Neural circuitry of emotion regulation: Effects of appraisal, attention, and cortisol administration.

Psychosocial well-being requires effective regulation of emotional responding in context of threat or stress. Neuroimaging studies have focused on instructed, volitional regulation (e.g., reappraisal or distancing), largely ignoring implicit regulation that does not involve purposeful effort to alter emotional experience. These implicit processes may or may not involve the same neural pathways as explicit regulatory strategies. We examined the neurobiology of implicit emotional regulation processes and the impact of the stress hormone cortisol on these processes. Our study task employed composite pictures of faces and places to examine neural activity during implicit emotional processing (of emotional faces), while these responses were implicitly regulated by attention shift away from the emotionally evocative stimuli, and while subjects reflectively appraised their own emotional response to them. Subjects completed the task in an fMRI scanner after random assignment to receive placebo or hydrocortisone (HCT), an orally administered version of cortisol. Implicit emotional processing activated insula/IFG, dACC/dMPFC, midbrain and amygdala. With attention shifting, we saw diminished signal in emotion generating/response regions (e.g., amygdala) and increased activations in task specific attention regions like parahippocampus. With appraisal of emotions, we observed robust activations in medial prefrontal areas, where activation is also seen in instructed reappraisal studies. We observed no main effects of HCT administration on brain, but males and females showed opposing neural effects in prefrontal areas. The data suggest that different types of emotion regulation utilize overlapping circuits, but with some strategy specific activation. Further study of the dimorphic sex response to cortisol is needed.

Predictors of satisfaction in patient with silicone breast implants and its association with drug intake habits.

BACKGROUND: Satisfaction is an important outcome variable in surgical success. The purpose of this study is to evaluate predictors of satisfaction in women submitted to silicone textured breast implant surgery. METHODS: A retrospective evaluation of women receiving textured silicone breast implants was performed. Patients were divided in four groups: cosmetic cohort (n = 104), reconstructive cohort (n = 120), general population control cohort (n = 120) and aesthetic control cohort (n = 54). Data were collected based on information retrieved from patient records, a planned consultation and a self-administered structured questionnaire. RESULTS: Patient satisfaction was influenced by preoperative information (p = .007), cohort (p < .001), and occurrence of postoperative complications (p < .001). The degree of satisfaction was also related with drug intake habits: women using psychotropic drugs were 3-fold more likely to report poor satisfaction than those that never used these drugs (p < .001). CONCLUSION: The purpose of the surgery, preoperative information and the occurrence of postoperative complications have an impact on the degree of satisfaction of women submitted to silicone breast implant surgery. Women using psychotropic drugs are more likely to report poor satisfaction.

Oxytocin facilitates the sensation of social stress.

Essentially all social species experience social stress which can be a catalyst for detriments in mental and physical health. The neuropeptide oxytocin (OXT) has been shown to produce anxiolytic and antistress effects, thereby qualifying the OXT system as a promising drug target in the treatment of stress-related disorders. However, recently it has been shown that OXT can have anxiogenic effects as well. In the present study, we used functional magnetic resonance imaging to scan the brains of 60 healthy men while they were exposed to social stress after they received either intranasal OXT (24 IU) or placebo treatment. Although OXT administration did not alter salivary cortisol levels as a surrogate marker of stress axis activity, our participants initially reported an increment in perceived social stress. This behavioral effect was paralleled on the neural level by increased activity in the precuneus and cingulate cortex. Taken together, our results support the hypothesis that OXT can induce a self-referential processing bias which facilitates the sensation of social stress in the absence of altered endocrine responses.

The Black Book of Psychotropic Dosing and Monitoring.

