Research Findings - Research on Medical Consequences of Drug Abuse

Disorders of Glucose Metabolism Among HIV-infected Women

Abnormal glucose metabolism in HIV-infected patients has largely been attributed to the use of protease inhibitors. However, most studies of glucose metabolism in HIV-infected patients have focused on men or have lacked appropriate control groups. Authors assessed the factors associated with previously diagnosed diabetes among 620 middle-aged women with or at risk for HIV infection. For a subset of 221 women without previously diagnosed diabetes, we performed an oral glucose tolerance test (OGTT) to measure glucose and insulin levels, and we assessed factors associated with abnormal glucose tolerance, insulin resistance, and insulin secretion. Thirteen percent of the women in the present study had previously diagnosed diabetes. Among women without previously diagnosed diabetes who underwent an OGTT, 6% had previously undiagnosed diabetes, and 12% had impaired glucose tolerance (IGT). According to multivariate analysis, factors that were associated with previously diagnosed diabetes included current methadone treatment, body mass index of >or =25, family history of diabetes, and physical inactivity. Factors that were independently associated with an abnormal result of an OGTT (i.e., a result consistent with IGT or diabetes) included age >or =50 years, family history of diabetes, physical inactivity, and a high number of pack-years of smoking. Factors independently associated with insulin resistance included waist circumference, Hispanic ethnicity, physical inactivity, and, among HIV-infected women, use of HAART that did not include protease inhibitors. Factors associated with lower levels of insulin secretion included current opiate use (i.e., methadone or heroin) and older age. The authors conclude that abnormal glucose metabolism is highly prevalent among middle-aged women with or at risk for HIV infection, particularly women who use opiates. Screening for diabetes in the HIV primary care setting should occur for women who have classic risk factors for diabetes, rather than solely for women who are taking PIs. Interventions that target modifiable risk factors, including obesity and physical inactivity, are also warranted. Howard, A.A., Floris-Moore, M., Arnsten, J.H., Santoro, N., Fleischer, N., Lo, Y. and Schoenbaum, E.E. Disorders of Glucose Metabolism Among HIV-infected Women. Clin Infect Dis. 40(10), pp. 1492-1499, 2005.

Depressive Symptoms, Quality of Life, and Neuropsychological Performance in HIV/AIDS: The Impact of Gender and Injection Drug Use

Limited attention has been paid to the potential impact of gender and injection drug use (IDU) on mood, quality of life, and neuropsychological performance in human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS). Several studies that describe the natural history of HIV/AIDS in terms of mental health and neuropsychological ability have focused solely on men or have excluded injection drug users. Women and injection drug users are two groups for whom the incidence of HIV infection is increasing. Additionally, the National Academy of Sciences recently recommended that studies concerned with health-related research include males and females, and that researchers analyze their data for gender differences. The goals of the current study were to investigate possible relationships between HIV and IDU status and depressive symptoms, quality of life, and neuropsychological performance in women and men matched for age, race, and education. Overall, women reported more depressive symptoms than men, and this gender difference was most evident in women who were both infected with HIV and who were also injection drug users. Women and HIV-infected individuals reported the poorest quality of life scores. Women outperformed men on a measure of verbal memory and HIV(-) participants outperformed HIV(+) participants on a measure of perceptual speed. Finally, gender and HIV status interacted such that uninfected women performed the best, and infected men performed the worst, on a test of verbal memory. A better understanding of how men and women with different drug use profiles respond to HIV/AIDS may substantially improve survival, as well as aspects of daily functioning, of affected individuals. Thus, further study and development of treatment protocols targeted at including women and IDU are needed. Wisniewski, A.B., Apel, S., Selnes, O.A., Nath, A., McArthur, J.C., Dobs, A.S. Depressive Symptoms, Quality of Life, and Neuropsychological Performance in HIV/AIDS: The Impact of Gender and Injection Drug Use. J Neurovirol. 11(2), pp. 138-143, 2005.

