query: serotonin

positive: Melatonin in traditional Mediterranean diets. Compared with other industrialized countries, the lower incidence of chronic-degenerative disorders in Mediterranean populations has been emphasized in recent decades. The health-promoting effects arising from Mediterranean dietary habits have been attributed to the large intake of plant foodstuffs rich in bioactive phytochemicals, such as melatonin. Recently, it has been suggested that melatonin present in edible plants may improve human health, by virtue of its biological activities and its good bioavailability. Plant melatonin, besides contributing to optimize the physiological functions regulated, in humans, by endogenous melatonin, may be involved in nutritional therapy to reduce the risk of cancer, cardiovascular and neurodegenerative diseases in western populations. In this view, the presence of melatonin in some Mediterranean foods and beverages adds a new element to the hypothesis of health benefits associated to Mediterranean dietary patterns, although the available data are still preliminary and incomplete.

positive: Effect of tart cherry juice (Prunus cerasus) on melatonin levels and enhanced sleep quality. BACKGROUND: Tart Montmorency cherries have been reported to contain high levels of phytochemicals including melatonin, a molecule critical in regulating the sleep-wake cycle in humans. PURPOSE: The aim of our investigation was to ascertain whether ingestion of a tart cherry juice concentrate would increase the urinary melatonin levels in healthy adults and improve sleep quality. METHODS: In a randomised, double-blind, placebo-controlled, crossover design, 20 volunteers consumed either a placebo or tart cherry juice concentrate for 7 days. Measures of sleep quality recorded by actigraphy and subjective sleep questionnaires were completed. Sequential urine samples over 48 h were collected and urinary 6-sulfatoxymelatonin (major metabolite of melatonin) determined; cosinor analysis was used to determine melatonin circadian rhythm (mesor, acrophase and amplitude). In addition, total urinary melatonin content was determined over the sampled period. Trial differences were determined using a repeated measures ANOVA. RESULTS: Total melatonin content was significantly elevated (P < 0.05) in the cherry juice group, whilst no differences were shown between baseline and placebo trials. There were significant increases in time in bed, total sleep time and sleep efficiency total (P < 0.05) with cherry juice supplementation. Although there was no difference in timing of the melatonin circardian rhythm, there was a trend to a higher mesor and amplitude. CONCLUSIONS: These data suggest that consumption of a tart cherry juice concentrate provides an increase in exogenous melatonin that is beneficial in improving sleep duration and quality in healthy men and women and might be of benefit in managing disturbed sleep.

positive: Application of LC and LC-MS to the analysis of melatonin and serotonin in edible plants. Melatonin is a neurohormone produced by the pineal gland of animals. Serotonin is a monoamine neurotransmitter and one of the precursors of melatonin biosynthesis. These two indoleamines have recently been reported to have widespread occurrence in many edible plants. Consuming foodstuffs containing melatonin and serotonin could raise their physiologic concentrations in blood and enhance human health. Literature concerning analytical methods suitable for determination of melatonin and serotonin in edible plants is limited, although several liquid chromatographic (LC) techniques have been used for their quantification. Liquid chromatography-mass spectrometry (LC-MS) methods combine selectivity, sensitivity, and high precision, and enable the simultaneous determination of melatonin and serotonin. This work reviews LC and LC-MS techniques used to determine melatonin and serotonin, and the available data on melatonin and serotonin levels in edible plants. © 2011 Crown Copyright

positive: Effects of a Tart Cherry Juice Beverage on the Sleep of Older Adults with Insomnia: A Pilot Study This study ascertained whether a proprietary tart cherry juice blend (CherryPharm, Inc., Geneva, NY, USA) associated with anecdotal reports of sleep enhancement improves subjective reports of insomnia compared to a placebo beverage. The pilot study used a randomized, double-blind, crossover design where each participant received both treatment and placebo for 2 weeks with an intervening 2-week washout period. Sleep continuity (sleep onset, wake after sleep onset, total sleep time, and sleep efficiency) was assessed by 2-week mean values from daily sleep diaries and disease severity by the Insomnia Severity Index in a cohort of 15 older adults with chronic insomnia who were otherwise healthy. The tart cherry juice beverage was associated with statistically significant pre- to post-treatment improvements on all sleep variables. When compared to placebo, the study beverage produced significant reductions in insomnia severity (minutes awake after sleep onset); no such improvements were observed for sleep latency, total sleep time, or sleep efficiency compared to placebo. Effect sizes were moderate and in some cases negligible. The results of this pilot study suggest that CherryPharm, a tart cherry juice blend, has modest beneficial effects on sleep in older adults with insomnia with effect sizes equal to or exceeding those observed in studies of valerian and in some, but not all, studies of melatonin, the two most studied natural products for insomnia. These effects, however, were considerably less than those for evidence-based treatments of insomnia: hypnotic agents and cognitive-behavioral therapies for insomnia.

positive: Diet promotes sleep duration and quality. Sleep, much like eating, is an essential part of life. The mechanisms of sleep are only partially clear and are the subject of intense research. There is increasing evidence showing that sleep has an influence on dietary choices. Both cross-sectional and epidemiologic studies have demonstrated that those who sleep less are more likely to consume energy-rich foods (such as fats or refined carbohydrates), to consume fewer portions of vegetables, and to have more irregular meal patterns. In this narrative review, we pose the opposite question: can ingested food affect sleep? The purpose of this review is to discuss the evidence linking diet and sleep and to determine whether what we eat and what kind of nutrients we obtain from the food consumed before bedtime matter. In addition, scientific evidence behind traditional sleep-promoting foods such as milk and some herbal products is briefly described. These are reviewed using data from clinical trials, mostly in healthy subjects. In addition, we discuss the possible mechanisms behind these observations. Lastly, we summarize our findings that emerging evidence confirms a link between diet and sleep. Overall, foods impacting the availability of tryptophan, as well as the synthesis of serotonin and melatonin, may be the most helpful in promoting sleep. Although there are clear physiological connections behind these effects, the clinical relevance needs to be studied further. Copyright © 2012 Elsevier Inc. All rights reserved.

positive: Melatonin for the prevention and treatment of jet lag. BACKGROUND: : Jet-lag commonly affects air travellers who cross several time zones. It results from the body's internal rhythms being out of step with the day-night cycle at the destination. Melatonin is a pineal hormone that plays a central part in regulating bodily rhythms and has been used as a drug to re-align them with the outside world. OBJECTIVES: : To assess the effectiveness of oral melatonin taken in different dosage regimens for alleviating jet-lag after air travel across several time zones. SEARCH STRATEGY: : We searched the Cochrane Controlled Trials Register, MEDLINE, EMBASE, PsychLit and Science Citation Index electronically, and the journals 'Aviation, Space and Environmental Medicine' and 'Sleep' by hand. We searched citation lists of relevant studies for other relevant trials. We asked principal authors of relevant studies to tell us about unpublished trials. Reports of adverse events linked to melatonin use outside randomised trials were searched for systematically in 'Side Effects of Drugs' (SED) and SED Annuals, 'Reactions Weekly', MEDLINE, and the adverse drug reactions databases of the WHO Uppsala Monitoring Centre (UMC) and the US Food & Drug Administration. SELECTION CRITERIA: : Randomised trials in airline passengers, airline staff or military personnel given oral melatonin, compared with placebo or other medication. Outcome measures should consist of subjective rating of jet-lag or related components, such as subjective wellbeing, daytime tiredness, onset and quality of sleep, psychological functioning, duration of return to normal, or indicators of circadian rhythms. DATA COLLECTION AND ANALYSIS: : Ten trials met the inclusion criteria. All compared melatonin with placebo; one in addition compared it with a hypnotic, zolpidem. Nine of the trials were of adequate quality to contribute to the assessment, one had a design fault and could not be used in the assessment. Reports of adverse events outside trials were found through MEDLINE, 'Reactions Weekly', and in the WHO UMC database. MAIN RESULTS: : Nine of the ten trials found that melatonin, taken close to the target bedtime at the destination (10pm to midnight), decreased jet-lag from flights crossing five or more time zones. Daily doses of melatonin between 0.5 and 5mg are similarly effective, except that people fall asleep faster and sleep better after 5mg than 0.5mg. Doses above 5mg appear to be no more effective. The relative ineffectiveness of 2mg slow-release melatonin suggests that a short-lived higher peak concentration of melatonin works better. Based on the review, the number needed to treat (NNT) is 2. The benefit is likely to be greater the more time zones are crossed, and less for westward flights. The timing of the melatonin dose is important: if it is taken at the wrong time, early in the day, it is liable to cause sleepiness and delay adaptation to local time. The incidence of other side effects is low. Case reports suggest that people with epilepsy, and patients taking warfarin may come to harm from melatonin. REVIEWER'S CONCLUSIONS: : Melatonin is remarkably effective in preventing or reducing jet-lag, and occasional short-term use appears to be safe. It should be recommended to adult travellers flying across five or more time zones, particularly in an easterly direction, and especially if they have experienced jet-lag on previous journeys. Travellers crossing 2-4 time zones can also use it if need be. The pharmacology and toxicology of melatonin needs systematic study, and routine pharmaceutical quality control of melatonin products must be established. The effects of melatonin in people with epilepsy, and a possible interaction with warfarin, need investigation.

positive: Effect of kiwifruit consumption on sleep quality in adults with sleep problems. Numerous studies have revealed that kiwifruit contains many medicinally useful compounds, among which antioxidants and serotonin may be beneficial in the treatment of the sleep disorders. The aim of this study was to evaluate the effects of kiwifruit on sleep patterns, including sleep onset, duration, and quality. In this study, we applied a free-living, self-controlled diet design. Twenty-four subjects (2 males, 22 females) 20 to 55 years of age consumed 2 kiwifruits 1 hour before bedtime nightly for 4 weeks. The Chinese version of the Pittsburgh Sleep Quality Index (CPSQI), a 3-day sleep diary, and the Actigraph sleep/activity logger watch were used to assess the subjective and objective parameters of sleep quality, including time to bed, time of sleep onset, waking time after sleep onset, time of getting up, total sleep time, and self-reported sleep quality and sleep onset latency, waking time after sleep onset, total sleep time, and sleep efficiency before and after the intervention. After 4 weeks of kiwifruit consumption, the subjective CPSQI score, waking time after sleep onset, and sleep onset latency were significantly decreased (42.4%, 28.9%, and 35.4%, respectively). Total sleep time and sleep efficiency were significantly increased (13.4% and 5.41%, respectively). Kiwifruit consumption may improve sleep onset, duration, and efficiency in adults with self-reported sleep disturbances. Further investigation of the sleep-promoting properties of kiwifruit may be warranted.

positive: Epidemiology of insomnia: what we know and what we still need to learn. Epidemiologists have published more than 50 studies of insomnia based on data collected in various representative community-dwelling samples or populations. These surveys provide estimates of the prevalence of insomnia according to four definitions: insomnia symptoms, insomnia symptoms with daytime consequences, sleep dissatisfaction and insomnia diagnoses. The first definition, based on insomnia criteria as defined by the DSM-IV, recognizes that about one-third of a general population presents at least one of them. The second definition shows that, when daytime consequences of insomnia are taken into account, the prevalence is between 9% and 15%. The third definition represents 8-18% of the general population. The last definition, more precise and corresponding to a decision-making diagnosis, sets the prevalence at 6% of insomnia diagnoses according to the DSM-IV classification. These four definitions of insomnia have higher prevalence rates in women than in men. The prevalence of insomnia symptoms generally increases with age, while the rates of sleep dissatisfaction and diagnoses have little variation with age. Numerous factors can initiate or maintain insomnia. Mental disorders and organic diseases are the factors that have been the most frequently studied. The association between insomnia and major depressive episodes has been constantly reported: individuals with insomnia are more likely to have a major depressive illness. Longitudinal studies have shown that the persistence of insomnia is associated with the appearance of a new depressive episode. Future epidemiological studies should focus on the natural evolution of insomnia. Epidemiological genetic links of insomnia are yet to be studied.

