A utilização de substâncias estimulantes tipo-anfetamínicos (ATS) por motoristas com objetivo de aumentar o tempo de vigília é um conhecido problema nacional com consequências sociais e legais. A dietilpropiona (DIE) e o femproporex (FEN) figuram entre os estimulantes do sistema nervoso central (SNC) mais utilizados por condutores no trânsito brasileiro. O metilfenidato (MPH) é um fármaco que apresenta propriedades similares à cocaína e à anfetamina (AMP). Sua utilização como droga de rua e recreacional tem aumentado nos últimos anos e seu uso tem ganhado espaço com a restrição da comercialização de DIE e FEN pela Agência Nacional de Vigilância Sanitária (ANVISA) em 2011. O estudo do trânsito implica necessariamente o conhecimento do perfil dos condutores e da prevalência do uso de substâncias. Para a monitorização do consumo de substâncias no trânsito, é necessário o emprego de métodos analíticos validados para as matrizes biológicas de interesse. Sabe-se ainda que muitos condutores compram medicamentos ATS ilegalmente, em postos de combustível e pela internet. Conhecer o perfil químico e detectar falsificações desses medicamentos é parte essencial no desenvolvimento e aplicação de políticas públicas preventivas do uso de substâncias no trânsito. Objetivos: avaliar dados do trânsito da região sul do Brasil, enfatizando o uso de substâncias, a idade e o sexo dos envolvidos em acidentes; desenvolver e validar métodos cromatográficos acoplados a detector de massas para quantificação simultânea de FEN, DIE e MPH em fluido oral e em plasma; avaliar o perfil de falsificações de medicamentos a base de ATS. Resultados: os dados de acidentes de trânsito com vítimas fatais no Estado de Santa Catarina no período de junho de 2008 a novembro de 2010, revelaram que 11,9 % dos casos apresentaram resultados toxicológicos positivos, sendo canabinóides (42 %) e cocaína (29,4 %) as substâncias mais prevalentes, seguidas de antidepressivos (10,3 %), anfetamínicos (9,5 %), benzodiazepínicos (7,1 %) e barbitúricos (1,6 %). A maioria das vítimas (44 %) era jovem – entre 16 e 30 anos – e do sexo masculino. O desenvolvimento e validação de método de extração e quantificação simultânea de AMP, FEN e DIE em plasma utilizando a técnica de imersão direta em micro-extração em fase sólida (SPME-DI) seguida de análise por cromatografia gasosa acoplada a espectrômetro de massas (GC-MS) compreendeu etapas de desproteinização da matriz e derivatização dos ATS. O método foi linear de 5,0 a 100 ng/ml. Os limites de detecção foram 1,0; 1,5; 2,0 ng/ml para AMP, DIE e FEN respectivamente. A exatidão variou de 85,58 a 108,33 % e a precisão, calculada pelo desvio padrão relativo, não excedeu 15 %. A recuperação esteve entre 46,35 – 84,46 %. Também foi desenvolvida e validada metodologia para análise simultânea de FEN, DIE e MPH em fluido oral por cromatografia líquida acoplada a detector de massas em tandem (LC-MS/MS). As curvas de calibração utilizando o padrão interno propranolol apresentaram linearidade entre 2,5 e 90 ng/ml. O limite inferior de quantificação e o limite de detecção foram de 2,5 ng/ml e 0,5 ng/ml respectivamente, para todos os ATS. Precisão e exatidão intra e inter-dias mantiveram-se dentro dos limites preconizados pelas guias regulatórias. Não foram observados efeito de matriz nem carry-over. Por fim, foram desenvolvidos e aplicados métodos para a análise de apreensões de ATS os quais revelaram a existência de ativo farmacêutico diverso (sibutramina) daquele especificado no rótulo do medicamento (FEN), em concentrações que variaram de 1/3 até 2 vezes a dose diária preconizada. Pela análise estatística dos espectros de infravermelho foi possível diferenciar amostras autênticas e amostras falsas e ainda agrupar falsificações com perfis semelhantes. Conclusões: os objetivos de estudo propostos nesta tese foram satisfatoriamente cumpridos e os resultados alcançados estão dispostos na forma de cinco artigos. Estes manuscritos contemplam temas relacionados ao uso de substâncias no trânsito, ao desenvolvimento e validação de metodologias analíticas e à análise de falsificações de medicamentos a base de ATS, demonstrando assim, a