Young Drug Abusers May be Predisposed to Developing Early Onset Rrain Aging Changes and Dementia

Drug abuse is a major problem worldwide. The incidence of drug-related deaths attributed to opiate abuse is increasing annually. Apart from routine examination, little is known of the neuropathology of drug abuse. Authors of the present study and others, have shown previously that drug abuse is associated with microglial activation. They hypothesized that neuroinflammation might lead to premature neurodegeneration in drug abusers. They investigated the brains of young opiate abusers (n = 34, all <40 years) for the presence of proteins associated with neurodegenerative diseases and compared them with the brains of age-matched, non-drug users (n = 16) all of whom died suddenly. Detailed immuno-histochemical analysis of the hippocampus, brainstem and basal ganglia for hyperphosphorylated tau, beta-amyloid, beta-amyloid precursor protein (betaAPP) and ubiquitin demonstrated an excess of AT8-positive neurofibrillary tangles (NFT) in the drug abusers. These were not only more prevalent in the drug abusers than in controls (44%vs. 19%) but also involved more brain areas. In controls NFT were confined to the entorhinal cortex whereas in drug users they were also found in the subiculum, temporal neocortex, nucleus basalis of Meynert and the locus coeruleus. Virtually no amyloid plaques were present but betaAPP positivity was again much more common in drug abusers than controls (73%vs. 20% in the brainstem and 59%vs. 23% in the temporal lobe). There is no suggestion that these drug abusers had displayed major cognitive impairment although detailed neuropsychological assessment is difficult in this subject group. Likely causes of hyperphosphorylated tau deposition in drug abuse include hypoxic-ischaemic injury, microglial-associated cytokine release and possibly drug-associated neurotoxicity or hepatitis. Head injury, which is another major risk factor, does not appear to have contributed to our findings. Genetic factors also merit consideration. It is unclear at present how much of the hyperphosphorylated tau detected in these young drug abusers represents a transitory phenomenon. Ramage, S.N., Anthony, I.C., Carnie, F.W., Busuttil, A., Robertson, R. and Bell, J.E. Hyperphosphorylated tau and Amyloid Precursor Protein Deposition is Increased in the Brains of Young Drug Abusers. Neuropathol Appl Neurobiol. 31(4), pp. 439-448, 2005.

Morphine Exacerbates HIV-1 Viral Protein gp120 Induced Modulation of Chemokine Gene Expression in U373 Astrocytoma Cells

HIV-1 affects microglia and astroglia, which subsequently contributes to the neurodegenerative changes. Viral proteins cause neurotoxicity by direct action on the CNS cells or by activating glial cells to cause the release of cytokines, chemokines or neurotoxic substances. Opioid abuse has been postulated as a cofactor in the immunopathogenesis of human immunodeficiency virus (HIV) infection and AIDS. HIV-induced pathogenesis is exacerbated by opiate abuse and the synergistic neurotoxicity is a direct effect of opiates on the CNS. Chemokines and their receptors have been implicated in the pathogenesis of neuroAIDS. Herein, authors describe the effects of morphine and/or gp120 on the expression of the genes for the beta-chemokine MIP-1beta and its receptors CCR3 and CCR5 by the U373 cells that are a human brain-derived astrocytoma/glioblastoma cell line. Results indicate that treatment of U373 cells with morphine significantly downregulated the gene expression of the beta chemokine, MIP-1 beta, while reciprocally upregulating the expression of its specific receptors, CCR3 and CCR5 suggesting that the capacity of mu-opioids to increase HIV-1 co-receptor expression may promote viral binding, trafficking of HIV-1-infected cells, and enhanced disease progression. Additionally, opiates can enhance the cytotoxicity of HIV-1 viral protein gp120 via mechanisms that involve intracellular calcium modulation resulting in direct actions on astroglia, making them an important cellular target for HIV-opiate interactions. Mahajan, S.D., Aalinkeel, R., Reynolds, J.L., Nair, B.B., Fernandez, S.F., Schwartz, S.A. and Nair, M.P. Morphine Exacerbates HIV-1 Viral Protein gp120 Induced Modulation of Chemokine Gene Expression in U373 Astrocytoma Cells. Curr HIV Res. 3(3), pp. 277-288, 2005.