positive: Short or Long Sleep Duration Is Associated with Memory Impairment in Older Chinese: the Guangzhou Biobank Cohort Study Study Objectives: To examine the association between sleep-related factors and memory impairment. Design: Cross-sectional study Setting: Community-based study in Guangzhou, China. Participants: 28,670 older Chinese (20,776 women and 7,894 men) aged 50 to 85 years. Measurements and Results: Demographic and socioeconomic data, sleep-related factors, and cognitive function were collected by face-to-face interview. Potential confounders, such as employment and occupational status, smoking, alcohol and tea use, physical activity, self-rated health, anthropometry, blood pressure, and fasting plasma glucose and lipids were measured. After adjusting for multiple potential confounders, an inverted U-shaped association between sleep duration and delayed word recall test (DWRT) score, a validated measure of memory impairment, was found, with 7 to 8 h of habitual sleep duration showing the highest score (P-values for trend from 3 to 7 h and from 7 to ≥ 10 h were all ≤ 0.001). Compared to sleep duration of 7 h, the adjusted odds ratio for memory impairment from the sleep duration of 3 to 4 or ≥ 10 h was 1.29 (95% confidence interval 1.07-1.56) and 1.52 (1.25-1.86), respectively. Subjects with daily napping, morning tiredness, or insomnia had significantly lower DWRT scores than those without (P ranged from < 0.001 to 0.01). Conclusions: Short or long sleep duration was an important sleep-related factor independently associated with memory impairment and may be a useful marker for increased risk of cognitive impairment in older people. Citation: Xu L; Jiang CQ; Lam TH; Liu B; Jin YL; Zhu T; Zhang WS; Cheng KK; Thomas GN. Short or long sleep duration is associated with memory impairment in older Chinese: the Guangzhou Biobank Cohort Study. SLEEP 2011;34(5):575-580.

positive: Association of Sleep Duration with Mortality from Cardiovascular Disease and Other Causes for Japanese Men and Women: the JACC Study Study Objectives: To examine sex-specific associations between sleep duration and mortality from cardiovascular disease and other causes. Design: Cohort study. Setting: Community-based study. Participants: A total of 98,634 subjects (41,489 men and 57,145 women) aged 40 to 79 years from 1988 to 1990 and were followed until 2003. Interventions: N/A. Measurements and Results: During a median follow-up of 14.3 years, there were 1964 deaths (men and women: 1038 and 926) from stroke, 881 (508 and 373) from coronary heart disease, 4287 (2297 and 1990) from cardiovascular disease, 5465 (3432 and 2033) from cancer, and 14,540 (8548 and 5992) from all causes. Compared with a sleep duration of 7 hours, sleep duration of 4 hours or less was associated with increased mortality from coronary heart disease for women and noncardiovascular disease/noncancer and all causes in both sexes. The respective multivariable hazard ratios were 2.32 (1.19–4.50) for coronary heart disease in women, 1.49 (1.02–2.18) and 1.47 (1.01–2.15) for noncardiovascular disease/noncancer, and 1.29 (1.02–1.64) and 1.28 (1.03–1.60) for all causes in men and women, respectively. Long sleep duration of 10 hours or longer was associated with 1.5- to 2-fold increased mortality from total and ischemic stroke, total cardiovascular disease, noncardiovascular disease/noncancer, and all causes for men and women, compared with 7 hours of sleep in both sexes. There was no association between sleep duration and cancer mortality in either sex. Conclusions: Both short and long sleep duration were associated with increased mortality from cardiovascular disease, noncardiovascular disease/noncancer, and all causes for both sexes, yielding a U-shaped relationship with total mortality with a nadir at 7 hours of sleep. Citation: Ikehara S; Iso H; Date C; Kikuchi S; Watanabe Y; Wada Y; Inaba Y; Tamakoshi A. Association of sleep duration with mortality from cardiovascular disease and other causes for Japanese men and women: the JACC study. SLEEP 2009;32(3):259–301.

positive: Restriction of meat, fish, and poultry in omnivores improves mood: A pilot randomized controlled trial Background Omnivorous diets are high in arachidonic acid (AA) compared to vegetarian diets. Research shows that high intakes of AA promote changes in brain that can disturb mood. Omnivores who eat fish regularly increase their intakes of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), fats that oppose the negative effects of AA in vivo. In a recent cross-sectional study, omnivores reported significantly worse mood than vegetarians despite higher intakes of EPA and DHA. This study investigated the impact of restricting meat, fish, and poultry on mood. Findings Thirty-nine omnivores were randomly assigned to a control group consuming meat, fish, and poultry daily (OMN); a group consuming fish 3-4 times weekly but avoiding meat and poultry (FISH), or a vegetarian group avoiding meat, fish, and poultry (VEG). At baseline and after two weeks, participants completed a food frequency questionnaire, the Profile of Mood States questionnaire and the Depression Anxiety and Stress Scales. After the diet intervention, VEG participants reduced their EPA, DHA, and AA intakes, while FISH participants increased their EPA and DHA intakes. Mood scores were unchanged for OMN or FISH participants, but several mood scores for VEG participants improved significantly after two weeks. Conclusions Restricting meat, fish, and poultry improved some domains of short-term mood state in modern omnivores. To our knowledge, this is the first trial to examine the impact of restricting meat, fish, and poultry on mood state in omnivores.

positive: Natural mood foods: The actions of polyphenols against psychiatric and cognitive disorders Objectives Polyphenols, natural compounds found in plant-based foods, possess special properties that can battle oxidative stress and stimulate the activation of molecules that aid in synaptic plasticity, a process that underlies cognitive function. Unlike many traditional treatments, polyphenols affect a broad range of mechanisms in the brain that can assist in the maintenance of cognitive and mental health, as well as the recovery from neurodegenerative diseases. Examining the molecular basis underlying the link between food intake and brain function has presented the exciting possibility of using diet as a viable method to battle cognitive and psychiatric disorders. Methods We will discuss the molecular systems that link polyphenols, the gut, and the brain, as well as introduce published human and animal studies demonstrating the effects of polyphenol consumption on brain plasticity and cognition. Results By influencing cellular energy metabolism and modulating the signaling pathways of molecules involved with brain plasticity, dietary factors – formerly recognized for just their effects on bodily systems – have emerged as affecters of the brain. Conclusion Thus, the consumption of diets enriched with polyphenols may present the potential of dietary manipulation as a non-invasive, natural, and inexpensive therapeutic means to support a healthy brain.

positive: Frequent consumption of vegetables predicts lower risk of depression in older Taiwanese - results of a prospective population-based study. OBJECTIVE: The study evaluated the association between consumption frequencies of the major food categories and the risk of new depression four years later in older Taiwanese. DESIGN: A prospective cohort study with multistage random sampling. Logistic regression analysis evaluated the significance of the longitudinal associations of intake frequencies of the major food categories with future (4 years later) risk of new depression, controlled for possible confounding factors with or without adjustment for cognitive status. SETTING: Population-based free-living elderly. SUBJECTS: Men and women (n 1609) ≥65 years of age. RESULTS: In a regression model that controlled for demographic, socio-economic, lifestyle and disease/health-related variables but not cognitive status, both fruits (OR = 0·66, 95 % CI 0·45, 0·98, P = 0·038) and vegetables (OR = 0·38, 95 % CI 0·17, 0·86, P = 0·021) were protective against depressive symptoms 4 years later. However, when the same regression model was also adjusted for cognitive status, only vegetables (OR = 0·40, 95 % CI 0·17, 0·95, P = 0·039) were protective against depressive symptoms. Higher consumption of eggs was close to being significant in both regression models (P = 0·087 and 0·069, respectively). Other food categories including meat/poultry, fish, seafood, dairy, legumes, grains and tea showed no significant associations. CONCLUSIONS: Results suggest that although confounding factors cannot be totally ruled out, more frequent consumption of vegetables seems to be protective against depressive symptoms in the elderly. Further studies are needed to elucidate the causal role and the mechanism of the association.

positive: Elevated monoamine oxidase a levels in the brain: an explanation for the monoamine imbalance of major depression. CONTEXT: The monoamine theory of depression proposes that monoamine levels are lowered, but there is no explanation for how monoamine loss occurs. Monoamine oxidase A (MAO-A) is an enzyme that metabolizes monoamines, such as serotonin, norepinephrine, and dopamine. OBJECTIVE: To determine whether MAO-A levels in the brain are elevated during untreated depression. SETTING: Tertiary care psychiatric hospital. PATIENTS: Seventeen healthy and 17 depressed individuals with major depressive disorder that met entry criteria were recruited from the care of general practitioners and psychiatrists. All study participants were otherwise healthy and nonsmoking. Depressed individuals had been medication free for at least 5 months. MAIN OUTCOME MEASURE: Harmine labeled with carbon 11, a radioligand selective for MAO-A and positron emission tomography, was used to measure MAO-A DVS (specific distribution volume), an index of MAO-A density, in different brain regions (prefrontal cortex, anterior cingulate cortex, posterior cingulate cortex, caudate, putamen, thalamus, anterior temporal cortex, midbrain, hippocampus, and parahippocampus). RESULTS: The MAO-A DVS was highly significantly elevated in every brain region assessed (t test; P=.001 to 3x10(-7)). The MAO-A DVS was elevated on average by 34% (2 SDs) throughout the brain during major depression. CONCLUSIONS: The sizable magnitude of this finding and the absence of other compelling explanations for monoamine loss during major depressive episodes led to the conclusion that elevated MAO-A density is the primary monoamine-lowering process during major depression.

positive: Monoamine oxidase inhibitors and the cheese effect. The behavior of inhibitors of monoamine oxidase-A (MAO-A) is considered in terms of the possibility of having an effective antidepressant that does not give rise to hypertensive interactions with dietary tyramine. Studies with punch-biopsy samples of human intestine and rat intestinal samples show MAO-A to be the predominant form of the enzyme in both species. Transport studies with everted rat intestinal preparations indicate that tyramine is extensively metabolized during transport through the intestine. Selective inhibition of MAO-A by clorgyline results in a large increase in the amount of unchanged tyramine transported, whereas selective inhibition of MAO-B with L-deprenyl (selegiline) has no significant effect. The behavior of reversible MAO-A inhibitors can significantly reduce, but not entirely eliminate, these effects on the intestinal metabolism of tyramine, but only if the inhibition is competitive in nature.

positive: Dietary inhibitors of monoamine oxidase A. Inhibition of monoamine oxidase is one way to treat depression and anxiety. The information now available on the pharmacokinetics of flavonoids and of the components of tobacco prompted an exploration of whether a healthy diet (with or without smoking) provides active compounds in amounts sufficient to partially inhibit monoamine oxidase. A literature search was used to identify dietary monoamine oxidase inhibitors, the levels of these compounds in foods, the pharmacokinetics of the absorption and distribution, and tissue levels observed. An estimated daily intake and the expected tissue concentrations were compared with the measured efficacies of the compounds as inhibitors of monoamine oxidases. Norharman, harman and quercetin dietary presence, pharmacokinetics, and tissue levels were consistent with significant levels reaching neuronal monoamine oxidase from the diet or smoking; 1,2,3,4-tetrahydroisoquinoline, eugenol, 1-piperoylpiperidine, and coumarin were not. Quercetin was equipotent with norharman as a monoamine oxidase A inhibitor and its metabolite, isorhamnetin, also inhibits. Total quercetin was the highest of the compounds in the sample diet. Although bioavailability was variable depending on the source, a healthy diet contains amounts of quercetin that might give sufficient amounts in brain to induce, by monoamine oxidase A inhibition, a small decrease in neurotransmitter breakdown.

positive: Monoamine theories of depression: historical impact on biomedical research. Monoamine theories associate depression with reduced brain monoamine levels. These theories achieved broad popularity in the mid-1960s. The present article reviews the historical development of monoamine theories and their subsequent impact on biomedical research. Alleged divisions between West European and US researchers over competing versions of the theories are investigated using bibliometrics. Subsequently, the application of monoamine theories in the NIMH Collaborative Program on the Psychobiology of Depression is covered. The article argues that the impact of monoamine theories is best explained by the ability of researchers, governmental agencies, and pharmaceutical companies to invoke theories that advance various projects and agendas.