amplitude e multidisciplinariedade envolvidas no estudo dos compostos anfetamínicos. / The use of amphetamine-type stimulants compounds (ATS) for drivers aiming to stay awake is a known national problem, with social and legal implications. Diethylpropion (DIE) and fenproporex (FEN) are among the central nervous system stimulant most used by drivers in Brazil. Methylphenidate (MPH) is a drug that has properties similar to cocaine and amphetamine (AMP). Its use as a recreational and street drug has increased in recent years and its use has achieved space by the restriction of the marketing of DIE and FEN by the National Agency for Sanitary Surveillance (ANVISA) in 2011. The traffic analysis necessarily implies knowledge of the profile of drivers and the prevalence of substance use. To monitor the consumption of substances in transit, validated analytical methods in different biological matrices should be employed and toxicological data interpreted according pharmacokinetics of each substance. It is also known that many motorists buy ATS illegally in gas stations and the Internet. Knowing the chemical profile and detect forgeries of these medications is an essential part in the development and implementation of public policies to prevent the use of ATS in traffic. Objectives: to evaluate the traffic data from southern Brazil, emphasizing the use of substances, age and sex of those involved in traffic accidents; develop and validate chromatographic methods coupled to mass spectrometry for quantification of FEN, DIE and MPH in oral fluid and in plasma; evaluate the profile of counterfeit medications based on ATS. Results: data analysis of traffic accidents with fatalities from June 2008 to November 2010 in the State of Santa Catarina revealed that 11.9 % of cases had positive toxicology results. Cannabinoids (42 %) and cocaine (29.4 %) had the highest prevalence, followed by antidepressants (10.3 %), amphetamines (9.5 %), benzodiazepines (7.1 %) and barbiturates (1.6 %). Most victims (44 %) were aged between 16 and 30 years old and male. A validated method for the simultaneous analysis of AMP, DIE and FEN in plasma samples employing direct immersion-solid phase microextraction (DI-SPME) followed by gas chromatographic/mass spectrometric analyses (GC-MS) was developed. Deproteinization and derivatization of ATS were employed. The method was linear from 5.0 ngml-1 at 100 ngml-1. The detection limits were 1.0, 1.5, 2.0 ngml-1 for AMP, DIE and FEN respectively. The accuracy ranged from 85.58 to 108.33 % and precision, calculated by the relative standard deviation did not exceed 15 %. The recovery was between 46.35 to 84.46 %. Also was developed and validated a new method for simultaneous determination of FEN, DIE and MPH in oral fluid by liquidchromatography coupled to atmospheric pressure ionization tandem mass spectrometry (LC-MS/MS). The calibration curves, using an internal standard, demonstrated good linearity throughout the concentration range from 2.5–90 ngml-1 in oral fluid. The lower limit of quantification and the limit of detection were 2.5 and 1.0 ngml-1 respectively for all ATS. Intra- and inter-assay precision and accuracy values were within regulatory limits. Matrix effect and carry-over were not detected. Finally, methods have been developed and applied to analysis of seizures of ATS and the results showed the existence of active pharmaceutical (sibutramine) other than that specified on the label of the drug (FEN). The concentrations founded ranging from 1/3 to 2 times the recommended daily dose. Through the statistical analysis of the infrared spectra was possible to distinguish between authentic samples and counterfeit samples and also cluster the counterfeit ATS by their similar profiles. Conclusions: the proposed objectives of this thesis were satisfactorily completed and the results are arranged in the form of five manuscripts. These articles address issues related to substance use in traffic, development and validation of analytical methodologies and analysis of counterfeit medications based on ATS, highlighting the extent and multidisciplinary in the study of amphetamine compounds.

