David A. Gorelick

Introduction to Behavioral Addictions

Background: Several behaviors, besides psychoactive substance ingestion, produce short-term reward that may engender persistent behavior, despite knowledge of adverse consequences, i.e., diminished control over the behavior. These disorders have historically been conceptualized in several ways. One view posits these disorders as lying along an impulsive-compulsive spectrum, with some classified as impulse control disorders. An alternate, but not mutually exclusive, conceptualization considers the disorders as non-substance or “behavioral” addictions. Objectives: Inform the discussion on the relationship between psychoactive substance and behavioral addictions. Methods: We review data illustrating similarities and differences between impulse control disorders or behavioral addictions and substance addictions. This topic is particularly relevant to the optimal classification of these disorders in the forthcoming fifth edition of the American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders (DSM-V). Results: Growing evidence suggests that behavioral addictions resemble substance addictions in many domains, including natural history, phenomenology, tolerance, comorbidity, overlapping genetic contribution, neurobiological mechanisms, and response to treatment, supporting the DSM-V Task Force proposed new category of Addiction and Related Disorders encompassing both substance use disorders and non-substance addictions. Current data suggest that this combined category may be appropriate for pathological gambling and a few other better studied behavioral addictions, e.g., Internet addiction. There is currently insufficient data to justify any classification of other proposed behavioral addictions. Conclusions and Scientific Significance: Proper categorization of behavioral addictions or impulse control disorders has substantial implications for the development of improved prevention and treatment strategies.

Agents in Development for the Management of Cocaine Abuse

Cocaine abuse is a serious health problem in many areas of the world, yet there are no proven effective medications for the treatment of cocaine dependence.Preclinical studies suggest that the reinforcing effect of cocaine that promotes its abuse is mediated by blockade of the presynaptic dopamine transporter. This results in increased dopamine activity in the mesolimbic or meso-accumbens dopamine reward system of brain. Development of new medications to treat cocaine dependence has focused on manipulation of this dopamine system, either by direct action on dopamine binding sites (transporter or receptors) or indirectly by affecting other neurotransmitter systems that modulate the dopamine system. In principle, a medication could act via one of three mechanisms: (i) as a substitute for cocaine by producing similar dopamine effects; (ii) as a cocaine antagonist by blocking the binding of cocaine to the dopamine transporter; or (iii) as a modulator of cocaine effects by acting at other than the cocaine binding site.The US National Institute on Drug Abuse has a Clinical Research Efficacy Screening Trial (CREST) programme to rapidly screen existing medications. CREST identified four medications warranting phase II controlled clinical trials: cabergoline, reserpine, sertraline and tiagabine. In addition, disulfiram and selegiline (deprenyl) have been effective and well tolerated in phase II trials. However, selegiline was found ineffective in a recent phase III trial.Promising existing medications probably act via the first or third aforementioned mechanisms. Sustained-release formulations of stimulants such as methyl-phenidate and amfetamine (amphetamine) have shown promise in a stimulant substitution approach. Disulfiram and selegiline increase brain dopamine concentrations by inhibition of dopamine-catabolising enzymes (dopamine-β-hydroxylase and monoamine oxidase B, respectively). Cabergoline is a direct dopamine receptor agonist, while reserpine depletes presynaptic stores of dopamine (as well as norepinephrine and serotonin). Sertraline, baclofen and vigabatrin indirectly reduce dopamine activity by increasing activity of neurotransmitters (serotonin and GABA) that inhibit dopamine activity.Promising new medications act via the second or third aforementioned mechanisms. Vanoxerine is a long-acting inhibitor of the dopamine transporter which blocks cocaine binding and reduces cocaine self-administration in animals. Two dopamine receptor ligands that reduce cocaine self-administration in animals are also undergoing phase I human safety trials. Adrogolide is a selective dopamine D1 receptor agonist; BP 897 is a D3 receptor partial agonist.A pharmacokinetic approach to treatment would block the entry of cocaine into the brain or enhance its catabolism so that less cocaine reached its site of action. This is being explored in animals using the natural cocaine-metabolising enzyme butyrylcholinesterase (or recombinant versions with enhanced capabilities), catalytic antibodies, and passive or active immunisation to produce anti-cocaine binding antibodies. A recent phase I trial of a ‘cocaine vaccine’ found it to be well tolerated and producing detectable levels of anti-cocaine antibodies for up to 9 months after immunisation.

