Differences in regional brain metabolism associated with marijuana abuse in methamphetamine abusers.
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Adult↗
Biomedical subjects
Walter Ling
Publications and source records attributed to Walter Ling.
Medications development: successes and challenges.
The National Institute on Drug Abuse has funded a medications program that has concentrated on the development of medications for opiate and cocaine dependence. Levomethadyl acetate (LAAM) and buprenorphine and buprenorphine/naloxone sublingual tablets were developed in conjunction with pharmaceutical partners and approved by the Food and Drug Administration. The remaining challenges for medications development for opiate dependence involves Phase IV studies in special populations, for example, pregnant opiate-dependent patients, and to translate neuroscience-based findings into treatments. Several marketed medications have shown initial efficacy to reduce cocaine use in well-controlled clinical trials. Disulfiram has been shown to reduce cocaine use in several clinical trials, while baclofen, modafinil, naltrexone, ondansetron, tiagabine, and topiramate have shown preliminary efficacy in initial clinical studies. Confirmatory studies of many of these medications is underway. More recently, the NIDA medications program has evaluated medications for their ability to reduce methamphetamine use. To date, no medications tested have shown efficacy to reduce methamphetamine use. Both marketed medications and investigational agents will be tested. Finally, NIDA has begun to test medications for efficacy to reduce cannabis use. Initial studies are underway. Both agonist and antagonist approaches will be evaluated. Additionally, medications will be tested in cannabis-dependent patients for the management of insomnia, withdrawal, and concurrent depression.
Animals↗
Randomized controlled pilot trial of cabergoline, hydergine and levodopa/carbidopa: Los Angeles Cocaine Rapid Efficacy Screening Trial (CREST).
AIM: This study tested three dopaminergic medications against a common unmatched placebo condition: hydergine 1 mg three times daily (n = 15); levodopa/carbidopa 25/100 mg three times daily (n = 15); cabergoline 0.5 mg per week (n = 15); and placebo three times daily (n = 15) as potential pharmacotherapies for cocaine dependence. DESIGN: The four-parallel group, Cocaine Rapid Efficacy Screening Trial (CREST) design featured a 2-week baseline period followed by randomization to an 8-week medication condition that included 1 hour per week of cognitive behavioral drug counseling. A safety evaluation was conducted 4 weeks after termination. MEASURES: Outcomes included cocaine metabolites measured in urine, retention and self-reports for drug use, cocaine craving, clinical improvement, mood and HIV risk behaviors. RESULTS: Participants assigned to receive cabergoline provided more urine samples negative for cocaine metabolites (42.4%) than those assigned to receive placebo (25.0%), a statistically significant difference after controlling for baseline differences in self-reported cocaine use (F = 2.95, df = 3; P = 0.05). Cabergoline-treated participants demonstrated a significant improvement over placebo from baseline to week 8 when measured using the Addiction Severity Index (ASI) employment subscale (overall change = - 0.09, SD = 0.10, t = 2.36, P < 0.05). Safety and adverse event measures showed similar rates and types of complaints by treatment condition. CONCLUSIONS: These results, combined with the apparent safety of cabergoline when used with this population, provide empirical support for conducting a larger study of the medication.
Adult↗
A multi-center randomized trial of buprenorphine-naloxone versus clonidine for opioid detoxification: findings from the National Institute on Drug Abuse Clinical Trials Network.
AIMS: The clinical effectiveness of buprenorphine-naloxone (bup-nx) and clonidine for opioid detoxification in in-patient and out-patient community treatment programs was investigated in the first studies of the National Institute of Drug Abuse Clinical Trials Network. DESIGN: Diagnostic and Statistical Manual version IV (DSM IV)-diagnosed opioid-dependent individuals seeking short-term treatment were randomly assigned, in a 2 : 1 ratio favoring bup-nx, to a 13-day detoxification using bup-nx or clonidine. METHODS: A total of 113 in-patients (77 bup-nx, 36 clonidine) and 231 out-patients (157 bup-nx, 74 clonidine) participated. Supportive interventions included appropriate ancillary medications and standard counseling procedures guided by a self-help handbook. The criterion for treatment success was defined as the proportion of participants in each condition who were both retained in the study for the entire duration and provided an opioid-free urine sample on the last day of clinic attendance. Secondary outcome measures included use of ancillary medications, number of side effects reported and withdrawal and craving ratings. FINDINGS: A total of 59 of the 77 (77%) in-patients assigned to the bup-nx condition achieved the treatment success criterion compared to eight of the 36 (22%) assigned to clonidine, whereas 46 of the 157 (29%) out-patients assigned to the bup-nx condition achieved the treatment success criterion, compared to four of the 74 (5%) assigned to clonidine. CONCLUSION: The benefits of bup-nx for opioid detoxification are supported and illustrate important ways in which clinical research can be conducted in community treatment programs.
