Psy. D., Antioch University, 2023, Antioch Santa Barbara: Clinical Psychology

MDMA refers to the psychoactive drug +/-3,4-methylenedioxymethamphetamine. In clinical settings, robust quantitative and qualitative research has demonstrated that MDMA is an effective adjunct to therapists' conduction of psychotherapy for the treatment of post-traumatic stress disorder (PTSD) and potentially various other psychological conditions (Barone et al., 2022; Jerome, 2020; Oehen, 2012; Ot'alora, 2018). This study serves as the first qualitative research to exclusively focus on people who have used MDMA without a therapist in non-clinical settings for the purpose of psychological healing (i.e., MDMA solo users). Eight MDMA solo users were recruited as participants from ads posted on internet forums. Each participant underwent a semi-structured interview. A thematic analysis of the interviews discovered themes among participants' experiences with MDMA solo sessions and the practices they found helpful or unhelpful for attaining psychological healing. Themes of experiences included mental health struggles leading up to sessions, introspection, empathy, compassion, emotional changes following sessions, lasting changes in outlook, and lasting increased compassion. Themes that emerged for helpful practices included being open, “following” emotions, and writing. Themes found for unhelpful practices included dosages being too high, using MDMA too frequently, and that nothing was unhelpful. These phenomenological findings were compared to those found in MDMA-AT and MDMA recreational use literature. Nearly all of participants' solo experiences are similar to those of participants from qualitive research on MDMA-AT. When phenomenologically compared to MDMA recreational users whose intentions for usage did not include psychological healing, participants of this study had some similar experiences, but also some directly opposite experiences. For instance, participants of this study reported increased interpersonal intimacy and attunement to emotions, while MDMA r (open full item for complete abstract)

Committee: Brett Kia-Keating Ed.D. (Committee Chair); Lynn Dhanak Ph.D. (Committee Member); Will Barone Psy.D. (Committee Member) Subjects: Clinical Psychology

Doctor of Philosophy, The Ohio State University, 2024, Educational Studies

The purpose of this study is to complete the first phase of development of the MDMA, a scale that will measure decision-making abilities among youth and young adults aged 5-30. While the scale can be used in a variety of settings, its specific goal is for use in juvenile transfer cases. There are currently no standardized assessments related to the Kent criteria, and the goal of this scale is to support objective determinations by judges and attorneys. For this study, the Delphi Method was used to gather expert opinions on the relevancy of each scale item. The researcher began by identifying experts and inviting them to participate in the survey. Next, the researcher employed two rounds of surveys using a Likert scale, along with qualitative feedback opportunities for each subscale. Following each of the two rounds of data collection, the researcher determined relevancy by identifying which items had at least 70% consensus with no more than 15% disagreement. This study extended the available literature and processes used in juvenile transfer cases in the following ways: (a) identify the dimensions within the construct of “decision-making;” (b) determine the optimal method of measuring these dimensions; (c) create scale items that measure each of the identified dimensions and connect them to the Kent criteria; and (d) summarize uses for this scale. Limitations of the study, directions for future research, and implications for practitioners are discussed.

Committee: Kisha Radliff (Advisor); Laurice Joseph (Committee Member); Scott Graves (Committee Member) Subjects: Educational Psychology; Law; Legal Studies; Psychology

Doctor of Philosophy (Ph.D.), Bowling Green State University, 2023, Biological Sciences

Globally abused phenethylamine drugs can cause “phenethylamine-induced-hyperthermia” (PIH), a serious health concern associated to sequela of complications including rhabdomyolysis, coagulopathy, kidney failure and death. In general, PIH is known to occur via activation of host sympathetic nervous system (SNS) leading to increased release of norepinephrine (NE) post phenethylamine exposure. NE then acts as signal to activate pathways which generate heat in various thermogenic tissues or prevent heat loss through vasoconstriction. Besides NE, recent research from our laboratory pointed towards potential involvement of gut bacteria in PIH, shown by altered PIH following gut microbial modulations such as via antibiotic treatment or fecal microbial transplantation (FMT). Here, we aimed to investigate the functional role of gut microbiome and bile acids as signal in PIH. We applied targeted LC-MS/MS, first time to our knowledge, to quantify serum concentrations of three important bacteria metabolized/associated bile acid species (BAs): cholic acid (CA), chenodeoxycholic acid (CDCA) and deoxycholic acid (DCA) prior to and post (hyperthermic dose of) 3,4-methylenedioxymethamphetamine (MDMA) (a phenethylamine) treatment. Male Sprague-Dawley rats were provided either sterile or antibiotic-water for five days prior to MDMA (20 mg/kg, sc)/saline administration. On day six BAs and body temperatures were measured at 0 minute before and 30 minutes and 60 minutes post MDMA/Saline challenge. We found all three focal BAs in serum to deplete significantly in MDMA treated rats compared to saline group at 60-minute, exactly the same time point when peak rise in core body temperature occurred, indicating contribution of these three BAs in PIH. While prior antibiotic cocktail (vancomycin, bacitracin and neomycin) treated groups had greatly reduced serum level of all three BAs and reversal of hyperthermia after MDMA. We also inferred metagenomic functions applying PICRUSt2 on 16S rRNA ge (open full item for complete abstract)

