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Informed consent practices among NIH-funded researchers
Abstract / Drug and Alcohol Dependence 156 (2015) e183–e245
Simultaneous determination of the effects of methamphetamine on GABA, glutamate and monoamines by microdialysis in the prefrontal cortex and hippocampus of rats H.L. Rowley ∗ , Lucy Pinder, Rajiv Kulkarni, Sharon Cheetham, David J. Heal RenaSci Ltd., Nottingham, United Kingdom Aims: Methamphetamine is a highly abused drug with complex pharmacological actions in the brain. Intracerebral microdialysis in freely-moving rats provides valuable insights in such cases, but is often limited by the number of neurotransmitters that can be measure in each sample. We have used this technique to investigate methamphetamine’s effects simultaneously on GABA, glutamate (GLU), dopamine (DA), noradrenaline (NA) and 5HT in the prefrontal cortex (PFC) and hippocampus (HIP). Methods: Under gaseous anaesthesia, 4.0 mm microdialysis probes were stereotaxically implanted into PFC (relative to bregma: AP +3.4 mm; ML ±0.8 mm; DV 5.0 mm relative to dura) and HIP (AP −5.3 mm; ML ±4.8 mm; DV −7.5 mm) of male, Wistar rats (250–350 g; n = 5). Dialysate samples were collected at 15 min intervals for 2 h. GABA, GLU were analysed by UHPLC-ECD and DA, NA, 5HT by HPLCECD using Antec ALEXYSTM systems. Methamphetamine (3.0 mg/kg) was dosed IP. Results: Compared with pre-intervention baseline values, methamphetamine produced rapid neurotransmitter changes that peaked 30-45 min after dosing. In PFC, there were increases in DA (533%, p < 0.001), NA (408%, p < 0.001), 5HT (1500%, p < 0.001), GABA (452%, p < 0.05) and a decrease in GLU (−56%, p < 0.001). In HIP the same pattern of effects was observed, but the changes in monoamines were much greater with increases in DA (1781%, p < 0.001), NA (765%, p < 0.001), 5HT (11.058%, p < 0.001), GABA (451%, p < 0.01) and a decrease in GLU (31%, p < 0.01). Conclusions: Methamphetamine produced large increases in DA and NA in PFC and HIP, but surprisingly its greatest effect was to potentiate 5HT efflux. The increases in extracellular monoamines were accompanied by concomitant reductions in GLU and increases in GABA in both regions. It is probable that decreased excitatory and enhanced inhibitory amino acid neurotransmission in PFC and HIP were homeostatic responses to attenuate the pharmacological effects of methamphetamine. The increases in 5HT may also have been part of this response. Financial support: None. http://dx.doi.org/10.1016/j.drugalcdep.2015.07.524 The changing nature of opioid-related mortality in Australia Amanda Roxburgh 1,∗ , Lucy Burns 1 , Wayne Hall 2,1 , Louisa Degenhardt 1,3 1 National Drug and Alcohol Research Centre, University of New South Wales, Sydney, NSW, Australia 2 Centre for Youth Substance Abuse Research, University of Queensland, Brisbane, QLD, Australia 3 School of Population and Global Health, University of Melbourne, Melbourne, VIC, Australia
Aims: To investigate trends in all opioid-related mortality in Australia over time (2000–2013), as well as analyse differences in characteristics between heroin and pharmaceutical opioid (PO) deaths. Methods: Data extracted from the National Coronial Information System (an online Australia-wide database that comprises all
e195
deaths reported to a coroner) on deaths where opioid toxicity was considered to have caused or contributed to the death. Results: Prior to the disruption of heroin availability in Australia in 2001, heroin-related deaths comprised approximately 70% of all opioid-related deaths. From 2001 onwards, heroin deaths have comprised between 30% and 44% of these deaths. More recently PO (including morphine, codeine, oxycodone, methadone and fentanyl) have comprised the majority (70%) of opioid deaths. Heroin decedents were significantly younger, and more likely to be male compared to PO decedents. Preliminary analysis shows the majority (83%) of heroin decedents had a recorded history of injecting drug use (IDU). This figure was also high (63%) among fentanyl deaths. High proportions of oxycodone deaths had a recorded history of chronic pain (49%) and mental health problems (54%). Conclusions: What distinguished heroin from PO deaths was that decedents were younger and more likely to be male. What