Neuropsychiatric effects of cocaine use disorders

Individuals who use cocaine report a variety of neuropsychiatric symptoms that are yet to be adequately targeted with treatment modalities. To address this problem requires an understanding of these symptoms and their neurobiological origins. Our paper reviewed the existing data on the neuropsychiatic implications of cocaine. We conducted a Medline search from 1984-2004 using terms, such as "cocaine", "cocaine addiction", "cocaine abuse", "cocaine neuropsychiatry" and "dual diagnosis". The search produced additional reference materials that were used in this review, although we focused on data that have likely clinical implications. The literature evidence suggested that, whereas acute cocaine overdose is potentially fatal, the ingestion of mild-to-moderate doses could result in fatal or nonfatal neuropsychiatric events. Also, chronic cocaine use may be associated with deficits in neurocognition, brain perfusion and brain activation patterns. Some of these deficits were unresolved with periods of abstinence ranging from 3-200 days. Taken together, these studies suggest the need for further investigations to fully characterize the neurobiological substrates of cocaine use disorders (CUDs) with the future possibility of more efficient treatment modalities.     

Intracerebral hemorrhage associated with cocaine abuse

With the current epidemic of cocaine abuse, there have been many clinical reports of cocaine toxicity, including stroke. Autopsy findings were reported in only one case of intracerebral hemorrhage associated with cocaine abuse. We describe the autopsy toxicological findings in a case of sudden death in a young person due to intracerebral hemorrhage associated with cocaine abuse. In view of the present epidemic of cocaine abuse, cocaine toxicity should be considered in the differential diagnosis of intracerebral hemorrhage. We suggest that the pharmacodynamic effects of cocaine on the cerebral vasculature is the most likely cause.     

Genetic and Environmental Influences on Transitions in Drug Use

Genetic and environmental factors influence drug abuse, but abuse represents the culmination of a sequence of events. Different levels of use may have different determinants and these determinants may differ across drug types. Approximately 3200 male–male twin pairs from the Vietnam Era Twin Registry were interviewed by telephone. Data were obtained regarding exposure to six categories of illicit drugs, initiation of use, continuation of use, regular usage, and diagnosis of drug abuse/dependence. Genetic, common environmental, and unique environmental influences on transitions of drug involvement, defined as movement from one level of drug use to the next, were investigated. Marijuana had the highest conditional probability for the transition from exposure to use, from use to use more than five times, and from use more than five times to regular use. The rate of transition to regular use of heroin was higher than the rate for amphetamine, cocaine, sedatives, and psychedelics. Cocaine had the highest conditional probability for the transition from regular use to abuse/dependence. Significant genetic influences were observed for a number of transitions in marijuana, amphetamine, and cocaine usage.     

Therapeutic vaccines for substance dependence

Immunotherapies are under development as a new approach to the treatment of substance dependence. The drugs of abuse currently being tested using this new approach are nicotine, cocaine, phencyclidine and methamphetamine. In laboratory animal models, a range of immunotherapies, including vaccines, monoclonal antibodies and catalytic antibodies, have been shown to reduce drug seeking. In human clinical trials, cocaine and nicotine vaccines have been shown to induce antibody titers while producing few side effects. Studies in humans determining how these vaccines interact in combination with their target drug are underway. Overall, immunotherapy offers a range of potential treatment options: drug treatment, as well as the treatment of overdose, prevention of brain or cardiac toxicity and fetal protection in pregnant drug abusers.     

Simultaneous acute thrombosis of two major coronary arteries following intravenous cocaine use

Myocardial infarction is now a well-recognized complication of cocaine abuse. This report describes a 38-year-old man who sustained simultaneous acute thrombosis of two major epicardial coronary arteries shortly after intravenous cocaine use. The finding of layers of mural thrombus of varying age, from acute to two to three days, in both coronary arteries represents a previously unreported finding (to our knowledge) in cocaine-associated cardiac death. Potential mechanisms for the association between cocaine use and infarction and the cardiac pathologic findings in cocaine-associated death are discussed.     

The co-occurrence of bipolar and substance use disorders

Substance use disorders are exceptionally common in bipolar patients. Although the frequency of this co-occurrence is well-documented, the reasons for this association are not clear. In this review, the authors examine four potential hypotheses for why substance use and bipolar disorders co-occur: (a) substance abuse occurs as a symptom of bipolar disorder; (b) substance abuse is an attempt by bipolar patients to self-medicate symptoms; (c) substance abuse causes bipolar disorder; and (d) substance use and bipolar disorders share a common risk factor. None of these four hypotheses have unequivocal support for explaining all cases of bipolar and substance use disorder co-occurrence, and it is probable that all four mechanisms play some role in the excess of substance abuse observed in bipolar patients. Additional studies are warranted to clarify the complex relationships between these two conditions as better understanding of this co-occurrence could lead to better treatment for patients afflicted with both disorders.     