Committee: Christopher Ward Ph.D. (Committee Chair); Benjamin Ward Ph.D. (Other); Raymond Larsen Ph.D. (Committee Member); Vipaporn Phuntumart Ph.D. (Committee Member); Jon Sprague Ph. D. (Committee Member) Subjects: Biology

Doctor of Philosophy (Ph.D.), Bowling Green State University, 2021, Photochemical Sciences

The purpose of this dissertation is to discuss the theory, methodology and assessment of the pharmacological and toxicological effects of phenylethylamines in two targeted areas: First, viability of utilizing a retrodialysis in vivo experimental model to assess the differences in synaptic dopamine (DA) concentrations under direct perfusion of two structurally and yet pharmacodynamically different synthetic cathinones (“bath salts”). Second, the relationship between the mechanisms underlying phenylethylamine-induced hyperthermia (PIH) and gut microbiome composition and diversity, a research area which remains poorly investigated in the current literature. For the first part of our research, we suggest the utilization of retrodialysis technique to locally deliver the drugs under investigation to the targeted brain area and assess the resulting changes in DA concentrations using High Performance Liquid Chromatography Coupled with Electrochemical Detection (HPLC-EC). We report that retrodialysis was successfully incorporated to deliver synthetic cathinones to the caudate putamen while utilizing HPLC-EC detection to assess extracellular DA changes within the targeted area. In the second part of our research, we suggest a new approach in exploring the relationship between PIH mechanisms and gut microbiome structure and richness by employing bidirectional fecal microbial transplant (FMT) via oral gavage as a method of transferring the hyperthermic phenotypic response upon methamphetamine (METH) treatment between male and female rat models. Through this modality, we can observe the changes in gut microbiome populations at each stage of treatment and how these changes affect PIH. We observe that although bidirectional FMT model employed repopulated the gut of the respective animals, gut microbiome does not seem to play a role in the sex-based differences in PIH between male and female rats. For the third part of the presented research, we explored the role of the gut-adre (open full item for complete abstract)

Committee: Jon Sprague Ph.D. (Advisor); Raymond Larsen Ph.D. (Committee Member); Travis Worst Ph.D. (Committee Member); Craig Zirbel Ph.D. (Other) Subjects: Chemistry; Pharmacology; Toxicology

Master of Science in Pharmaceutical Science (MSP), University of Toledo, 2020, Pharmaceutical Sciences (Pharmacology/Toxicology)

In response to legal restrictions on methamphetamine (MA) and 3,4- methylenedioxymethamphetamine (MDMA), there has been an increase in the use of synthetic psychoactive cathinone's (SPCs). SPCs are structurally similar to MA and MDMA, sharing many of their psychostimulant properties, however, there is some question as to whether the drugs in this class share similar hyperthermic, lethal, and neurotoxic effects as MA and MDMA. While the mechanisms of action of these drugs are still being studied, clinical reports suggest that they produce hepatocellular damage, contributing to their potential lethal effects. In studies in mice and zebrafish, the Hall laboratory has shown that MA, MDMA and SPCs induce lethal effects that are associated with seizures, perhaps indicative of uncontrolled glutamatergic activation. In a series of experiments, Halpin and Yamamoto (Halpin et al., 2013; Halpin and Yamamoto, 2012) have shown that MA induces liver impairments and elevations in plasma ammonia that contribute to increased glutamatergic activity. In our own studies we have also observed that liver tissue was severely damaged by exposure to these drugs, encouraging the use of liver cells to further understand how these drugs work. In the following project different concentrations of MA and MDMA were used in order to determine the IC50 values and the mechanism of cell death. The obtained IC50 values of MA and MDMA, through MTT assay, were used to define dose ranges for subsequent studies: a concentration which would not cause any cell death (0 mM), a concentration which is below our observed IC50 (1 mM), a concentration just above the observed IC50 values (3 mM), and a concentration which would almost completely inhibit cell survival (10 mM). In order to determine the mechanism of cell death, this study included MTT assays, LDH assays, ROS assays, and Western blots, as well as data obtained through the Incucyte live cell imaging system. MTT assays determine the concentration of drug (open full item for complete abstract)