distinguished PO deaths from heroin deaths was a history of chronic pain and mental health problems. Different clinical responses are clearly required in reducing both heroin and PO related mortality. While PO deaths are of increasing concern in Australia, heroin deaths are on the rise again after a sharp decline in 2001. Financial support: The National Illicit Drug Indicators Project (part of the Drug Trends program at the National Drug and Alcohol Research Centre) is funded by the Australian Government under the Substance Misuse Prevention and Service Improvement Grants. http://dx.doi.org/10.1016/j.drugalcdep.2015.07.525 Informed consent practices among NIH-funded researchers Caitlin Ryan ∗ , Brittany Seymour, Michael Stephens, Rachel Comly, Chloe Sierka, Thea G. Musselman, Karen L. Dugosh, David Festinger Section on Law and Ethics, Treatment Research Institute, Philadelphia, PA, United States Aims: Participation in a study must be intelligent, knowing, and voluntary. The extent to which investigators utilize effective strategies to protect study participants is unclear. In this study, we surveyed researchers funded by NIH agencies including NIDA and NIAAA to determine what procedures they use to help ensure informed consent. Methods: We invited principal investigators who received NIH R01 grant funding in 2012 (identified through NIH RePORTER) to complete a web-based survey. The 26-item survey took approximately 10 minutes to complete. A total of 673 investigators agreed to take part in the survey. Of these, 384 (57%) conducted research that required consent and were eligible for participation. Results: Fifty-nine percent (N = 220) conducted research with vulnerable populations. The majority (89%) relied on observation to determine capacity of subjects. Only 18% used a consent quiz to evaluate understanding of consent information. These quizzes utilized open-ended (67%) and true/false (34%) response formats. Almost all (97%) researchers provided participants with copies of the consent and 55% reminded them about their rights throughout the study. To ensure autonomy, researchers told potential participants that the decision to enroll was voluntary (99%), it would not affect their treatment (88%), delayed consent for further consideration (40%), and lowered compensation rates (37%). Most researchers (92%) indicated it was very important to remember consent information over the course of a study but less than half felt that this actually occurred. Conclusions: Results from this study suggest that researchers generally do not employ standard procedures to determine
e196
Abstract / Drug and Alcohol Dependence 156 (2015) e183–e245
whether consent is intelligent, knowing, and voluntary. It is necessary to identify ways to promote the widespread use of effective consent strategies. This is particularly true for research that is conducted with vulnerable populations including substance abusers, prisoners, and adolescents. Financial support: NIDA R01-DA-025687. http://dx.doi.org/10.1016/j.drugalcdep.2015.07.526
Regional grey matter volume and externalizing score: Not yet related in middle childhood Joseph Sakai 1,∗ , Manish Dalwani 1 , Mary A. McMahon 1 , Susan K. Mikulich-Gilbertson 1 , Jody Tanabe 1 , Shannon K. McWilliams 1 , Kristen Raymond 1 , M.T. Banich 2 , Thomas J. Crowley 1 1
University of Colorado, Aurora, CO, United States University of Colorado Boulder, Boulder, CO, United States 2
Association of alcohol use with drug use and weapon carrying among Thai adolescents On-anong Saiphoklang 1,∗ , Kua Wongboonsin 1 , Patcharawalai Wongboonsin 1 , Usaneya Perngparn 3 , Linda Cottler 2 1 College of Population Studies, Chulalongkorn University, Bangkok, Thailand 2 Epidemiology, University of Florida, Gainesville, FL, United States 3 College of Public Health Sciences, Chulalongkorn University, Patumwan, Thailand
