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Effects of L-Theanine Administration on Stress-Related Symptoms and Cognitive Functions in Healthy Adults: A Randomized Controlled Trial.
Hidese, S, Ogawa, S, Ota, M, Ishida, I, Yasukawa, Z, Ozeki, M, Kunugi, H
Nutrients. 2019;11(10)
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L-theanine (γ-glutamylethylamide) is a unique non-protein amino acid found in green tea (Camellia sinensis), a widely consumed beverage associated with human health. The aim of this study was to examine the effects of four weeks L-theanine administration (200 mg/day, four weeks) in a healthy population, i.e., individuals without any major psychiatric disorder. This study is a randomized, placebo-controlled, crossover, and double-blind trial. The study enrolled thirty individuals (n = 9 men and n = 21 women). Participants received either an enzymatic synthetic product L-theanine or placebo tablets who had to orally self-administer before sleep each night for four weeks. Results show that four weeks L-theanine administration has positive effects on stress-related symptoms and cognitive function in a healthy population. Furthermore, the reduction in sleep quality problems (disturbances in sleep latency, sleep disturbance and use of sleep medication) was greater in the L-theanine administration compared to the placebo administration, while verbal fluency, especially letter fluency, was improved in the L-theanine administration among individuals who showed relatively low performance at pre-treatment. Authors conclude that L-theanine may be a suitable nutraceutical ingredient for improving mental conditions in a healthy population.
Abstract
This randomized, placebo-controlled, crossover, and double-blind trial aimed to examine the possible effects of four weeks L-theanine administration on stress-related symptoms and cognitive functions in healthy adults. Participants were 30 individuals (nine men and 21 women; age: 48.3 ± 11.9 years) who had no major psychiatric illness. L-theanine (200 mg/day) or placebo tablets were randomly and blindly assigned for four-week administration. For stress-related symptoms, Self-rating Depression Scale, State-Trait Anxiety Inventory-trait, and Pittsburgh Sleep Quality Index (PSQI) scores decreased after L-theanine administration (p = 0.019, 0.006, and 0.013, respectively). The PSQI subscale scores for sleep latency, sleep disturbance, and use of sleep medication reduced after L-theanine administration, compared to the placebo administration (all p < 0.05). For cognitive functions, verbal fluency and executive function scores improved after L-theanine administration (p = 0.001 and 0.031, respectively). Stratified analyses revealed that scores for verbal fluency (p = 0.002), especially letter fluency (p = 0.002), increased after L-theanine administration, compared to the placebo administration, in individuals who were sub-grouped into the lower half by the median split based on the mean pretreatment scores. Our findings suggest that L-theanine has the potential to promote mental health in the general population with stress-related ailments and cognitive impairments.
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Gut feelings: A randomised, triple-blind, placebo-controlled trial of probiotics for depressive symptoms.
Chahwan, B, Kwan, S, Isik, A, van Hemert, S, Burke, C, Roberts, L
Journal of affective disorders. 2019;253:317-326
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Depression is a debilitating psychiatric disorder that is the leading cause of disability world-wide. Multiple causes of depression have been identified, including genetic, neurological, inflammatory, personality, cognitive, and environmental factors. The aim of this study was to investigate the effectiveness of the multispecies probiotic Ecologic® Barrier for reducing symptoms in adults with mild to severe levels of depression. The study was a triple-blinded parallel, placebo-controlled randomised clinical trial. Participants were randomly allocated into two groups; probiotic and placebo. 71 participants with depressive symptoms were recruited and allocated sequentially over 12 months. Results indicate that all participants across both probiotic and placebo groups exhibited a reduction in depressive symptoms over the time-period of the trial. Thus, the routine involved with daily preparation and consumption of the probiotic and scheduled appointments, as well as involvement in these behaviours with the aim of seeking improvement in depressive symptoms had positive impacts on mood, irrespective of whether the probiotic or placebo was consumed. Authors conclude that their findings offer evidence to indicate that probiotic consumption can exert change on cognitive patterns associated with depression.
Expert Review
Conflicts of interest:
None
Take Home Message:
- This study offers evidence to indicate that probiotic consumption can exert change on cognitive patterns associated with depression.
- The study suggests that probiotics, rather than having a direct effect on depressive symptoms, potentially act on immune system activity, inflammation and gut barrier integrity which contribute to the expression of depression.