New treatments for cocaine dependence: a focused review.

Cocaine, already a significant drug problem in North and South America, has become a more prominent part of the European drug scene. Cocaine dependence has major somatic, psychological, psychiatric, socio-economic, and legal implications. No specific effective pharmacological treatment exists for cocaine dependence. Recent advances in neurobiology have identified various neuronal mechanisms implicated in cocaine addiction and suggested several promising pharmacological approaches. Data were obtained from Medline, EMBASE, and PsycINFO searches of English-language articles published between 1985 and June 2007 using the key words: cocaine, addiction, cocaine dependence, clinical trials, pharmacotherapy(ies) singly and in combination. Large well-controlled studies with appropriate statistical methods were preferred. Pharmacological agents such as GABA agents (topiramate, tiagabine, baclofen and vigabatrin) and agonist replacement agents (modafinil, disulfiram, methylphenidate) seem to be the most promising in treatment of cocaine dependence. The results from trials of first- and second-generation neuroleptics are largely negative. Aripiprazole, a partial dopaminergic agonist that may modulate the serotonergic system, shows some promise. Preliminary results of human studies with anti-cocaine vaccine, N-acetylcysteine, and ondansetron, are promising, as are several compounds in preclinical development. While no medication has received regulatory approval for the treatment of cocaine dependence, several medications marketed for other indications have shown efficacy in clinical trials. An anti-cocaine vaccine and several compounds in preclinical development have also shown promise. Findings from early clinical trials must be confirmed in larger, less selective patient populations.

Myocardial Ischemia during Cocaine Withdrawal

STUDY OBJECTIVE To determine the prevalence of myocardial ischemia in patients with cocaine addiction. DESIGN Myocardial ischemia in chronic cocaine users was detected by serial 24-hour electrocardiographic ambulatory (Holter) monitoring and exercise treadmill testing in chronic cocaine users. The Holter tapes were coded, scanned in a blinded manner, and mixed with the tapes of 42 normal volunteers and 119 patients with either stable or unstable angina. SETTING A 28-day inpatient, substance abuse treatment program followed by an outpatient treatment program. PATIENTS Twenty-one consecutive male chronic cocaine users. MAIN RESULTS Eight of the 21 patients with cocaine addiction had frequent episodes of ST elevation during Holter monitoring; these episodes occurred almost exclusively during the first 2 weeks of withdrawal. None of the volunteers and patients with stable angina and only 4% of the patients with unstable angina had episodes of ST elevation during Holter monitoring (cocaine users compared with volunteers, P = 0.0004). Of the 20 cocaine patients who had exercise treadmill testing, only 1 had a positive test for ischemia. CONCLUSIONS Cocaine users frequently develop silent myocardial ischemia manifesting as episodes of ST elevation during the first weeks of withdrawal. The underlying mechanisms for these changes remain unknown, but our observations support the hypothesis that coronary vasospasm plays an important role in cocaine-related ischemic syndromes.

Imaging brain mu-opioid receptors in abstinent cocaine users: Time course and relation to cocaine craving

BACKGROUND Cocaine treatment upregulates brain mu-opioid receptors (mOR) in animals. Human data regarding this phenomenon are limited. We previously used positron emission tomography (PET) with [11C]-carfentanil to show increased mOR binding in brain regions of 10 cocaine-dependent men after 1 and 28 days of abstinence. METHODS Regional brain mOR binding potential (BP) was measured with [11C]carfentanil PET scanning in 17 cocaine users over 12 weeks of abstinence on a research ward and in 16 healthy control subjects. RESULTS Mu-opioid receptor BP was increased in the frontal, anterior cingulate, and lateral temporal cortex after 1 day of abstinence. Mu-opioid receptor BP remained elevated in the first two regions after 1 week and in the anterior cingulate and anterior frontal cortex after 12 weeks. Increased binding in some regions at 1 day and 1 week was positively correlated with self-reported cocaine craving. Mu-opioid receptor BP was significantly correlated with percentage of days with cocaine use and amount of cocaine used per day of use during the 2 weeks before admission and with urine benzoylecgonine concentration at the first PET scan. CONCLUSIONS These results suggest that chronic cocaine use influences endogenous opioid systems in the human brain and might explain mechanisms of cocaine craving and reinforcement.