Attention Deficit/Hyperactivity Disorder (ADHD) was originally thought to occur only in children, but is increasingly recognised as causing functional impairment also in adulthood. The overall aim of this thesis was to achieve a comprehensive understanding of ADHD in adulthood. A questionnaire based on the DSM-IV criteria of ADHD, reported childhood symptoms, reading and spelling problems, difficulties and suffering and general assessment of functioning (GAF) was distributed to three samples: the general population (GP), outpatient psychiatry (OPP) and female prison inmates. Symptoms consistent with ADHD were more than three times higher in the OPP sample than in the GP sample (6.6 versus 2.1%). ADHD symptoms and related problems occurred in 50% of the prison inmates. A cohort of 168 patients diagnosed with ADHD in adulthood was interviewed about current ADHD symptoms and psychiatric comorbidity on axis I and II. The lifetime prevalence of psychiatric comorbidity on axis I was 92% and current comorbidity, including autism spectrum disorders and Tourette’s syndrome, was 47%. The sex-specific pattern of the comorbid disor-ders was similar to that in the general population. Forty-six per cent of the patients endorsed the specific criteria for at least one personality disorder. After a mean follow-up of six years, there was remission of adult ADHD in about 30% of the patients, regardless of whether there was ongoing medication or not. There were no differences in function and quality of life, except for global general improvement, which was better in patients currently on medication. The most prevalent long-term side effects of pharmacological treatment with mainly stimulants were decreased appetite, dry mouth, anxiousness/restlessness and an increase in pulse frequency. The discontinuation rate was about 50%: 29% discontinued because of a perceived lack of effect, followed by elevated mood or hypomania (11%). No detectable evidence of tolerance and increased need for dosage over time was observed. To conclude, Symptoms of ADHD is highly overrepresented in OPP and in female inmates compared with the GP. Furthermore, adults diagnosed with ADHD have a high lifetime prevalence of psychiatric comorbidity. Long-term pharmacological treatment with stimulants is safe with relatively mild and tolerable adverse effects. Continued medication, however, is not related to remission.

Neonatal quinpirole treatment has been shown to produce an increase in dopamine D2-like receptor sensitivity that persists throughout the subject's lifetime. The objective was to analyze the effects of neonatal quinpirole treatment on effects of amphetamine in adolescent rats using locomotor sensitization and conditioned place preference procedures. Sprague-Dawley rats were treated with quinpirole (1 mg/kg) or saline from postnatal days (P)1 to P11 and raised to adolescence. For locomotor sensitization, subjects were given amphetamine (1 mg/kg) or saline every second day from P35 to P47 and were placed into a locomotor arena. In female rats, neonatal quinpirole treatment enhanced amphetamine locomotor sensitization compared with quinpirole-free controls sensitized to amphetamine. Male rats demonstrated sensitization to amphetamine, although this was muted compared with female rats, and were unaffected by neonatal quinpirole. For conditioned place preference, subjects were conditioned for 8 consecutive days (P32-39) with amphetamine (1 mg/kg) or saline and a drug-free preference test was conducted at P40. Rats treated with neonatal quinpirole enhanced time spent in the amphetamine-paired context compared with quinpirole-free controls conditioned with amphetamine, but only female controls conditioned with amphetamine spent more time in the drug-paired context compared with saline-treated controls. Increased D₂-like receptor sensitivity appears to have enhanced the behavioral effects of amphetamine, but these effects were more prevalent in adolescent female rats compared with male rats.