Pregnancy and substance abuse

Summary The fetal consequences of drug abuse during pregnancy remain underestimated. Obstetrical complications of cigarette smoking include growth retardation, spontaneous abortion and sudden infant death syndrome; alcohol abuse leads to nutritional deficiencies and fetal alcohol syndrome. Heroin and cocaine consumption result in medical, nutritional and social neglect; cocaine and amphetamine cause hypertension, abruptio placentae; all three drugs of abuse cause preterm labor, with neonates being small for gestational age. Intravenous abuse also increases the risk of contracting infectious disease. The recommended treatment standard is to maintain pregnant, opioid-dependent women on synthetic opioids such as methadone, but newer substances like slow-release morphine and buprenorphine may also be beneficial. Treatment should be interdisciplinary and consider the high prevalence of substance dependent partners. Programmes should be initiated to identify women at risk and provide early treatment to improve the outcome for mother and child. Care must be provided in a supportive, proactive and non-judgemental fashion.     

Cocaine abuse and the bipolar spectrum in 1090 heroin addicts: clinical observations and a proposed pathophysiologic model

BACKGROUND: Several studies indicate a specific relationship between bipolar disorder and stimulant use and abuse. It has generally been assumed that cocaine use represents self-enhancement or attempts to optimize one's level of hypomania, cyclothymia or hyperthymia. This topic required further examination among heroin abusers because cocaine abuse is commonly comorbid with heroin abuse. METHODS: Cocaine abuse by bipolar subjects was investigated in a group of 1090 treatment-seeking heroin addicts enrolled between 1994 and 2005. We collected data with 1) the Drug Addiction History Rating Scale; and 2) the Semi-structured Interview for Depression, which inquires systematically among others, about hypomania, cyclothymia, hyperthymia and depressive temperament. Subjects were aged 29+/-6 years, and predominantly male (76.2%). RESULTS: Univariate and multivariate analyses provided correlations in favour of a link between current cocaine abuse and double diagnosis, with special relevance to the bipolar spectrum, as well as psychotic disorders (p<0.0001). LIMITATION: The modality of access to cocaine in different communities and the difficulty to distinguish cocaine use from abuse by the rating scale administered may have limited the interpretation of results. CONCLUSIONS: If cocaine abuse precedes that of heroin or is concomitant, heroin may hypothetically serve as a "mood balancer" which transiently dampens subthreshold excitatory states and mood swings. Our data further suggest the need for a more complex model linking cocaine and bipolarity: subthreshold bipolarity, including hyperthymic and cyclothymic temperaments, seems to predispose to heroin addiction, but craving for the suppressed hypomania in turn could lead to cocaine abuse, which eventually unmasks a frank bipolar disorder - in some cases leading to mixed state, severe mania, as well as psychosis beyond mania. Prospective observations would shed further insight on this complex interface of major clinical and public health importance.     

Therapeutic vaccines for substance dependence

Several immunotherapies are under development for nicotine, cocaine and phencyclidine and a cocaine vaccine has started human trials. These therapies promise a new approach to diseases that have had limited treatment success and tremendous morbidity. Both the cocaine and nicotine addiction immunotherapies have reduced 'relapse' to drug use in animal model systems. To date, the active cocaine vaccine has few side effects and induces considerable antibody titers after active immunization in humans. Studies with the monoclonal phencyclidine immunotherapy provide intriguing evidence of sustained protection for months after single-dose administration. Other immunotherapy may include treatment of drug overdose, prevention of brain or cardiac toxicity and protection of a fetus during pregnancy in a drug abuser.     

