Frank Vocci

The effects of NMDA receptor antagonists and nitric oxide synthase inhibitors on opioid tolerance and withdrawal: Medication development issues for opiate addiction**

This article is an exploration of the National Institute on Drug Abuse (NIDA) Technical Review on the role of glutamatergic systems in the development of opiate addiction. The effects of “glutamate antagonist” medications on opioid tolerance and withdrawal are examined. In rodents, mu opioid tolerance can be inhibited by noncompetitive N-methyl D-aspartate (NMDA) receptor antagonists [MK801, dextromethorphan (DM), ketamine, phencyclidine (PCP)], competitive NMDA receptor antagonists (LY274614, NPC17742, LY235959), partial glycine agonists (ACPC), glycine antagonists (ACEA-1328), and nitric oxide synthase (NOS) inhibitors [L-NNA, L-NMMA, methylene blue (MB)]. Similarly, some of the symptoms of opioid withdrawal observed in opioid-dependent rodents also can be inhibited by noncompetitive NMDA receptor antagonists (MK801, DM, ketamine), competitive NMDA receptor antagonists (LY274614), glycine antagonists (felbamate), and NOS inhibitors (L-NNA, L-NMMA, L-NAME, L-NIO, 7-NI, MB). There are some serious toxicological effects associated with the administration of some of the noncompetitive NMDA receptor antagonists in rodent but not in squirrel monkey brain, and some medications induce PCP-like behavioral effects. zThe medications with the most immediate clinical appeal are those that could be coadministered with methadone to decrease mu opioid tolerance and dependence; they include DM, MB, 7-NI, ACPC, and ACEA-1328.

Characterization of Sodium‐Dependent [3H]GBR‐12935 Binding in Brain: A Radioligand for Selective Labelling of the Dopamine Transport Complex

Abstract: High‐affinity and saturable binding sites for the diphenyl‐substituted piperazine derivative [3H]GBR‐12935 have been characterized in crude synaptosomal membranes prepared from rat brain. The specific binding of [3H]GBR‐12935 is sodium‐dependent and is unevenly distributed among various brain regions, with the highest concentration of binding sites being found in the corpus striatum and nucleus accumbens. Sodium‐dependent [3H]GBR‐12935 binding in all other brain areas was 10% or less of the binding found in the striatum. The affinity of [3H]GBR‐12935 for binding sites in the striatum is increased in the presence of Na+ but other cations, including K+, Ca2+, or Mg2+, inhibit specific binding. There is an excellent correlation (r= 0.96, p < 0.01) between the potencies of a series of drugs in inhibiting [3H]GBR‐12935 binding to striatal membranes and their potencies in inhibiting [3H]3,4‐dihydroxyphenylethylamine ([3H]dopamine) uptake in synaptosomes. Agonists and antagonists of other neurotransmitter receptor or drug recognition sites have little or no effect on specific [3H]GBR‐12935 binding to striatal membranes. In addition, prior intracerebroventricular administration of 6‐hydroxydopamine results in a decrease in the number of specific [3H]GBR‐12935 binding sites in the striatum. These data indicate that [3H]GBR‐12935 is a selective radioligand of the presynaptic dopamine transport complex in brain.

Bupropion for the Treatment of Methamphetamine Dependence

Bupropion was tested for efficacy in increasing weeks of abstinence in methamphetamine-dependent patients, compared to placebo. This was a double-blind placebo-controlled study, with 12 weeks of treatment and a 30-day follow-up. Five outpatient substance abuse treatment clinics located west of the Mississippi participated in the study. One hundred and fifty-one treatment-seekers with DSM-IV diagnosis of methamphetamine dependence were consented and enrolled. Seventy-two participants were randomized to placebo and 79 to sustained-release bupropion 150 mg twice daily. Patients were asked to come to the clinic three times per week for assessments, urine drug screens, and 90-min group psychotherapy. The primary outcome was the change in proportion of participants having a methamphetamine-free week. Secondary outcomes included: urine for quantitative methamphetamine, self-report of methamphetamine use, subgroup analyses of balancing factors and comorbid conditions, addiction severity, craving, risk behaviors for HIV, and use of other substances. The generalized estimating equation regression analysis showed that, overall, the difference between bupropion and placebo groups in the probability of a non-use week over the 12-week treatment period was not statistically significant (p=0.09). Mixed model regression was used to allow adjustment for baseline factors in addition to those measured (site, gender, level of baseline use, and level of symptoms of depression). This subgroup analysis showed that bupropion had a significant effect compared to placebo, among male patients who had a lower level of methamphetamine use at baseline (p<0.0001). Comorbid depression and attention-deficit/hyperactivity disorder did not change the outcome. These data suggest that bupropion, in combination with behavioral group therapy, was effective for increasing the number of weeks of abstinence in participants with low-to-moderate methamphetamine dependence, mainly male patients, regardless of their comorbid condition.