Aims: Alcohol, drug use, and weapon carrying are a public health concern especially among students because they can have deleterious effects on physical and mental health. This study determined the prevalence of and gender specific factors associated with these behaviors among Thai adolescent students. Methods: A cross-sectional study in high school and vocational school in Bangkok, Thailand was conducted in 2014. Self-administrated questionnaires assessed past 30 day behaviors among students between 11 and 18 years of age (2561 students from 26 schools). Results: Overall, one fourth (24.4%) of students reported past 30 day alcohol use, 2.5% reported drug use, and 7.8% reported weapon carrying. Older youth were more likely to report drinking than those younger (p < .0001). Multivariate logistic regression analyses showed that alcohol use was almost four times higher among drug users than nondrug users (OR 3.93). Students who carried a weapon had nearly three times the risk of drinking than their counterparts (OR 2.74). Overall, females who used drugs or who carried a weapon were 7.94 and 3.15 times respectively to report drinking compared to males. All other factors adjusted for were also more strongly associated with drinking among females than males; factors include number of friends who smoke (OR 2.66 vs OR 1.77), weight issues (OR 2.10), smoking (OR 5.36 vs OR 4.59), and energy drink use (OR 3.41 vs OR 2.04). Conclusions: An increased association of drug use and weapon carrying with alcohol use was found for adolescent females in Thailand. Findings indicate gender specific interventions are needed for adolescents for these behaviors. Financial support: Financial support from the Thailand Research Fund through the Royal Golden Jubilee Ph.D. Program (Grant No. PHD/0184/2553) to On-anong Saiphoklang and Professor Kua Woongboonsin, PhD is acknowledged. And University of Florida Substance Abuse Training Center in Public Health (DA-T32035167). http://dx.doi.org/10.1016/j.drugalcdep.2015.07.527
Aims: Adolescents (ages 14–18 years) in treatment for substance use disorder (SUD) have less brain grey matter volume (GMV) than controls, a finding replicated for SUD and related phenotypes. Such results might either pre-exist and predict SUD, or could result from adolescent substance exposure. Methods: We recruited 9–11 year old subjects (n = 66, 32 female) about equally from control families and patient families (i.e., at least one first degree relative in SUD treatment). Subjects had no or minimal lifetime substance exposure. Brain structural scans were obtained using a 3T GE MRI scanner. Voxel-based morphometry analyses regressed regional brain volume against a predictor of future substance problems (Child Behavior Checklist externalizing behavior scores), while controlling for exact age and sex. Results: No regions of GMV were significantly (positively or negatively) related to externalizing behavior scores. Conclusions: We find that GMV, reduced in adolescents with SUD, is not reduced in younger children who are unexposed but at risk for SUD. Thus, GMV differences in adolescents with SUD may be related to substance exposure or developmental changes, which occur in adolescence. Although our sample size is similar to those in our prior studies, we may lack power to detect small differences, and large, longitudinal imaging studies are needed to confirm these findings. FreeSurfer analyses of cortical thickness in this sample will also be presented. Financial support: NIDA DA 09842, 11015 and 031761, The Kane Family and Hewit Family Foundations. http://dx.doi.org/10.1016/j.drugalcdep.2015.07.528 Taurine effectively inhibits cocaine preference in male and female rats: Candidate for SUD treatment Kaliris Salas-Ramirez 1,∗ , Kevin Uribe 2 , Eitan Friedman 1 , Shailesh Banerjee 1 1 Physiology, Pharmacology and Neuroscience, The City College of New York, New York, NY, United States 2 Biology, The City College of New York, New York, NY, United States
Aims: Cocaine (COC) is a commonly abused psychostimulant that causes alterations to the mesocorticolimbic circuitry and addiction-related behaviors characterized by loss of inhibition to use. Females have been shown to be more vulnerable to the effects of COC when compared to males, requiring lower doses and less time of exposure before the onset of addiction. Taurine (TAU) is an organic acid with neuroprotective and neuromodulatory roles. This study aimed to determine if taurine could reduce cocaine preference in male and female subjects. Methods: Male and female rats were pretreated with TAU (pre-tau; 100 mg/kg) for two weeks before undergoing a conditioned place preference protocol. They were randomly divided into four groups (n = 9/group): (1) TAU pretreatment (pre-TAU) and TAU + COC co-administration during conditioning, (1) pre- TAU and
