treating opioid withdrawal. Lofwall, M.R., Walsh, S.L., Bigelow, G.E., and Strain, E.C., Modest Opioid Withdrawal Suppression Efficacy of Oral Tramadol in Humans. E-publication Psychopharmacology, 2007.

Antagonist Effects of Depot Naltrexone on the Reinforcing, Subjective, and Physiological Effects of Heroin

Although naltrexone is highly effective in completely antagonizing the effects of opioids, noncompliance has been an ongoing obstacle to treatment with this medication. This study evaluated the time course, safety, and effectiveness of a depot formulation of naltrexone (Depotrex(R) ). Five heroin-dependent individuals participated in an 8-week inpatient study. Following a 1-week detoxification period, the effects of a range of heroin doses (0, 6.25, 12.5, and 25 mg, iv) were examined. Participants then received 384 mg depot naltrexone, and the effects of heroin were again evaluated for the next 6 weeks. One dose of heroin was tested per day, and the entire dose range was tested per week. During a morning sample session, participants received a dose of heroin and $20 and subjective, performance, and physiological effects were measured both before and after drug administration. During an afternoon choice session, participants were given the opportunity to choose the sampled heroin dose and/or amount of money using a modified progressive ratio procedure. In this study, depot naltrexone antagonized both the reinforcing and subjective effects of heroin for 4-5 weeks. Subjective ratings of withdrawal were reduced after week 2 and throughout the remainder of the study. The effects of heroin on mean trough pupil diameter began to emerge by week 5. The findings extended previous findings by this group that the reinforcing effects of heroin are reduced for 4-5 weeks after administration of 384 mg depot naltrexone. Sullivan, M.A., Vosburg, S.K., and Comer, S.D. Depot Naltrexone: Antagonism of the Reinforcing, Subjective, and Physiological Effects of Heroin. Psychopharmacology 189, pp. 37-46, 2006.

Memantine Produces Modest Reductions in Heroin-Induced Subjective Responses in Human Research Volunteers

The objective of this study was to evaluate the utility of a noncompetitive NMDA antagonist as a treatment medication for opioid dependence. In this 8-week inpatient study, 8 participants were maintained on the low-affinity, NMDA antagonist memantine (0, 30, and 60 mg/day, PO) and under each maintenance dose condition, the effects of IN heroin (0, 12.5, and 50 mg, IN) were examined. Following a 1-week detoxification period, all participants received all of the memantine and heroin dose combinations. Participants first sampled a dose of heroin and $20. During a subsequent choice session, participants could self-administer heroin and/or money. Responses were made under a progressive ratio schedule, and subjective, performance, and physiological effects were measured. In this study, memantine produced modest reductions in subjective ratings of drug quality, liking, willingness to pay for the drug, and craving for heroin. However, memantine produced few changes in the reinforcing effects of heroin. Comer, S.D. and Sullivan, M.A. Memantine Produces Modest Reductions in Heroin-induced Subjective Responses in Human Research Volunteers. Psychopharmacology, 193, pp. 235-245, 2007.

Low, Repeated Doses of Buprenorphine /Naloxone May be an Effective Mechanism for Safely Dosing this Medication in Persons with Higher Levels of Physical Dependence

