Substance use disorders: psychoneuroimmunological mechanisms and new targets for therapy.

An estimated 76.4 million people worldwide meet criteria for alcohol use disorders, and 15.3 million meet criteria for drug use disorders. Given the high rates of addiction and the associated health, economic, and social costs, it is essential to develop a thorough understanding of the impact of substance abuse on mental and physical health outcomes and to identify new treatment approaches for substance use disorders (SUDs). Psychoneuroimmunology is a rapidly expanding, multidisciplinary area of research that may be of particular importance to addiction medicine, as its focus is on the dynamic and complex interactions among behavioral factors, the central nervous system, and the endocrine and immune systems (Ader, 2001). This review, therefore, focuses on: 1) the psychoneuroimmunologic effects of SUDs by substance type and use pattern, and 2) the current and future treatment strategies, including barriers that can impede successful recovery outcomes. Evidence-based psychosocial and pharmacotherapeutic treatments are reviewed. Psychological factors and central nervous system correlates that impact treatment adherence and response are discussed. Several novel therapeutic approaches that are currently under investigation are introduced; translational data from animal and human studies is presented, highlighting immunotherapy as a promising new direction for addiction medicine.

Clinical value of morphine, pholcodine and poppy seed IgE assays in drug-abusers and allergic people.

BACKGROUND: The diagnosis of anaphylactic reactions due to opiates during anaesthesia can be difficult, since in most cases various drugs may have been administered. Detection of specific IgE to poppy seed might be a marker for sensitisation to opiates in allergic people and heroin-abusers. This study assessed the clinical value of morphine, pholcodine and poppy seed skin-prick and IgE determination in people suffering hypersensitivity reactions during anaesthesia or analgesia and drug-abusers with allergic symptoms. METHODS: We selected heroin abusers and patients who suffered severe reactions during anaesthesia and analgesia from a database of 23,873 patients. The diagnostic yield (sensitivity, specificity and predictive value) of prick and IgE tests in determining opiate allergy was analysed. RESULTS: Overall, 149 patients and 200 controls, mean age 32.9 ± 14.7 years, were included. All patients with positive prick to opiates showed positive prick and IgE to poppy seeds, but not to morphine or pholcodine IgE. Among drug-abusers, 13/42 patients (31%) presented opium hypersensitivity confirmed by challenge tests. Among non-drug abusers, sensitisation to opiates was higher in people allergic to tobacco (25%), P<.001. Prick tests and IgE against poppy seed had a good sensitivity (95.6% and 82.6%, respectively) and specificity (98.5% and 100%, respectively) in the diagnosis of opiate allergy. CONCLUSIONS: Opiates may be significant allergens. Drug-abusers and people sensitised to tobacco are at risk. Both the prick and specific IgE tests efficiently detected sensitisation to opiates. The highest levels were related to more-severe clinical profiles.

Soluble interleukin-2 receptor levels correlated with positive symptoms during quetiapine treatment in schizophrenia-spectrum disorders.