Introduction Since the last edition of the Black Book, several innovative agents have been approved or are poised to be approved in the coming year. These include novel antidepressants, the first muscarine agonist for the treatment of schizophrenia, the first psychedelic which may be approved for the treatment of PTSD (Post Traumatic Stress Disorder), and the first disease modifying drug for the treatment of Alzheimer's disease. Three new antidepressants have come to the market in the past 18 months. The first of those, Auvelity, the combination of bupropion and dextromethorphan, takes advantage of a pharmacokinetic and pharmacodynamic synergism between the two drugs.85 Dextromethorphan has several pharmacodynamic properties including actions on the NMDA receptor and the Sigma 1 receptor, adding to the indirect norepinephrine agonist properties of bupropion. How Dextromethorphan is rapidly metabolized via the CYP2D6 isoenzyme to dextrophan that may have mu opioid agonist properties. The combination with bupropion, a CYP2D6 inhibitor, inhibits the metabolism of dextromethorphan allowing for more consistent therapeutic levels. The combination of dextromethorphan 45 mg twice per day and bupropion SR 105 mg twice daily appears to be more effective than an equivalent dose of bupropion alone both in speeding up antidepressant response and achieving remission. However, it's not clear at this time how the combination would compare with a more typical dose of bupropion of 300-450 milligrams a day range. The phase III program for Auvelity, showed that the drug was well tolerated with the most common side effects being dizziness, headache, and dry mouth.86 Another novel antidepressant agent approved in 2023 is zuranolone (Zurzuvae). Zuranolone is an oral analog of IV brexanalone, and like brexanolone, was approved for the treatment of post-partum depression.83 The advantages of zuranolone over brexanalone are many. While brexanolone is a 60-hour intravenous infusion that must be administered in a health care facility, zuranolone is a once/day oral medication that is usually taken at home. Like brexanolone, and unlike most antidepressants, zuranolone has a short course of treatment, lasting just 14 days. Zuranolone's, as does brexanolone, is thought to act primarily as allosteric modulator of the GABA-a receptors. Despite only 14 days of treatment, zuranolone produced in depression in post-partum patients a clinically and significantly meaningful improvement at day 15 and continued to day 45 or 1 month past the end of treatment. Zuranolone is a schedule IV drug. The most common side effect in clinical trials was somnolence with 36% of participants reporting this side effect vs only 6% of those on placebo.84 Other common side effects included dizziness, diarrhea and fatigue. While the FDA declined to approve zuranolone as monotherapy or as an adjunctive treatment to standard antidepressants in major depression itself, there are positive studies in non-post-partum major depression albeit with smaller effect sizes and less consistent duration of activity. It is likely that zuranolone will continue to be studied in other depressive syndromes such as depression with anxious distress. The third "new" antidepressant approved late 2023 was gepirone (Exxua). Gepirone is not exactly a new or novel antidepressant and originally sought approval in the US about 20 years ago.88 There had been two positive studies of gepirone during the original NDA application but also a number of failed, negative, or non-informative studies as well. Thus, the FDA declined to originally approve the drug. However, failed and negative trials are common with antidepressants and after much internal debate, the FDA ultimately agreed to approve the drug based on the positive trials and a relatively favorable side effect profile. Gepirone, like buspirone, is a partial agonist of the 5HT1a receptor and a 5HT2 antagonist. As such, gepirone does not tend to be associated with sexual side effects, weight gain, or sedation. The most common side effects are dizziness, nausea, and insomnia which tend to improve in many patients over time. Second generation antipsychotics (SGAs) continue to be the only class of agents [other than esketamine (Spravato)] approved in adjunctive treatment of resistant major depression. In addition to olanzapine (combined with fluoxetine; Symbyax), aripiprazole (Abilify), quetiapine (Seroquel), brexpiprazole (Rexulti), cariprazine (Vraylar) became the latest SGA to be approved in 2022.90 Adjunctive cariprazine at 1.5 mg daily was significantly more effective than adjunctive placebo in patients with MDD who had failed to achieve an adequate response with an antidepressant alone after 6 weeks of treatment. Interestingly, a 3 mg dose of cariprazine was less consistently effective.91 The major advantage of cariprazine over some of the other approved adjunctive SGA's is easy dosing, with the starting 1.5 mg dose being the optimal therapeutic dose for most people, and a lower metabolic side effect burden with most subjects having limited or no weight gain in short term trials. The most common side effect were akathisia/restlessness, fatigue, and nausea. Lumateperone (Caplyta) is also has positive phase III data in the adjunctive treatment of major depression and is expective file for approval in late 2024. Another recent major development in psychopharmacology is the reemergence of psychedelics in the treatment of psychiatric disorders. The first of these is MDMA (phenethylamine 3,4-methylenedioxymethamphetamine) assisted psychotherapy for the treatment of PTSD. A New Drug Application (NDA) was accepted by the FDA for MDMA in the treatment of PTSD in late 2023.87 Because the drug is being fast tracked as a "breakthrough" treatment by the FDA, it was expected to see approval in the summer of 2024. The phase II and III data for MDMA assisted psychotherapy in the treatment of PTSD have been quite consistent and impressive. However, independent reviews have pointed to significant deficiencies in these studies including the bias introduced because of functional unblinding; virtually all patients in psychedelic studies can guess whether they got the active drug or placebo. The functional unblinding, the lack of standardization of adjunctive psychotherapy as well as the abuse potential of MDMA, may delay an FDA approval. The typical regimen in these trials included 3 preparatory psychotherapy sessions followed by once/month dosing sessions (lasting about 8 hours) and using doses of 120-160 mg in a split dose. There were typically 3 monthly dosing sessions, each followed by 3 integrative psychotherapy sessions to help subjects process and understand their experiences during the dosing sessions. In the most recent phase 3 trials, over 70% of subjects no longer met criteria for PTDS compared to 46% of those treated with psychotherapy and placebo alone.89 The only approved medications for treating PTSD are two SSRIs, paroxetine and sertraline. These drugs effect only some dimensions of PTSD with only 20-30% achieving a remission level response with these drugs. Thus, MDMA assisted psychotherapy appears to achieve much higher levels of remission and response than has been true for the SSRIs. Since MDMA is not taken continuously, side effects from MDMA tend to be short lived. Side effects have included muscle tightness, nausea, diminished appetite, excessive sweating, feeling cold and dizziness among others. Since MDMA is currently a schedule I drug, it is likely that a rigorous Risk Evaluation Mitigation (REMs) program will be put in place and a limited number of centers and clinicians will be designated to perform MDMA assisted psychotherapy for PTSD. In addition to MDMA, psilocybin-assisted psychotherapy is in phase 3 trials for treating resistant depression but unlikely to be available before late 2025 at the earliest. An argument can be made that there has not been a truly novel antipsychotic since the introduction of clozapine in the US in 1990. All first-generation antipsychotics have been dopamine 2 antagonists and second-generation drugs have involved some ratio of 5HT2 antagonism to D2 blockade. In 2023, the FDA accepted the application of xenomaline/tropsium (KarXT) which may become the first muscarinic M1M4 agonist approved for the treatment of schizophrenia.82,83 Tropsium is added as a muscarine antagonist to block the peripheral cholinergic effects of a muscarine agonist. Xenomaline/tropsium appears to be effective in treating both positive and negative symptoms of schizophrenia. In a phase 3 study of 407 patients with schizophrenia, xenomaline/tropsium at doses of xenomaline/50 mg/tropsium 20 mg twice daily up to 125 mg/30 mg twice daily was significantly more effective than placebo in treating both and negative symptoms over 5 weeks of treatment. As would be expected, the side effect profile of xenomaline/tropsium is very different that all currently available antipsychotics. There is no risk of EPS as it is not a dopamine antagonist, and xenomaline/tropsium is not associated with significant metabolic effects. The side effects are cholinergic in nature and include constipation, dry mouth, and nausea. A decision is expected in September of 2024. The year 2023 also saw the approval of the first disease modifying drug in the treatment of Alzheimer's disease, lecanemab (Lequembi). While acetylcholinesterase inhibitors and memantine have been available for decades, these drugs modestly improve cognition in Alzheimer's disease patients and do not alter the progressive course of the illness. Lecanemab is an IV monoclonal antibody that targets the removal of beta-amyloid in the brain as well proto-fibrils that are also known to be toxic to neuronal tissue. When given early in the course of the illness, patients treated with Lecanemab showed 27% less decline on some measures of cognition and function thandid patients treated with a placebo over 18 months (about 1 and a half years). It is not known whether treatment for longer than 18 months would show lesser or greater decline over time. However, there are simulation studies that suggest that Lecanemab may modestly reduce the number of patients who progress to severe Alzheimer's disease and require institutional care. The standard dose is 10 mg/kg given via IV over one hour every 2 weeks for 18 months. Lecanemab is typically administered in an infusion center so that side effects can be monitored. The most serious side effects of Lecanemab are amyloid related imaging abnormalities (ARIA) that are associated with brain edema and microhemorrhages. ARIA can occur in up to 15% of patients. More common side effects are headache and nausea. While it remains to be seen how useful these new agents will be in clinical practice, they do represent an approach to treating neuropsychiatric disorders that are a notable departure from the pharmacotherapy of the past half century. It seems likely that some patients who have not been able to respond to or tolerate traditional pharmacotherapy will find hope in these new medications.