Cocaine Modulates Dendritic Cell-specific C Type Intercellular Adhesion Molecule-3-grabbing Nonintegrin Expression by Dendritic Cells in HIV-1 Patients

Authors report that cocaine may act as cofactor in HIV pathogenesis by increasing dendritic cell-specific C type ICAM-3-grabbing nonintegrin (DC-SIGN) expression on dendritic cells (DC). Their results show that cocaine-using, long-term nonprogressors and normal progressors of HIV infection manifest significantly higher levels of DC-SIGN compared with cocaine-nonusing long-term nonprogressors and normal progressors, respectively. Furthermore, in vitro HIV infection of MDC from normal subjects cultured with cocaine and/or HIV peptides up-regulated DC-SIGN, confirming their in vivo finding. Cocaine, in synergy with HIV peptides, also up-regulates DC-SIGN gene expression by MDC. Furthermore, the cocaine-induced effects were reversed by a D1 receptor antagonist demonstrating the specificity of the reaction. These results indicate that cocaine exacerbates HIV infection by up-regulating DC-SIGN on DC and these effects are mediated via dysregulation of MAPKs. These data are the first evidence that cocaine up-regulates the expression of DC-SIGN on DC. A better understanding of the role of DC-SIGN in HIV infection may help to design novel therapeutic strategies against the progression of HIV disease in the drug-using population. Nair, M.P., Mahajan, S.D., Schwartz, S.A., Reynolds, J., Whitney. R., Bernstein, Z., Chawda, R.P., Sykes, D., Hewitt, R. and Hsiao, C.B. Cocaine Modulates Dendritic Cell-specific C Type Intercellular Adhesion Molecule-3-grabbing Nonintegrin Expression by Dendritic Cells in HIV-1 Patients. J Immunol. 174(11), pp. 6617-6626, 2005.

Influence of Depression and HIV Serostatus on the Neuropsychological Performance of Injecting Drug Users

Depression is common in injecting drug users (IDUs), a group at significant risk for HIV infection. Moreover, both HIV infection and depression have been shown to adversely effect neurocognitive abilities. Understanding the effects of depression and HIV infection on the neurocognitive functioning of drug users is essential for appropriate management and/or treatment of these deficits in this population. Therefore, the purpose of the present study was to investigate the effects of depression and HIV status on cognitive functioning in 100 male and female IDUs. Participants were categorized into three groups of depression severity based on their scores on the Beck Depression Inventory: no depression, mild depression, and moderate to severe depression. The effects of depression and HIV serostatus as well as their interaction were assessed. Results indicated that regardless of serostatus, those with moderate to severe depression had lower scores on cognitive measures. These findings suggest that although depression contributes to poor neuropsychological performance in IDUs, this effect was not exacerbated by HIV infection. The finding also illustrates the importance of addressing depression-related neurocognitive deficits in IDUs. Waldrop-Valverde, D., Ownby, R.L. and Kumar, M. Influence of Depression and HIV Serostatus on the Neuropsychological Performance of Injecting Drug Users. Psychiatry Clin Neurosci. 59(4), pp. 372-378, 2005.