Committee: Scott Hall (Committee Chair); Terry Hinds (Committee Member); Amit Tiwari (Committee Member) Subjects: Biology; Cellular Biology; Experiments; Health Sciences; Morphology; Pharmaceuticals; Pharmacology; Pharmacy Sciences; Toxicology

Master of Science (MS), Bowling Green State University, 2019, Biological Sciences

Hyperthermia induced by 3,4-methylenedioxymethamphetamine (MDMA) and synthetic cathinones such as methylone (β-keto MDMA) can be life-threatening. The long-term use of these sympathomimetic drugs can lead to the development of tolerance in users contributing to dependency and addiction to the drugs. Recently, the role of the gut microbiome has been implicated in many diseases of the nervous system. This thesis focuses on identifying the role of the gut microbiome in MDMA-mediated hyperthermia (Chapter 2) and understanding the gender-wise differences in development of tolerance to the long-term use of methylone (Chapter 3). In chapter 2, fourteen days prior to treatment with MDMA subcutaneously, male Sprague-Dawley rats were provided water or water laced with antibiotics. Animals that had received antibiotics displayed a reduction in gut bacteria and an attenuated hyperthermic response to MDMA (20 mg/kg). The expression of genes associated with hyperthermia in skeletal muscle (SKM) and in brown adipose tissue (BAT) was measured by qRT-PCR. MDMA-treated animals showed increased uncoupling protein 1 (UCP1) and TGR5 expression levels in BAT and SKM while increased ex-pression of UCP3 was observed only in SKM. Antibiotics prior to MDMA administration significantly blunted these increases in gene expression. These findings suggest a contributing role for the gut microbiota in MDMA-mediated hyperthermia with changes in expression of different genes. In chapter 3, male and female rats were treated weekly with methylone (10 mg/kg) via subcutaneous route. The females developed a tolerance to the methylone-induced hyperthermia by week two of drug exposure. By the third week, females displayed a hypothermic response to methylone. Conversely, males continued to display a hyperthermic response up to and including week four. At week four, the males demonstrated a significantly lower hyperthermia, and a complete tolerance seen at week five with no significant hyperthermia. Tissue (open full item for complete abstract)

Committee: Vipaporn Phuntumart PhD (Advisor); Raymond Larsen PhD (Committee Member); Jon Sprague PhD (Committee Member) Subjects: Biology; Molecular Biology

Master of Science (MS), Bowling Green State University, 2018, Biological Sciences

The gut microbiome is known to be home to 105 to 106 micro-organisms which are known to be phylogenetically diverse. There is growing evidence that the composition of the gut microbiota plays a large role in the health and well-being of its host. Changes gut microbial populations are associated with the pathogenesis of variety of metabolic, malignant, and inflammatory diseases. Evidence suggests the existence of a `gut-brain axis' as the involving interactions between gut microbiome and the central nervous system (CNS). Little is known about the involvement of this axis in modulating gut microbial populations in response to drugs of abuse. The present study investigates the effect of 3,4 methylene dioxymethamphetamine (MDMA) on the gut microbiome of male Sprague-Dawley rats. Treatment with MDMA resulted in a rapid compositional shift of the cultivatable bacterial population in the rat cecum. Specifically, the cecal contents of normal MDMA-treated rats yielded a large number of swarming bacteria when cultured on nutrient agar at dilutions suitable for colony counting, whereas organisms with a swarming phenotype were not present at levels detectible in similarly diluted cecal contents from animals that did not receive MDMA. When plated on media containing bile salts, swarming was inhibited, allowing recovery of pure isolates. These isolates were found to be gram-negative rods and non-lactose fermenting rods. Bioinformatic analysis using the 16S rRNA gene from these isolates confirmed then to be members of the genus Proteus.

Committee: Vipaporn Phuntumart Dr. (Advisor); Raymond Anthony Larsen Dr. (Committee Member); Jon Eric Sprague Dr. (Committee Member) Subjects: Microbiology; Molecular Biology

PhD, University of Cincinnati, 2016, Pharmacy: Pharmaceutical Sciences/Biopharmaceutics