Randomized, double-blind, placebo-controlled, crossover study of the efficacy and safety of lisdexamfetamine dimesylate in adults with attention-deficit/hyperactivity disorder: novel findings using a simulated adult workplace environment design.

BACKGROUND: Duration of efficacy and safety of lisdexamfetamine dimesylate (LDX) was assessed in adults (18-55 years) with attention-deficit/hyperactivity disorder (ADHD) using the simulated adult workplace environment. METHODS: After open-label dose optimization (4-week) with LDX, 30-70 mg/d, subjects entered a 2-week randomized, double-blind, placebo-controlled crossover phase. Efficacy assessments included the Permanent Product Measure of Performance (PERMP) total score (attempted+correct) measured predose and from 2 to 14 hours postdose, averaged across postdose sessions (primary) and at each time point vs placebo (secondary), and ADHD Rating Scale IV (ADHD-RS-IV) with adult prompts at baseline and crossover visits. Safety assessments included treatment-emergent adverse events (TEAEs), vital signs, and electrocardiograms. RESULTS: Of 127 randomized subjects, 105 were in the intention-to-treat population and 103 completed the study. While receiving LDX vs placebo, adults had greater improvement (P < .0001) in average PERMP total scores as measured by difference in least squares (LS) mean (95% CI): 23.4 (15.6, 31.2). Absolute (P or=10%) during dose optimization were decreased appetite, dry mouth, headache, and insomnia; no TEAEs >or=5% were reported during crossover phase for adults receiving LDX. CONCLUSIONS: LDX significantly improved PERMP scores vs placebo and maintained improvement throughout the day from the first (2 hours) to last (14 hours) postdose time point vs placebo in adults with ADHD. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00697515. Safety and Efficacy Workplace Environment Study of Lisdexamfetamine Dimesylate (LDX) in Adults With Attention-Deficit Hyperactivity Disorder (ADHD) http://www.clinicaltrials.gov/ct2/show/NCT00697515?term=NCT00697515&rank=1.