Humoral Immune Response in Acute Hepatitis C Virus Infection

There is little information on the timing, magnitude, specificity, and clinical relevance of the antibody response to acute hepatitis C virus (HCV) infection. Authors investigated the specificity, titer, and neutralizing potential of antibody responses to acute infection by examining 12 injection drug users before, during, and after infection. Seroconversion was defined as incident detection of HCV-specific antibodies by using a commercially available enzyme-linked immuosorbent assay (ELISA). HCV protein-specific antibody responses were measured using recombinant antigens in an ELISA. For neutralization assays, plasma was incubated with human immunodeficiency virus (HIV)-HCV H77 or control HIV-murine leukemia virus (MLV) pseudotype virus and then allowed to infect Hep3B hepatoma cells. The mean time to HCV seroconversion was 6 weeks after the onset of viremia. Antibody responses to nonstructural proteins were detected before responses to the structural proteins, and antibodies to both were primarily restricted to the immunoglobulin G1 (IgG1) subclass. The maximum median end point titers for antibody responses to structural and nonstructural proteins were 1:600 and 1:6400, respectively. Antibodies that neutralized a retroviral pseudotype bearing HCV 1a envelope glycoproteins were detected at seroconversion in only 1 subject and at 6-8 months after seroconversion in 3 subjects. The delayed appearance of neutralizing antibodies was consistent with the late development of antibodies specific for the viral envelope glycoproteins, which are believed to mediate virus neutralization. The humoral immune response to acute HCV infection is of relatively low titer, is restricted primarily to the IgG1 subclass, and is delayed. A better understanding of why production of neutralizing antibody is delayed may improve efforts to prevent HCV infection. Netski, D.M., Mosbruger, T., Depla, E., Maertens, G., Ray, S.C., Hamilton, R.G., Roundtree, S., Thomas, D.L., McKeating, J. and Cox, A. Humoral Immune Response in Acute Hepatitis C Virus Infection. Clin Infect Dis. 41(5), pp. 667-675, 2005.

Liver Enzyme Values in Injection Drug Users with Chronic Hepatitis C

Liver enzymes fluctuate in chronic hepatitis C virus infection. However, the range that can be attributed to the course of hepatitis C virus (versus an intercurrent cause of hepatitis) is unknown. The aim of the present study was to characterize the range of liver enzyme values as a function of the upper limit of normal (ULN) of the assay among persons chronically infected with hepatitis C virus. One thousand and fifty-nine hepatitis C virus chronically infected individuals with >/=5 semi-annual evaluations. Alanine aminotransferase and aspartate aminotransferase levels were prospectively obtained. Potential causes of elevations were examined using serologic testing. Among 1059 individuals, 11,463 enzyme measurements were obtained over 6.5 years, of which 63.5% were <1.25x ULN, 26.5% were 1.25-2.5x ULN, 8.3% were 2.5-5x ULN, and 1.6% were 5-10x ULN; only 0.2% were >10x ULN. Elevations >10x ULN were transient, the alanine aminotransferase/aspartate aminotransferase ratio tended to be different at the time of the elevation compared to before and after and 24% were associated with acute viral hepatitis. On the other hand, subjects with elevations 5-10x ULN tended to have elevated levels throughout follow-up and only 8% were associated with acute viral hepatitis. Liver enzymes fluctuate up to 5x ULN in most hepatitis C virus-infected persons; clinicians should seek alternate explanations for those with higher alanine aminotransferase or aspartate aminotransferase levels, especially among hepatitis C virus-infected persons with greater than 10-fold elevations. Mehta, S.H., Netski, D., Sulkowski, M.S., Strathdee, S.A., Vlahov, D. and Thomas, D.L. Liver Enzyme Values in Injection Drug Users with Chronic Hepatitis C. Dig Liver Dis. June 9, 2005 [Epub ahead of print].