MDMA is a unique psychostimulant that continues to be a popular drug of abuse. It is well documented that MDMA produces persistent reductions in markers of 5-HT axon terminals in rodents, as well as humans. To date, there has been little recognition of potential MDMA neurotoxicity to neuronal populations beyond 5-HT axon terminals in brain regions, such as the hippocampus, in which damage may account for the neurologic/cognitive effects associated with repeated exposure to MDMA. In the present study, we examined the hypothesis that MDMA produces glutamate-dependent damage to GABAergic neurons, as assessed from GAD67-positive neurons in the hippocampus, which results in an increase in seizure susceptibility. Repeated exposure to MDMA (3x10mg/kg, ip) resulted in a reduction of approximately 35- 55% in the number of GAD67 positive cells in the dentate gyrus, CA1, and CA3 regions. These reductions were significantly less in animals treated with MK-801 (an NMDA antagonist) or ceftriaxone (an inducer of GLT-1). In further support of overall hypothesis is the finding that MDMA increases the extracellular concentration of glutamate; this glutamate response was diminished in rats treated previously with either ceftriaxone or SC-51089 (a prostanoid EP1 receptor antagonist). Repeated administration of MDMA also resulted in an increased susceptibility to kainic acid-induced seizures that persisted for at least 30 days following MDMA treatment. Kainic acid (8 mg/kg, sc) produced seizures in approximately 20% of control animals, whereas approximately 85% of MDMA-treated animals exhibited kainic acid-induced seizures. The MDMA-induced increase in seizure susceptibility was not evident in rats treated with MK-801, ceftriaxone, or SC-51089. These findings substantiate a role for glutamate in the MDMA-induced damage to GABAergic neurons within the hippocampus and the subsequent increase in seizure susceptibility. Additional evidence is provided to support the hypothesis (open full item for complete abstract)

Committee: Gary Gudelsky Ph.D. (Committee Chair); Steve Danzer Ph.D. (Committee Member); Jiukuan Hao Ph.D. (Committee Member); James Herman Ph.D. (Committee Member); Georg Weber M.D. Ph.D. (Committee Member) Subjects: Pharmaceuticals

Doctor of Philosophy (Ph.D.), Bowling Green State University, 2016, Psychology/Clinical

I designed two studies to evaluate the Theory of Planned Behavior (TPB; Attitudes, Subjective Norms, Perceived Behavioral Control, Intention) plus Habit Strength (i.e., habitual engagement in a behavior) as a model predicting how often ecstasy users engaged in three specific harm reduction strategies. In study one I recruited 136 participants from several websites to complete baseline TPB and Habit Strength measures in relation to hydrating (drinking water/electrolyte-rich beverages) and pre/post-loading (consuming vitamins/supplements) while using MDMA/ecstasy. I also included Passionate Attachment to using MDMA/ecstasy as a predictor of Intention to engage in both strategies. After two months, participants reported how often they hydrated and pre/post-loaded during the study. The regression model predicting Intention to pre/post-load was significant, and Attitudes was the only significant predictor. The regression model predicting pre/post-loading at follow-up was also significant, and Intention and Habit Strength were significant predictors. The regression model predicting Intention to hydrate was significant, and Attitudes and Perceived Behavioral Control were significant predictors. However, the regression model predicting hydration during the two-month follow-up was not significant. In study two I recruited 100 participants from Facebook to complete baseline TPB and Habit Strength measures in relation to pre/post-loading and pill-testing/checking (i.e., attempting to determine chemical composition of ecstasy) while using MDMA/ecstasy. After two months, participants reported how often they pre/post-loaded and pill tested/checked during the study. The regression model predicting Intention to pre/post-load was significant, and Attitudes was the only significant predictor. The regression model predicting pre/post-loading at follow-up was also significant, and Habit Strength was the only significant predictor. The regression model predicting Intention to pill test/ (open full item for complete abstract)

Committee: Harold Rosenberg (Committee Chair); John Tisak (Committee Member); Robert Carels (Committee Member); Melissa Burek (Committee Member) Subjects: Clinical Psychology

PhD, University of Cincinnati, 2010, Medicine : Neuroscience/Medical Science Scholars Interdisiplinary

The availability and perceived safety of the club drug “ecstasy” (3,4-methylenedioxymethamphetamine; MDMA) has contributed to a steady increase in recreational use by teenagers and young adults. Because these individuals are of child-bearing age, the risk for accidental prenatal exposure to MDMA has risen as well. In order to determine whether fetal exposure has lasting effects on neurodevelopment, our laboratory has created a rodent model of prenatal MDMA exposure. In previous studies, we have shown that prenatal exposure to MDMA increased dopaminergic neurite density in target structures, including the prefrontal cortex, the striatum, and the nucleus accumbens. The objective of these studies was to determine whether prenatal MDMA had a comparable effect on the developing noradrenergic system, to assess whether the observed anatomical changes were associated with behavioral deficits, and to determine the mechanism underlying MDMA's ability to induce hyperinnervation of target structures. Using techniques including computer-assisted stereology and direct tissue autoradiography we showed that prenatal MDMA exposure increased noradrenergic fiber density and binding of the norepinephrine transporter in the hippocampus. High performance liquid chromatography demonstrated that prenatal MDMA was associated with an increase in basal norepinephrine levels in the prefrontal cortex and the nucleus accumbens. Behavioral assays designed to assess attention demonstrated that adult rats that had been exposed prenatally to MDMA failed to habituate, and showed a reduction in anxiety-like behavior, when placed in a novel environment. MDMA-exposed rats also showed signs of cognitive inflexibility during a cued Morris Water Maze task. These results suggest that prenatal MDMA exposure has lasting effects on the circuitry associated with attention and working memory. Finally, using an in vitro model developed by our laboratory, we demonstrate that target-derived factors in both the pref (open full item for complete abstract)