positive: Coffee, tea, and mortality. Except for conflicting evidence about coffee and risk of coronary disease, coffee and tea are not linked to major causes of death. Because of widespread use of both beverages and limitations of prior studies, concern persists. Using Cox models (ten covariates) we studied relations in 128,934 persons to 4501 subsequent deaths. Except for slightly increased risk from acute myocardial infarction among heavier (> or = 4 cups/d) coffee users (relative risk versus nondrinkers = 1.4, 95% confidence interval = 1.0 to 1.9, P = 0.07), there was no increased risk of mortality for all deaths (relative risk per cup of coffee per day = 0.99, 95% confidence interval = 0.97 to 1.01; relative risk per cup of tea per day = 0.98, 95% confidence interval = 0.96 to 1.00) or major causes in adjusted analyses. Coffee was related to lower risk of liver cirrhosis death (relative risk per cup of coffee per day = 0.77, 95% confidence interval = 0.67 to 0.89). Use of both beverages was related to a lower risk of suicide, progressively lower at higher coffee intake (relative risk per cup of coffee per day = 0.87, 95% confidence interval = 0.77 to 0.98). We conclude that coffee and tea have no overall relation to mortality risk. If coffee increases coronary risk, this is balanced by an unexplained lower risk of other conditions, notably cirrhosis and suicide.

positive: Coffee, caffeine, and risk of completed suicide: results from 3 prospective cohorts of American adults Objective To evaluate the association between coffee and caffeine consumption and suicide risk in three large-scale cohorts of U.S. men and women. Methods We accessed data of 43,599 men enrolled in the Health Professionals Follow-up Study (HPFS, 1988–2008), 73,820 women in the Nurses’ Health Study (NHS, 1992–2008), and 91,005 women in the NHS II (1993–2007). Consumption of caffeine, coffee, and decaffeinated coffee, was assessed every four years by validated food-frequency questionnaires. Deaths from suicide were determined by physician review of death certificates. Multivariate adjusted relative risks (RRs) were estimated with Cox proportional hazard models. Cohort specific RRs were pooled using random-effect models. Results We documented 277 deaths from suicide. Compared to those consuming ≤1 cup/week of caffeinated coffee (≤8 oz/237 ml), the pooled multivariate RR (95% confidence interval [CI]) of suicide was 0.55 (0.38–0.78) for those consuming 2–3 cups/day and 0.47 (0.27–0.81) for those consuming ≥4 cups/day (P trend <0.001). The pooled multivariate RR (95% CI) for suicide was 0.75 (0.63–0.90) for each increment of 2 cups/day of caffeinated coffee and 0.77 (0.63–0.93) for each increment of 300 mg/day of caffeine. Conclusions These results from three large cohorts support an association between caffeine consumption and lower risk of suicide.

positive: Possible neurologic effects of aspartame, a widely used food additive. The artificial sweetener aspartame (L-aspartyl-L-phenylalanyl-methyl ester), is consumed, primarily in beverages, by a very large number of Americans, causing significant elevations in plasma and, probably, brain phenylalanine levels. Anecdotal reports suggest that some people suffer neurologic or behavioral reactions in association with aspartame consumption. Since phenylalanine can be neurotoxic and can affect the synthesis of inhibitory monoamine neurotransmitters, the phenylalanine in aspartame could conceiveably mediate neurologic effects. If mice are given aspartame in doses that elevate plasma phenylalanine levels more than those of tyrosine (which probably occurs after any aspartame dose in humans), the frequency of seizures following the administration of an epileptogenic drug, pentylenetetrazole, is enhanced. This effect is simulated by equimolar phenylalanine and blocked by concurrent administration of valine, which blocks phenylalanine's entry into the brain. Aspartame also potentiates the induction of seizures by inhaled fluorothyl or by electroconvulsive shock. Perhaps regulations concerning the sale of food additives should be modified to require the reporting of adverse reactions and the continuing conduct of mandated safety research.

positive: Direct and indirect cellular effects of aspartame on the brain. The use of the artificial sweetener, aspartame, has long been contemplated and studied by various researchers, and people are concerned about its negative effects. Aspartame is composed of phenylalanine (50%), aspartic acid (40%) and methanol (10%). Phenylalanine plays an important role in neurotransmitter regulation, whereas aspartic acid is also thought to play a role as an excitatory neurotransmitter in the central nervous system. Glutamate, asparagines and glutamine are formed from their precursor, aspartic acid. Methanol, which forms 10% of the broken down product, is converted in the body to formate, which can either be excreted or can give rise to formaldehyde, diketopiperazine (a carcinogen) and a number of other highly toxic derivatives. Previously, it has been reported that consumption of aspartame could cause neurological and behavioural disturbances in sensitive individuals. Headaches, insomnia and seizures are also some of the neurological effects that have been encountered, and these may be accredited to changes in regional brain concentrations of catecholamines, which include norepinephrine, epinephrine and dopamine. The aim of this study was to discuss the direct and indirect cellular effects of aspartame on the brain, and we propose that excessive aspartame ingestion might be involved in the pathogenesis of certain mental disorders (DSM-IV-TR 2000) and also in compromised learning and emotional functioning.

positive: Sugar substitutes: Health controversy over perceived benefits Sugar is an inseparable part of the food we consume. But too much sugar is not ideal for our teeth and waistline. There have been some controversial suggestions that excessive sugar may play an important role in certain degenerative diseases. So artificial sweeteners or artificially sweetened products continue to attract consumers. A sugar substitute (artificial sweetener) is a food additive that duplicates the effect of sugar in taste, but usually has less food energy. Besides its benefits, animal studies have convincingly proven that artificial sweeteners cause weight gain, brain tumors, bladder cancer and many other health hazards. Some kind of health related side effects including carcinogenicity are also noted in humans. A large number of studies have been carried out on these substances with conclusions ranging from “safe under all conditions” to “unsafe at any dose”. Scientists are divided in their views on the issue of artificial sweetener safety. In scientific as well as in lay publications, supporting studies are often widely referenced while the opposing results are de-emphasized or dismissed. So this review aims to explore the health controversy over perceived benefits of sugar substitutes.

positive: Adverse reactions to aspartame: double-blind challenge in patients from a vulnerable population. This study was designed to ascertain whether individuals with mood disorders are particularly vulnerable to adverse effects of aspartame. Although the protocol required the recruitment of 40 patients with unipolar depression and a similar number of individuals without a psychiatric history, the project was halted by the Institutional Review Board after a total of 13 individuals had completed the study because of the severity of reactions within the group of patients with a history of depression. In a crossover design, subjects received aspartame 30 mg/kg/day or placebo for 7 days. Despite the small n, there was a significant difference between aspartame and placebo in number and severity of symptoms for patients with a history of depression, whereas for individuals without such a history there was not. We conclude that individuals with mood disorders are particularly sensitive to this artificial sweetener and its use in this population should be discouraged.

positive: Sweetened Beverages, Coffee, and Tea and Depression Risk among Older US Adults Sweetened beverages, coffee, and tea are the most consumed non-alcoholic beverages and may have important health consequences. We prospectively evaluated the consumption of various types of beverages assessed in 1995–1996 in relation to self-reported depression diagnosis after 2000 among 263,923 participants of the NIH-AARP Diet and Health Study. Odds ratios (OR) and 95% confidence intervals (CI) were derived from multivariate logistic regressions. The OR (95% CI) comparing ≥4 cans/cups per day with none were 1.30 (95%CI: 1.17–1.44) for soft drinks, 1.38 (1.15–1.65) for fruit drinks, and 0.91 (0.84–0.98) for coffee (all P for trend<0.0001). Null associations were observed for iced-tea and hot tea. In stratified analyses by drinkers of primarily diet versus regular beverages, the ORs were 1.31 (1.16–1.47) for diet versus 1.22 (1.03–1.45) for regular soft drinks, 1.51 (1.18–1.92) for diet versus 1.08 (0.79–1.46) for regular fruit drinks, and 1.25 (1.10–1.41) for diet versus 0.94 (0.83–1.08) for regular sweetened iced-tea. Finally, compared to nondrinkers, drinking coffee or tea without any sweetener was associated with a lower risk for depression, adding artificial sweeteners, but not sugar or honey, was associated with higher risks. Frequent consumption of sweetened beverages, especially diet drinks, may increase depression risk among older adults, whereas coffee consumption may lower the risk.

positive: Heavy coffee drinking and the risk of suicide. Earlier research has implicated coffee drinking as a possible protective factor for suicide. We followed-up 43,166 subjects for the mean 14.6 years, and 213 suicides were committed. Daily coffee drinking had a J-shaped association with the risk of suicide. Using the Cox model we controlled for potential covariates, and found that among heavy coffee drinkers (> or = 8 cups/day) the risk of suicide was 58% higher compared with more moderate drinkers.

positive: The potential toxicity of artificial sweeteners. Since their discovery, the safety of artificial sweeteners has been controversial. Artificial sweeteners provide the sweetness of sugar without the calories. As public health attention has turned to reversing the obesity epidemic in the United States, more individuals of all ages are choosing to use these products. These choices may be beneficial for those who cannot tolerate sugar in their diets (e.g., diabetics). However, scientists disagree about the relationships between sweeteners and lymphomas, leukemias, cancers of the bladder and brain, chronic fatigue syndrome, Parkinson's disease, Alzheimer's disease, multiple sclerosis, autism, and systemic lupus. Recently these substances have received increased attention due to their effects on glucose regulation. Occupational health nurses need accurate and timely information to counsel individuals regarding the use of these substances. This article provides an overview of types of artificial sweeteners, sweetener history, chemical structure, biological fate, physiological effects, published animal and human studies, and current standards and regulations.

positive: Neurobehavioral effects of aspartame consumption. Despite its widespread use, the artificial sweetener aspartame remains one of the most controversial food additives, due to mixed evidence on its neurobehavioral effects. Healthy adults who consumed a study-prepared high-aspartame diet (25 mg/kg body weight/day) for 8 days and a low-aspartame diet (10 mg/kg body weight/day) for 8 days, with a 2-week washout between the diets, were examined for within-subject differences in cognition, depression, mood, and headache. Measures included weight of foods consumed containing aspartame, mood and depression scales, and cognitive tests for working memory and spatial orientation. When consuming high-aspartame diets, participants had more irritable mood, exhibited more depression, and performed worse on spatial orientation tests. Aspartame consumption did not influence working memory. Given that the higher intake level tested here was well below the maximum acceptable daily intake level of 40-50 mg/kg body weight/day, careful consideration is warranted when consuming food products that may affect neurobehavioral health. © 2014 Wiley Periodicals, Inc.

positive: Coffee, Caffeine, and Risk of Depression Among Women Background Caffeine is the world’s most widely used central nervous system stimulant, with about 80% consumed in form of coffee. However, studies that analyzed prospectively the relation of coffee or caffeine consumption and depression risk are scarce. Methods A total of 50,739 U.S. women (mean age=63 years) free from depressive symptoms at baseline (1996) were prospectively followed until 2006. Caffeine and coffee consumption, and other caffeinated and decaffeinated beverages, were obtained from validated questionnaires completed between 1980 through 2002 and computed as cumulative average of consumption with a 2-year latency applied. Clinical depression was defined as reporting both physician-diagnosed depression and antidepressant use. Relative risks of clinical depression were estimate using Cox proportional hazards regression models. Results During 10 years of follow-up (1996–2006), 2,607 incident cases of depression were identified. Compared to women consuming caffeinated coffee less frequently (≤1 cup/wk), multivariate relative risk of depression was 0.85 (95% confidence interval [CI], 0.75 to 0.95) for those consuming 2–3 cups/d and 0.80 (95%CI, 0.64 to 0.99; P trend <0.001) for those consuming ≥4 cups/d. Multivariate relative risk for depression was 0.80 (95%CI, 0.68 to 0.95; P trend=0.02) for women in the highest (≥550 mg/d) vs. lowest (<100 mg/d) of the 5 caffeine consumption categories. Decaffeinated coffee was not associated with depression risk. Conclusions In this large longitudinal study we found that depression risk decreases with increasing caffeinated coffee consumption. Further investigations are needed to confirm this finding and to determine whether usual caffeinated coffee consumption may contribute to depression prevention.

positive: No influence of melatonin on cerebral blood flow in humans. Melatonin has been attributed a role in a number of physiological processes. Changes in distal skin temperature and blood pressure after intake of melatonin suggest that melatonin induces peripheral vasodilation. The effect on the cerebral blood flow is still unknown. We examined the effect of a single pulse of melatonin on cerebral and peripheral blood flow, using the latter as a positive control. Ten male healthy volunteers (mean age, 22 +/- 3.2 yr) participated in a double-blind, randomized, placebo-controlled, cross-over study. On one occasion 10 microg melatonin were infused i.v., and on the other occasion saline was infused as the matching placebo. Cerebral blood flow was measured using phase contrast magnetic resonance imaging. Peripheral blood flow was determined from changes in the distal to proximal skin temperature gradient and finger pulse volume. Serum melatonin concentration increased from 12 +/- 5 pg/ml at baseline to 487 +/- 377 pg/ml at 5 min and 156 +/- 68 pg/ml at 10 min after melatonin administration. There was no significantly different time course for cerebral blood flow and cerebrovascular resistance. Compared with placebo, melatonin significantly increased peripheral blood flow, as measured by distal to proximal skin temperature gradient and finger pulse volume. These data demonstrate that melatonin does not have an acute regulatory effect on cerebral blood flow in humans.