HCV Therapeutic Success Increases, Yet HIV/HCV Coinfected IDUs Significantly Less Likely to Receive HCV Therapeutic Benefits

Although hepatic manifestations of opportunistic infections are now rare, chronic HCV is found in approximately one-third of HIV-infected individuals. The severity of HCV-related liver disease is greater in those with HIV than in those uninfected. Among HIV-HCV-coinfected individuals, advanced immunosuppression has been associated with more severe liver disease, supporting the hypothesis that reversal or prevention of immunosuppression with ART will slow the progression of HCV disease. However, effective ART use may also contribute to liver disease as most protease inhibitors have been associated with metabolic abnormalities, hyperlipidemia, and decreased insulin sensitivity, which themselves have been linked to hepatic steatosis. The objective of this study was to ascertain the prevalence and severity of hepatic steatosis among patients coinfected with HIV and HCV who have been taking antiretroviral therapy (ART); to investigate if steatosis is associated with more advanced liver disease, and to identify factors that might contribute to the process. Steatosis was assessed among a randomly selected subset of HIV-HCV-coinfected patients who had received at least 2 years of ART in a cohort study at the Johns Hopkins University HIV clinic. The results of liver histology were assessed in 112 patients, 74% of whom were taking ART at the time of biopsy. In multivariate analysis, steatosis was independently associated with Caucasian race, weight > 86 kg, hyperglycemia, and stavudine use. Patients with steatosis also were more likely to have greater hepatic fibrosis and necroinflammatory activity. Steatosis was observed in 40% of HIV-HCV-coinfected patients with extensive ART exposure and was associated with more severe HCV-related liver disease. Metabolic abnormalities (excess weight and hyperglycemia) and stavudine use were modifiable risk factors for steatosis in this population. Authors conclude that the disparity between HIV/HCV infected IDUs who are significantly less likely to be eligible for HCV therapy becomes more compelling as the success of HCV therapy increases. The investigators plan further analysis to assess the relationship(s) of clinical and socioeconomic covariates and treatment eligibility. Sulkowski, M.S., Mehta, S.H., Afdhal, N.H., Moore, R.D., Thomas, D.L., Torbenson, M., Brinkley, S., Mirel, L., Chaisson, R.E., Moore, R.D. and Sulkowski, M.S. Hepatic Steatosis and Antiretroviral Drug Use Among Adults Coinfected with HIV and Hepatitis C Virus. AIDS. 19(6), pp. 585-592, March 24, 2005. The critical significance of this work is in defining the burden of liver disease among HCV-infected IDUs, and thereby identify and target medical needs for anti-HCV therapy. Additional data regarding eligibility and actual acceptance of therapy among population groups will yield fundamental information with respect to the delivery of HCV therapy to IDUs. The data supports and expands upon recently published preliminary findings from the study by the authors Mehta, S.H., Thomas, D.L., Torbenson, M., Brinkley, S., Mirel, L., Chaisson, R.E. and Sulkowski, M.S. The Effect of Antiretroviral Therapy on Liver Disease Among Adults with HIV and Hepatitis C Coinfection. Hepatology. 41(1), pp. 123-131, January 2005.

CD8+ Cell Responses to Hepatitis C Virus (HCV) in the Liver of Persons with HCV-HIV Coinfection Versus HCV Monoinfection

Cellular immune responses are difficult to detect in the peripheral blood of persons with chronic hepatitis C virus (HCV) infection. Authors of the present study sought to determine whether T cell responses were present in the liver of patients with human immunodeficiency virus (HIV) and HCV coinfection. T cells were expanded from liver-biopsy samples from 10 patients coinfected with HIV and HCV (median CD4(+) cell count, 456 cells/mm(3)) and 8 patients infected with HCV alone. CD8(+) cell responses were detected by use of a modified enzyme-linked immunospot (ELISpot) assay with recombinant vaccinia virus, and CD4(+) cell responses were detected by use of ELISpot with recombinant HCV proteins core, nonstructural (NS) 3, and NS5. Intrahepatic CD8(+) cell responses to HCV were detected in 7 of 10 patients coinfected with HCV and HIV (median frequency, 638 spot-forming cells [sfc]/1 x 10(6) cells) and were similar to those observed in patients singly infected with HCV (7/8; median, 647 sfc/1 x 10(6) cells). Intrahepatic HCV-specific CD4(+) cell responses were also comparable in both groups and correlated with the intrahepatic CD8(+) cell responses (r=0.59; P=.03). HCV-specific CD8(+) cell responses are present in the liver of persons with chronic HCV infection even when they are coinfected with HIV; these correlate with intrahepatic HCV-specific CD4(+) cell responses. Alatrakchi, N., Graham, C.S., He, Q., Sherman, K.E. and Koziel, M.J. CD8+ Cell Responses to Hepatitis C Virus (HCV) in the Liver of Persons with HCV-HIV Coinfection Versus HCV Monoinfection. J Infect Dis., 191(5), pp. 702-709, 2005.