Dysfunctional gene splicing as a potential contributor to neuropsychiatric disorders

Alternative pre‐mRNA splicing is a major mechanism by which the proteomic diversity of eukaryotic genomes is amplified. Much akin to neuropsychiatric disorders themselves, alternative splicing events can be influenced by genetic, developmental, and environmental factors. Here, we review the evidence that abnormalities of splicing may contribute to the liability toward these disorders. First, we introduce the phenomenon of alternative splicing and describe the processes involved in its regulation. We then review the evidence for specific splicing abnormalities in a wide range of neuropsychiatric disorders, including psychotic disorders (schizophrenia), affective disorders (bipolar disorder and major depressive disorder), suicide, substance abuse disorders (cocaine abuse and alcoholism), and neurodevelopmental disorders (autism). Next, we provide a theoretical reworking of the concept of “gene‐focused” epidemiologic and neurobiologic investigations. Lastly, we suggest potentially fruitful lines for future research that should illuminate the nature, extent, causes, and consequences of alternative splicing abnormalities in neuropsychiatric disorders. © 2011 Wiley‐Liss, Inc.     

Survey of 500 callers to a national cocaine helpline

Information gathered during extensive telephone interviewing of 500 cocaine users calling the 800-COCAINE helpline revealed a high incidence of dysfunctional cocaine use associated with numerous physical, psychological, and social problems. The typical caller was a white, middle-income male between 25 and 40 years old with no history of drug dependence or serious psychiatric problems. The findings are discussed with regard to the high abuse potential of cocaine and adverse effects.     

Incidental myocarditis with intravenous drug abuse: the pathology, immunopathology, and potential implications for human immunodeficiency virus-associated myocarditis.

Human immunodeficiency virus (HIV)-associated myocarditis is well reported. Many of these patients are also intravenous (IV) drug abusers. This study examined sudden death victims from the Office of the Chief Medical Examiner, State of Maryland, for active myocarditis. A group of HIV-negative drug abusers is compared with a group of HIV-negative victims without any known risk factors for the acquired immunodeficiency syndrome. Using modified Dallas criteria combined with an avidin-biotin-labeled immunoperoxidase procedure, the cases were classified as active, borderline, or absent myocarditis. Serologic analysis for circulating antimyocardial antibody was performed along with phenotypic analysis of the infiltrate. Of the 15 IV drug abuse cases examined, none were positive for HIV (enzyme-linked immunosorbent assay and Western blot). With IV drug abuse as the primary risk factor, five cases demonstrated active myocarditis, while five others had borderline myocarditis. Only one of 10 low-risk patients had a lymphocytic infiltrate consistent with borderline myocarditis. Drug abuse-related myocarditis was associated with cardiac pathology resulting in sudden death in only one case. Antimyocardial antibodies were positive in four of the 15 IV drug abuse cases, including patients with active, borderline, and absent myocarditis. The phenotypic expression of the lymphocytic infiltrates was similar to the findings reported for idiopathic and HIV-related myocarditis (Am J Pathol 137:1365-1371, 1990). Toxicology studies did not implicate any particular drug of abuse, but the increased frequency of myocarditis observed may reflect complications of cocaine or the combined effects of opiates and cocaine. Intravenous drug abuse is an independent risk factor for myocarditis and must be taken into consideration in studies of HIV-associated myocarditis.     

A history of bingeing on fat enhances cocaine seeking and taking

Binge eating and substance dependence are disorders characterized by a loss of control over consummatory behaviors. Given the common characteristics of these two types of disorders, it is not surprising that the comorbidity between eating disorders and substance abuse disorders is high (20-40%; Conason et al., 2006). It is unknown, however, whether loss of control in one disorder predisposes an individual to loss of control in the other. The present study, therefore, used a rodent model to test whether a history of binge eating would augment subsequent responding for cocaine. Using the limited access protocol described by Corwin et al. (1998), 45 adult male Sprague-Dawley rats were maintained on one of four dietary protocols for a period of six weeks: chow only (Chow; n = 9), continuous access to an optional source of dietary fat (Ad Lib; n = 12), 1-h access to an optional source of dietary fat daily (Daily; n = 12), or 1-h access to an optional source of dietary fat on Monday, Wednesday, and Friday (MWF; n = 12). All four groups also had unrestricted access to a nutritionally complete diet of chow and water. Fat-bingeing behaviors developed in the MWF rats, the group with the most restricted access to the optional fat. Thereafter, cocaine-seeking and -taking behaviors were assessed in all rats using a self-administration protocol modified from that described by Deroche-Gamonet et al. (2004), which focused on the motivation for and preoccupation with obtaining and consuming drug (assessed using a progressive ratio [PR] schedule of reinforcement) and persistence in responding for drug during periods of signaled drug non-availability (SNA). Rats with the MWF history tended to take more cocaine late in fixed ratio (FR) training, they persisted in their efforts to obtain cocaine in the face of signaled non-availability, worked harder for cocaine on a PR schedule of reinforcement, and exhibited more goal-directed behavior toward the cocaine-associated operandum. These results demonstrate a link between binge-type intake of fat and the development of drug-seeking and -taking behaviors, suggesting that a history of fat bingeing may predispose individuals to exhibit more robust "addiction-like" behaviors toward a substance of abuse. Thus, it appears that conditions promoting excessive behavior toward one substance (e.g., a palatable fatty food) beget excessive behavior toward another (e.g., cocaine).     