Prospective examination of synthetic 5-methoxy-N,N-dimethyltryptamine inhalation: effects on salivary IL-6, cortisol levels, affect, and non-judgment.

RATIONALE: 5-methoxy-N,N-dimethyltryptamine is a psychotropic substance found in various plant and animal species and is synthetically produced. 5-methoxy-N,N-dimethyltryptamine is used in naturalistic settings for spiritual exploration, recreation, or to address negative affect and mood problems. However, scientific knowledge on the effects of 5-methoxy-N,N-dimethyltryptamine in humans is scarce. OBJECTIVES: The first objective was to assess the effects of inhalation of vaporized synthetic 5-methoxy-N,N-dimethyltryptamine on neuroendocrine markers. The second objective was to assess effects of the substance on affect and mindfulness. In addition, we assessed whether ratings of subjective measures were associated with changes in stress biomarkers (i.e., cortisol) and immune response (i.e., IL-6, CRP, IL-1ß), as well as the acute psychedelic experience. METHODS: Assessments (baseline, immediately post-session, and 7-day follow-up) were made in 11 participants. Salivary samples were collected at baseline and post-session and analyzed by high-sensitivity enzyme-linked immunosorbent assay (ELISA). RESULTS: 5-methoxy-N,N-dimethyltryptamine significantly increased cortisol levels and decreased IL-6 concentrations in saliva immediately post-session. These changes were not correlated to ratings of mental health or the psychedelic experience. Relative to baseline, ratings of non-judgment significantly increased, and ratings of depression decreased immediately post-session and at follow-up. Ratings of anxiety and stress decreased from baseline to 7-day follow-up. Participant ratings of the psychedelic experience correlated negatively with ratings of affect and positively with ratings of non-judgment. CONCLUSION: Inhalation of vaporized synthetic 5-methoxy-N,N-dimethyltryptamine produced significant changes in inflammatory markers, improved affect, and non-judgment in volunteers. Future research should examine the effect of 5-methoxy-N,N-dimethyltryptamineamine with healthy volunteers in a controlled laboratory setting.

[Dental pain among psychoactive substance users in CAPS AD in Vitoria, Vila Velha and Serra, ES, Brazil]. / Dor dentária em usuários de Substâncias Psicoativas dos CAPS AD de Vitória, Vila Velha e Serra, ES, Brasil.

Toothache is a public health problem that causes great inconvenience to psychoactive substances users. The objective was to verify the prevalence of dental pain and its associations among psychoactive substances users from Alcohol and Drug Psychosocial Care Centers (CAPS AD) in Vitoria, Vila Velha and Serra, Espírito Santo, Brazil. A transversal study was conducted with 280 participants between June 2015 and February 2016, using five scripts: one for socio-demographic data and health perception; another for oral health; the Oral Health Impact Profile; the Alcohol Smoking and Substance Involvement Screening Test and the World Health Organization Quality of Life Test. Data were organized in frequency tables and analyzed with the SPSS 20 statistical package. Comparisons were made with Fisher's test and the Odds Ratio (OR) was used to check the strength of the association between the variables. The prevalence of pain in the population studied was 59.3%, and individuals whose quality of life was impacted due to their oral conditions were 2.2 times more likely to report toothache in the last 6 months. The population studied showed a high prevalence of dental pain and the study indicates that dental pain interferes in the quality of life of psychoactive substances users who are treated at CAPS AD services in these three cities.

A dor dentária é um problema de saúde pública que causa grande incômodo aos usuários de substâncias psicoativas. Objetivou-se determinar a prevalência de dor dentária e suas associações em usuários de substâncias psicoativas dos CAPS AD dos municípios de Vitória, Vila Velha e Serra, ES, Brasil. Um estudo transversal foi realizado com 280 participantes, entre junho de 2015 e fevereiro de 2016, por meio de cinco roteiros, um para os dados sociodemográficos e percepção de saúde, outro para saúde bucal, o Oral Health Impact Profile, o Alcohol Smoking and Substance Involvement Screening Test e o World Health Organization Quality of Life. Os dados foram organizados em tabelas de frequência, analisados com o pacote estatístico SPSS 20, as comparações foram feitas com o teste de Fisher e Odds Ratio (OR) foi utilizado para verificar a força da associação entre as variáveis. A prevalência de dor na população estudada foi de 59,3% e os indivíduos que apresentaram impacto das condições bucais na qualidade de vida, tiveram 2,2 vezes mais chances de relatar dor de dente nos últimos 6 meses. A população estudada apresentou alta prevalência de dor dentária, o estudo aponta que a dor dentária interfere na qualidade de vida dos usuários de substâncias psicoativas que utilizam os serviços dos CAPS AD dos três municípios.