Committee: Jack Lipton PhD (Committee Chair); Timothy Collier PhD (Committee Member); James Herman PhD (Committee Member); Caryl Sortwell PhD (Committee Member); Kenneth Greis PhD (Committee Member) Subjects: Neurology

PhD, University of Cincinnati, 2010, Pharmacy : Pharmaceutical Sciences

3,4-Methylenedioxymethamphetamine (MDMA), an analog of the amphetamine class, is a psychostimulant and a popular drug of abuse. MDMA is considered to be selectively neurotoxic to serotonergic nerve terminals in different brain regions. Repeated exposure to MDMA during adolescence is neuroprotective against a subsequent neurotoxic regimen of MDMA in adulthood. This phenomenon is similar to ischemic preconditioning, where repeated exposure to sub-lethal insults results in neuroprotection against a subsequent deleterious insult. The purpose of this study was to evaluate whether repeated exposure (preconditioning) to a non-toxic dose of MDMA in adult rats provides neuroprotection against subsequent MDMA induced 5-HT depletion and to evaluate the mechanisms involved. Preconditioning with MDMA (10 mg/kg i.p.) daily for 4 days provided significant protection against MDMA-induced 5-HT depletion in the striatum, hippocampus and cortex. Preconditioning with MDMA (10 mg/kg i.p.) daily for 4 days provided significant protection against methamphetamine (METH)-induced 5-HT, but not DA, depletion in the striatum. Since the neuroprotection is specific to the serotonergic neurons, it is possible that preconditioning with MDMA results in neuroadaptive changes in 5-HT containing neurons. The role for alterations in MDMA-induced hyperthermia and brain MDMA concentrations was ruled out. Repeated exposure to Clozapine, at doses known to produce 5-HT2 receptor downregulation, provided significant protection against MDMA-induced 5-HT depletion in the striatum, hippocampus and cortex. However, it is inconclusive whether repeated exposure to MDMA results in downregulation of 5-HT2 receptor function and expression. Repeated exposure to MDMA resulted in the downregulation of serotonin transporter (SERT) expression. Steady state 5-HT uptake in hippocampal synaptosomal preparations in rats previously exposed to MDMA was significantly reduced when compared to vehicle treated animals. SERT plays (open full item for complete abstract)

Committee: Gary Gudelsky PhD (Committee Chair); Jack Lipton PhD (Committee Member); J. Nash PhD (Committee Member); Kenneth Skau PhD (Committee Member); Karen Gregerson PhD (Committee Member) Subjects: Pharmacology

MS, University of Cincinnati, 2008, Pharmacy : Pharmaceutical Sciences

The acute administration of MDMA has been shown to promote glycogenolysis and increase the extracellular concentration of glucose in the striatum. In the present study the role of 5-HT and/or NE pathways in the MDMA induced increase in extracellular glucose and glycogenolysis was assessed. The relationship of this response to MDMA induced hyperthermia also was determined. The administration of MDMA (10mg/kg, ip) resulted in a significant and sustained increase (50-100%) in the extracellular concentration of glucose not only in the striatum but also in the prefrontal cortex and hippocampus without altering peripheral blood glucose concentrations. Treatment of rats with fluoxetine (10mg/kg, ip) significantly attenuated the MDMA induced increase in extracellular glucose in the striatum but had no effect on MDMA induced hyperthermia or glycogenolysis. Treatment with prazosin (1mg/kg, ip) did not alter the glucose or glycogen responses to MDMA but completely suppressed the MDMA induced hyperthermia. Finally, propranolol (3mg/kg, ip) significantly attenuated the MDMA induced increase in extracellular glucose and glycogenolysis but did not alter MDMA induced hyperthermia. The present results suggest that MDMA increases extracellular glucose in multiple brain regions, and that this response involves both 5HT and NE mechanisms. Furthermore, β adrenergic and α adrenergic receptors appear to contribute to MDMA-induced glycogenolysis and hyperthermia, respectively. Finally, hyperthermia, glycogenolysis and elevated extracellular glucose appear to be independent unrelated responses to acute MDMA administration.