positive: Sweet and sour cherry phenolics and their protective effects on neuronal cells. The identification of phenolics from various cultivars of fresh sweet and sour cherries and their protective effects on neuronal cells were comparatively evaluated in this study. Phenolics in cherries of four sweet and four sour cultivars were extracted and analyzed for total phenolics, total anthocyanins, and their antineurodegenerative activities. Total phenolics in sweet and sour cherries per 100 g ranged from 92.1 to 146.8 and from 146.1 to 312.4 mg gallic acid equivalents, respectively. Total anthocyanins of sweet and sour cherries ranged from 30.2 to 76.6 and from 49.1 to 109.2 mg cyanidin 3-glucoside equivalents, respectively. High-performance liquid chromatography (HPLC) analysis revealed that anthocyanins such as cyanidin and peonidin derivatives were prevalent phenolics. Hydroxycinnamic acids consisted of neochlorogenic acid, chlorogenic acid, and p-coumaric acid derivatives. Glycosides of quercetin, kaempferol, and isorhamnetin were also found. Generally, sour cherries had higher concentrations of total phenolics than sweet cherries, due to a higher concentration of anthocyanins and hydroxycinnamic acids. A positive linear correlation (r2 = 0.985) was revealed between the total anthocyanins measured by summation of individual peaks from HPLC analysis and the total anthocyanins measured by the pH differential method, indicating that there was in a close agreement with two quantifying methods for measuring anthocyanin contents. Cherry phenolics protected neuronal cells (PC 12) from cell-damaging oxidative stress in a dose-dependent manner mainly due to anthocyanins. Overall results showed that cherries are rich in phenolics, especially in anthocyanins, with a strong antineurodegenerative activity and that they can serve as a good source of biofunctional phytochemicals in our diet.

positive: Non-vertebrate melatonin. Melatonin has been detected in bacteria, eukaryotic unicells, macroalgae, plants, fungi and various taxa of invertebrates. Although precise determinations are missing in many of these organisms and the roles of melatonin are still unknown, investigations in some species allow more detailed conclusions. Non-vertebrate melatonin is not necessarily circadian, and if so, not always peaking at night, although nocturnal maxima are frequently found. In the cases under study, the major biosynthetic pathway is identical with that of vertebrates. Mimicking of photoperiodic responses and concentration changes upon temperature decreases have been studied in more detail only in dinoflagellates. In plants, an involvement in photoperiodism seems conceivable but requires further support. No stimulation of flowering has been demonstrated to date. A participation in antioxidative protection might be possible in many aerobic non-vertebrates, although evidence for a contribution at physiological levels is mostly missing. Protection from stress by oxidotoxins or/and extensions of lifespan have been shown in very different organisms, such as the dinoflagellate Lingulodinium, the ciliate Paramecium, the rotifer Philodina and Drosophila. Melatonin can be taken up from the food, findings with possible implications in ecophysiology as well as for human nutrition and, with regard to high levels in medicinal plants, also in pharmacology.

positive: Consumption of vegetables alters morning urinary 6-sulfatoxymelatonin concentration. Melatonin, which is contained in certain vegetables, may have an influence on circulatory melatonin concentrations. This study examined the effects of the consumption of vegetables on 6-sulfatoxymelatonin concentrations in morning urine. Ninety-four healthy women aged 24-55 were recruited through a city public health center in Japan. The women randomly allocated to the intervention group were requested to consume high amounts of six selected vegetables, with a target of 350 g/day for 65 days, while those in the control group were asked to avoid the same six vegetables during the same period. First-void morning urine was collected before and at the end of the intervention period, and creatinine-adjusted 6-sulfatoxymelatonin concentrations were measured. At the end of the intervention period, daily mean intake of melatonin from the six vegetables was 1288.0 ng in the intervention group and 5.3 ng in the control group. In the intervention group, the mean concentration of 6-sulfatoxymelatonin changed from 48.1 [95% confidence interval (CI): 40.4-57.2] ng/mg creatinine to 49.6 (95% CI: 42.8-57.3) ng/mg creatinine across the intervention period. In the control group, the mean concentration of 6-sulfatoxymelatonin changed from 55.5 (95% CI: 48.7-63.2) ng/mg creatinine to 50.8 (95% CI: 44.0-58.7) ng/mg creatinine across the intervention period. A comparison of the two groups with regard to the changes in the 6-sulfatoxymelatonin concentrations across the intervention period showed a significant difference (P = 0.03). The results indicate that increased consumption of vegetables raises circulatory melatonin concentrations.

positive: Normative data on the daily profile of urinary 6-sulfatoxymelatonin in healthy subjects between the ages of 20 and 84. Although the hormone melatonin is a key factor for the proper functioning of the circadian timing system (CTS) and exogenous melatonin has been shown to be beneficial in cases of CTS disturbances, a deficit of melatonin has yet to be defined as a disorder. The aim of our study was to collect a normative data set on 24-h melatonin excretion in healthy human adults living in a natural environment. Urine samples were collected from 75 healthy subjects (45 women/30 men; mean age 47.2, SD 19.5, range 20-84) after five consecutive periods: 2300-0700, 0700-1100, 1100-1800, 1800-2300 and 2300-0700 h. 6-Sulfatoxymelatonin (aMT6s) concentrations were analyzed in duplicate by IBL (Hamburg) using a highly sensitive, competitive ELISA kit. Twenty-four hour-aMT6s total amount (rho=-0.68, p<0.001), aMT6s nighttime excretion (rho=-0.69, p<0.001), aMT6s morning excretion (rho=-0.66, p<0.001) and evening excretion (r=-0.26, p=0.023) were negatively associated with age, whereas daytime excretion (r=-0.17, p=0.15) was not. The intra-subject night-day ratio varied up to 10.5 (mean 6.0) in young subjects (aged 20-35) and up to 5.4 (mean 2.8) in older individuals (age>65). The total amount of 24 h-aMT6s (range 7.5-58 microg) as well as the amount of aMT6s excreted during the nighttime period (range 327-6.074 ng/h) varied as much as 20-fold between individuals. Our data show an age-related decline in melatonin excretion in healthy subjects living in a natural environment. The high inter-individual variability of excretion rates may explain why a normative data set is of no use in replacement strategies.

positive: Jerte Valley cherry-enriched diets improve nocturnal rest and increase 6-sulfatoxymelatonin and total antioxidant capacity in the urine of middle-a... Tryptophan, serotonin, and melatonin, present in Jerte Valley cherries, participate in sleep regulation and exhibit antioxidant properties. The effect of the intake of seven different Jerte Valley cherry cultivars on the sleep-wake cycle, 6-sulfatoxymelatonin levels, and urinary total antioxidant capacity in middle-aged and elderly participants was evaluated. Volunteers were subjected to actigraphic monitoring to record and display the temporal patterns of their nocturnal activity and rest. 6-sulfatoxymelatonin and total antioxidant capacity were quantified by enzyme-linked immunosorbent assay and colorimetric assay kits, respectively. The intake of each of the cherry cultivars produced beneficial effects on actual sleep time, total nocturnal activity, assumed sleep, and immobility. Also, there were significant increases in 6-sulfatoxymelatonin levels and total antioxidant capacity in urine after the intake of each cultivar. These findings suggested that the intake of Jerte Valley cherries exerted positive effect on sleep and may be seen as a potential nutraceutical tool to counteract oxidation.

positive: Detection and quantification of the antioxidant melatonin in Montmorency and Balaton tart cherries (Prunus cerasus). The antioxidant melatonin was recently identified in a variety of edible plants and seeds in high concentrations. In plants, as in animals, melatonin is believed to function as a free radical scavenger and possibly in photoperiodism. In this study, melatonin was detected and quantified in fresh-frozen Balaton and Montmorency tart cherries (Prunus cerasus) using high-performance liquid chromatography. Both cherry species contain high levels of melatonin compared to the melatonin concentrations in the blood of mammals. Montmorency cherries (13.46 +/- 1.10 ng/g) contain approximately 6 times more melatonin than do Balaton cherries (2.06 +/- 0.17 ng/g). Neither the orchard of origin nor the time of harvest influenced the amount of melatonin in fresh cherries. The implication of the current findings is that consuming cherries could be an important source of dietary melatonin inasmuch as melatonin is readily absorbed when taken orally. Also, previously published data and the results presented here show that melatonin is not only endogenously produced but also present in the diet.

positive: Simultaneous analysis of serotonin, melatonin, piceid and resveratrol in fruits using liquid chromatography tandem mass spectrometry. An analytical method was developed for the simultaneous quantification of serotonin, melatonin, trans- and cis-piceid, and trans- and cis-resveratrol using reversed-phase high performance liquid chromatography coupled to mass spectrometry (HPLC-MS) with electrospray ionization (ESI) in both positive and negative ionization modes. HPLC optimal analytical separation was achieved using a mixture of acetonitrile and water with 0.1% formic acid as the mobile phase in linear gradient elution. The mass spectrometry parameters were optimized for reliable quantification and the enhanced selectivity and sensitivity selected reaction monitoring mode (SRM) was applied. For extraction, the direct analysis of initial methanol extracts was compared with further ethyl acetate extraction. In order to demonstrate the applicability of this analytical method, serotonin, melatonin, trans- and cis-piceid, and trans- and cis-resveratrol from 24 kinds of commonly consumed fruits were quantified. The highest serotonin content was found in plantain, while orange bell peppers had the highest melatonin content. Grape samples possessed higher trans- and cis-piceid, and trans- and cis-resveratrol contents than the other fruits. The results indicate that the combination of HPLC-MS detection and simple sample preparation allows the rapid and accurate quantification of serotonin, melatonin, trans- and cis-piceid, and trans- and cis-resveratrol in fruits. Copyright © 2011 Elsevier B.V. All rights reserved.

positive: Antioxidant and antiinflammatory activities of anthocyanins and their aglycon, cyanidin, from tart cherries. The anthocyanins (1-3) and cyanidin isolated from tart cherries exhibited in vitro antioxidant and antiinflammatory activities comparable to commercial products. The inhibition of lipid peroxidation of anthocyanins 1-3 and their aglycon, cyanidin, were 39, 70, 75, and 57%, respectively, at 2-mM concentrations. The antioxidant activities of 1-3 and cyanidin were comparable to the antioxidant activities of tert-butylhydroquinone and butylated hydroxytoluene and superior to vitamin E at 2-mM concentrations. In the antiinflammatory assay, cyanidin gave IC50 values of 90 and 60 mM, respectively, for prostaglandin H endoperoxide synthase-1 and prostaglandin H endoperoxide synthase-2 enzymes.

positive: Efficacy of a tart cherry juice blend in preventing the symptoms of muscle damage Background Numerous antioxidant and anti‐inflammatory agents have been identified in tart cherries. Objective To test the efficacy of a tart cherry juice blend in preventing the symptoms of exercise induced muscle damage. Methods This was a randomised, placebo controlled, crossover design. Fourteen male college students drank 12 fl oz of a cherry juice blend or a placebo twice a day for eight consecutive days. A bout of eccentric elbow flexion contractions (2 × 20 maximum contractions) was performed on the fourth day of supplementation. Isometric elbow flexion strength, pain, muscle tenderness, and relaxed elbow angle were recorded before and for four days after the eccentric exercise. The protocol was repeated two weeks later with subjects who took the placebo initially, now taking the cherry juice (and vice versa). The opposite arm performed the eccentric exercise for the second bout to avoid the repeated bout protective effect. Results Strength loss and pain were significantly less in the cherry juice trial versus placebo (time by treatment: strength p<0.0001, pain p  =  0.017). Relaxed elbow angle (time by treatment p  =  0.85) and muscle tenderness (time by treatment p  =  0.81) were not different between trials. Conclusions These data show efficacy for this cherry juice in decreasing some of the symptoms of exercise induced muscle damage. Most notably, strength loss averaged over the four days after eccentric exercise was 22% with the placebo but only 4% with the cherry juice.