Caffeine intake, toxicity and dependence and lifetime risk for psychiatric and substance use disorders: an epidemiologic and co-twin control analysis

BACKGROUND: Although caffeine is the most commonly used psychoactive substance and often produces symptoms of toxicity and dependence, little is known, especially in community samples, about the association between caffeine use, toxicity and dependence and risk for common psychiatric and substance use disorders. METHOD: Assessments of lifetime maximal caffeine use and symptoms of caffeine toxicity and dependence were available on over 3600 adult twins ascertained from the population-based Virginia Twin Registry. Lifetime histories of major depression (MD), generalized anxiety disorder (GAD) and panic disorder, alcohol dependence, adult antisocial behavior and cannabis and cocaine abuse/dependence were obtained at personal interview. Logistic regression analyses in the entire sample and within monozygotic (MZ) twin pairs were conducted in SAS. RESULTS: In the entire sample, measures of maximal caffeine use, heavy caffeine use, and caffeine-related toxicity and dependence were significantly and positively associated with all seven psychiatric and substance use disorders. However, within MZ twin pairs, controlling for genetic and family environmental factors, these associations, while positive, were all non-significant. These results were similar when excluding twins who denied regular caffeine use. CONCLUSIONS: Maximal lifetime caffeine intake and caffeine-associated toxicity and dependence are moderately associated with risk for a wide range of psychiatric and substance use disorders. Analyses of these relationships within MZ twin pairs suggest that most of the observed associations are not causal. Rather, familial factors, which are probably in part genetic, predispose to both caffeine intake, toxicity and dependence and the risk for a broad array of internalizing and externalizing disorders.     

Cocaine and apoptosis in myocardial cells

Toxic effects of cocaine on the heart muscle have been known for many years. Cardiovascular complications related to cocaine abuse include myocardial ischemia and infarction, inflammation, and disease of the heart muscle, rhythm disturbances, and sudden cardiac death. Cocaine toxicity-related cardiac morbidity and mortality are often due to several interacting mechanisms. Cocaine also has a potent pharmacological effect, indirectly stimulating the sympathetic nervous system, and it has a direct toxic effect on the heart. Although apoptosis (also called programmed cell death) has been shown to play an important role in the pathogenesis of several diseases in the heart, including heart failure and ischemic myocardial infarction, the role of apoptosis in the toxic effect of cocaine on the heart has not been explored. Recent studies indicated that cocaine causes apoptotic cell death in both adult and fetal heart muscles. Increased oxidative stress and reactive oxygen species, and the subsequent activation of a "stress responsive" enzyme (p38-mitogen-activated protein kinase) in the heart may play an important role in cocaine-induced apoptosis in the heart muscle. These findings suggest a new way to understand the cardiotoxic effects of cocaine, and may have potential clinical implications in the better management of cocaine-induced heart diseases. Anat Rec (New Anat): 257:208-216, 1999.     

Adverse health consequences of cocaine abuse

Cocaine creates a strong physical addiction and is becoming recognized as one of the most dangerous illicit drugs abused today. The myth is that cocaine is harmless and nonaddictive. An estimated 30 million Americans have used cocaine, but the number may be as high as 40 million. Five to six million individuals are compulsive users. A review of the current literature revealed multiple reports of acute myocardial infarction and cerebrovascular accident with a temporal relation to cocaine use. Cocaine has also been associated with acute rupture of the aorta, cardiac arrhythmia, and sudden death. Cocaine has multisystem toxicity involving neurologic, psychiatric, obstetric, pulmonary, dermatologic, and gastrointestinal systems. The dopamine depletion hypothesis may explain why cocaine is repeatedly administered; cocaine produces a transient increase in synaptic dopamine. Alterations in dopamine neurotransmission may be responsible for the development of compulsive use patterns. When cocaine use becomes compulsive, psychosocial dysfunction, deviant behaviors, and a wide spectrum of social, financial, and family problems invariably result. Addiction, major medical complications, and death are true hazards of cocaine use.