- Probiotics may be a useful adjunct to potentiate the effects of other therapies, such as CBT.
- This study points to the validity of managing physical health as part of mental health treatment.
Evidence Category:
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A: Meta-analyses, position-stands, randomized-controlled trials (RCTs)
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B: Systematic reviews including RCTs of limited number
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C: Non-randomized trials, observational studies, narrative reviews
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D: Case-reports, evidence-based clinical findings
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E: Opinion piece, other
Summary Review:
With evidence suggesting that decreased gut barrier function and inflammation are correlated with depression, this study set out to determine the effect of consumption of probiotic supplements on depressive symptoms from a sample of 71 participants with depression. The study was a triple-blinded parallel, placebo-controlled randomised clinical trial conducted over 8 weeks in Australia. Pre and post intervention measures of symptoms and vulnerability markers of depression as well as gut microbiota were compared alongside psychological variables and gut microbiota composition to non-depressed, placebo and probiotic groups. All the clinical trial participants demonstrated an improvement in symptoms – participants in the probiotic group demonstrated a significantly greater reduction in cognitive reactivity compared with the placebo group. Probiotics did not significantly alter the microbiota of depressed individuals, however a significant correlation was found between Ruminococcus gnavus and one of the metrics for depression.
Clinical practice applications:
This study was small and carried out over a short period of time. While significant results were found, which signify potential considerations for clinical practice, the results from this study do not offer evidence that the probiotics used had a direct effect on depressive symptoms – they suggest that probiotics potentially act on cognitive processes contributing to depression which may include immune system activity, inflammation, and gut barrier integrity. Overall, this study offers evidence to indicate that probiotic consumption can exert change on cognitive patterns associated with depression. In clinical practice, probiotics may be a useful adjunct to potentiate the effects of therapies, such as CBT. Finally, the use of probiotics promotes the concept of managing physical health as part of mental health treatment.
Considerations for future research:
These preliminary results are promising and offer a number of future research and clinical avenues to build upon. The results do however, indicate that a longer trial may be needed to fully assess the effects of probiotics on mood and the mechanisms by which probiotics may be influencing this. The study also suggests that further research using a range of concentrations in a dose response study may be warranted to determine the optimal dose; a greater dose over a longer period may produce detectable changes in microbiota as well as further differences in psychological data.
Abstract
BACKGROUND Depression is the leading cause of disability worldwide; with evidence suggesting that decreased gut barrier function and inflammation are correlated with depressive symptoms. We conducted a clinical trial to determine the effect of consumption of probiotic supplements (Winclove's Ecologic® Barrier) on depressive symptoms in a sample of participants with mild to severe depression. METHOD 71 participants were randomly allocated to either probiotic or placebo, which was, consumed daily over eight weeks. Pre- and post-intervention measures of symptoms and vulnerability markers of depression as well as gut microbiota composition were compared. Clinical trial participants were also compared on psychological variables and gut microbiota composition to a non-depressed group (n = 20). RESULTS All clinical trial participants demonstrated improvement in symptoms, suggesting non-specific therapeutic effects associated with weekly monitoring visits. Participants in the probiotic group demonstrated a significantly greater reduction in cognitive reactivity compared with the placebo group, particularly in the mild/moderate subgroup. Probiotics did not significantly alter the microbiota of depressed individuals, however, a significant correlation was found between Ruminococcus gnavus and one depression metric. LIMITATIONS There was a high attrition rate, which may be attributed to weekly monitoring visits. Additionally, modulation of the gut microbiota may need more specific testing to distinguish subtle changes. CONCLUSIONS While microbiota composition was similar between all groups, probiotics did affect a psychological variable associated with susceptibility to depression. Further research is needed to investigate how probiotics can be utilised to modify mental wellbeing, and whether they can act as an adjunct to existing treatments.
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Gut feeling: randomized controlled trials of probiotics for the treatment of clinical depression: Systematic review and meta-analysis.