positive: Cherries and health: a review. Cherries, and in particular sweet cherries, are a nutritionally dense food rich in anthocyanins, quercetin, hydroxycinnamates, potassium, fiber, vitamin C, carotenoids, and melatonin. UV concentration, degree of ripeness, postharvest storage conditions, and processing, each can significantly alter the amounts of nutrients and bioactive components. These constituent nutrients and bioactive food components support the potential preventive health benefits of cherry intake in relation to cancer, cardiovascular disease, diabetes, inflammatory diseases, and Alzheimer's disease. Mechanistically, cherries exhibit relatively high antioxidant activity, low glycemic response, COX 1 and 2 enzyme inhibition, and other anti-carcinogenic effects in vitro and in animal experiments. Well-designed cherry feeding studies are needed to further substantiate any health benefits in humans.

positive: The cumulative cost of additional wakefulness: dose-response effects on neurobehavioral functions and sleep physiology from chronic sleep restricti... OBJECTIVES: To inform the debate over whether human sleep can be chronically reduced without consequences, we conducted a dose-response chronic sleep restriction experiment in which waking neurobehavioral and sleep physiological functions were monitored and compared to those for total sleep deprivation. DESIGN: The chronic sleep restriction experiment involved randomization to one of three sleep doses (4 h, 6 h, or 8 h time in bed per night), which were maintained for 14 consecutive days. The total sleep deprivation experiment involved 3 nights without sleep (0 h time in bed). Each study also involved 3 baseline (pre-deprivation) days and 3 recovery days. SETTING: Both experiments were conducted under standardized laboratory conditions with continuous behavioral, physiological and medical monitoring. PARTICIPANTS: A total of n = 48 healthy adults (ages 21-38) participated in the experiments. INTERVENTIONS: Noctumal sleep periods were restricted to 8 h, 6 h or 4 h per day for 14 days, or to 0 h for 3 days. All other sleep was prohibited. RESULTS: Chronic restriction of sleep periods to 4 h or 6 h per night over 14 consecutive days resulted in significant cumulative, dose-dependent deficits in cognitive performance on all tasks. Subjective sleepiness ratings showed an acute response to sleep restriction but only small further increases on subsequent days, and did not significantly differentiate the 6 h and 4 h conditions. Polysomnographic variables and delta power in the non-REM sleep EEG-a putative marker of sleep homeostasis--displayed an acute response to sleep restriction with negligible further changes across the 14 restricted nights. Comparison of chronic sleep restriction to total sleep deprivation showed that the latter resulted in disproportionately large waking neurobehavioral and sleep delta power responses relative to how much sleep was lost. A statistical model revealed that, regardless of the mode of sleep deprivation, lapses in behavioral alertness were near-linearly related to the cumulative duration of wakefulness in excess of 15.84 h (s.e. 0.73 h). CONCLUSIONS: Since chronic restriction of sleep to 6 h or less per night produced cognitive performance deficits equivalent to up to 2 nights of total sleep deprivation, it appears that even relatively moderate sleep restriction can seriously impair waking neurobehavioral functions in healthy adults. Sleepiness ratings suggest that subjects were largely unaware of these increasing cognitive deficits, which may explain why the impact of chronic sleep restriction on waking cognitive functions is often assumed to be benign. Physiological sleep responses to chronic restriction did not mirror waking neurobehavioral responses, but cumulative wakefulness in excess of a 15.84 h predicted performance lapses across all four experimental conditions. This suggests that sleep debt is perhaps best understood as resulting in additional wakefulness that has a neurobiological "cost" which accumulates over time.

positive: Monoaminergic neurotransmission: the history of the discovery of antidepressants from 1950s until today. The 1950s saw the clinical introduction of the first two specifically antidepressant drugs: iproniazid, a monoamine-oxidase inhibitor that had been used in the treatment of tuberculosis, and imipramine, the first drug in the tricyclic antidepressant family. Iproniazid and imipramine made two fundamental contributions to the development of psychiatry: one of a social-health nature, consisting in an authentic change in the psychiatric care of depressive patients; and the other of a purely pharmacological nature, since these agents have constituted an indispensable research tool for neurobiology and psychopharmacology, permitting, among other things, the postulation of the first aetiopathogenic hypotheses of depressive disorders. The clinical introduction of fluoxetine, a selective serotonin reuptake inhibitor, in the late 1980s, once again revolutionized therapy for depression, opening the way for new families of antidepressants. The present work reviews, from a historical perspective, the entire process that led to the discovery of these drugs, as well as their contribution to the development of the neuroscientific disciplines. However, all of these antidepressants, like the rest of those currently available for clinical practice, share the same action mechanism, which involves the modulation of monoaminergic neurotransmission at a synaptic level, so that the future of antidepressant therapy would seem to revolve around the search for extraneuronal non-aminergic mechanisms or mechanisms that modulate the intraneuronal biochemical pathways.

positive: Contribution of monoamine oxidase (MAO) inhibition to tobacco and alcohol addiction. Whole-body PET-scan studies in brains of tobacco smokers have shown a decrease in monoamine oxidase (MAO) activity, which reverts to control level when they quit smoking. The observed decrease in MAO activity in smokers is presumably due to their exposure to tobacco constituents that possess MAO-inhibiting properties. The inhibition of MAO activity seems, however, not to be a unique feature of tobacco smoking as subjects with Type II alcoholism have been reported to show a similar decrease in MAO activity that reverses when they cease to use alcohol. The present review summarizes the data on MAO-inhibiting tobacco constituents and explains that the decrease in MAO activity observed in alcoholics is probably due to concomitant tobacco use. It is concluded that the inhibition of MAO by constituents contained in tobacco and tobacco smoke, enhances the addiction induced by tobacco smoking.

positive: Macronutrient intake, plasma large neutral amino acids and mood during weight-reducing diets. Influence of diet composition on mood during weight-reducing diets was studied in healthy young women of normal weight. A broad range of macronutrient intake was achieved by means of divergent dietary instructions for the composition of a 1,000 kcal per day diet adhered to for six weeks. Global mood during the last three weeks of the diet was significantly better in the "vegetarian" than in the "mixed" diet group. During this time a significant correlation was observed between relative carbohydrate intake and global mood (r = -0.74; p less than 0.01) and between the ratio of plasma tryptophan to other large neutral amino acids (a predictor of tryptophan flow into brain) and global mood (r = -0.52; p less than 0.05). Results suggest that group differences are related to differences in carbohydrate intake. It is hypothesized that impairment of central serotonergic function due to reduced tryptophan availability can prompt mood deterioration in situations of relatively low carbohydrate intake.

positive: Brain serotonin content: physiological regulation by plasma neutral amino acids. When plasma tryptophan is elevated by the injection of tryptophan or insulin, or by the consumption of carbohydrates, brain tryptophan and serotonin also rise; however, when even larger elevations of plasma tryptophan are produced by the ingestion of protein-containing diets, brain tryptophan and serotonin do not change. The main determinant of brain tryptophan and serotonin concentrations does not appear to be plasma tryptophan alone, but the ratio of this amino acid to other plasma neutral amino acids (that is, tyrosine, phenylalanine, leucine, isoleucine, and valine) that compete with it for uptake into the brain.

positive: Effect of nutrient intake on premenstrual depression. We examined the occurrence and coincidence of depressed mood and excessive carbohydrate intake in 19 patients who claimed to suffer from severe premenstrual syndrome and in nine control subjects, all as inpatients, during the early follicular and late luteal phases of their menstrual cycles. Mood was assessed with the Hamilton Depression Scale and an addendum that evaluated fatigue, sociability, appetite, and carbohydrate craving. Calorie and nutrient intakes were measured directly. The subjects with premenstrual syndrome significantly increased calorie intake during the late luteal phase (from 1892 +/- 104 to 2395 +/- 93 kcal, mean +/- SEM); carbohydrate intake increased by 24% from meals and by 43% from snacks. Protein intake failed to change, whereas intake of fat, a fixed constituent of all of the test foods, rose in proportion to calorie intake. The Hamilton Depression Scale and addendum scores rose from 2.0 +/- 0.5 to 21.2 +/- 0.8 (Hamilton Scale) and from 0.5 +/- 0.5 to 10.2 +/- 0.6 (addendum) among subjects with premenstrual syndrome during the luteal phase but failed to change among the controls (2.1 +/- 0.8 to 2.4 +/- 0.8, and 0.4 +/- 0.3 to 0.6 +/- 0.3). Consumption of a carbohydrate-rich, protein-poor evening test meal during the late luteal phase of the menstrual cycle improved depression, tension, anger, confusion, sadness, fatigue, alertness, and calmness scores (p less than 0.01) among patients with premenstrual syndrome. No effect of the meal was observed during the follicular phase or among the control subjects during either phase. Because synthesis of brain serotonin, which is known to be involved in mood and appetite, increases after carbohydrate intake, premenstrual syndrome subjects may overconsume carbohydrates in an attempt to improve their dysphoric mood state.

negative: Antioxidants as antidepressants: fact or fiction? Depression is a medical condition with a complex biological pattern of aetiology, involving genetic and epigenetic factors, along with different environmental stressors. Recent evidence suggests that oxidative stress processes might play a relevant role in the pathogenic mechanism(s) underlying many major psychiatric disorders, including depression. Reactive oxygen and nitrogen species have been shown to modulate levels and activity of noradrenaline (norepinephrine), serotonin, dopamine and glutamate, the principal neurotransmitters involved in the neurobiology of depression. Major depression has been associated with lowered concentrations of several endogenous antioxidant compounds, such as vitamin E, zinc and coenzyme Q10, or enzymes, such as glutathione peroxidase, and with an impairment of the total antioxidant status. These observations introduce new potential targets for the development of therapeutic interventions based on antioxidant compounds. The present review focuses on the possible role of oxidative stress processes in the pathogenesis of depression. The therapeutic potential of antioxidant compounds as a co-adjuvant treatment to conventional antidepressants is discussed. For instance, N-acetyl-cysteine has been shown to have a significant benefit on depressive symptoms in a randomized placebo-controlled trial. Additionally, curcumin, the yellow pigment of curry, has been shown to strongly interfere with neuronal redox homeostasis in the CNS and to possess antidepressant activity in various animal models of depression, also thanks to its ability to inhibit monoamine oxidases. There is an urgent need to develop better tolerated and more effective treatments for depressive disorders and several antioxidant treatments appear promising and deserve further study.

negative: Update on the management of postoperative nausea and vomiting and postdischarge nausea and vomiting in ambulatory surgery. Postoperative nausea and vomiting (PONV) continues to be one of the most common complaints following surgery, occurring in more than 30% of surgeries, or as high as 70% to 80% in certain high-risk populations without prophylaxis. The 5-hydroxytryptamine type 3 (5-HT(3)) receptor antagonists continue to be the mainstay of antiemetic therapy, but newer approaches, such as neurokinin-1 antagonists, a longer-acting serotonin receptor antagonist, multimodal management, and novel techniques for managing high-risk patients are gaining prominence. The related problem of postdischarge nausea and vomiting (PDNV) has received increasing attention from health care providers. The issues of PONV and PDNV are especially significant in the context of ambulatory surgeries, which comprise more than 60% of the combined 56.4 million ambulatory and inpatient surgery visits in the United States. Because of the relatively brief period that ambulatory patients spend in health care facilities, it is particularly important to prevent and treat PONV and PDNV swiftly and effectively. Copyright (c) 2010. Published by Elsevier Inc.

negative: The drugs don’t work? antidepressants and the current and future pharmacological management of depression Depression is a potentially life-threatening disorder affecting millions of people across the globe. It is a huge burden to both the individual and society, costing over £9 billion in 2000 alone: the World Health Organisation (WHO) cited it as the third leading cause of global disability in 2004 (first in the developed world), and project it will be the leading cause by 2030. The serendipitous discovery of antidepressants has revolutionized both our understanding and management of depression: however, their efficacy in the treatment of depression has long been debated and recently been brought very much into the public limelight by a controversial publication by Kirsch, in which the role of placebo response in antidepressant efficacy trials is highlighted. Whilst antidepressants offer benefits in both the short and long term, important problems persist such as intolerability, delayed therapeutic onset, limited efficacy in milder depression and the existence of treatment-resistant depression.