Acute doses of bupenorphine can precipitate withdrawal in opioid dependent persons. The likelihood of this withdrawal increases as a function of the level of physical dependence. The objective of this study was to test the acute effects of sublingual buprenorphine/naloxone tablets in subjects with a high level of physical dependence, and identify a dose that would precipitate withdrawal, then determine if withdrawal could be attenuated by splitting this dose. In Phase 1 of this randomized, double blind, triple dummy, residential laboratory study, 16 subjects maintained on 100 mg/day methadone were given sublingual buprenorphine/naloxone (4/1, 8/2, 16/4, 32 mg/8kg), intramuscular naloxone (0.2 mg), oral methadone (100 mg) or placebo. Medication conditions were randomized, but buprenorphine/naloxone were ascending within the randomization. In Phase 2 of the study, conditions were methadone, placebo, naloxone, 100% of the buprenorphine/naloxone dose that precipitated withdrawal in Phase 1 (full dose) and 50% of this dose administered twice in a session (split dose). Six patients did not complete the study. Of the 10 who completed, 3 tolerated up to 32 mg/8 mg buprenorphine/naloxone without evidence of precipitated withdrawal. For the 7 subjects completing both phases, split doses generally produced less precipitated withdrawal compared to full doses. The conclusion of the study was that there is considerable between subject variability in sensitivity to buprenorphine's antagonist effects, and that low, repeated doses of buprenorphine/naloxone (e.g. 2 mg/0.5 mg) may be an effective mechanism for safely dosing this medication in persons with higher levels of physical dependence. Rosado, J., Walsh, S., Bigelow, G.E., and Strain, E. Sublingual Buprenorphine/Naloxone Precipitated Withdrawal in Subjects Maintained on 100 mg of Daily Methadone. Drug and Alcohol Dep 2007 (e-publication ahead of print).

Buprenorphine's Pharmacological Profile may Permit Intermittent Dosing that may be Effective Over Periods of Up to 98 h

Buprenorphine has a long duration of action that allows less than daily dosing for opioid dependence. Pharmacologic characterization of buprenorphine's duration of effects over multiple days has not been fully explored. The purpose of this study was to assess opioid blockade and spontaneous withdrawal effects of buprenorphine/naloxone (B/N) over a 98 h period. 8 residential opioid-dependent volunteers were maintained, in randomized sequence, on each of three different daily sublingual B/N doses (8/2, 16/4, 32/8 mg). After 2 weeks on each maintenance dose, participants underwent challenge sessions on each weekday for 1 week. Challenges consisted of within-session, ascending dose administration of IM Hydromorphone (0, 6, and 12 mg). During that week, active B/N dose was given only on Monday; double-blind placebo was administered on the remaining weekdays. These sessions assessed the extent of both opioid blockade and spontaneous withdrawal at 2, 26, 50, 74, and 98 h after the last active B/N dose. All three maintenance doses provided substantial but incomplete blockade against opioid agonist effects for 98 h. The extent of blockade diminished steadily but modestly over time and did not differ as a function of B/N maintenance dose. Withdrawal did not differ as a function of B/N maintenance dose. Study results suggest that there are no substantial differences between buprenorphine doses, both with respect to spontaneous withdrawal assessments and blockade efficacy, over the 98 h period, and that buprenorphine/naloxone doses greater than 8/2 mg may provide minimal incremental value in terms of opioid blockade and withdrawal suppression. The results also suggest that although the efficacy of B/N diminishes over 98 h at a steady rate, there remains blockade efficacy even after 4 days of placebo dosing without substantial or distressing opioid withdrawal. Correia, C.J., Walsh, S.L., Bigelow, G.E., and Strain, E.C. Effects Associated with Double-blind Omission of Buprenorphine/Naloxone Over a 98-h Period. Psychopharmacology 189, pp. 297-306, 2006.

Acute d-Amphetamine Pretreatment Does Not Alter Stimulant Self-administration in Humans