Modafinil for the treatment of cocaine dependence

AIM Modafinil was tested for efficacy in facilitating abstinence in cocaine-dependent patients, compared to placebo. METHODS This was a double-blind placebo-controlled study, with 12 weeks of treatment and a 4-week follow-up. Six outpatient substance abuse treatment clinics participated in the study. There were 210 treatment-seekers randomized, having a diagnosis of cocaine dependence; 72 participants were randomized to placebo, 69 to modafinil 200mg, and 69 to modafinil 400mg, taken once daily on awakening. Participants came to the clinic three times per week for assessments and urine drug screens, and had one hour of individual psychotherapy weekly. The primary outcome measure was the weekly percentage of cocaine non-use days. RESULTS The GEE regression analysis showed that for the total sample, there was no significant difference between either modafinil group and placebo in the change in average weekly percent of cocaine non-use days over the 12-week treatment period (p>0.79). However, two secondary outcomes showed significant effects by modafinil 200mg: the maximum number of consecutive non-use days for cocaine (p=0.02), and a reduction in craving (p=0.04). Also, a post hoc analysis showed a significant effect of modafinil that increased the weekly percentage of non-use days in the subgroup of those cocaine patients who did not have a history of alcohol dependence (p<0.02). CONCLUSIONS These data suggest that modafinil, in combination with individual behavioral therapy, was effective for increasing cocaine non-use days in participants without co-morbid alcohol dependence, and in reducing cocaine craving.

[3H]GBR-12935 binding to the dopamine transporter is decreased in the caudate nucleus in Parkinson's disease

The specific binding of [3H]GBR‐12935 to membranes prepared from human caudate nucleus is saturable (Bmax 1.36 ± 0.18 pmol/mg protein), sodium dependent, and of high affinity (KD 2.34 ± 0.18 nM). Freezing of tissue from rat brain, or refrigeration followed by freezing, results in a small but significant (20%) decrease in specific [3H]GBR‐12935 binding when compared to the binding observed in fresh (nonfrozen) tissue, and this decrease may account, in part, for the differences in specific binding between rat and human brain membranes. Despite small differences in binding site density between fresh and frozen tissue there is a good correlation (r= 0.98; p < 0.01) between the potencies of a series of drugs in displacing specific [3H]GBR‐12935 binding to human caudate membranes and rat striatum as well as in inhibiting dopamine uptake in rat striatal synaptosomes (r= 0.96; p < 0.01). The specific binding of [3H]GBR‐12935 to membranes prepared from the caudate nuclei of patients with Parkinsons disease is decreased compared to membranes prepared from age‐and sex‐matched controls. These data suggest that [3H]GBR‐12935 binds in a sodium‐dependent fashion to the dopamine transport complex in human brain and that specific binding is decreased by a pathological degeneration of dopaminergic neurons to the caudate nucleus.

Pharmacotherapy and other treatments for cocaine abuse and dependence.

Purpose of review This review examines progress being made in the treatment of cocaine abuse and dependence, with a particular focus on pharmacotherapies. Medications with apparently very different mechanisms of action have been reported to reduce cocaine use in controlled clinical trials in outpatient settings. This review will summarize the latest findings in this area. Recent findings Of all the medications tested to date, disulfiram has demonstrated the most consistent effect to reduce cocaine use. Several medications have been reported to reduce cocaine use in double-blind, placebo-controlled clinical trials, namely baclofen, modafinil, tiagabine, and topiramate. All pharmacotherapy trials in cocaine-dependent patients include a behavioral therapy that is common to all participants. Consequently, these pharmacotherapy trials can be considered to evaluate whether the medication is adding to the effect of the behavioral therapy. Summary Confirmatory clinical studies are necessary to replicate the initial efficacy findings for baclofen, modafinil, tiagabine, and topiramate. More research is needed in both cocaine and cocaine–alcohol dependent populations. Once confirmatory studies have been carried out, testing of rational medication combinations with different behavioral therapies is an obvious next step to increase the ability to manage cocaine dependence.