negative: Antioxidants as potential therapeutics for neuropsychiatric disorders Oxidative stress has been implicated in the pathophysiology of many neuropsychiatric disorders such as schizophrenia, bipolar disorder, major depression etc. Both genetic and nongenetic factors have been found to cause increased cellular levels of reactive oxygen species beyond the capacity of antioxidant defense mechanism in patients of psychiatric disorders. These factors trigger oxidative cellular damage to lipids, proteins and DNA, leading to abnormal neural growth and differentiation. Therefore, novel therapeutic strategies such as supplementation with antioxidants can be effective for long-term treatment management of neuropsychiatric disorders. The use of antioxidants and PUFAs as supplements in the treatment of neuropsychiatric disorders has provided some promising results. At the same time, one should be cautious with the use of antioxidants since excessive antioxidants could dangerously interfere with some of the protective functions of reactive oxygen species. The present article will give an overview of the potential strategies and outcomes of using antioxidants as therapeutics in psychiatric disorders.

negative: Dietary correlates of urinary 6-sulfatoxymelatonin concentrations in the Nurses' Health Study cohorts Background: Age and certain lifestyle factors, including a higher body mass index and exposure to light at night, are related to lower circulating concentrations of melatonin—a hormone with probable cancer-protective properties. Although melatonin is a direct derivative of the essential amino acid tryptophan, little is known about the relation of diet with melatonin concentrations. Objective: The objective was to examine cross-sectional associations of various nutrients and dietary factors as well as food groups with creatinine-adjusted first morning urinary melatonin (6-sulfatoxymelatonin; aMT6s) concentrations. Design: Participants were 998 healthy women from 2 independent cohorts: the Nurses' Health Study (NHS; n = 585) and NHS II (n = 413). We computed least-squares mean hormone concentrations across categories of dietary variables, with adjustment for total energy intake, age, and other nondietary factors known to be associated with aMT6s concentrations. Results: In multivariate analyses, we found no significant associations between the intake of various nutrients, including tryptophan and urinary melatonin concentrations. A higher intake of meat, particularly red meat, was associated with lower concentrations of aMT6s (adjusted mean concentrations of aMT6s across increasing quartiles of red meat intake were 17.9, 17.0, 18.1, and 15.3 ng/mg creatinine; P for trend = 0.02). In contrast, neither poultry intake (including turkey) nor fish intake was associated with aMT6s concentrations. Conclusion: Although no specific nutrients were associated with altered concentrations of melatonin, our findings raise the possibility that several specific foods, including red meat, could affect cancer risk through the lowering of melatonin concentrations.

negative: Improvements in hostility and depression in relation to dietary change and cholesterol lowering. The Family Heart Study. OBJECTIVE: To describe changes in negative emotions among participants of a cholesterol-lowering study. DESIGN: Cohort study. Quantitative evaluation of changes in negative emotions in relation to diet and plasma cholesterol levels before and after a 5-year dietary intervention program aimed at reducing plasma cholesterol levels. SETTING: Community-dwelling families of the Family Heart Study, Portland, Oregon. PARTICIPANTS: One hundred forty-nine men and 156 women from 233 families (mean age, 37.7 years). MEASUREMENTS: Changes in negative emotions including depression and aggressive hostility as measured by the Hopkins Symptom Checklist (SCL-90). RESULTS: Improvement in overall emotional state was noted for the entire sample. Those who consumed a low-fat, high complex-carbohydrate diet at the end of the study showed significantly greater improvements in depression (P = 0.044; difference in improvement, 2.9 points) and aggressive hostility (P = 0.035; difference in improvement, 3.3 points) as well as a reduction in their plasma cholesterol levels (P = 0.024; difference in improvement, 2.7%) compared with those who ate a high-fat "American diet." CONCLUSIONS: Participation in a cholesterol-lowering program may not be associated with a worsening in emotional state. To the contrary, improvements in diet appear to be associated with reductions in depression and aggressive hostility as well as with lowered plasma cholesterol levels.

negative: Coriander (Coriandrum sativum L.): a potential source of high-value components for functional foods and nutraceuticals--a review. Coriander (Coriandrum sativum L.), a herbal plant, belonging to the family Apiceae, is valued for its culinary and medicinal uses. All parts of this herb are in use as flavoring agent and/or as traditional remedies for the treatment of different disorders in the folk medicine systems of different civilizations. The plant is a potential source of lipids (rich in petroselinic acid) and an essential oil (high in linalool) isolated from the seeds and the aerial parts. Due to the presence of a multitude of bioactives, a wide array of pharmacological activities have been ascribed to different parts of this herb, which include anti-microbial, anti-oxidant, anti-diabetic, anxiolytic, anti-epileptic, anti-depressant, anti-mutagenic, anti-inflammatory, anti-dyslipidemic, anti-hypertensive, neuro-protective and diuretic. Interestingly, coriander also possessed lead-detoxifying potential. This review focuses on the medicinal uses, detailed phytochemistry, and the biological activities of this valuable herb to explore its potential uses as a functional food for the nutraceutical industry. Copyright © 2012 John Wiley & Sons, Ltd.

negative: Update on the management of postoperative nausea and vomiting. New antiemetic drug developments, formulations, guidelines, risk evaluation, and controversies have occurred in the area of postoperative nausea and vomiting (PONV). These developments have helped improve our understanding of the prevention and treatment of PONV in the postanesthesia care unit and after discharge home or to the hospital ward. Antiemetic drug research has resulted in the introduction of the second-generation 5-hydroxytryptamine-3 (5-HT3) receptor antagonist palonosetron and the neurokinin-1 (NK-1) receptor antagonist aprepitant, as well as new data on existing antiemetics. The next frontier and need for further nausea and vomiting research and therapy is the area of postdischarge nausea and vomiting after the patient is discharged home from phase II of the ambulatory stepdown unit or to the hospital ward. Antiemetic drug selection depends on efficacy, cost, safety, and ease of dosing. Safety concerns have arisen regarding the side effects of antiemetics, specifically their effect on the ECG with prolongation of the QTc interval by the butyrophenones and the first-generation 5-HT3 receptor antagonist class of antiemetics. The impact of pharmocogenetics on antiemetic drug metabolism and their resulting efficacy has been correlated with genetic makeup affecting drug response. A discussion of ethics in PONV research has been initiated by the meta-analysis of PONV studies. To help guide antiemetic selection and PONV therapy for clinical practitioners, the Society of Ambulatory Anesthesia (SAMBA) PONV consensus guidelines have been introduced and updated.

negative: Antidepressants and the placebo response. AIMS: To evaluate new generation antidepressants in relation to the placebo response. METHODS: I review meta-analyses in which response to antidepressant medication and response to placebo were calculated. RESULTS: All but one of these meta-analyses included unpublished as well as published trials. Most trials failed to show a significant advantage of SSRIs over inert placebo, and the differences between drug and placebo are not clinically significant for most depressed patients. Documents obtained from the U.S. Food and Drug Administration (FDA) revealed an explicit decision to keep this information from the public and from prescribing physicians. CONCLUSIONS: Because they do not incur drug risks, exercise and psychotherapy, which show at benefits at least equal to those of antidepressants, may be a better treatment choice for depressed individuals.

negative: Genetic Analysis of Chemosensory Traits in Human Twins We explored genetic influences on the perception of taste and smell stimuli. Adult twins rated the chemosensory aspects of water, sucrose, sodium chloride, citric acid, ethanol, quinine hydrochloride, phenylthiocarbamide (PTC), potassium chloride, calcium chloride, cinnamon, androstenone, Galaxolide™, cilantro, and basil. For most traits, individual differences were stable over time and some traits were heritable (h2 from 0.41 to 0.71). Subjects were genotyped for 44 single nucleotide polymorphisms within and near genes related to taste and smell. The results of these association analyses confirmed previous genotype–phenotype results for PTC, quinine, and androstenone. New associations were detected for ratings of basil and a bitter taste receptor gene, TAS2R60, and between cilantro and variants in three genes (TRPA1, GNAT3, and TAS2R50). The flavor of ethanol was related to variation within an olfactory receptor gene (OR7D4) and a gene encoding a subunit of the epithelial sodium channel (SCNN1D). Our study demonstrates that person-to-person differences in the taste and smell perception of simple foods and drinks are partially accounted for by genetic variation within chemosensory pathways.

negative: Dehydroepiandrosterone and ageing. Dehydroepiandrosterone (DHEA) is the major steroid produced by the adrenal zona reticularis and, in contrast to cortisol and aldosterone, its secretion declines with ageing. This has generated major interest in its putative role as an 'anti-ageing' hormone. However, it is not clear that the age-associated, physiological decline in DHEA secretion represents a harmful deficiency. DHEA exhibits its action mainly by conversion to sex steroids. In addition, DHEA has neurosteroidal properties and may exhibit direct action via specific binding sites on endothelial cells. There is convincing evidence for beneficial effects of DHEA in patients with adrenal insufficiency and future research will hopefully elucidate its role in patients receiving pharmacological glucocorticoid treatment. However, in healthy elderly subjects, current evidence from randomised, controlled trials does not justify the use of DHEA, with no major beneficial effects reported and, in addition, potentially adverse effects on sex steroid-dependent tumour growth need to be considered. Copyright 2004 Elsevier Ltd.

negative: Exercise and Pharmacotherapy in the Treatment of Major Depressive Disorder Objective To assess whether patients receiving aerobic exercise training performed either at home or in a supervised group setting achieve reductions in depression comparable to standard antidepressant medication (sertraline) and greater reductions in depression compared to placebo controls. Methods Between October 2000 and November 2005, we performed a prospective, randomized controlled trial (SMILE study) with allocation concealment and blinded outcome assessment in a tertiary care teaching hospital. A total of 202 adults (153 women; 49 men) diagnosed with major depression were assigned randomly to one of four conditions: supervised exercise in a group setting; home-based exercise; antidepressant medication (sertraline, 50–200 mg daily); or placebo pill for 16 weeks. Patients underwent the structured clinical interview for depression and completed the Hamilton Depression Rating Scale (HAM-D). Results After 4 months of treatment, 41% of the participants achieved remission, defined as no longer meeting the criteria for major depressive disorder (MDD) and a HAM-D score of <8. Patients receiving active treatments tended to have higher remission rates than the placebo controls: supervised exercise = 45%; home-based exercise = 40%; medication = 47%; placebo = 31% (p = .057). All treatment groups had lower HAM-D scores after treatment; scores for the active treatment groups were not significantly different from the placebo group (p = .23). Conclusions The efficacy of exercise in patients seems generally comparable with patients receiving antidepressant medication and both tend to be better than the placebo in patients with MDD. Placebo response rates were high, suggesting that a considerable portion of the therapeutic response is determined by patient expectations, ongoing symptom monitoring, attention, and other nonspecific factors.

negative: Does food addiction exist? A phenomenological discussion based on the psychiatric classification of substance-related disorders and addiction. The relationship between overeating, substance abuse and (behavioral) addiction is controversial. Medically established forms of addiction so far pertain to substance use disorders only. But the preliminary Diagnostic and Statistical Manual for Mental Disorders V (DSM V) suggests replacing the previous category 'Substance-Related Disorders' with 'Addiction and Related Disorders', thus for the first time allowing the diagnosis of behavioral addictions. In the past psychiatrists and psychologists have been reluctant to systematically delineate and classify the term behavioral addiction. However, there is a broad overlap between chemical and behavioral addiction including phenomenological, therapeutic, genetic, and neurobiological aspects. It is of interest to point out that the hormone leptin in itself has a pronounced effect on the reward system, thus suggesting an indirect link between overeating and 'chemical' addiction. Thus, leptin-deficient individuals could be classified as fulfilling criteria for food addiction. In our overview we first review psychological findings in chemical (substance-based) and subsequently in behavioral addiction to analyze the overlap. We discuss the diagnostic validity of food addiction, which in theory can be chemically and/or behaviorally based. Copyright © 2012 S. Karger GmbH, Freiburg.