Committee: Gary Gudelsky PhD (Advisor); Kenneth Skau PhD (Committee Member); J. Frank Nash PhD (Committee Member) Subjects: Pharmacology

PhD, University of Cincinnati, 2006, Medicine : Neuroscience/Medical Science Scholars Interdisiplinary

±3,4-Methylenedioxymethamphetamine (MDMA) is a popular drug of abuse that produces long-term decreases in neurochemical markers of 5-HT that are believed to be indicative of selective toxicity to the 5-HT nerve terminal. A potential mechanism underlying this proposed neurotoxicity involves reactive nitrogen species. In vivo microdialysis studies demonstrated that MDMA increases extracellular nitrite/nitrate (NOx), a marker of NO, and that this is iNOS dependent. However, iNOS-dependent MDMA-induced NOx formation is unrelated to long-term 5-HT toxicity, as iNOS inhibition had no effect on long-term MDMA-induced 5-HT depletion. Histological evidence of MDMA-induced 5-HT nerve terminal damage is inconsistent. Antibodies to the cleaved form of the microtubule associated protein tau (C-tau) were used to characterize neurotoxicity produced by psychostimulant drugs. Amphetamine (AMPH) and methamphetamine (METH), both DA-depleting compounds, produced an increase in C-tau immunoreactivity, whereas the 5-HT-depleting drugs MDMA, para-methoxyamphetamine (PMA) and the prototypic 5-HT neurotoxin 5,7-dihydroxytryptamine (5,7-DHT) did not. C-tau was localized to astrocytes, not neurons, suggesting that C-tau is not a direct marker of neuronal damage, but may be an alternative indicator of reactive gliosis. Furthermore, these data are in agreement with previous findings that AMPH and METH produce reactive gliosis, whereas MDMA, PMA and 5,7-DHT do not. Human users of MDMA have reported cognitive/behavioral deficits following chronic use, including impaired sexual function and reduced sexual motivation. In the rat, prior treatment with MDMA may alter the rewarding properties of other drugs of abuse. Given the potential similarities in neural pathways mediating the rewarding properties of drugs and sex, studies were designed to assess the effect of MDMA on the response to a natural reward, i.e., sex, in the conditioned place preference (CPP) paradigm. Rats treated with a 5-HT-depletin (open full item for complete abstract)

Committee: Dr. Gary Gudelsky (Advisor) Subjects: Biology, Neuroscience

PhD, University of Cincinnati, 2006, Medicine : Molecular and Developmental Biology

3,4-Methylenedioxymethamphetamine (MDMA) is a ring substituted amphetamine similar in structure to mescaline. Exposure to MDMA from postnatal days (P)11-20 has been shown to induce deficits in spatial learning and memory as well as in path integration learning when the animals are tested as adults. These learning and memory deficits emerge at P30 and persist until P360. This dosing regimen has been shown to decrease serotonin and alter serotonin signaling in the adult brain; however these effects were independent of the learning and memory deficits observed. Finally, dosing on P11 has been shown to increase corticosterone levels during the stress hyporesponsive period, a time when there are attenuated CORT levels. While these areas appear to be important in elucidating the mechanisms underlying MDMA, it is important to investigate systems that may not have been previously implicated in MDMA pharmacology. Microarray analysis revealed 71 genes with altered expression (66 up-regulated and 5 down-regulated) in the hippocampus of adult animals treated from P11-20 with MDMA. Real-time PCR analysis verified 8 out of the 24 genes selected for verification. The 8 verified genes were examined in the striatum of adult animals, with the gene encoding angiotensinogen (AOGEN) up-regulated approximately 75%. Following examination in the hippocampus and striatum, the 8 verified genes were examined in the hippocampi of P12 and P21 MDMA-exposed animals. In P12 animals, nuclear orphan receptor 1 was up-regulated by ~600% and AOGEN was down regulated by 50%; while AOGEN was up-regulated by 3 fold on P21. One gene was selected for further investigation. CAPON, the gene that showed the highest up-regulation during microarray analysis, was analyzed with common pathway members nNOS, PSD-95, and the NMDA receptor subunit 1 (NR1). While CAPON protein was unchanged, the remaining proteins were increased in the dentate gyrus of adult animals. Together with the protein changes associated with N (open full item for complete abstract)