Previous studies have demonstrated that rats exposed to methamphetamine (MA) during the neonatal period display deficits in spatial learning and memory. The underlying correlates are; therefore, this study was devised to determine whether neuronal changes occur in the dentate gyrus (DG), nucleus accumbens (NAcc) and cortex of adult rats exposed to 10 mg/kg MA administered four times daily from P11-20 using Golgi-Cox staining [Gibb, R. & Kolb, B. (1998) J. Neurosci. Meth., 79, 1-4]. The DG and NAcc demonstrated a decrease in the number of spines per neuron and the NAcc showed an associated decrease in dendritic length. Selective changes in cortex were observed because increased dendritic length in the parietal cortex occurred with no change in the number of spines, and no differences were noted for either dendritic length or spines in the medial frontal cortex. The data suggest a potential cause for the learning and memory deficits induced by neonatal MA exposure; however, the underlying mechanism that produces these neuronal changes is.

The goal of this study was to determine the extent, motivations, and justifications of nonmedical prescription stimulant use among the population at a large public university in the North Texas region. Participants consisted of 526 undergraduate students enrolled at the studied university during the spring and summer 2014 semesters. The findings of the study suggest that the nonmedical use by students was higher than the findings in much of the current literature, but was within the parameters established in the literature. The primary motivation for nonmedical use was academic in nature and was justified by moderation of nonmedical use to strategic academic times.

INTRODUÇAO: Recentes achados experimentais sugerem que a cocaína na forma crack é mais neurotóxica quando comparada à cocaína inalada. Estes estudos são congruentes com os achados clínicos de que pacientes com transtorno por uso da cocaína e usuários de crack têm pior prognóstico e mais consequências adversas para à saúde. OBJETIVO: Investigar alterações diferenciais em substância cinzenta cerebral (SC) e prejuízos neurocognitivos entre usuários de crack (CRACK), cocaína inalada (COC) e controles. MÉTODOS: 78 indivíduos adultos foram avaliados neste estudo (16 CRACK, 26 COC e 36 controles). Todos indivíduos realizaram uma bateria abrangente de testes neurocognitivos. Dados estruturais do cérebro foram analisados através de um protocolo de morfometria baseada em voxels (VBM) e do Statistical Parametric Mapping (SPM) 12. Diferenças em volume de substância cinzenta entre os três grupos foram avaliadas através de um modelo fatorial tendo idade e escolaridade como covariáveis. Foram realizados testes de correlação entre variáveis de uso da cocaína e volume de substância cinzenta. RESULTADOS: Participantes do grupo CRACK apresentaram volumes menores de SC no córtex orbitofrontal esquerdo (p < 0,001), cingulado anterior bilateral (p < 0,001), córtex precentral direito e córtex temporal medial (p < 0,05) em relação aos controles. Em comparação aos indivíduos do grupo COC, os indivíduos do grupo CRACK tiveram volumes menores de SC no córtex orbitofrontal esquerdo (p < 0,001), cingulado anterior direito (p < 0,05) e giro parietal superior esquerdo (p < 0,001). A idade de início de uso da cocaína mais precoce foi associada a volumes menores de SC no córtex temporal superior esquerdo (p < 0,05) e lóbulo paracentral direito (p < 0,05) no grupo total de usuários e CRACK. Anos de uso da cocaína foram associados negativamente ao volume de SC no polo temporal medial direito (p < 0,05) no grupo CRACK. O uso da droga no último mês foi associado a volumes menores de SC em córtex parahipocampal e hipocampo direito (p < 0,05) no grupo total de usuários e CRACK e cíngulo anterior direito apenas no grupo CRACK (p < 0,05). CRACK e COC desempenharam pior que os controles em funções executivas globais e impulsividade. CONCLUSÕES: Nossos resultados sugerem que usuários de crack apresentam alterações mais graves em região pré-frontal e prejuízos em funções cognitivas como auto-monitorização e funções executivas quando comparados a usuários de cocaína inalada. Variáveis como idade de início da cocaína, anos de uso e dias de uso da droga no último mês foram associadas a volumes menores de SC em regiões corticais relacionadas ao funcionamento executivo e controle inibitório. Em conclusão, usuários de crack apresentaram mais prejuízos em região pré-frontal do cérebro e novos estudos longitudinais poderão contribuir para uma melhor compreensão de como tais alterações podem impactar negativamente o curso clínico e resultados no tratamento / BACKGROUND: Recent experimental studies have shown that smoked crack is more neurotoxic when compared with intranasal cocaine. These reports are congruent with clinical findings that crack-addicted patients have a worse prognosis and more severe health consequences. AIM: To examine differential gray matter (GM) alterations and neurocognitive impairments in crack-addicted patients (CRACK) compared with intrasanal cocaine-addicted patients (COC) and controls. METHODS: 78 adult male subjects were evaluated in this study (16 CRACK, 26 COC and 36 controls). Subjects were submitted to an extensive battery of neurocognitive tests. Structural brain data were analyzed using a voxel-based morphometry (VBM) protocol and the Statistical Parametric Mapping (SPM) 12. Differences in gray matter volume among the three groups were investigated with a full-factorial model controlling for age and years of education. We have performed a correlation analysis between variables of cocaine use and gray matter volume. RESULTS: CRACK presented significantly reduced GM volume in left orbitofrontal (p < .001), bilateral anterior cingulate (p < .001), right precentral gyrus (p < .05), and right medial temporal cortex (p < .05) compared with controls. When directly compared with COC, CRACK had reduced GM volume in left orbitofrontal (p < .001), right anterior cingulate (p < .05), and left superior parietal gyrus (p < .001). Age at first cocaine use was positively associated with GM volume in the left superior temporal cortex (p < .05) and paracentral lobe (p < .05) in the total sample and CRACK. Years of cocaine use were negatively associated with GM volume in the right medial temporal pole (p < .05) in CRACK. Past-30 days cocaine use was associated with reduced GM in the parahippocampal and hippocampus (p < .05) in the total sample and reduced right anterior cingulus in CRACK (p < .05). Both CRACK and COC participants performed worse than controls in global measures of executive functioning and impulsivity. CONCLUSION: Our results suggest that participants with cocaine use disorder who use crack present more severe prefrontal cortex abnormalities and self-monitoring/executive alterations when compared with intrasanal cocaine users. Age of first cocaine use, years of cocaine exposure, and past-30 days cocaine use were associated with GM reductions in cortical areas implicated in executive functioning and inhibitory control. In conclusion, crack users presented more alterations in the prefrontal cortex and further longitudinal studies are warranted to a better comprehension of how such alterations may impact negatively treatment outcomes

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Purpose: Nonmedical use of stimulant medications (NMUS) among college students is an important and growing problem. The annual prevalence of NMUS among four-year college students has nearly doubled since 2008 and exceeds NMUS in non-college peers. Community college students are an understudied population regarding NMUS. Given noted NMUS differences in 4-year students and non-college peers, one cannot assume community college students’ cognitions, perceptions, and behaviors mirror either peer cohort. We conducted a web-based survey across 10 community colleges in Tennessee (TN) to assess correlates and consequences of NMUS. Methods: We developed an initial version of the 60-item survey questionnaire using previously validated, theoretically based survey items and other items developed by the research team. The survey instrument was then reviewed and assessed for content validity by our research team, and thereafter pilot tested with East Tennessee State University undergraduate students for range measures, item order, and best practices for survey construction. The final 55-item survey instrument was designed using web-based survey software (i.e., Qualtrics). Ten of 13 community colleges in TN granted approval for their students to participate in the study (N=53096). A modified Tailored Design Method approach was utilized to maximize response rate across four email contacts, and monetary incentives were offered to encourage participation in the study. Regulatory authorities (e.g., institutional review boards, institutional offices) from East Tennessee State University and participating community colleges approved the conduct of this study. Data were analyzed using SPSS (version 22). Descriptive statistics were calculated to evaluate prevalence, source, motives and consequences of NMUS. Student’s t-tests and chi-square tests were conducted to compare nonmedical stimulant users and nonusers across a number of variables. Results were considered significant