negative: The Efficacy of Paroxetine and Placebo in Treating Anxiety and Depression: A Meta-Analysis of Change on the Hamilton Rating Scales Background Previous meta-analyses of published and unpublished trials indicate that antidepressants provide modest benefits compared to placebo in the treatment of depression; some have argued that these benefits are not clinically significant. However, these meta-analyses were based only on trials submitted for the initial FDA approval of the medication and were limited to those aimed at treating depression. Here, for the first time, we assess the efficacy of a selective serotonin reuptake inhibitor (SSRI) in the treatment of both anxiety and depression, using a complete data set of all published and unpublished trials sponsored by the manufacturer. Methods and Findings GlaxoSmithKline has been required to post the results for all sponsored clinical trials online, providing an opportunity to assess the efficacy of an SSRI (paroxetine) with a complete data set of all trials conducted. We examined the data from all placebo-controlled, double-blind trials of paroxetine that included change scores on the Hamilton Rating Scale for Anxiety (HRSA) and/or the Hamilton Rating Scale for Depression (HRSD). For the treatment of anxiety (k = 12), the efficacy difference between paroxetine and placebo was modest (d = 0.27), and independent of baseline severity of anxiety. Overall change in placebo-treated individuals replicated 79% of the magnitude of paroxetine response. Efficacy was superior for the treatment of panic disorder (d = 0.36) than for generalized anxiety disorder (d = 0.20). Published trials showed significantly larger drug-placebo differences than unpublished trials (d’s = 0.32 and 0.17, respectively). In depression trials (k = 27), the benefit of paroxetine over placebo was consistent with previous meta-analyses of antidepressant efficacy (d = 0.32). Conclusions The available empirical evidence indicates that paroxetine provides only a modest advantage over placebo in treatment of anxiety and depression. Treatment implications are discussed.

negative: High-dose ascorbic acid increases intercourse frequency and improves mood: a randomized controlled clinical trial. BACKGROUND: Ascorbic acid (AA) modulates catecholaminergic activity, decreases stress reactivity, approach anxiety and prolactin release, improves vascular function, and increases oxytocin release. These processes are relevant to sexual behavior and mood. METHODS: In this randomized double-blind, placebo-controlled 14 day trial of sustained-release AA (42 healthy young adults; 3000 mg/day Cetebe) and placebo (39 healthy young adults), subjects with partners recorded penile-vaginal intercourse (FSI), noncoital partner sex, and masturbation in daily diaries, and also completed the Beck Depression Inventory before and after the trial. RESULTS: The AA group reported greater FSI (but, as hypothesized, not other sexual behavior) frequency, an effect most prominent in subjects not cohabiting with their sexual partner, and in women. The AA but not placebo group also experienced a decrease in Beck Depression scores. CONCLUSIONS: AA appears to increase FSI, and the differential benefit to noncohabitants suggests that a central activation or disinhibition, rather than peripheral mechanism may be responsible.

negative: Post-epidemic eosinophilia myalgia syndrome associated with L-Tryptophan Eosinophilia–myalgia syndrome (EMS) is characterized by subacute onset of myalgias and peripheral eosinophilia, followed by chronic neuropathy and skin induration. An epidemic of EMS in 1989 was linked to L-tryptophan consumption originating from a single source. Following the Food and Drug Administration (FDA) ban on the sale of L-tryptophan, the incidence of EMS declined rapidly. Moreover, no new cases have been published since the FDA ban was lifted in 2005. We report the clinical, histopathological and immunogenetic features of a new case of L-tryptophan-associated EMS along with evidence of activated transforming growth factor-ß and interleukin-4 signaling in the lesional skin.

negative: Protein-source tryptophan as an efficacious treatment for social anxiety disorder: a pilot study. Until recently, intact protein that is rich in tryptophan was not seen as an alternative to pharmaceutical-grade tryptophan because protein also contains large neutral amino acids (LNAAs) that compete for transport sites across the blood-brain barrier. Recent evidence indicates that when deoiled gourd seed (a rich source of tryptophan with approximately 22 mg/g protein) is combined with glucose (a carbohydrate that reduces serum levels of competing LNAAs) a clinical effect similar to that of pharmaceutical-grade tryptophan is achieved. Objective and subjective measures of anxiety in those suffering from social phobia (also known as social anxiety disorder) were employed to measure changes in anxiety in response to a stimulus as part of a double-blind, placebo-controlled, crossover study with a wash-out period of 1 week between study sessions. Subjects were randomly assigned to start with either (i) protein-source tryptophan (deoiled gourd seed) in combination with carbohydrate or (ii) carbohydrate alone. One week after the initial session, subjects returned for a follow-up session and received the opposite treatment of that received at the first session. All 7 subjects who began the study completed the 2-week protocol. Protein-source tryptophan with carbohydrate, but not carbohydrate alone, resulted in significant improvement on an objective measure of anxiety. Protein-source tryptophan combined with a high glycemic carbohydrate is a potential anxiolytic to those suffering from social phobia.

negative: Triptans (serotonin, 5-HT1B/1D agonists) in migraine: detailed results and methods of a meta-analysis of 53 trials. The triptans, selective serotonin 5-HT1B/1D agonists, are very effective acute migraine drugs. Soon, seven different triptans will be clinically available at 13 different oral doses, making evidence-based selection guidelines necessary. Triptan trials have similar designs, facilitating meta-analysis. We wished to provide an evidence-based foundation for using triptans in clinical practice, and to review the methodological issues surrounding triptan trials. We asked pharmaceutical companies and the principal investigators of company-independent trials for the 'raw patient data' of all double-blind, randomized, controlled, clinical trials with oral triptans in migraine. All data were cross-checked with published or presented data. We calculated summary estimates across studies for important efficacy and tolerability parameters, and compared these with those from direct, head-to-head, comparator trials. Out of 76 eligible clinical trials, 53 (12 not yet published) involving 24089 patients met the criteria for inclusion. Mean results (and 95% confidence intervals) for sumatriptan 100 mg, the first available and most widely prescribed oral triptan, are 59% (57-60) for 2 h headache response (improvement from moderate or severe to mild or no pain); 29% (27-30) for 2 h pain free (improvement to no pain); 20% (18-21) for sustained pain free (pain free by 2 h and no headache recurrence or use of rescue medication 2-24 h post-dose), and 67% (63-70) for consistency (response in at least two out of three treated attacks); placebo-subtracted proportions for patients with at least one adverse event (AE) are 13% (8-18), for at least one central nervous system AE 6% (3-9), and for at least one chest AE 1.9% (1.0-2.7). Compared with these data: rizatriptan 10 mg shows better efficacy and consistency, and similar tolerability; eletriptan 80 mg shows better efficacy, similar consistency, but lower tolerability; almotriptan 12.5 mg shows similar efficacy at 2 h but better sustained pain-free response, consistency, and tolerability; sumatriptan 25 mg, naratriptan 2.5 mg and eletriptan 20 mg show lower efficacy and better tolerability; zolmitriptan 2.5 mg and 5 mg, eletriptan 40 mg, and rizatriptan 5 mg show very similar results. The results of the 22 trials that directly compared triptans show the same overall pattern. We received no data on frovatriptan, but publicly available data suggest substantially lower efficacy. The major methodological issues involve the choice of the primary endpoint, consistency over multiple attacks, how to evaluate headache recurrence, use of placebo-subtracted proportions to control for across-study differences, and the difference between tolerability and safety. In addition, there are a number of methodological issues specific for direct comparator trials, including encapsulation and patient selection. At marketed doses, all oral triptans are effective and well tolerated. Differences among them are in general relatively small, but clinically relevant for individual patients. Rizatriptan 10 mg, eletriptan 80 mg and almotriptan 12.5 mg provide the highest likelihood of consistent success. Sumatriptan features the longest clinical experience and the widest range of formulations. All triptans are contra-indicated in the presence of cardiovascular disease.

negative: Beta-casomorphins-7 in infants on different type of feeding and different levels of psychomotor development. Casomorphins are the most important during the first year of life, when postnatal formation is most active and milk is the main source of both nutritive and biologically active material for infants. This study was conducted on a total of 90 infants, of which 37 were fed with breast milk and 53 were fed with formula containing cow milk. The study has firstly indicated substances with immunoreactivity of human (irHCM) and bovine (irBCM) beta-casomorphins-7 in blood plasma of naturally and artificially fed infants, respectively. irHCM and irBCM were detected both in the morning before feeding (basal level), and 3h after feeding. Elevation of irHCM and irBCM levels after feeding was detected mainly in infants in the first 3 months of life. Chromatographic characterization of the material with irBCM has demonstrated that it has the same molecular mass and polarity as synthetic bovine beta-casomorphin-7. The highest basal irHCM was observed in breast-fed infants with normal psychomotor development and muscle tone. In contrast, elevated basal irBCM was found in formula-fed infants showing delay in psychomotor development and heightened muscle tone. Among formula-fed infants with normal development, the rate of this parameter directly correlated to basal irBCM. The data indicate that breast feeding has an advantage over artificial feeding for infants' development during the first year of life and support the hypothesis for deterioration of bovine casomorphin elimination as a risk factor for delay in psychomotor development and other diseases such as autism.

negative: Treatment-emergent sexual dysfunction related to antidepressants: a meta-analysis. BACKGROUND: Sexual dysfunction (SD) is an important underestimated adverse effect of antidepressant drugs. Patients, in fact, if not directly questioned, tend to scarcely report them. The aim of the present meta-analysis was to quantify SD caused by antidepressants on the basis of studies where sexual functioning was purposely investigated through direct inquiry and specific questionnaires. METHODS: A literature search was conducted using MEDLINE, ISI Web of Knowledge, and references of selected articles. Selected studies performed on patients without previous SD were entered in the Cochrane Collaboration Review Manager (RevMan version 4.2). Our primary outcome measure was the rate of total treatment-emergent SD. Our secondary outcome measures were the rates of treatment-emergent desire, arousal, and orgasm dysfunction. RESULTS: Our analyses indicated a significantly higher rate of total and specific treatment-emergent SD and specific phases of dysfunction compared with placebo for the following drugs in decreasing order of impact: sertraline, venlafaxine, citalopram, paroxetine, fluoxetine, imipramine, phenelzine, duloxetine, escitalopram, and fluvoxamine, with SD ranging from 25.8% to 80.3% of patients. No significant difference with placebo was found for the following antidepressants: agomelatine, amineptine, bupropion, moclobemide, mirtazapine, and nefazodone. DISCUSSION: Treatment-emergent SD caused by antidepressants is a considerable issue with a large variation across compounds. Some assumptions, such as the inclusion of open-label studies or differences in scales used to assess SD, could reduce the significance of our findings. However, treatment-emergent SD is a frequent adverse effect that should be considered in clinical activity for the choice of the prescribed drug.

negative: Treatment of abdominal pain in irritable bowel syndrome. Functional abdominal pain in the context of irritable bowel syndrome (IBS) is a challenging problem for primary care physicians, gastroenterologists and pain specialists. We review the evidence for the current and future non-pharmacological and pharmacological treatment options targeting the central nervous system and the gastrointestinal tract. Cognitive interventions such as cognitive behavioral therapy and hypnotherapy have demonstrated excellent results in IBS patients, but the limited availability and labor-intensive nature limit their routine use in daily practice. In patients who are refractory to first-line therapy, tricyclic antidepressants (TCA) and selective serotonin reuptake inhibitors are both effective to obtain symptomatic relief, but only TCAs have been shown to improve abdominal pain in meta-analyses. A diet low in fermentable carbohydrates and polyols (FODMAP) seems effective in subgroups of patients to reduce abdominal pain, bloating, and to improve the stool pattern. The evidence for fiber is limited and only isphagula may be somewhat beneficial. The efficacy of probiotics is difficult to interpret since several strains in different quantities have been used across studies. Antispasmodics, including peppermint oil, are still considered the first-line treatment for abdominal pain in IBS. Second-line therapies for diarrhea-predominant IBS include the non-absorbable antibiotic rifaximin and the 5HT3 antagonists alosetron and ramosetron, although the use of the former is restricted because of the rare risk of ischemic colitis. In laxative-resistant, constipation-predominant IBS, the chloride-secretion stimulating drugs lubiprostone and linaclotide, a guanylate cyclase C agonist that also has direct analgesic effects, reduce abdominal pain and improve the stool pattern.

negative: 99th Dahlem Conference on Infection, Inflammation and Chronic Inflammatory Disorders: Psycho-neuroimmunology and the intestinal microbiota: clinical observations and basic mechanisms This is a rapidly emerging field. The application of knowledge regarding the relationship between neural and immune systems in order to gain a better understanding of human conditions has been slow. In this discussion we describe how the brain and microbiota interact, and try to bring this into a context that is clinically relevant. We begin by describing established facts pertaining to the gut–brain axis and the role of gut bacteria. We then focus upon emerging data that will contribute to the generation of a new conceptual framework about the microbiota–gut–brain axis. In the final section we anticipate future directions of this field.