Committee: Dr. Charles Vorhees (Advisor) Subjects: Biology, Neuroscience

MS, University of Cincinnati, 2006, Medicine : Cell and Molecular Biology

3,4-Methylenedioxymethamphetamine (MDMA) is an amphetamine analog. MDMA causes cognitive impairment in humans. Work done in primates corroborates this evidence. A reliable rat model of cognitive deficits has not been established. Experiment 1 examined the effect of a single-day dose regimen of MDMA (4 x 15mg/kg) on Sprague-Dawley rats in spatial learning on the Morris water maze (MWM), path integration learning in the Cincinnati water maze (CWM), and novel object recognition (NOR). The MDMA-treated animals made more errors than controls on the last three days of CWM testing. MWM and NOR revealed no differences. At the end of behavioral testing, serotonin (5-HT) was depleted in the MDMA-treated group in the hippocampus, striatum and prefrontal cortex and dopamine (DA) was depleted in the striatum. Since human MDMA use likely involves multiple doses, Experiment 2 examined the effects of a multiple-day dose regimen of MDMA on behavior. There were 3 treatment groups: (1) a 1-day/week for 5 weeks regimen of MDMA (15 mg/kg x 4/day), (2) a 1-day/week for 5 weeks regimen of saline (SAL, 4/day), and (3) a 1-day/week for 4 weeks regimen of saline and a 1-day regimen of MDMA on the fifth week. Subjects were given the following behavioral tests: elevated zero maze (EZM), locomotor activity, marble burying, CWM, MWM (3 phases), NOR, locomotion with methamphetamine challenge, and a delayed MWM probe trial. There were no differences between controls and the MDMA-treated groups in MWM or NOR. In the CWM, both MDMA treated groups showed significant deficits in learning. The 5-dose MDMA group showed increased anxiety in EZM and more locomotor activity following methamphetamine challenge. Examination of monoamines had 5-HT and DA reductions, similar to Experiment 1. Experiment 3 was designed to determine the time-course (across 5 weeks) for the DA depletions resulting from a single-day of MDMA administration. MDMA treatment depleted DA in the striatum during the first week, but levels (open full item for complete abstract)

Committee: Dr. Michael Williams (Advisor) Subjects:

PhD, University of Cincinnati, 2005, Arts and Sciences : Psychology

Use of ecstasy (3,4-Methylenedioxymethamphetamine, MDMA) is becoming an increasing health problem across the United States. Numerous studies have demonstrated that ecstasy is a selective serotonin neurotoxin in several animal species and in humans. However, until recently, the cognitive consequences of ecstasy use have been relatively unknown. Studies to date have consistently demonstrated deficits in verbal memory among ecstasy users; while only some have examined impairments in visual memory, working memory, abstract reasoning, planning, attention, and problem solving. To date, there are no published studies that adequately assess the effects of ecstasy exposure on cognitive functioning while controlling for other drugs of abuse, gender, and demographic variables known to be associated with cognitive performance. The primary goal of the proposed project was to assess the relationship between exposure to the psychoactive drug ecstasy and cognitive functioning among 65 men and women. It was hypothesized that increased lifetime and past year ecstasy exposure would be related to poorer performance on cognitive tasks after controlling statistically for consumption of other drugs and potential confounding factors such as age, education, gender, premorbid intelligence, and ethnicity. The primary finding was that increased ecstasy exposure was significantly related to poorer verbal memory and learning ability, while no such relationship was found between executive functioning. Furthermore, gender was found to moderate the relationship with ecstasy exposure and cognitive functioning, including verbal memory retention, visual memory ability, working memory, visual fluency, and cognitive inhibition.

Committee: Dr. Paula Shear (Advisor) Subjects: Psychology, Clinical

Doctor of Philosophy, The Ohio State University, 2005, Educational Services and Research

The topic of criminogenic cognitive distortions among substance abusers has largely been ignored in the literature despite that studies indicate a high comorbidity between drug usage and involvement in the criminal justice system. This proposal involves the use of archival data from an inner city residential drug treatment program for offenders. Subjects are 129 men referred by the criminal justice system for drug treatment for a period of three to nine months. An investigation using a General Linear Multivariate Analysis (MANCOVA) of demographic data that includes a self-report of the frequency of substance usage, along with assessment of cognitive distortions from the How I Think Questionnaire (HIT) is utilized. Five drug classes (Ecstasy, Alcohol, Opiates, LSD/hallucinogens and Amphetamines) along with four categories of cognitive distortion on the HIT (Self-Centered, Blaming Others, Minimizing/Mislabeling and Assuming the Worst) were analyzed along with covariates of age of subject and number of drugs used. Results indicate that only the drug Ecstasy (3,4-Methylendioxymethamphetamine) exhibited significant main effect for patterns of cognitive distortions and present on three of the four scales of the HIT. Implications for cognitive distortions as reinforcement of MDMA usage are discussed. A review of critical items found on the HIT, normative comparisons, and cluster analysis of drug usage patterns are presented. For the total model, drug usage increases are associated with increases in measured criminogenic cognitive distortions.