Simultaneous determination of the effects of methamphetamine on GABA, glutamate and monoamines by microdialysis in the prefrontal cortex and hippocampus of rats H.L. Rowley ∗ , Lucy Pinder, Rajiv Kulkarni, Sharon Cheetham, David J. Heal RenaSci Ltd., Nottingham, United Kingdom Aims: Methamphetamine is a highly abused drug with complex pharmacological actions in the brain. Intracerebral microdialysis in freely-moving rats provides valuable insights in such cases, but is often limited by the number of neurotransmitters that can be measure in each sample. We have used this technique to investigate methamphetamine’s effects simultaneously on GABA, glutamate (GLU), dopamine (DA), noradrenaline (NA) and 5HT in the prefrontal cortex (PFC) and hippocampus (HIP). Methods: Under gaseous anaesthesia, 4.0 mm microdialysis probes were stereotaxically implanted into PFC (relative to bregma: AP +3.4 mm; ML ±0.8 mm; DV 5.0 mm relative to dura) and HIP (AP −5.3 mm; ML ±4.8 mm; DV −7.5 mm) of male, Wistar rats (250–350 g; n = 5). Dialysate samples were collected at 15 min intervals for 2 h. GABA, GLU were analysed by UHPLC-ECD and DA, NA, 5HT by HPLCECD using Antec ALEXYSTM systems. Methamphetamine (3.0 mg/kg) was dosed IP. Results: Compared with pre-intervention baseline values, methamphetamine produced rapid neurotransmitter changes that peaked 30-45 min after dosing. In PFC, there were increases in DA (533%, p < 0.001), NA (408%, p < 0.001), 5HT (1500%, p < 0.001), GABA (452%, p < 0.05) and a decrease in GLU (−56%, p < 0.001). In HIP the same pattern of effects was observed, but the changes in monoamines were much greater with increases in DA (1781%, p < 0.001), NA (765%, p < 0.001), 5HT (11.058%, p < 0.001), GABA (451%, p < 0.01) and a decrease in GLU (31%, p < 0.01). Conclusions: Methamphetamine produced large increases in DA and NA in PFC and HIP, but surprisingly its greatest effect was to potentiate 5HT efflux. The increases in extracellular monoamines were accompanied by concomitant reductions in GLU and increases in GABA in both regions. It is probable that decreased excitatory and enhanced inhibitory amino acid neurotransmission in PFC and HIP were homeostatic responses to attenuate the pharmacological effects of methamphetamine. The increases in 5HT may also have been part of this response. Financial support: None. http://dx.doi.org/10.1016/j.drugalcdep.2015.07.524 The changing nature of opioid-related mortality in Australia Amanda Roxburgh 1,∗ , Lucy Burns 1 , Wayne Hall 2,1 , Louisa Degenhardt 1,3 1 National Drug and Alcohol Research Centre, University of New South Wales, Sydney, NSW, Australia 2 Centre for Youth Substance Abuse Research, University of Queensland, Brisbane, QLD, Australia 3 School of Population and Global Health, University of Melbourne, Melbourne, VIC, Australia
Aims: To investigate trends in all opioid-related mortality in Australia over time (2000–2013), as well as analyse differences in characteristics between heroin and pharmaceutical opioid (PO) deaths. Methods: Data extracted from the National Coronial Information System (an online Australia-wide database that comprises all
e195
deaths reported to a coroner) on deaths where opioid toxicity was considered to have caused or contributed to the death. Results: Prior to the disruption of heroin availability in Australia in 2001, heroin-related deaths comprised approximately 70% of all opioid-related deaths. From 2001 onwards, heroin deaths have comprised between 30% and 44% of these deaths. More recently PO (including morphine, codeine, oxycodone, methadone and fentanyl) have comprised the majority (70%) of opioid deaths. Heroin decedents were significantly younger, and more likely to be male compared to PO decedents. Preliminary analysis shows the majority (83%) of heroin decedents had a recorded history of injecting drug use (IDU). This figure was also high (63%) among fentanyl deaths. High proportions of oxycodone deaths had a recorded history of chronic pain (49%) and mental health problems (54%). Conclusions: What distinguished heroin from PO deaths was that decedents were younger and more likely to be male. What distinguished PO deaths from heroin deaths was a history of chronic pain and mental