Adult↗
Structural abnormalities in the brains of human subjects who use methamphetamine.
We visualize, for the first time, the profile of structural deficits in the human brain associated with chronic methamphetamine (MA) abuse. Studies of human subjects who have used MA chronically have revealed deficits in dopaminergic and serotonergic systems and cerebral metabolic abnormalities. Using magnetic resonance imaging (MRI) and new computational brain-mapping techniques, we determined the pattern of structural brain alterations associated with chronic MA abuse in human subjects and related these deficits to cognitive impairment. We used high-resolution MRI and surface-based computational image analyses to map regional abnormalities in the cortex, hippocampus, white matter, and ventricles in 22 human subjects who used MA and 21 age-matched, healthy controls. Cortical maps revealed severe gray-matter deficits in the cingulate, limbic, and paralimbic cortices of MA abusers (averaging 11.3% below control; p < 0.05). On average, MA abusers had 7.8% smaller hippocampal volumes than control subjects (p < 0.01; left, p = 0.01; right, p < 0.05) and significant white-matter hypertrophy (7.0%; p < 0.01). Hippocampal deficits were mapped and correlated with memory performance on a word-recall test (p < 0.05). MRI-based maps suggest that chronic methamphetamine abuse causes a selective pattern of cerebral deterioration that contributes to impaired memory performance. MA may selectively damage the medial temporal lobe and, consistent with metabolic studies, the cingulate-limbic cortex, inducing neuroadaptation, neuropil reduction, or cell death. Prominent white-matter hypertrophy may result from altered myelination and adaptive glial changes, including gliosis secondary to neuronal damage. These brain substrates may help account for the symptoms of MA abuse, providing therapeutic targets for drug-induced brain injury.
Adult↗
Cochrane systematic reviews: time for an introduction and appraisal.
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Cooperative Behavior↗
Mood disturbances and regional cerebral metabolic abnormalities in recently abstinent methamphetamine abusers.
BACKGROUND: Mood disturbances in methamphetamine (MA) abusers likely influence drug use, but the neurobiological bases for these problems are poorly understood. OBJECTIVE: To assess regional brain function and its possible relationships with negative affect in newly abstinent MA abusers. DESIGN: Two groups were compared by measures of mood and cerebral glucose metabolism ([18F]fluorodeoxyglucose positron emission tomography) during performance of a vigilance task. SETTING: Participants were recruited from the general community to a research center. PARTICIPANTS: Seventeen abstaining (4-7 days) MA abusers (6 women) were compared with 18 control subjects (8 women). MAIN OUTCOME MEASURES: Self-reports of depressive symptoms and anxiety were measured, as were global and relative glucose metabolism in the orbitofrontal, cingulate, lateral prefrontal, and insular cortices and the amygdala, striatum, and cerebellum. RESULTS: Abusers of MA provided higher self-ratings of depression and anxiety than control subjects and differed significantly in relative regional glucose metabolism: lower in the anterior cingulate and insula and higher in the lateral orbitofrontal area, middle and posterior cingulate, amygdala, ventral striatum, and cerebellum. In MA abusers, self-reports of depressive symptoms covaried positively with relative glucose metabolism in limbic regions (eg, perigenual anterior cingulate gyrus and amygdala) and ratings of state and trait anxiety covaried negatively with relative activity in the anterior cingulate cortex and left insula. Trait anxiety also covaried negatively with relative activity in the orbitofrontal cortex and positively with amygdala activity. CONCLUSIONS: Abusers of MA have abnormalities in brain regions implicated in mood disorders. Relationships between relative glucose metabolism in limbic and paralimbic regions and self-reports of depression and anxiety in MA abusers suggest that these regions are involved in affective dysregulation and may be an important target of intervention for MA dependence.
Adult↗
The effect of relapse on cognition in abstinent methamphetamine abusers.