Successful Resolution of Prominent Somatic Delusions Following Bi-temporal Electroconvulsive Therapy in a patient with Treatment-Resistant Schizoaffective Disorder.

Somatic delusions occur in a variety of psychiatric disorders including schizophrenia, major depressive disorder, and bipolar disorder. Somatization is associated with lower quality of life and greater risk for suicide. Treatment of somatic delusions is extremely challenging. Here we report an interesting case of severe somatic delusions in a 48-year-old African-American female with a long history of treatment resistant schizoaffective disorder, with multiple somatic complaints surrounding constipation, pregnancy, jaw pain, body aches, vaginal itch, malodorous urine, and neck pain, despite normal clinical examinations and negative medical work up. Additionally, she endorsed persistent auditory and visual hallucinations. Her symptoms remained resistant to several trials of psychotropic medications, including clozapine. Chart review of past hospitalizations revealed significant improvement with Electroconvulsive Therapy (ECT), so the team decided to perform a course of six bi-temporal ECT treatments administered over two weeks. Stimulation was applied at a current of 800 mA for 4.5s, with a pulse width of 1 ms and frequency of 60 Hz. This case illustrates the successful use of ECT in treating prominent somatic delusions in a patient with treatment-resistant schizoaffective disorder.

Acute Pharmacokinetic Profile of Smoked and Vaporized Cannabis in Human Blood and Oral Fluid.

Currently, an unprecedented number of individuals can legally access cannabis. Vaporization is increasingly popular as a method to self-administer cannabis, partly due to perception of reduced harm compared with smoking. Few controlled laboratory studies of cannabis have used vaporization as a delivery method or evaluated the acute effects of cannabis among infrequent cannabis users. This study compared the concentrations of cannabinoids in whole blood and oral fluid after administration of smoked and vaporized cannabis in healthy adults who were infrequent users of cannabis. Seventeen healthy adults, with no past-month cannabis use, self-administered smoked or vaporized cannabis containing Δ9-tetrahydrocannabinol (THC) doses of 0, 10 and 25 mg in six double-blind outpatient sessions. Whole blood and oral fluid specimens were obtained at baseline and for 8 h after cannabis administration. Cannabinoid concentrations were assessed with enzyme-linked immunosorbent assay (ELISA) and liquid chromatography-tandem mass spectrometry (LC-MS-MS) methods. Sensitivity, specificity and agreement between ELISA and LC-MS-MS results were assessed. Subjective, cognitive performance and cardiovascular effects were assessed. The highest concentrations of cannabinoids in both whole blood and oral fluid were typically observed at the first time point (+10 min) after drug administration. In blood, THC, 11-OH-THC, THCCOOH and THCCOOH-glucuronide concentrations were dose-dependent for both methods of administration, but higher following vaporization compared with smoking. THC was detected longer in oral fluid compared to blood and THCCOOH detection in oral fluid was rare and highly erratic. For whole blood, greater detection sensitivity for ELISA testing was observed in vaporized conditions. Conversely, for oral fluid, greater sensitivity was observed in smoked sessions. Blood and/or oral fluid cannabinoid concentrations were weakly to moderately correlated with pharmacodynamic outcomes. Cannabis pharmacokinetics vary by method of inhalation and biological matrix being tested. Vaporization appears to be a more efficient method of delivery compared with smoking.

Nonadherence to Geriatric-Focused Practices in Older Intensive Care Unit Survivors.

BACKGROUND: Older adults account for more than half of all admissions to intensive care units; most remain alive at 1 year, but with long-term sequelae. OBJECTIVE: To explore geriatric-focused practices and associated outcomes in older intensive care survivors. METHODS: In a 1-year, retrospective, cohort study of patients admitted to the medical intensive care unit and subsequently transferred to the medicine service, adherence to geriatric-focused practices and associated clinical outcomes during intensive care were determined. RESULTS: A total of 179 patients (mean age, 80.5 years) met inclusion criteria. Nonadherence to geriatric-focused practices, including nothing by mouth (P = .004), exposure to benzodiazepines (P = .007), and use of restraints (P < .001), were associated with longer stay in the intensive care unit. Nothing by mouth (P = .002) and restraint use (P = .003) were significantly associated with longer hospital stays. Bladder catheters were associated with hospital-acquired pressure injuries (odds ratio, 8.9; 95% CI, 1.2-67.9) and discharge to rehabilitation (odds ratio, 8.9; 95% CI, 1.2-67.9). Nothing by mouth (odds ratio, 3.2; 95% CI, 1.2-8.0) and restraints (odds ratio, 2.8; 95% CI, 1.4-5.8) were also associated with an increase in 30-day readmission. Although 95% of the patients were assessed at least once by using the Confusion Assessment Method for the Intensive Care Unit (overall 2334 assessments documented), only 3.4% had an assessment that indicated delirium; 54.6% of these assessments were inaccurate. CONCLUSION: Although initiatives have increased awareness of the challenges, implementation of geriatric-focused practices in intensive care is inconsistent.