Antigen-specific Immune Responses and Liver Histology in HIV and Hepatitis C Cinfection

The objective of this study was to test the hypothesis that antigen-specific interferon (IFN) gamma responses are correlated with milder liver disease in subjects coinfected with HIV-1 and hepatitis C virus (HCV). Cellular immune responses were studied in a cohort with HIV/HCV coinfection (n = 107) who underwent liver biopsy. Authors measured HCV-specific and recall responses in peripheral blood mononuclear cells using IFNgamma and interleukin (IL)-10 ELISpots, and correlated these immune responses with liver histology. The relationship of immunologic, virologic and clinical variables to inflammation and fibrosis was modeled using recursive partitioning. There were significant negative correlations between inflammatory scores and IFNgamma production in response to the HCV proteins core, NS5 and summed HCV responses. Lower fibrosis scores were also correlated with higher IFNgamma production in response to NS5 and summed HCV proteins. Higher IFNgamma production in response to Candida was significantly associated with lower inflammatory and fibrosis scores. In multivariable models, factors associated with severe fibrosis were lower IFNgamma responses to Candida and summed HCV proteins. Factors associated with severe inflammation were detectable HIV viral load and lower HCV viral load, while predictors of mild inflammation included undetectable HIV viral load and higher IFNgamma response to Candida. In this cohort of subjects coinfected with HIV and HCV, antigen-specific IFNgamma responses are correlated with milder inflammation and fibrosis. Immunological responses best predicted severity of fibrosis, while clinical variables and recall antigen responses best predicted severity of inflammation. Graham, C.S., Wells, A., Liu, T., Sherman, K.E., Peters, M., Chung, R.T., Bhan, A.K., Andersen, J., Koziel, M.J. and ACTG 5071 Study Team. Antigen-specific Immune Responses and Liver Histology in HIV and Hepatitis C Coinfection. AIDS.19(8), pp. 767-773, 2005.

Prediction of Hepatic Fibrosis in HIV/HCV Co-infected Patients Using Serum Fibrosis Markers: The SHASTA Index

The aim of this study was to examine if serum fibrosis biomarkers could accurately identify the stage of liver disease amongst hepatitis C (HCV) and HIV co-infected patients. One hundred and thirty seven HIV/HCV co-infected persons were randomly selected from the Johns Hopkins HIV Clinic cohort. Ninety five had complete testing for fibrosis markers in sera collected at the time of liver biopsy. Biopsies were scored according to Ishak modified histological activity index (F0 no fibrosis to F6 cirrhosis). Fibrosis was evaluated against alanine aminotransferase (ALT), aspartate aminotransferase (AST), AST to platelet ratio (APRI), albumin, total bilirubin, hyaluronic acid (HA) and YKL-40. Sixty nine (73%) had no or minimal portal fibrosis (F0-2) and were compared with remaining subjects (F3-6). Fibrosis scores > or =F3 were found 27 times more often in persons with HA levels >86 ng/ml and 5.5 times more often in persons with HA levels 41-86 ng/ml. Less substantial associations were detected with levels of albumin <3.5 g/dl (OR 4.85) and AST >60 iu (OR 5.91). All 35 subjects who had favorable results of HA, albumin, and AST had minimal fibrosis (F0-2). Amongst HIV/HCV co-infected patients, serum testing for HA, albumin, and AST (SHASTA Index) was able to accurately stage mild and advanced fibrosis. Kelleher, T.B., Mehta, S.H., Bhaskar, R., Sulkowski, M., Astemborski, J., Thomas, D.L., Moore, R.E. and Afdhal, N.H. Prediction of Hepatic Fibrosis in HIV/HCV Co-infected Patients Using Serum Fibrosis Markers: The SHASTA Index. J Hepatol. 43(1), pp. 78-84, 2005.