BACKGROUND: Some but not all antipsychotics have been shown to modulate plasma cytokine levels in schizophrenia patients. Thus far, the most consistent finding has been the increase in plasma levels of soluble interleukin (IL)-2 receptor (sIL-2R) associated with clozapine treatment. Quetiapine is a second-generation antipsychotic with a pharmacological profile similar to that of clozapine, but its immunomodulatory effects have not been investigated in schizophrenia yet. The purpose of this exploratory study was to examine the changes in plasma levels of sIL-2R in schizophrenia during quetiapine treatment and association with psychopathology. METHODS: Participants were 29 schizophrenia-spectrum disorder patients (DSM-IV criteria), and 28 healthy controls. Patients had a comorbid substance use disorder (cannabis>alcohol>cocaine), since quetiapine is increasingly used in this population of dual diagnosis. No participant suffered from infection or overt inflammatory diseases. On baseline, patients taking mostly second-generation antipsychotics were switched to quetiapine for a 12-week open-label trial. Five patients were drop-outs. Mean dose of quetiapine for trial completers (n=24) was 466.6mg±227.3. Psychiatric variables were evaluated with the Positive and Negative Syndrome Scale and the Calgary Depression Scale for Schizophrenia. Plasma sIL-2R levels were assessed at baseline, weeks 6 and 12 in patients, and in healthy controls, using sandwich immunoassay. Plasma IL-6 and IL-1 receptor antagonist (IL-1RA) were measured for comparison purposes. RESULTS: On baseline, plasma sIL-2R, IL-6 and IL-1RA levels were higher in dual-diagnosis patients, compared to controls. Plasma sIL-2R further increased after quetiapine treatment (p=0.037), while plasma IL-6 and IL-1RA did not change. Clinical improvements were observed in positive, negative and depressive symptoms, and substance abuse severity (all p<0.01). Interestingly, changes in sIL-2R levels during treatment were inversely correlated with changes in positive symptoms (r=-0.524; p=0.009). That is, increases in sIL-2R levels were associated with reductions in positive symptoms. CONCLUSION: These data show that quetiapine elevates, like clozapine, sIL-2R levels in schizophrenia. Furthermore, the results suggest that sIL-2R alterations in schizophrenia rely on complex interplays between antipsychotics and the positive symptoms of the disorder. Future randomized controlled trials involving larger samples of schizophrenia patients are warranted to determine whether changes in plasma sIL-2R are quetiapine-related.

Novel pharmacological approaches to drug abuse treatment.

The field of pharmacologic addiction treatment is expanding rapidly. While there are currently several FDA-approved medications for nicotine, alcohol, and opiate dependence, research into novel pharmacological approaches for these and additional substances is legion. Each drug of abuse, while sharing a common final neural pathway of increasing dopaminergic tone, has unique and individual characteristics that are important in developing improved and varied treatments. In this chapter, we discuss such research and present the neurobiological underpinnings of these explorations. In general, addiction treatment is focused on four areas: (1) reducing withdrawal discomfort, (2) diminishing cravings, (3) blocking rewarding effects of the drug, and (4) treating comorbidities, such as depression or ADHD. We present current ideas in pharmacologic research for nicotine, alcohol, cannabis, stimulants, and opiates.

Toxicant-induced loss of tolerance.

Drug addiction and multiple chemical intolerance (abdiction) appear to be polar opposites--the former characterized by craving and dependency, the latter by aversion. However, when the two are viewed in juxtaposition similarities emerge, revealing a common underlying dynamic, one which appears to be a new paradigm of disease. TILT, or toxicant-induced loss of tolerance, bridges the gap between addiction and abduction and has the potential to explain a variety of illnesses, including certain cases of asthma, migraine headaches and depression, as well as chronic fatigue syndrome, fibromyalgia and "Gulf War syndrome". This paper argues that both addiction and chemical intolerance involve a fundamental breakdown in innate tolerance, resulting in an amplification of various biological effects, particularly withdrawal symptoms. While addicts seek further exposures so as to avoid unpleasant withdrawal symptoms, chemically intolerant individuals shun their problem exposures, but for the same reason--to avoid unpleasant withdrawal symptoms. These observations raise critical questions: do addictive drugs and environmental pollutants initiate an identical disease process? Once this process begins, can both addictants and pollutants trigger symptoms and cravings? TILT opens a new window between the fields of addiction and environmental medicine, one that has the potential to transform neighboring realms of medicine, psychology, psychiatry and toxicology.

Modulation of immune responses by anabolic androgenic steroids.

