Charles A. Dackis

A Double-Blind, Placebo-Controlled Trial of Modafinil for Cocaine Dependence

Despite years of active research, there are still no approved medications for the treatment of cocaine dependence. Modafinil is a glutamate-enhancing agent that blunts cocaine euphoria under controlled conditions, and the current study assessed whether modafinil would improve clinical outcome in cocaine-dependent patients receiving standardized psychosocial treatment. This was a randomized, double-blind, placebo-controlled trial conducted at a university outpatient center (from 2002 to 2003) on a consecutive sample of 62 (predominantly African American) cocaine-dependent patients (aged 25–63) free of significant medical and psychiatric conditions. After screening, eligible patients were randomized to a single morning dose of modafinil (400 mg), or matching placebo tablets, for 8 weeks while receiving manual-guided, twice-weekly cognitive behavioral therapy. The primary efficacy measure was cocaine abstinence based on urine benzoylecgonine levels. Secondary measures were craving, cocaine withdrawal, retention, and adverse events. Modafinil-treated patients provided significantly more BE-negative urine samples (p=0.03) over the 8-week trial when compared to placebos, and were more likely to achieve a protracted period (⩾3 weeks) of cocaine abstinence (p=0.05). There were no serious adverse events, and none of the patients failed to complete the study as a result of adverse events. This study provides preliminary evidence, which should be confirmed by a larger study, that modafinil improves clinical outcome when combined with psychosocial treatment for cocaine dependence.

Cocaine dependence: A disease of the brain's reward centers.

Cocaine addiction affects brain reward centers that have evolved to ensure survival. Cocaine euphoria is intensely pleasurable and results from mesolimbic dopamine (DA) neurotransmission. DA signal-receiving neurons in the nucleus accumbens synthesize endogenous opioids and project to numerous reward regions. Cocaine-induced neuroadaptations, including DA depletion, may underlie craving and hedonic dysregulation. Cue-induced craving is vigorously triggered by conditioned elements of the drug environment and associated with measurable limbic activation. Reduced frontal lobe metabolism in cocaine-addicted individuals could explain important clinical phenomena such as denial and the loss of control over limbic impulses. Cocaine addiction is rapidly progressive and associated with severe medical, psychiatric, and psychosocial consequences. Denial shields addicted individuals from their predicament and must be addressed in treatment. Lacking pharmacological options, clinicians must rely entirely on psychosocial approaches. Treatment principles, including engagement, motivational enhancement, abstinence strategies, and craving reduction are discussed in terms of biological rationales.

Neurobiology of addiction: treatment and public policy ramifications

In the United States, efforts to treat addiction are hampered by prejudice and a public view that treats it as a disorder of self-control, not a disease. We highlight select advances in addiction research that, if disseminated to the public, could reverse these misconceptions and facilitate changes in policy to improve treatment access and care delivery for this highly prevalent disease.

Modafinil and cocaine: a double-blind, placebo-controlled drug interaction study

Modafinil is a novel compound that is approved for the treatment of narcolepsy. It is now being studied as a potential treatment for cocaine dependence. Cocaine withdrawal symptoms are associated with poor clinical outcome and are likely to be reversed by modafinil. In addition, the neurotransmitter actions of modafinil are opposite to cocaine-induced neuroadaptations affecting dopamine and glutamate reward circuits. Since cocaine-dependent subjects might use cocaine during a clinical trial with modafinil, this study tested the safety of intravenous cocaine (30 mg) in combination with modafinil. Each of seven subjects received a baseline (open-label) cocaine infusion. Three subsequent cocaine infusions were administered after subjects received 4 days of low dose modafinil (200 mg/day), high dose modafinil (400 mg/day), or placebo in randomized double-blind sequences. One subject received placebo prior to all infusions. Our results indicate that co-administering modafinil and a single dose of intravenous cocaine is not associated with medical risk in terms of blood pressure, pulse, temperature, or electrocardiogram measures. Furthermore, pretreatment with modafinil did not intensify cocaine euphoria or cocaine-induced craving. In fact, cocaine euphoria was significantly blunted (P=0.02) in one of our subjective measures.

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.