Hot melt extrusion as an approach to improve solubility, permeability and oral absorption of a psychoactive natural product, piperine.

OBJECTIVE: The aims of the current research project were to investigate the efficiency of various polymers to enhance the solubility and increase the systemic absorption of piperine using hot melt extrusion technology. METHODS: Piperine 10-40% w/w and Eudragit(®) EPO/Kollidon(®) VA 64 or Soluplus(®) were mixed, and the resulting blends were extruded using a twin-screw extruder (Process 11, Thermo Fisher Scientific). Drug release profiles and piperine solubility studies of the extrudates were evaluated. A non-everted intestinal sac was employed for the most promising formulation, 10% w/w piperine/Soluplus(®) , and pure piperine to study the permeability characteristics. KEY FINDINGS: Dissolution studies demonstrated enhancement in piperine per cent release of 10% and 20% w/w piperine/Soluplus(®) extrudates up to 95% and 74%, respectively. The solubility of 10% and 20% piperine/Soluplus(®) increased more than 160- and 45-fold in water, respectively. Furthermore, permeability studies demonstrated the enhancement in piperine absorption of 10% w/w piperine/Soluplus(®) extrudates up to 158.9 µg/5 ml compared with pure piperine at 1.3 µg/5 ml within 20 min. CONCLUSION: These results demonstrated that increasing the bioavailability of piperine may be achieved as demonstrated by findings in this study.

Emerging toxicity of 5,6-methylenedioxy-2-aminoindane (MDAI): Pharmacokinetics, behaviour, thermoregulation and LD50 in rats.

MDAI (5,6-Methylenedioxy-2-aminoindane) has a reputation as a non-neurotoxic ecstasy replacement amongst recreational users, however the drug has been implicated in some severe and lethal intoxications. Due to this, and the fact that the drug is almost unexplored scientifically we investigated a broad range of effects of acute MDAI administration: pharmacokinetics (in sera, brain, liver and lung); behaviour (open field; prepulse inhibition, PPI); acute effects on thermoregulation (in group-/individually-housed rats); and systemic toxicity (median lethal dose, LD50) in Wistar rats. Pharmacokinetics of MDAI was rapid, maximum median concentration in serum and brain was attained 30min and almost returned to zero 6h after subcutaneous (sc.) administration of 10mg/kg MDAI; brain/serum ratio was ~4. MDAI particularly accumulated in lung tissue. In the open field, MDAI (5, 10, 20 and 40mg/kg sc.) increased exploratory activity, induced signs of behavioural serotonin syndrome and reduced locomotor habituation, although by 60min some effects had diminished. All doses of MDAI significantly disrupted PPI and the effect was present during the onset of its action as well as 60min after treatment. Unexpectedly, 40mg/kg MDAI killed 90% of animals in the first behavioural test, hence LD50 tests were conducted which yielded 28.33mg/kg sc. and 35mg/kg intravenous but was not established up to 40mg/kg after gastric administration. Disseminated intravascular coagulopathy (DIC) with brain oedema was concluded as a direct cause of death in sc. treated animals. Finally, MDAI (10, 20mg/kg sc.) caused hyperthermia and perspiration in group-housed rats. In conclusion, the drug had fast pharmacokinetics and accumulated in lipohilic tissues. Behavioural findings were consistent with mild, transient stimulation with anxiolysis and disruption of sensorimotor processing. Together with hyperthermia, the drug had a similar profile to related entactogens, especially 3,4-metyhlenedioxymethamphetamine (MDMA, ecstasy) and paramethoxymethamphetamine (PMMA). Surprisingly subcutaneous MDAI appears to be more lethal than previously thought and its serotonergic toxicity is likely exacerbated by group housing conditions. MDAI therefore poses greater risks to physical and mental health than recognised hitherto.

A human tendency to anthropomorphize is enhanced by oxytocin.

In the course of human evolution, the brain has evolved into a highly sensitive detector of social signals. As a consequence of this socially driven adaptation, humans display a tendency to anthropomorphize, that is they attribute social meaning to non-social agents. The evolutionarily highly conserved hypothalamic peptide oxytocin (OXT) has been identified as a key factor attaching salience to socially relevant cues, but whether it contributes to spontaneous anthropomorphism is still elusive. In the present study involving 60 healthy female participants, we measured salivary OXT concentrations and explored the effect of a single intranasal dose of synthetic OXT (24 IU) or placebo (PLC) on anthropomorphic tendencies during participants׳ verbal descriptions of short video clips depicting socially and non-socially moving geometric shapes. Our results show that endogenous OXT concentrations at baseline positively correlated with the attribution of animacy to social stimuli. While intranasal OXT had no modulatory effect on arousal ratings and did not make the participants more talkative, the treatment boosted anthropomorphic descriptions specifically for social stimuli. In conclusion, we here provide first evidence indicating that spontaneous anthropomorphism in women is facilitated by oxytocin, thereby enabling a context-specific upregulation of the propensity to anthropomorphize environmental cues.