Data from 75 participants in a longitudinal study of methamphetamine (MA) abuse were used to differentiate the cognitive performance of those who remained abstinent, relapsed, or continued to use during treatment. Participants were divided into three groups: continuous abstinence, initial abstinence but relapse, and continuous use. Groups did not differ on age, education, gender or ethnicity. Participants in the longitudinal study completed a battery of cognitive tests within 7 days of their last use of MA, then were re-tested monthly for up to 6 months (average time for this analysis was 92 days). For episodic memory, the relapse groups performance was worse than the abstinent and significantly worse than that of the continued use group who had the best performance on all measures. Relapse to methamphetamine use may affect episodic memory differently than it affects the other cognitive functions measured.
Adult↗
Association between quantitative EEG and neurocognition in methamphetamine-dependent volunteers.
OBJECTIVE: Exposure to methamphetamine is associated with long-lasting reductions in markers for dopaminergic neurons in preclinical models and in humans. These changes may be associated with alterations in brain electrical activity and in cognition. METHODS: The sample included 9 methamphetamine-dependent subjects and 10 non-drug-using volunteers. Methamphetamine-dependent subjects were hospitalized for 4 days to document abstinence; non-drug-using volunteers were studied as outpatients. EEGs were recorded in the eyes-closed resting state, and absolute EEG power in each frequency band (0.5-4 Hz, 4-8 Hz, 8-12 Hz, and 12-20 Hz) was measured using a fast Fourier transform. EEG power was log-transformed prior to analysis. Cognition was measured using computerized reaction time tasks. RESULTS: Within the methamphetamine-dependent group only, increased theta quantitative EEG (QEEG) power correlated significantly with reaction time on tasks that were more difficult or that were degraded by fatigue. Increased theta QEEG power also correlated with reduced accuracy on a working memory task. CONCLUSIONS: Increased QEEG power in the theta band is associated with worse performance on reaction time tasks in the methamphetamine-dependent sample but not in the non-drug-using volunteers. SIGNIFICANCE: Methamphetamine dependence is associated with pathological alterations in brain electrical activity and in cognitive performance. QEEG appears to provide a sensitive measure of methamphetamine-associated alterations in brain function.
Adult↗
Participants receiving dehydroepiandrosterone during treatment for cocaine dependence show high rates of cocaine use in a placebo-controlled pilot study.
Twenty-three cocaine-dependent participants were randomly assigned to receive either dehydroepiandrosterone (DHEA; n = 11; 100 mg/day) or placebo (n = 12) in the context of 12 weeks of thrice weekly cognitive-behavioral group counseling. Outcomes were retention, urine drug screening, cocaine craving, adverse experiences, and medication compliance. DHEA-treated participants averaged 45.8 (SD = 28.8) days in treatment, compared with 70.7 (SD = 20.6) days for placebo, r(21) = -2.4, p =.03, and provided 26.8% (SD = 29.3) of urine samples free of cocaine metabolite compared with 70.6% (SD = 39.9) for the placebo condition, r(21) = -3.0, p =.01. No differences were detected between conditions for cocaine craving or adverse experiences. High levels of medication compliance were documented. Results argue against using high doses of DHEA as a pharmacotherapy for cocaine dependence.
Adolescent↗
Diffusion of substance abuse treatment: will buprenorphine be a success?
The availability of buprenorphine promises to return the treatment of heroin addiction to mainstream medicine in the United States for the first time in nearly a century. This new treatment also provides an opportunity to reflect on the introduction of methadone and LAAM and their subsequent successes and failures in clinical implementation. The three articles that follow in this issue highlight the potential pharmacological, clinical, and logistic advantages of buprenorphine and provide clinicians with guidelines for its use in an integrated treatment setting. The clinical success of buprenorphine, however, depends in large part on factors beyond its pharmacological advantages. Clinician attitude and the extent to which they embrace buprenorphine will play an important role in determining the future success of this medication.
Buprenorphine↗
Substance use and treatment options in Cambodia.
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Cambodia↗
Bringing buprenorphine-naloxone detoxification to community treatment providers: the NIDA Clinical Trials Network field experience.