The future of endocannabinoid-oriented clinical research after CB1 antagonists

IntroductionGreat interest has been shown by the medical community and the public in the cannabinoid CB1 receptor antagonists, such as rimonabant, for treatment of obesity, metabolic syndrome, and possibly drug addiction.DiscussionThis novel class of drug has therapeutic potential for other disorders, as the endocannabinoid system is involved in various health conditions. However, rimonabant, the first clinically available member of this class of drugs, has been linked to increased risk of anxiety, depression, and suicidality. Due to those risks, the European Medicines Agency called for its withdrawal from the market in October, 2008. Shortly after this decision, several pharmaceutical companies (Sanofi-aventis, Merck, Pfizer, Solvay) announced that they would stop further clinical research on this class of drug. Here, we provide an overview of those events and make several suggestions for continuing such clinical research, while safeguarding the safety of patients and clinical trial subjects.

Randomized trial of buprenorphine for treatment of concurrent opiate and cocaine dependence

Buprenorphine is a partial μ‐opiate agonist and κ‐opiate antagonist with established efficacy in the treatment of opiate dependence. Its efficacy for cocaine dependence is uncertain. This study evaluated buprenorphine for the treatment of concomitant cocaine and opiate dependence.

Enhancing cocaine metabolism with butyrylcholinesterase as a treatment strategy

Existing pharmacodynamic approaches to cocaine abuse treatment have not been widely successful. An alternative, pharmacokinetic, approach is to enhance cocaine metabolism by administration of butyrylcholinesterase (BChE), a major cocaine-metabolizing enzyme in primates. Initial studies in rodents suggest that BChE pretreatment can substantially reduce the acute physiological and behavioral effects of cocaine, at enzyme doses that themselves have no behavioral or toxic effects. A single enzyme injection may increase plasma BChE activity for several days, suggesting that exogenous administration may be practical. BChE treatment may also produce a favorable pattern of cocaine metabolites. Further research is needed to evaluate the long-term effects of BChE administration.

The accuracy of the CAGE, the Brief Michigan Alcoholism Screening Test, and the Alcohol Use Disorders Identification Test in screening trauma center patients for alcoholism.

OBJECTIVE To evaluate the accuracy of questionnaire screening instruments to identify lifetime alcohol dependence among trauma center patients. METHODS The study was conducted at a Level I trauma center between September 1994 and November 1996. Patients meeting eligibility requirements (> or = 18 years old, admission from injury scene, > or = 2 days of hospitalization, intact cognition) were evaluated for alcohol abuse and dependence. Screening instruments consisted of the CAGE, the Brief Michigan Alcoholism Screening Test, and the Alcohol Use Disorders Identification Test. Screening results were compared with lifetime alcohol dependence diagnoses made using the in-depth Psychoactive Substance Use Disorders section of the Structured Clinical Interview. Accuracy was quantified as sensitivity, specificity, positive/negative predictive values, and receiver operating characteristic curves (used to calculate area under the curve). RESULTS Of the 1,118 patients studied, lifetime alcohol dependence was diagnosed by Structured Clinical Interview in 397 (35.5%), and abuse was diagnosed in 90 (8.1%) others. The CAGE was the best predictor of lifetime alcohol dependence, i.e., had the largest area under the curve (93%) and the highest sensitivity (84%), specificity (90%), positive predictive value (82%), and negative predictive value (91%). Among patients testing positive for alcohol, 63% had a lifetime alcohol dependence diagnosis. CONCLUSION The CAGE is an efficient screening test to detect alcohol dependence in trauma center populations. It should be used in combination with alcohol testing to identify patients at risk of alcohol use problems.

Cannabis Withdrawal Among Non-Treatment-Seeking Adult Cannabis Users

This study investigates the clinical significance of a cannabis withdrawal syndrome in 104 adult, non-treatment-seeking, primarily cannabis users who reported at least one serious attempt to stop using cannabis. Retrospective self-report data were obtained on eighteen potential cannabis withdrawal symptoms derived from the literature, including co-occurrence, time course, and any actions taken to relieve the symptom. Study findings provide evidence for the clinical significance of a cannabis withdrawal syndrome, based on the high prevalence and co-occurrence of multiple symptoms that follow a consistent time course and that prompt action by the subjects to obtain relief, including serving as negative reinforcement for cannabis use.