A Double-Blind, Placebo-Controlled Trial Combining Sertraline and Naltrexone for Treating Co-Occurring Depression and Alcohol Dependence

OBJECTIVE Empirical evidence has only weakly supported antidepressant treatment for patients with co-occurring depression and alcohol dependence. While some studies have demonstrated that antidepressants reduce depressive symptoms in individuals with depression and alcohol dependence, most studies have not found antidepressant treatment helpful in reducing excessive drinking in these patients. The authors provide results from a double-blind, placebo-controlled trial that evaluated the efficacy of combining approved medications for depression (sertraline) and alcohol dependence (naltrexone) in treating patients with both disorders. METHOD A total of 170 depressed alcohol-dependent patients were randomly assigned to receive 14 weeks of treatment with sertraline (200 mg/day [N=40]), naltrexone (100 mg/day [N=49]), the combination of sertraline plus naltrexone (N=42), or double placebo (N=39) while receiving weekly cognitive-behavioral therapy. RESULTS The sertraline plus naltrexone combination produced a higher alcohol abstinence rate (53.7%) and demonstrated a longer delay before relapse to heavy drinking (median delay=98 days) than the naltrexone (abstinence rate: 21.3%; delay=29 days), sertraline (abstinence rate: 27.5%; delay=23 days), and placebo (abstinence rate: 23.1%; delay=26 days) groups. The number of patients in the medication combination group not depressed by the end of treatment (83.3%) approached significance when compared with patients in the other treatment groups. The serious adverse event rate was 25.9%, with fewer reported with the medication combination (11.9%) than the other treatments. CONCLUSIONS More depressed alcohol-dependent patients receiving the sertraline plus naltrexone combination achieved abstinence from alcohol, had delayed relapse to heavy drinking, reported fewer serious adverse events, and tended to not be depressed by the end of treatment.

Single-dose bromocriptine reverses cocaine craving

Thirteen hospitalized cocaine addicts complaining of cocaine craving were given a single dose of bromocriptine, a dopamine agonist, in a randomized, double-blind, placebo-controlled study design. Compared to placebo, bromocriptine caused a significant reduction in craving ratings. These data suggest that bromocriptine may be effective as a new, nonaddictive pharmacological treatment for cocaine addicts and support the notion that functional dopamine depletion occurs with chronic cocaine use. Open trials indicate that low-dose bromocriptine may be useful in cocaine detoxification.

Taste of nutrients: Amino acids, vitamins, and fatty acids

Multidimensional scaling techniques were used to determine the range in taste of nutrients for human subjects. The nutrients tested (amino acids, vitamins, and fatty acids) span the traditional sweet, sour, salty, and bitter gustatory quality range. The results also suggest that alkaline, sulfurous, and fatty qualities exist as well; the possibility that these three quality groupings are due to olfactory or tactile rather than gustatory input is discussed.

Glutamatergic Agents for Cocaine Dependence

Abstract: Effective medications for cocaine dependence are needed to improve outcome in this chronic, relapsing disorder. Medications affecting glutamate function are reasonable candidates for investigation, given the involvement of glutamate circuits in reward‐related brain regions and evdence of cocaine‐induced glutamatergic dysregulation. In addition, it is increasingly apparent that glutamatergic mechanisms underlie several clinical aspects of cocaine dependence, including euphoria, withdrawal, craving, and hedonic dysfunction. Even denial, traditionally viewed as purely psychological, may result, in part, from dysfunctional glutamate‐rich cortical regions. We review the involvement of glutamate in reward‐related circuits, the acute and chronic effects of cocaine on these pathways, and glutamatergic mechanisms that contribute to the neurobiology of cocaine dependence. We also present preliminary data from our research of modafinil, a glutamate‐enhancing agent with promise in the treatment of cocaine‐addicted individuals.

A double-blind, placebo-controlled trial of modafinil for cocaine dependence.

This is a randomized, double-blind, placebo-controlled study of modafinil treatment for cocaine dependence. Patients (N = 210) who were actively using cocaine at baseline were randomized to 8 weeks of modafinil (0 mg/day, 200 mg/day, or 400 mg/day) combined with once-weekly cognitive-behavioral therapy. Our primary efficacy measure was cocaine abstinence, based on urine benzoylecgonine (BE) levels, with secondary measures of craving, cocaine withdrawal, retention, and tolerability. We found no significant differences between modafinil and placebo patients on any of these measures. However, there was a significant gender difference in that male patients treated with 400 mg/day tended to be more abstinent than their placebo-treated counterparts (p = .06). Our negative findings might be explained by gender differences and/or inadequate psychosocial treatment intensity in patients with severe cocaine dependence.