Respiratory Effects of Marijuana and Tobacco Use in a U.S. Sample

Although a number of studies have examined the respiratory impact of marijuana smoking, such studies have generally used convenience samples of marijuana and tobacco users. The current study examined respiratory effects of marijuana and tobacco use in a nationally representative sample while controlling for age, gender, and current asthma. Analysis of the nationally representative third National Health and Nutrition Examination Survey (NHANES III). U.S. households. A total of 6,728 adults age 20 to 59 who completed the drug, tobacco, and health sections of the NHANES III questionnaire in 1988 and 1994. Current marijuana use was defined as self-reported 100+ lifetime use and at least 1 day of use in the past month. Self-reported respiratory symptoms included chronic bronchitis, frequent phlegm, shortness of breath, frequent wheezing, chest sounds without a cold, and pneumonia. A medical exam also provided an overall chest finding and a measure of reduced pulmonary functioning. Marijuana use was associated with respiratory symptoms of chronic bronchitis (P=.02), coughing on most days (P=.001), phlegm production (P=.0005), wheezing (P<.0001), and chest sounds without a cold (P=.02). The impact of marijuana smoking on respiratory health has some significant similarities to that of tobacco smoking. Efforts to prevent and reduce marijuana use, such as advising patients to quit and providing referrals for support and assistance, may have substantial public health benefits associated with decreased respiratory health problems. Moore, B.A., Augustson, E.M., Moser, R.P. and Budney, A.J. Respiratory Effects of Marijuana and Tobacco Use in a U.S. Sample. J Gen Intern Med. 20(1), pp. 33-37, 2005.

Gender Effects Following Repeated Administration of Cocaine and Alcohol in Humans

Use of cocaine, alcohol, and the two drugs simultaneously is common and the risk of morbidity and mortality associated with these drugs is widely reported. This double-blind, placebo-controlled, randomized study examined gender differences in response to administration of these drugs alone and in combination. Current users of cocaine and alcohol (n = 17) who met diagnostic criteria (DSM-IV) for cocaine dependence and alcohol abuse or dependence (not physiologically dependent on alcohol) and who were not seeking treatment for substance use disorders gave voluntary, written, informed consent to participate in three drug administration sessions:1) four doses of intranasal cocaine (1 mg/kg every 30 min) with oral alcohol (1 g/kg following the initial cocaine dose and a second drink at +60 min (120 mg/kg) calculated to maintain a plasma alcohol concentration of approximately 100 mg/dL; 2)four doses of cocaine and alcohol placebo; 3) cocaine placebo and alcohol. Pharmacokinetics were obtained by serial blood sampling, physiological measurements (heart rate and blood pressure) were obtained with automated equipment, and subjective effects were assessed using visual analog scales over 480 min. Responses to cocaine, alcohol, and cocaine-alcohol were equivalent by gender for most measurements. Women had higher heart rates following alcohol administration (p = .02). Women consistently reported higher ratings for "Feel Good", a measure of overall mental/physical well-being, for all study conditions, reaching statistical significance for cocaine (p = .05) and approaching significance for alcohol administration (p = .1). Women showed equivalent responses to drug administration with the exception of perception of well-being, which was significantly increased for women. These findings may have implications for differential risk for acute and chronic toxicity in women. McCance-Katz, E.F., Hart, C.L., Boyarsky, B., Kosten, T. and Jatlow, P. Gender Effects Following Repeated Administration of Cocaine and Alcohol in Humans. Subst Use Misuse. 40(4), pp. 511-528, 2005.