negative: Assessment of psychotropic-like properties of a probiotic formulation (Lactobacillus helveticus R0052 and Bifidobacterium longum R0175) in rats and... In a previous clinical study, a probiotic formulation (PF) consisting of Lactobacillus helveticus R0052 and Bifidobacterium longum R0175 (PF) decreased stress-induced gastrointestinal discomfort. Emerging evidence of a role for gut microbiota on central nervous system functions therefore suggests that oral intake of probiotics may have beneficial consequences on mood and psychological distress. The aim of the present study was to investigate the anxiolytic-like activity of PF in rats, and its possible effects on anxiety, depression, stress and coping strategies in healthy human volunteers. In the preclinical study, rats were daily administered PF for 2 weeks and subsequently tested in the conditioned defensive burying test, a screening model for anti-anxiety agents. In the clinical trial, volunteers participated in a double-blind, placebo-controlled, randomised parallel group study with PF administered for 30 d and assessed with the Hopkins Symptom Checklist (HSCL-90), the Hospital Anxiety and Depression Scale (HADS), the Perceived Stress Scale, the Coping Checklist (CCL) and 24 h urinary free cortisol (UFC). Daily subchronic administration of PF significantly reduced anxiety-like behaviour in rats (P < 0·05) and alleviated psychological distress in volunteers, as measured particularly by the HSCL-90 scale (global severity index, P < 0·05; somatisation, P < 0·05; depression, P < 0·05; and anger-hostility, P < 0·05), the HADS (HADS global score, P < 0·05; and HADS-anxiety, P < 0·06), and by the CCL (problem solving, P < 0·05) and the UFC level (P < 0·05). L. helveticus R0052 and B. longum R0175 taken in combination display anxiolytic-like activity in rats and beneficial psychological effects in healthy human volunteers.

negative: A double-blind, randomized controlled clinical trial comparing eicosapentaenoic acid versus docosahexaenoic acid for depression. OBJECTIVE: To compare 2 omega-3 (n-3) preparations enriched with eicosapentaenoic acid (EPA) versus docosahexaenoic acid (DHA) as monotherapy for major depressive disorder (MDD) in a 2-site, placebo-controlled, randomized, double-blind clinical trial. METHOD: 196 adults (53% female; mean [SD] age = 44.7 [13.4] years) with DSM-IV MDD and a baseline 17-item Hamilton Depression Rating Scale (HDRS-17) score ≥ 15 were randomized equally from May 18, 2006, to June 30, 2011, to 8 weeks of double-blind treatment with oral EPA-enriched n-3 1000 mg/d, DHA-enriched n-3 1,000 mg/d, or placebo. RESULTS: 154 subjects completed the study. Modified intent-to-treat (mITT) analysis (n = 177 subjects with ≥ 1 postbaseline visit; 59.3% female, mean [SD] age 45.8 [12.5] years) employed mixed-model repeated measures (MMRM). All 3 groups demonstrated statistically significant improvement in the HDRS-17 (primary outcome measure), 16-item Quick Inventory of Depressive Symptomatology-Self Report (QIDS-SR-16), and Clinical Global Improvement-Severity Scale (CGI-S) (P < .05), but neither n-3 preparation separated from placebo (P > .05). Response and remission rates were in the range of 40%-50% and 30%, respectively, for all treatments, with no significant differences between groups. One subject receiving EPA-enriched n-3 discontinued due to worsening depression, and 1 subject receiving placebo discontinued due to an unspecified "negative reaction" to pills. CONCLUSIONS: Neither EPA-enriched nor DHA-enriched n-3 was superior to placebo for the treatment of MDD. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00517036. © Copyright 2015 Physicians Postgraduate Press, Inc.

negative: Plasma concentrations of homocysteine and other aminothiol compounds are related to food intake in healthy human subjects. We investigated total, free and protein-bound plasma homocysteine, cysteine and cysteinylglycine in 13 subjects aged 24-29 y after a breakfast at 0900 h containing 15-18 g of protein and a dinner at 1500 h containing approximately 50 g of protein. Twelve subjects had normal fasting homocysteine (mean +/- SD, 7.6 +/- 1.1 mumol/L) and methionine concentrations (22.7 +/- 3.5 mumol/L) and were included in the statistical analyses. Breakfast caused a small but significant increase in plasma methionine (22.2 +/- 20.6%) and a brief, nonsignificant increase followed by a significant decline in free homocysteine. However, changes in total and bound homocysteine were small. After dinner, there was a marked increase in plasma methionine by 16.7 +/- 8.9 mumol/L (87.9 +/- 49%), which was associated with a rapid and marked increase in free homocysteine (33.7 +/- 19.6%, 4 h after dinner) and a moderate and slow increase in total (13.5 +/- 7.5%, 8 h) and protein-bound (12.6 +/- 9.4%, 8 h) homocysteine. After both meals, cysteine and cysteinylglycine concentrations seemed related to changes in homocysteine, because there were parallel fluctuations in the free:bound ratios of all three thiols. Dietary changes in plasma homocysteine will probably not affect the evaluation of vitamin deficiency states associated with moderate to severe hyperhomocysteinemia but may be of concern in the risk assessment of cardiovascular disease in patients with mild hyperhomocysteinemia. Synchronous fluctuations in the free:bound ratio of the plasma aminothiol compounds indicate that biological effects of homocysteine may be difficult to separate from effects due to associated changes in other aminothiol compounds.

negative: Hydro-alcoholic extract of Crocus sativus L. versus fluoxetine in the treatment of mild to moderate depression: a double-blind, randomized pilot tr... Depressive disorders are very common in clinical practice, with approximately 11.3 of all adults afflicted during any a year. Saffron is the world's most expensive spice and apart from its traditional value as a food additive, recent studies indicate several therapeutic effects for saffron. It is used for depression in Persian traditional medicine. Our objective was to compare the efficacy of hydro-alcoholic extract of Crocus sativus (stigma) with fluoxetine in the treatment of mild to moderate depression in a 6-week double-blind, randomized trial. Forty adult outpatients who met the Diagnostic and Statistical Manual of Mental Disorders, fourth edition for major depression based on the structured clinical interview for DSM-IV and with mild to moderate depression participated in the trial. In this double-blind, single-center trial and randomized trial, patients were randomly assigned to receive capsules of saffron 30 mg/day (BD) (Group 1) and capsule of fluoxetine 20 mg/day (BD) (Group 2) for a 6-week study. Saffron at this dose was found to be effective similar to fluoxetine in the treatment of mild to moderate depression (F = 0.13, d.f. = 1, P = 0.71). There were no significant differences in the two groups in terms of observed side effects. The results of this study indicate the efficacy of Crocus sativus in the treatment of mild to moderate depression. A large-scale trial is justified.

negative: Opiate receptor: demonstration in nervous tissue. Tritiated naloxone, a powerful opiate antagonist, specifically binds to an opiate receptor of mammalian brain and guinea pig intestine. Competition for the opiate receptor by various opiates and their antagonists closely parallels their pharmacological potency. The opiate receptor is confined to nervous tissue.

negative: Sub-clinical neurobehavioral abnormalities associated with low level of mercury exposure through fish consumption. In order to assess early neurotoxic effects associated with relatively low levels of mercury absorbed through fish eating, two groups of 22 adult male subjects, habitual consumers of tuna fish, and 22 controls were examined using a cross-sectional field study. The assessment included neurobehavioral tests of vigilance and psychomotor function, hand tremor measurements and serum prolactin assessment. Mercury in urine (U-Hg) and serum prolactin (sPRL) were measured in all exposed subjects and controls, whereas measurements of the organic component of mercury in blood (O-Hg) were available for only 10 exposed and six controls. U-Hg was significant higher among exposed subjects (median 6.5 microg/g of creatinine, range 1.8-21.5) than controls (median 1.5 microg/g of creatinine, range 0.5-5.3). The median values of O-Hg were 41.5 microg/l among the tuna fish eaters and 2.6 microg/l in the control group. Both U-Hg and O-Hg were significantly correlated with the quantity of fish consumed per week. Significant differences in sPRL were found between exposed (12.6 ng/ml) and controls (9.1 ng/ml). Individual sPRL were significantly correlated with both U-Hg and O-Hg levels. The neurobehavioral performance of subjects who consumed tuna fish regularly was significantly worse on color word reaction time, digit symbol reaction time and finger tapping speed (FT). After considering the education level and other covariates, the multiple stepwise regression analysis indicated that O-Hg concentration was most significantly associated with individual performance on these tests, accounting for about 65% of the variance in test scores.

negative: Is whole-body hydration an important consideration in dry eye? PURPOSE: To identify if whole-body hydration plays an important role in dry eye (DE). We hypothesized that individuals classified as DE have higher plasma osmolality (Posm), indicating suboptimal hydration, compared with those classified as non-DE. METHODS: Using a hospital-based observational cross-sectional design, assessment of DE and hydration was performed upon admission in 111 participants (N = 56 males and 55 females; mean ± SD age 77 ± 8 years). Assessments of DE included tear osmolarity (Tosm), the 5-item dry eye questionnaire (DEQ-5), rating of eye dryness using a visual analogue scale (VAS), and noninvasive tear film breakup time (NITBUT). Hydration assessment was performed by measuring Posm using freezing-point depression osmometry. RESULTS: Posm was higher in DE than control (CON), indicating suboptimal hydration when using the 316 mOsm/L Tosm cutoff for DE (mean Posm + 11 mOsm/kg versus CON, P = 0.004, Cohen's effect size [d]) = 0.83) and the more conservative Tosm classification for DE where Tosm >324 and CON <308 mOsm/L (mean Posm + 12 mOsm/kg versus CON, P = 0.006, d = 0.94). Posm was also higher in DE than CON when using composite DE assessments, including Tosm and DEQ-5 (P = 0.021, d = 1.07); Tosm and NITBUT (P = 0.013, d = 1.08); and the VAS and DEQ-5 (P = 0.034, d = 0.58). CONCLUSIONS: These are the first published data to show that individuals classified as DE have higher Posm, indicating suboptimal hydration, compared with non-DE. These findings indicate that whole-body hydration is an important consideration in DE.

negative: Formaldehyde, aspartame, and migraines: a possible connection. Aspartame is a widely used artificial sweetener that has been linked to pediatric and adolescent migraines. Upon ingestion, aspartame is broken, converted, and oxidized into formaldehyde in various tissues. We present the first case series of aspartame-associated migraines related to clinically relevant positive reactions to formaldehyde on patch testing.

negative: An introduction to migraine: from ancient treatment to functional pharmacology and antimigraine therapy. Migraine treatment has evolved from the realms of the supernatural into the scientific arena, but it seems still controversial whether migraine is primarily a vascular or a neurological dysfunction. Irrespective of this controversy, the levels of serotonin (5-hydroxytryptamine; 5-HT), a vasoconstrictor and a central neurotransmitter, seem to decrease during migraine (with associated carotid vasodilatation) whereas an i.v. infusion of 5-HT can abort migraine. In fact, 5-HT as well as ergotamine, dihydroergotamine and other antimigraine agents invariably produce vasoconstriction in the external carotid circulation. The last decade has witnessed the advent of sumatriptan and second generation triptans (e.g. zolmitriptan, rizatriptan, naratriptan), which belong to a new class of drugs, now known as 5-HT1B/1D/1F receptor agonists. Compared to sumatriptan, the second-generation triptans have a higher oral bioavailability and longer plasma half-life. In line with the vascular and neurogenic theories of migraine, all triptans produce selective carotid vasoconstriction (via 5-HT1B receptors) and presynaptic inhibition of the trigeminovascular inflammatory responses implicated in migraine (via 5-HT1D/5-ht1F receptors). Moreover, selective agonists at 5-HT1D (PNU-142633) and 5-ht1F (LY344864) receptors inhibit the trigeminovascular system without producing vasoconstriction. Nevertheless, PNU-142633 proved to be ineffective in the acute treatment of migraine, whilst LY344864 did show some efficacy when used in doses which interact with 5-HT1B receptors. Finally, although the triptans are effective antimigraine agents producing selective cranial vasoconstriction, efforts are being made to develop other effective antimigraine alternatives acting via the direct blockade of vasodilator mechanisms (e.g. antagonists at CGRP receptors, antagonists at 5-HT7 receptors, inhibitors of nitric oxide biosynthesis, etc). These alternatives will hopefully lead to fewer side-effects.