Effects of Cortisol on Reconsolidation of Reactivated Fear Memories.

The return of conditioned fear after successful extinction (eg, following exposure therapy) is a significant problem in the treatment of anxiety disorders and posttraumatic stress disorder (PTSD). Targeting the reconsolidation of fear memories may allow a more lasting effect as it intervenes with the original memory trace. Indeed, several pharmacological agents and behavioral interventions have been shown to alter (enhance, impair, or otherwise update) the reconsolidation of reactivated memories of different types. Cortisol is a stress hormone and a potent modulator of learning and memory, yet its effects on fear memory reconsolidation are unclear. To investigate whether cortisol intervenes with the reconsolidation of fear memories in healthy males and how specific this effect might be, we built a 3-day reconsolidation design with skin conductance response (SCR) as a measure of conditioned fear: Fear acquisition on day 1; reactivation/no-reactivation of one conditioned stimulus and pharmacological intervention on day 2; extinction learning followed by reinstatement and reinstatement test on day 3. The groups differed only in the experimental manipulation on day 2: Reactivation+Cortisol Group, Reactivation+Placebo Group, or No-reactivation+Cortisol Group. Our results revealed an enhancing effect of cortisol on reconsolidation of the reactivated memory. The effect was highly specific, strengthening only the memory of the reactivated conditioned stimulus and not the non-reactivated one. Our findings are in line with previous findings showing an enhancing effect of behavioral stress on the reconsolidation of other types of memories. These results have implications for the understanding and treatment of anxiety disorders and PTSD.

Long-term health status of Danish women with silicone breast implants.

Long-term safety data are important in the evaluation of possible adverse health outcomes related to silicone breast implants. The authors evaluated long-term symptoms and conditions and medication use among 190 Danish women with cosmetic silicone breast implants compared with 186 women who had undergone breast reduction surgery and with 149 women from the general population. Breast implant and reduction surgeries were performed from 1973 to 1988 at one public hospital and one private plastic surgery clinic. Among women with breast implants, the average implantation time was 19 years, 60 percent (n = 114) had only one implantation, and 10 percent (n = 19) had undergone explantation before the time of study (1997 to 1998). The authors found no material differences in self-reported diseases or symptoms among study groups, except for breast pain, which was reported nearly three times as often by women with implants than by women with breast reduction (odds ratio, 2.8; 95 percent confidence interval, 1.4 to 5.3). Approximately 80 percent of women in each study group reported at least one symptom. No consistent differences were observed in the seroprevalences of antinuclear antibodies or other autoantibodies. Self-reported use of psychotropic drugs was higher among women with breast implants than among either control group. The authors conclude that long-term cosmetic breast implantation may cause capsular contracture and breast pain but does not appear to be associated with other symptoms, diseases, or autoimmune reactivity. The authors' finding of excess use of drugs for treatment of depression and anxiety among women with breast implants may warrant further investigation.

[Tardive dyskinesia--diagnosis and treatment].

Tardive dyskinesia is defined as a syndrome consisting of abnormal, stereotypical involuntary movements usually of choreoathetoid type, principally affected the mouth, face, limbs and trunk, which occurs relatively late in the course of neuroleptic drug treatment and in the etiology of which the drug treatment is a necessary factor. Presently, the prevalence of tardive dyskinesia in the hospitalized patients in psychiatric hospitals in Japan is estimated to be 20-30%. Epidemiology, possible pathophysiology and symptomatology of tardive dyskinesia are briefly described. Differential diagnosis between this syndrome and other involuntary movements such as psychotic mannerism, senile orofacial dyskinesia, rabbit's syndrome, Pisa syndrome or Meige's syndrome is discussed. Several drugs to suppress involuntary movements of tardive dyskinesia are described. However, there appears to be no consistently reliable therapies for patients who develop the tardive dyskinesia. Treatment for this syndrome, other than neuroleptic withdrawal, are still uncertain.

Dor dentária em usuários de Substâncias Psicoativas dos CAPS AD de Vitória, Vila Velha e Serra, ES, Brasil / Dental pain among psychoactive substance users in CAPS AD in Vitoria, Vila Velha and Serra, ES, Brazil

Resumo A dor dentária é um problema de saúde pública que causa grande incômodo aos usuários de substâncias psicoativas. Objetivou-se determinar a prevalência de dor dentária e suas associações em usuários de substâncias psicoativas dos CAPS AD dos municípios de Vitória, Vila Velha e Serra, ES, Brasil. Um estudo transversal foi realizado com 280 participantes, entre junho de 2015 e fevereiro de 2016, por meio de cinco roteiros, um para os dados sociodemográficos e percepção de saúde, outro para saúde bucal, o Oral Health Impact Profile, o Alcohol Smoking and Substance Involvement Screening Test e o World Health Organization Quality of Life. Os dados foram organizados em tabelas de frequência, analisados com o pacote estatístico SPSS 20, as comparações foram feitas com o teste de Fisher e Odds Ratio (OR) foi utilizado para verificar a força da associação entre as variáveis. A prevalência de dor na população estudada foi de 59,3% e os indivíduos que apresentaram impacto das condições bucais na qualidade de vida, tiveram 2,2 vezes mais chances de relatar dor de dente nos últimos 6 meses. A população estudada apresentou alta prevalência de dor dentária, o estudo aponta que a dor dentária interfere na qualidade de vida dos usuários de substâncias psicoativas que utilizam os serviços dos CAPS AD dos três municípios.