In October 2002, the U.S. Food and Drug Administration approved buprenorphine-naloxone (Suboxone) sublingual tablets as an opioid dependence treatment available for use outside traditionally licensed opioid treatment programs. The NIDA Center for Clinical Trials Network (CTN) sponsored two clinical trials assessing buprenorphine-naloxone for short-term opioid detoxification. These trials provided an unprecedented field test of its use in twelve diverse community-based treatment programs. Opioid-dependent men and women were randomized to a thirteen-day buprenorphine-naloxone taper regimen for short-term opioid detoxification. The 234 buprenorphine-naloxone patients averaged 37 years old and used mostly intravenous heroin. Direct and rapid induction onto buprenorphine-naloxone was safe and well tolerated. Most patients (83%) received 8 mg buprenorphine-2 mg naloxone on the first day and 90% successfully completed induction and reached a target dose of 16 mg buprenorphine-4 mg naloxone in three days. Medication compliance and treatment engagement was high. An average of 81% of available doses was ingested, and 68% of patients completed the detoxification. Most (80.3%) patients received some ancillary medications with an average of 2.3 withdrawal symptoms treated. The safety profile of buprenorphine-naloxone was excellent. Of eighteen serious adverse events reported, only one was possibly related to buprenorphine-naloxone. All providers successfully integrated buprenorphine-naloxone into their existing treatment milieus. Overall, data from the CTN field experience suggest that buprenorphine-naloxone is practical and safe for use in diverse community treatment settings, including those with minimal experience providing opioid-based pharmacotherapy and/or medical detoxification for opioid dependence.
Administration, Sublingual↗
Office-based treatment of opiate addiction with a sublingual-tablet formulation of buprenorphine and naloxone.
BACKGROUND: Office-based treatment of opiate addiction with a sublingual-tablet formulation of buprenorphine and naloxone has been proposed, but its efficacy and safety have not been well studied. METHODS: We conducted a multicenter, randomized, placebo-controlled trial involving 326 opiate-addicted persons who were assigned to office-based treatment with sublingual tablets consisting of buprenorphine (16 mg) in combination with naloxone (4 mg), buprenorphine alone (16 mg), or placebo given daily for four weeks. The primary outcome measures were the percentage of urine samples negative for opiates and the subjects' self-reported craving for opiates. Safety data were obtained on 461 opiate-addicted persons who participated in an open-label study of buprenorphine and naloxone (at daily doses of up to 24 mg and 6 mg, respectively) and another 11 persons who received this combination only during the trial. RESULTS: The double-blind trial was terminated early because buprenorphine and naloxone in combination and buprenorphine alone were found to have greater efficacy than placebo. The proportion of urine samples that were negative for opiates was greater in the combined-treatment and buprenorphine groups (17.8 percent and 20.7 percent, respectively) than in the placebo group (5.8 percent, P<0.001 for both comparisons); the active-treatment groups also reported less opiate craving (P<0.001 for both comparisons with placebo). Rates of adverse events were similar in the active-treatment and placebo groups. During the open-label phase, the percentage of urine samples negative for opiates ranged from 35.2 percent to 67.4 percent. Results from the open-label follow-up study indicated that the combined treatment was safe and well tolerated. CONCLUSIONS: Buprenorphine and naloxone in combination and buprenorphine alone are safe and reduce the use of opiates and the craving for opiates among opiate-addicted persons who receive these medications in an office-based setting.
Administration, Sublingual↗
Clinical efficacy of buprenorphine: comparisons to methadone and placebo.
Buprenorphine has been studied extensively since 1978 when it was initially proposed as an alternative to methadone for treatment of opioid dependence. Early work by Jasinski et al., 1978; Mello and Mendelson, 1980; Mello et al., 1982; Mello et al., 1983 and Mendelson et al., 1984 and their colleagues demonstrated buprenorphine's low physical abuse potential and its ability to substitute for heroin and reduce heroin self-administration in opiate-dependent humans. The subsequent early clinical studies suggested that, in clinical settings, buprenorphine was a safe and efficacious opiate dependence pharmacotherapy. Formal approval for general clinical use, however, required that systematic data be gathered on buprenorphine's safety and efficacy in larger groups and a series of controlled clinical trials was designed to evaluate its utility from a medication development perspective. In general, these trials adhered to one of three basic protocol designs: comparison of buprenorphine to methadone; dose comparisons using dose response as an indicator of efficacy; and comparison of buprenorphine to placebo. Retention in treatment, reduction in illicit drug use and craving, and patient and staff ratings of improvements were the most frequently used outcome indicators in these trials. Additional data collected included optimum dosing and dosage schedules, adverse reactions and common side-effects, and other information intended to clarify buprenorphine's benefit-risk relationship and to help prepare guidelines for its safe marketing and utilization by physicians in general clinical practice. This paper presents a review of the buprenorphine/methadone comparison trials conducted in the United States and two such trials conducted in Europe. Also reviewed are three placebo-controlled trials and a buprenorphine/methadone detoxification study. Overall, this series of studies did firmly establish the efficacy of buprenorphine alone and in comparison to methadone.