health problems. Different clinical responses are clearly required in reducing both heroin and PO related mortality. While PO deaths are of increasing concern in Australia, heroin deaths are on the rise again after a sharp decline in 2001. Financial support: The National Illicit Drug Indicators Project (part of the Drug Trends program at the National Drug and Alcohol Research Centre) is funded by the Australian Government under the Substance Misuse Prevention and Service Improvement Grants. http://dx.doi.org/10.1016/j.drugalcdep.2015.07.525 Informed consent practices among NIH-funded researchers Caitlin Ryan ∗ , Brittany Seymour, Michael Stephens, Rachel Comly, Chloe Sierka, Thea G. Musselman, Karen L. Dugosh, David Festinger Section on Law and Ethics, Treatment Research Institute, Philadelphia, PA, United States Aims: Participation in a study must be intelligent, knowing, and voluntary. The extent to which investigators utilize effective strategies to protect study participants is unclear. In this study, we surveyed researchers funded by NIH agencies including NIDA and NIAAA to determine what procedures they use to help ensure informed consent. Methods: We invited principal investigators who received NIH R01 grant funding in 2012 (identified through NIH RePORTER) to complete a web-based survey. The 26-item survey took approximately 10 minutes to complete. A total of 673 investigators agreed to take part in the survey. Of these, 384 (57%) conducted research that required consent and were eligible for participation. Results: Fifty-nine percent (N = 220) conducted research with vulnerable populations. The majority (89%) relied on observation to determine capacity of subjects. Only 18% used a consent quiz to evaluate understanding of consent information. These quizzes utilized open-ended (67%) and true/false (34%) response formats. Almost all (97%) researchers provided participants with copies of the consent and 55% reminded them about their rights throughout the study. To ensure autonomy, researchers told potential participants that the decision to enroll was voluntary (99%), it would not affect their treatment (88%), delayed consent for further consideration (40%), and lowered compensation rates (37%). Most researchers (92%) indicated it was very important to remember consent information over the course of a study but less than half felt that this actually occurred. Conclusions: Results from this study suggest that researchers generally do not employ standard procedures to determine
e196
Abstract / Drug and Alcohol Dependence 156 (2015) e183–e245
whether consent is intelligent, knowing, and voluntary. It is necessary to identify ways to promote the widespread use of effective consent strategies. This is particularly true for research that is conducted with vulnerable populations including substance abusers, prisoners, and adolescents. Financial support: NIDA R01-DA-025687. http://dx.doi.org/10.1016/j.drugalcdep.2015.07.526
Regional grey matter volume and externalizing score: Not yet related in middle childhood Joseph Sakai 1,∗ , Manish Dalwani 1 , Mary A. McMahon 1 , Susan K. Mikulich-Gilbertson 1 , Jody Tanabe 1 , Shannon K. McWilliams 1 , Kristen Raymond 1 , M.T. Banich 2 , Thomas J. Crowley 1 1
University of Colorado, Aurora, CO, United States University of Colorado Boulder, Boulder, CO, United States 2
Association of alcohol use with drug use and weapon carrying among Thai adolescents On-anong Saiphoklang 1,∗ , Kua Wongboonsin 1 , Patcharawalai Wongboonsin 1 , Usaneya Perngparn 3 , Linda Cottler 2 1 College of Population Studies, Chulalongkorn University, Bangkok, Thailand 2 Epidemiology, University of Florida, Gainesville, FL, United States 3 College of Public Health Sciences, Chulalongkorn University, Patumwan, Thailand