Abstract Toothache is a public health problem that causes great inconvenience to psychoactive substances users. The objective was to verify the prevalence of dental pain and its associations among psychoactive substances users from Alcohol and Drug Psychosocial Care Centers (CAPS AD) in Vitoria, Vila Velha and Serra, Espírito Santo, Brazil. A transversal study was conducted with 280 participants between June 2015 and February 2016, using five scripts: one for socio-demographic data and health perception; another for oral health; the Oral Health Impact Profile; the Alcohol Smoking and Substance Involvement Screening Test and the World Health Organization Quality of Life Test. Data were organized in frequency tables and analyzed with the SPSS 20 statistical package. Comparisons were made with Fisher's test and the Odds Ratio (OR) was used to check the strength of the association between the variables. The prevalence of pain in the population studied was 59.3%, and individuals whose quality of life was impacted due to their oral conditions were 2.2 times more likely to report toothache in the last 6 months. The population studied showed a high prevalence of dental pain and the study indicates that dental pain interferes in the quality of life of psychoactive substances users who are treated at CAPS AD services in these three cities.

The rise of new psychoactive substance use in Australia.

New Psychoactive Substances are now a feature of Australia's recreational drug market. Little is known, however, about the prevalence of use, the characteristics of people who use them and the relationship between the NPS and ecstasy markets. This study examined the prevalence and correlates of NPS use amongst a group of regular ecstasy users in Australia. Participants were recruited if they had used ecstasy at least six times in the previous six months, lived in a capital city and were over 16 years of age. Purposive sampling was used, recruiting through universities and colleges, word of mouth and street press. 654 participants were recruited in 2013. Respondents who had used an NPS in the past six months were compared to those who had not. NPS were used by 44% of the total sample. In 2013 2C-I (14%) and 2C-B (8%) were the most prevalent NPS. Respondents in the NPS group were younger and reported more frequent use of more types of drugs. They were also more likely to rate the purity of ecstasy as low relative to those in the no NPS group. NPS are now an established part of Australia's recreational drug scene and NPS with hallucinogenic effects are now used most commonly. Monitoring systems need to develop capacity to monitor this highly dynamic market.

[Oral health of users of psychoactive substances]. / Santé buccodentaire des usagers de substances psychoactives.

The oral health of drug users is increasingly part of the medical universe of caregivers. For too long, the place of oral health in the "good living" was very thin. The mouth of a patient interests very few people, and still less the person himself who begins to worry that very late. His entourage has a lot of other reasons for concern and the dentist is infrequently associated to support teams in a global approach to public health, and a fortiori as caregiver.

Characterisation of different nanoparticles with a potential use for drug delivery in neuropsychiatric disorders.

OBJECTIVES: Nanoparticles are promising tools for targeted delivery of drugs in the treatment of different diseases, including neuropsychiatric disorders. However, they need to be carefully characterised for any adverse effects which may occur in their presence. In this study, we evaluated the applicability of nanoparticles that belong to three different groups: (i) aggregates from amphiphilic diblock copolymers composed of poly(2-ethyl-2-oxazoline) (PEtOx) and poly(2-phenyl-2-oxazoline) (PPhOx) in different ratios, (ii) stabilised polymeric micelles (SPM) based on poly(ethylene oxide)-b-poly(propylene oxide)-bpoly(ethylene oxide) (PEO-PPO-PEO) and (iii) star-like polymer with poly(acrylic acid) arms and branched polystyrene interior (PSPAA). METHODS: Using cultured human neural progenitor cells, we characterised six nanoparticles (POx-9, POx-23 and POx-46 - the polyoxazoline group, SPM-F38 and SPMMS - the SPM group, and PSPAA - the star-like polymer) for neurotoxicity and effect on neurodevelopmental genes. Nanoparticles ability to activate complement system in blood was assessed by ELISA. RESULTS: None of the nanoparticles exhibited neurotoxicity. However, POx-9, POx-23, POx-46 and SPM-F38 activated complement system. POx-9 and SPM-F38 resulted in inhibition of expression of 19 and 26 out of 30 tested neurodevelopmental genes, respectively. CONCLUSIONS: Considering the properties of the studied nanoparticles, only PSPAA and SPMMS can be used at high concentrations for drug delivery without compromising neurogenesis and neurodevelopment, and activation of complement system.