Buprenorphine↗
Opioid effects and opioid withdrawal during a 24 h dosing interval in patients maintained on buprenorphine.
In maintenance patients methadone has been shown to produce considerable changes in opioid effects and withdrawal over the dosing interval. As a partial agonist buprenorphine may be expected to produce smaller changes, but the nature and magnitude of these changes have only been described for single doses. In the present study opioid effects and withdrawal were described in patients maintained on buprenorphine. Twenty four opioid dependent subjects were administered 16 mg buprenorphine tablets sublingually for 10 days. On day 10 plasma samples were collected and physiological, subjective and observer-rated measures collected pre-dose and at 14 time points during the dosing interval. No significant respiratory depression was observed. Consistent with the partial agonist properties of buprenorphine, other physiological and subjective changes were also of small magnitude. However, even at a once daily dose of 16 mg some patients experienced significant opioid withdrawal that was maximal at the end of the dosing interval. Buprenorphine maintenance should be associated with a high level of safety and a low level of disruption caused by changing opioid effects over the dosing interval, but some patients may require high doses or other strategies to completely suppress withdrawal.
Administration, Sublingual↗
Irritability following abstinence from cocaine predicts euphoric effects of cocaine administration.
This study evaluated the association between negative affective symptoms during initial abstinence and euphorigenic response to experimentally administered cocaine. Cocaine-dependent individuals achieved 5 days of abstinence in a hospital setting. Forty milligrams of cocaine was given intravenously on the fifth day of abstinence, and participants were asked to rate the subjective effects produced by the drug. The associations between irritability, self-reported depression, and the subjective "high" produced by cocaine were evaluated. Increased levels of irritability and depression both correlated positively and statistically significantly with heightened response to experimentally administered cocaine as indexed by self-reported subjective "high." The positive association between irritability and subjective "high" remained after controlling for self-reported depressive symptoms. The opponent process model predicts that increased levels of negative affect should be associated with diminished euphoric response to cocaine; however, the opposite was observed. If these findings are replicated in a larger sample, then it may be necessary to reconsider the applicability of the opponent process model to cocaine addiction in humans.
Adult↗
Quantitative EEG abnormalities in recently abstinent methamphetamine dependent individuals.
OBJECTIVE: Methamphetamine exposure is associated with long-lasting reductions in markers for dopaminergic neurons in preclinical models and probably in humans. Quantitative electroencephalography (EEG) has been used to characterize abnormalities in brain function in a number of disorders, including cocaine dependence, but this technique has not been used to characterize abnormalities associated with methamphetamine dependence. METHODS: The sample included 11 methamphetamine dependent subjects and 11 non-drug using volunteers. Methamphetamine dependent subjects were hospitalized for 4 days to document abstinence; non-drug using volunteers were studied as outpatients. EEGs were recorded in the eyes-closed resting state, and absolute EEG power in each frequency band (0.5-4, 4-8, 8-12, and 12-20 Hz) was quantitated using a fast Fourier transform. EEG power was log-transformed prior to analysis. Conventional, EEG tracings were interpreted by a qualified electroencephalographer who was blinded to the subjects' identity. RESULTS: Methamphetamine dependent volunteers with 4 days of abstinence had increased EEG power in the delta and theta bands. Power in the alpha and beta bands did not differ between the groups. Within the methamphetamine dependent group, a majority of the conventional EEGs were abnormal (64%), compared to 18% in the non-methamphetamine using group. CONCLUSIONS: Recently abstinent methamphetamine dependent subjects demonstrate QEEG abnormalities that are consistent with a generalized encephalopathy. SIGNIFICANCE: Encephalopathic changes in brain electrical activity, as found here in methamphetamine dependence, are frequently associated with a range of cognitive and psychiatric abnormalities, suggesting further avenues of investigation.
Adult↗