Pharmacotherapy of Methamphetamine Addiction: An Update

ABSTRACT Methamphetamine dependence is a serious public health problem worldwide for which there are no approved pharmacological treatments. Psychotherapy is still the mainstay of treatment; however, relapse rates are high. The search for effective pharmacological treatment has intensified in the last decade. This review will highlight progress in pharmacological interventions to treat methamphetamine dependence as well as explore new pharmacological targets. Published data from clinical trials for stimulant addiction were searched using PubMed and summarized, as well as highlights from a recent symposium on methamphetamine pharmacotherapy presented at the ISAM 2006 meeting, including interim analysis data from an ongoing D-amphetamine study in Australia. Early pilot data are encouraging for administering D-amphetamine and methylphenidate as treatment for heavy amphetamine users. Abilify at 15 mg/day dose increased amphetamine use in an outpatient pilot study. Sertraline, ondansetron, baclofen, tyrosine, and imipramine were ineffective in proof-of-concept studies. Development of pharmacotherapy for methamphetamine dependence is still in an early stage. Data suggesting D-amphetamine and methylphenidate as effective pharmacotherapy for methamphetamine addiction will need to be confirmed by larger trials. Preclinical data suggest that use of GVG, CB1 antagonist, and lobeline are also promising therapeutic strategies.

Psychological treatments for stimulant misuse, comparing and contrasting those for amphetamine dependence and those for cocaine dependence.

Purpose of review The aim is to compare and contrast psychological treatments for amphetamine and cocaine dependence. Recent findings Stimulant dependence, in the form of cocaine or amphetamine/methamphetamine dependence, is prevalent worldwide, and their ratio may vary across different countries and regions of countries. The treatment of stimulant disorders has greatly advanced in recent years, and scientific evaluation of behavioral therapies, using randomized clinical trials designs and a stage-wise approach, have demonstrated the safety and efficacy of interventions. Psychological interventions such as cognitive behavioral therapy and contingency management for cocaine and methamphetamines use disorders are well tolerated and moderately effective in achieving drug abstinence. There is evidence that contingency management interventions can help to improve retention in treatment and, in turn, other treatment outcomes. Although there are important differences in the neuropsychiatric and medical consequences of cocaine and amphetamine use disorders, there is currently no evidence for a differential treatment effect of any psychosocial treatment in the management of these disorders. Summary As there are no Food and Drug Administration-approved medications for the treatment of these disorders, psychological interventions form the basis of their treatment. More research is needed to address the specific psychosocial needs of cocaine and amphetamine-dependent individuals in order to improve their treatment outcomes.

Cognitive remediation in the treatment of stimulant abuse disorders: a research agenda.

Treatment of substance abuse disorders is often characterized by high dropout rates. Patients who fail to complete a treatment course often are worse at follow-up than those patients who received the full treatment course. Cognitive deficits, including impulsivity, have been noted as a major determinant of treatment retention and successful outcomes. This review summarizes the recent literature on cognitive deficits in stimulant users and their remediation. Cognitive deficits can be remediated through computer-assisted cognitive rehabilitation in residential settings. A few studies have shown this can be transferred to the outpatient setting although much research remains to be done in this setting. Pharmacological remediation of cognitive deficits is a new target for medications development in the treatment of substance abuse disorders. Psychiatric disorders; for example, attention deficit hyperactivity disorder, are amenable to pharmacological remediation of cognitive deficits. Several cognitive deficits (set-shifting, attentional bias, reversal learning, impulsivity, and risky decision making) and their possible remediation with pharmacological agents are presented in the review. Recommendations for the research agenda include comments on testing hierarchies, clinical trial design issues, and types of pharmacological agents.

Marijuana neurobiology and treatment.

ABSTRACT Marijuana is the number one illicit drug of abuse worldwide and a major public health problem, especially in the younger population. The objective of this article is to update and review the state of the science and treatments available for marijuana dependence based on a pre-meeting workshop that was presented at ISAM 2006. At the workshop, several papers were presented addressing the neurobiology and pharmacology of marijuana and treatment approaches, both psychotherapy and medications, for marijuana withdrawal. Medicolegal and ethical issues concerning marijuana medical use were also discussed. Concise summaries of these presentations are incorporated in this article, which is meant to be an updated review of the state of the science. Major advances have been made in understanding the underpinning of marijuana dependence and the role of the CNS cannabinoid system, which is a major area for targeting medications to treat marijuana withdrawal and dependence, as well as other addictions. Behavioral therapies are efficacious for facilitating abstinence from marijuana. Nefazadone, Marinol, and buspirone are showing early positive signals for efficacy in ameliorating marijuana withdrawal symptoms. Effective psychotherapeutic approaches are available and promising medications studies need to be confirmed in outpatient trials. The next few years looking promising for translational research efforts to make treatment widely accessible to patients with marijuana dependence.