Anabolic androgenic steroids (AS) have recently been placed on the Food and Drug Administration's (FDA's) list of controlled substances, because of the adverse effects seen in athletes taking accelerated dosages in attempts to enhance performance. Reported deleterious effects on abusers include sterility, gynecomastia in males, acne, balding, psychological changes, and increased risks of heart disease and liver neoplasia. Considering the roles of the immune and neuroendocrine systems and their interactions in many of these pathologies, it is important to determine the effects of these derivitized androgens on this connection. Little is known in this respect. We therefore determined the effects of anabolic steroids on certain immune responses and their effects on the extrapituitary production of corticotropin by lymphocytes. We present evidence that (1) both 17-beta and 17-alpha esterified AS, nandrolone decanoate and oxymethenelone, respectively, significantly inhibited production of antibody to sheep red blood cells in a murine abuse model; (2) the control androgens testosterone and dehydroepian-drosterone (DHEA) or sesame seed oil vehicle had no significant effects on antibody production; (3) nandrolone decanoate and oxymethenelone directly induced the production of the inflammatory cytokines IL-1 beta and TNF-alpha from human peripheral blood lymphocytes but had no effect on IL-2 or IL-10 production; (4) control androgens had no direct cytokine inducing effect; (5) nandrolone decanoate significantly inhibited IFN production in human WISH and murine L-929 cells; and (6) nandrolone decanoate significantly inhibited the production of corticotropin in human peripheral blood lymphocytes following viral infection. These data indicate that high doses of anabolic steroids can have significant effects on immune responses and extrapituitary production of corticotropin. Furthermore, the mouse model should provide an effective means by which to study other deleterious effects of anabolic steroid abuse in humans.

HLA-antigens in oral submucous fibrosis.

HLA-typing was carried out on 122 areca nut chewers who attended hospitals for complaints unrelated to the habit. The subjects were South Africans of Indian extraction. The study did not include haplotypes. Palpable fibrous bands in the mouth indicated oral submucous fibrosis. The subjects were divided into 4 groups based on specific oral symptoms and signs. Groups A and B were without fibrous bands. Group A (47 subjects) included those with one or no symptoms while group B (28 subjects) suffered from 2 to 7 oral symptoms. Group C (17 subjects) had oral symptoms and represented early or mild oral submucous fibrosis and exhibited at least one discrete palpable fibrous band. Group D (30 subjects) were classic oral submucous fibrosis cases with multiple bands. The high occurrence of oral submucous fibrosis in this study group (39%) is similar to the occurrence in comparable age groups reported earlier in South Africa and is conceivably due to the higher age range of the subjects and their relatively long exposure to the areca nut. We were unable to demonstrate a specific pattern of HLA-antigen frequencies in chewers with or without the disease. Furthermore, there were no differences between the study population and the controls. It is concluded that there is not necessarily a HLA-associated susceptibility in oral submucous fibrosis.

Indicators of nutritional status among clients from a New York City methadone treatment center.

As the AIDS epidemic in the United States moves steadily into the IV drug-abusing population, knowledge of factors related to immune suppression and disease progression gain in public health importance. Indicators of nutritional status, consisting of anthropometric and hematologic data as well as demographic data, were obtained from a random sample of 130 clients in a New York City methadone treatment center. Subjects for this study were selected according to the entry criteria established for inclusion in a large-scale study of the role of nutritional factors and cell-mediated immunity in a group at high risk of HIV seropositivity. Our results indicate a larger than U.S. population-average heterogeneity for Body Mass Index, hematocrit, and hemoglobin concentration, parameters which are conventionally thought to be proxies for general nutritional status. The findings indicate that while some methadone treatment clients are at low nutritional risk, others are probably at very high risk of adverse drug-nutrient and drug-body habitus interactions as well as being at high risk of acquiring infections commonly associated with HIV-related immunodeficiency.

Immunologic studies on drug addiction: III. Antibodies reactive with cocaine metabolites and their use for drug detection.

Antisera which react with the major metabolites of cocaine have been prepared in rabbits and a hemagglutination-inhibition (HI) test which detects these metabolites in urine or serum in concentrations of 1 ng/ml is described. A comparison of this test with alternate detection procedures shows excellent agreement at comparable sensitivity levels. HI tests on simian and human biological specimens suggest that the use of cocaine remains detectable for at least 3 days after administration of a minimal pharmacologically active dose. Combination of physical separation of drug metabolites with immunoassay procedures indicates that benzoylecgonine and ecgonine are the immunoreactive cocaine metabolites found in human urine. While it was possible to apply the HI test at maximal sensitivity to human sera and to murine or simian urine specimens, interference was encountered with some human urine specimens. Preliminary data suggest that by reducing the sensitivity of the test to a threshold of 200 ng/ml this interference can be overcome.