Aims: Alcohol, drug use, and weapon carrying are a public health concern especially among students because they can have deleterious effects on physical and mental health. This study determined the prevalence of and gender specific factors associated with these behaviors among Thai adolescent students. Methods: A cross-sectional study in high school and vocational school in Bangkok, Thailand was conducted in 2014. Self-administrated questionnaires assessed past 30 day behaviors among students between 11 and 18 years of age (2561 students from 26 schools). Results: Overall, one fourth (24.4%) of students reported past 30 day alcohol use, 2.5% reported drug use, and 7.8% reported weapon carrying. Older youth were more likely to report drinking than those younger (p < .0001). Multivariate logistic regression analyses showed that alcohol use was almost four times higher among drug users than nondrug users (OR 3.93). Students who carried a weapon had nearly three times the risk of drinking than their counterparts (OR 2.74). Overall, females who used drugs or who carried a weapon were 7.94 and 3.15 times respectively to report drinking compared to males. All other factors adjusted for were also more strongly associated with drinking among females than males; factors include number of friends who smoke (OR 2.66 vs OR 1.77), weight issues (OR 2.10), smoking (OR 5.36 vs OR 4.59), and energy drink use (OR 3.41 vs OR 2.04). Conclusions: An increased association of drug use and weapon carrying with alcohol use was found for adolescent females in Thailand. Findings indicate gender specific interventions are needed for adolescents for these behaviors. Financial support: Financial support from the Thailand Research Fund through the Royal Golden Jubilee Ph.D. Program (Grant No. PHD/0184/2553) to On-anong Saiphoklang and Professor Kua Woongboonsin, PhD is acknowledged. And University of Florida Substance Abuse Training Center in Public Health (DA-T32035167). http://dx.doi.org/10.1016/j.drugalcdep.2015.07.527
Aims: Adolescents (ages 14–18 years) in treatment for substance use disorder (SUD) have less brain grey matter volume (GMV) than controls, a finding replicated for SUD and related phenotypes. Such results might either pre-exist and predict SUD, or could result from adolescent substance exposure. Methods: We recruited 9–11 year old subjects (n = 66, 32 female) about equally from control families and patient families (i.e., at least one first degree relative in SUD treatment). Subjects had no or minimal lifetime substance exposure. Brain structural scans were obtained using a 3T GE MRI scanner. Voxel-based morphometry analyses regressed regional brain volume against a predictor of future substance problems (Child Behavior Checklist externalizing behavior scores), while controlling for exact age and sex. Results: No regions of GMV were significantly (positively or negatively) related to externalizing behavior scores. Conclusions: We find that GMV, reduced in adolescents with SUD, is not reduced in younger children who are unexposed but at risk for SUD. Thus, GMV differences in adolescents with SUD may be related to substance exposure or developmental changes, which occur in adolescence. Although our sample size is similar to those in our prior studies, we may lack power to detect small differences, and large, longitudinal imaging studies are needed to confirm these findings. FreeSurfer analyses of cortical thickness in this sample will also be presented. Financial support: NIDA DA 09842, 11015 and 031761, The Kane Family and Hewit Family Foundations. http://dx.doi.org/10.1016/j.drugalcdep.2015.07.528 Taurine effectively inhibits cocaine preference in male and female rats: Candidate for SUD treatment Kaliris Salas-Ramirez 1,∗ , Kevin Uribe 2 , Eitan Friedman 1 , Shailesh Banerjee 1 1 Physiology, Pharmacology and Neuroscience, The City College of New York, New York, NY, United States 2 Biology, The City College of New York, New York, NY, United States
Aims: Cocaine (COC) is a commonly abused psychostimulant that causes alterations to the mesocorticolimbic circuitry and addiction-related behaviors characterized by loss of inhibition to use. Females have been shown to be more vulnerable to the effects of COC when compared to males, requiring lower doses and less time of exposure before the onset of addiction. Taurine (TAU) is an organic acid with neuroprotective and neuromodulatory roles. This study aimed to determine if taurine could reduce cocaine preference in male and female subjects. Methods: Male and female rats were pretreated with TAU (pre-tau; 100 mg/kg) for two weeks before undergoing a conditioned place preference protocol. They were randomly divided into four groups (n = 9/group): (1) TAU pretreatment (pre-TAU) and TAU + COC co-administration during conditioning, (1) pre- TAU and