for p < 0.05. Results: A total of 3113 students completed the survey (response-rate = 5.8%), of which 302 (9.7%) were past-year nonmedical stimulant users. A significantly greater proportion of users were diagnosed with a mental health condition (22.2%) than non-users (9.6%). Compared to non-users, significantly greater proportions of users reported using tobacco products, such as cigarettes (34.5% vs. 14%), e-cigarettes (12.5% vs. 4%), and vapors (18.4% vs. 6.7%). Users further reported using more types of illicit drugs (1.9 ± 0.1), more alcoholic drinks per week (2.9±0.3), and more occasions of binge drinking per month (1.8±0.2) than non-users (1.1±0.02, 1.3±0.07, 0.7±0.04, respectively). Only 14.2% of users (n=43 from 302) reported having prescriptions for prescription stimulants. Common sources of prescription stimulants were friends (62.9%), family members (12.3%), and street suppliers (9.9%). Commonly endorsed reasons for NMUS were ‘to improve academic performance’ (63.9%), ‘to have more energy’ (49.7 %), ‘to relieve tension’ (22.2%), and ‘to feel good or get high’ (16.6 %). Adverse effects resulting from NMUS included: lack of appetite (45.4%), difficulty sleeping (38.4 %), and racing heart (31.1%). Unlike the published findings from 4-year college students, low GPA, male gender, Caucasian race and membership in fraternity organizations were not associated with NMUS in community colleges. Conclusion: The present study provides useful information on characteristics of users and patterns and consequences of NMUS in community colleges students. NMUS appears to be associated with illicit substance use, binge drinking and disrupted mental health in community college students in TN. Friends are the most common source and desire to enhance academic performance is the most salient motive for NMUS. Despite facing adverse consequences, college students continued using stimulants nonmedically. These findings underscore the need for development of public health programs that target prevention of NMUS in community colleges.

Lifetime prevalence estimates of psychotropic medicine use as well as prevalence of DSM-IV prescription drug use disorders from the baseline investigation of the Early Developmental Stages of Psychopathology (EDSP) Study are presented. Use of prescription medication at some time in their life was reported by 27.4% of the respondents. Illicit use of prescription drugs, which means an intake without medical legitimation, was reported by 4.5% of the sample. The findings suggest that abuse of and dependence on prescription drugs, with most cases reporting polysubstance use, is quite rare in the 14- to 24-year-olds. DSM-IV abuse was more prevalent than dependence (0.5 vs. 0.3%). In general, women reported higher prevalence rates of prescription drug use, whereas men reported higher prevalence rates of prescription drug disorders. This result suggests that men have a higher risk to develop a substance-use-related disorder.

Objective: To determine incidence and patterns of natural course of ecstasy/stimulant/hallucinogen (ESH) use and disorders as well as cohort effects in a community sample of adolescents and young adults. Method: Cumulative incidence and patterns of ecstasy use and disorders were examined in a prospective longitudinal design (mean follow-up period=42 months) in a representative sample (N=2446) aged 14–24 years at the outset of the study. Patterns of DSM-IV defined ESH use, abuse and dependence were assessed with the Munich Composite International Diagnostic Interview (M-CIDI). Results: (1) Cumulative lifetime incidence for use of ESH at second follow-up: 9.1%, 1.0% for abuse, 0.6% for dependence; (2) men used and abused ESH more often than women; (3) the younger birth cohort (1977–81) tended to start earlier with substance (ab)use compared to the older birth cohort (1970–77); (4) use of ESH was associated with increasing rates of concomitant use of other licit and illicit drugs; (5) the majority of the lifetime ESH users without disorder had stopped to use these substances and not consumed them during the 12 months preceding the second follow-up; (6) those who had stopped to take ecstasy and related drugs at follow-up also took other illicit drugs less often than those who continued to consume ESH. Conclusions: Use of designer drugs is widespread in our sample, but the probability of developing use disorders is fairly low (1.6%). The majority of the ESH users stopped their use spontaneously in their twenties (80% of the prior users without disorder, 67% of the prior abusers), but 50% of those that once had fulfilled DSM-IV criteria of dependence continued to use these substances.