d-Amphetamine has been reported as currently being tested as an agonist therapy for cocaine and methamphetamine dependence. There is a concern, however, that d-amphetamine may increase drug-taking behavior because acute administration of d-amphetamine decreases inhibition in cocaine-using individuals. The purpose of this study was to determine whether acute d-amphetamine pretreatment would alter the reinforcing, subject-rated, and cardiovascular effects of d-amphetamine in 7 subjects with prior experiences in stimulant abuse. Subjects sampled doses of oral d-amphetamine (0, 8, and 16 mg), then were allowed to self-administer these sampled doses using a modified progressive-ratio procedure in two sessions in which they received pretreatment with either 0 or 15 mg oral d-amphetamine 2 h prior to completing the modified progressive-ratio procedure. d-Amphetamine produced prototypical stimulant-like effects and maintained responding on the modified progressive-ratio schedule. Pretreatment with 15 mg d-amphetamine also produced prototypical stimulant-like effects, but failed to alter break points for d-amphetamine on the modified progressive-ratio procedure relative to placebo pretreatment. These results indicate that acute d-amphetamine pretreatment does not increase stimulant self-administration. Stoops, W.W., Vansickel, A.R., Lile, J.A., and Rush, C.R. Acute d-Amphetamine Pretreatment Does Not Alter Stimulant Self-administration in Humans. Pharmacology, Biochemistry, and Behavior 87, pp. 20-29, 2007.

Women and Men Do Not Appear to Differ in Response to the Discriminative-Stimulus Effects of d-Amphetamine

The results of animal and human laboratory studies are mixed regarding gender differences in response to stimulant drugs. This study performed a retrospective analysis of six studies conducted by this team that used identical procedures and methods. Thirteen women and 14 men learned to discriminate 15 mg of oral d-amphetamine, then the effects of a range of doses of d-amphetamine (0, 2.5, 5, 10, and 15 mg) alone and in combination with other drugs, were assessed. In these studies, d-amphetamine functioned as a discriminative stimulus and dose-dependently increased drug-appropriate responding. Women and men did not differ in their ability to discriminate d-amphetamine, but differed on participant-ratings of high (women < men), nausea (women > men) and sluggish (women < men); women also experienced greater increases in diastolic pressure than men following the administration of higher d-amphetamine doses (10 and 15 mg). Changes in menstrual cycle and hormone levels were not evaluated in the current study. Because the study results may have been confounded by the training procedures, future research should use other behavioral arrangements (e.g. drug self-administration) to determine if women and men respond differently to the effects of d-amphetamine. Vansickel, A.R., Lile, J.A., Stoops, W.W., and Rush, C.R. Similar Discriminative-Stimulus Effects of d-Amphetamine in Women and Men. Pharmacology, Biochemistry and Behavior, 87, pp. 289-296, 2007.

Varenicline is a Partial Agonist at alpha4beta2 and a Full Agonist at alpha7 Neuronal Nicotinic Receptors

In rat nicotinic receptors expressed in Xenopus laevis oocytes, varenicline was shown as being a potent, partial agonist at alpha4beta2 receptors and having a lower potency and higher efficacy at alpha3beta4, alpha3beta2 and alpha6-containing receptors. In addition, varenicline is a potent, full agonist at alpha7 receptors. Thus, varenicline is a partial agonist at some heteromeric neuronal nicotinic receptors, but a full agonist at the homomeric alpha7 receptor. Combination of these actions may be involved in its mechanism as a smoking cessation aid. Mihalak, K.B., Carroll, F.I., and Luetje, C.W. Mol Pharmacol 70(3), pp. 801-805, 2006.

Trace Amine-associated Receptor 1 is a Modulator of the Dopamine Transporter

This study reported that Rhesus monkey TAAR1 expressed with DAT in human embryonic kidney 293 cells was dose-dependently activated by dopamine or (+)-methamphetamine and resulted in large cAMP increases and a transient reduction in [3H]dopamine accumulation within the cells. TAAR1 effects on dopamine uptake could be blocked by a protein kinase A or protein kinase C (PKC) inhibitor. [3H]Dopamine efflux in Eagle's medium was TAAR1-dependent and dose-dependently augmented by dopamine or (+)-methamphetamine but blocked by either methylphenidate or a PKC inhibitor. This study provides evidence that TAAR1 is involved in functional regulation of DAT and suggests that TAAR1 is a potentially important target for therapeutics for methamphetamine addiction. Xie, Z., and Miller, G.M., J Pharmacol Exp Ther. 321(1), pp. 128-136, 2007.


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