Committee: Michael Klein (Advisor) Subjects: Psychology, Clinical

Master of Arts (MA), Bowling Green State University, 2012, Psychology/Clinical

Numerous questionnaires have been published to assess craving for a wide variety of drugs, but no such instrument has been developed to assess craving for MDMA/ecstasy. Therefore, this study was designed to develop and evaluate the psychometric properties of such a questionnaire. First, I developed a pool of 19 potential items by modifying questions from other instruments assessing craving for other substances and writing new items that applied specifically to MDMA/Ecstasy. Next, using three websites (bluelight.ru, pillreports.com, facebook.com), I recruited 217 regular users of MDMA/ecstasy to complete a series of ecstasy-related questionnaires. Following an initial rating of their agreement with 19 craving items, participants watched one of two 3-minute cue-exposure videos: (a) dancing plus music at a club/rave with interspersed photos of ecstasy pills or (b) marching band on a football field and music with interspersed photos of peanuts. Following cue-exposure, subjects re-rated their agreement with the same 19 items, and completed questionnaires to assess their motivations for using ecstasy, refusal self-efficacy, obsessive/harmonious engagement in ecstasy use, drug/alcohol use and problems, and demographic information. Based on a conceptualization of craving that emphasized current desire, intention to consume and loss of control, I eliminated 11 potential items that appeared redundant or assessed outcome expectancies to yield the final 8-item version of the Ecstasy Craving Questionnaire-Current Craving (ECQ-CC). None of these 8 items were “unbalanced” (i.e., 80+% agreed or disagreed) nor were any pairs of the 8 items highly inter-correlated (r > 0.70). Internal reliability consistency across the 8 items was high (α = 0.93). The criterion validity of the ECQ-CC was supported by significant positive correlations of craving scores with motives for use, number of problems related to drug use, frequency of ecstasy use, and levels of obsessive/harmonious engagement (open full item for complete abstract)

Committee: Harold Rosenberg Ph.D. (Committee Chair); Robert Carels Ph.D. (Committee Member); John Tisak Ph.D. (Committee Member) Subjects: Psychology

PhD, University of Cincinnati, 2012, Pharmacy: Pharmaceutical Sciences/Biopharmaceutics

±-3,4-Methylenedioxymethamphetamine (MDMA, ecstasy) is a ring-substituted amphetamine derivative, and a popular psychoactive drug of abuse. This drug evokes a well-documented acute increase in the release of serotonin, dopamine, and acetylcholine, as well as persistent reductions in markers of serotonin axon terminals across several brain regions. Little is known concerning the effect of MDMA exposure on the glutamatergic neurotransmitter system. Excitotoxicity resulting from excessive glutamate release has the potential to contribute to the long-term toxicity of MDMA, including neurochemical and behavioral deficits. The purpose of the present study was to assess the effect of repeated MDMA exposure on extracellular glutamate concentrations in the rat brain, the mechanism(s) underlying this potential response, and the potential behavioral consequences of altered glutamate release. It was found that two and four injections of MDMA (10 mg/kg, i.p.), but not one, significantly elevated the concentration of extracellular glutamate in the dorsal hippocampus. Furthermore, this increase was not observed in either the prefrontal cortex or the striatum. Direct infusion of MDMA to the hippocampus evoked a similar increase, suggesting a local, intrahippocampal site of action of the drug. Furthermore, serotonergic signaling through the 5HT2A/C receptor was implicated in the underlying mechanism of glutamate release by the attenuation of the MDMA effect with either the SSRI fluoxetine or the 5-HT2A/C inhibitor ketanserin. Local administration of the sodium-channel blocker TTX did not prevent the MDMA-induced increase in glutamate efflux, indicating a non-neuronal, e.g. glial, source of glutamate release. In agreement with this conclusion is the finding that pharmacological modulation of glutamate regulatory mechanisms, including upregulation of the GLT-1 glutamate transporter with ceftriaxone, mGluR2/3 stimulation via LY379268, and inhibition of the cystine-glutamate antiporter (open full item for complete abstract)

Committee: Gary Gudelsky PhD (Committee Chair); J. F. Nash PhD (Committee Member); Jiukuan Hao PhD (Committee Member); Neil Richtand MD (Committee Member); Georg Weber MD PhD (Committee Member) Subjects: Pharmacology