Nikolova, V, Zaidi, SY, Young, AH, Cleare, AJ, Stone, JM
Therapeutic advances in psychopharmacology. 2019;9:2045125319859963
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Major depression is a common and complex illness that significantly diminishes quality of life. Currently, most pharmacological treatments target neurotransmitter activity in the brain and are known to have a delayed onset of effect as well as a range of side-effects. The aim of this study was to identify and synthesize all published data from randomized controlled trials (RCTs) on the efficacy of probiotics as treatment for depression in clinically depressed patients. This study is a systematic review of three studies. Within the three included RCTs, a total of 229 clinically depressed patients were randomized, with an average age of 36 years and a gender distribution of 76% female. Results indicate a non-significant difference in depressive symptoms between the probiotic and placebo groups post-intervention. Authors conclude that further larger studies in well-defined clinical populations are needed, both to determine the clinical utility of this novel treatment approach, and to investigate potential underlying mechanisms.
Abstract
BACKGROUND Recently the gut microbiota has attracted significant interest in psychiatric research due to the observed bidirectional gut-brain communication. A growing body of evidence from preclinical work has suggested that probiotics may be effective in reducing stress and anxiety and alleviating low mood. It is unclear to what extent these effects are seen in clinical populations. We aimed to identify all published evidence on the efficacy of probiotics as treatment for depression in clinically depressed populations. METHODS Randomized controlled trials of patients with depression where probiotics were used as supplementary or standalone treatment were considered eligible. A literature search with the terms (probiotic* OR bacteria OR Lactobacillus OR Bifidobacterium) AND depress* was performed in PubMed and Web of Science. Data on study population characteristics, treatment effectiveness, tolerability and risk of bias were extracted from eligible studies. A random effects model was used for meta-analyses. RESULTS Only three studies met inclusion criteria (229 individuals randomized), two of which administered probiotics as a supplementary treatment to antidepressants and one as a standalone treatment. Upon removal of the latter study from the meta-analysis due to clinical heterogeneity, there was an overall positive effect of probiotics on depressive symptoms (standardized mean difference = 1.371, 95% confidence interval 0.130-2.613). CONCLUSIONS There is limited evidence for the efficacy of probiotics in depression at present, although there may be a beneficial effect of probiotics on depressive symptoms when administered in addition to antidepressants. Further studies are required to investigate this and explore potential mechanisms.
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Tryptophan Metabolism in Inflammaging: From Biomarker to Therapeutic Target.
Sorgdrager, FJH, Naudé, PJW, Kema, IP, Nollen, EA, Deyn, PP
Frontiers in immunology. 2019;10:2565
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Inflammation is a normal physiological process activated by the immune system in response to injury or infection. As we age, the immune system changes and the balance between pro- and anti-inflammatory agents can shift. This causes a chronic inflammatory state referred to as inflammaging. The rate of inflammaging is strongly associated with age-related disability, disease and mortality. The way in which the essential amino acid tryptophan (Trp) is broken down affects inflammation. If it is converted to kynurenine (Kyn) and its metabolites, inflammation is modulated. Studies have shown that the Kyn/Trp ratio, measured in blood, is strongly associated with ageing in humans. It could therefore be a useful marker to predict the onset of age-related diseases. This review discusses the metabolism of Trp and the links to inflammation. The authors hypothesize how intervening in these pathways could impact health- and lifespan. Future studies are needed to confirm the value of Trp metabolism as a biomarker for (un)healthy ageing and as drug target for inflammaging-related disease.
Abstract
Inflammation aims to restore tissue homeostasis after injury or infection. Age-related decline of tissue homeostasis causes a physiological low-grade chronic inflammatory phenotype known as inflammaging that is involved in many age-related diseases. Activation of tryptophan (Trp) metabolism along the kynurenine (Kyn) pathway prevents hyperinflammation and induces long-term immune tolerance. Systemic Trp and Kyn levels change upon aging and in age-related diseases. Moreover, modulation of Trp metabolism can either aggravate or prevent inflammaging-related diseases. In this review, we discuss how age-related Kyn/Trp activation is necessary to control inflammaging and alters the functioning of other metabolic faiths of Trp including Kyn metabolites, microbiota-derived indoles and nicotinamide adenine dinucleotide (NAD+). We explore the potential of the Kyn/Trp ratio as a biomarker of inflammaging and discuss how intervening in Trp metabolism might extend health- and lifespan.
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Effects of Diet Based on IgG Elimination Combined with Probiotics on Migraine Plus Irritable Bowel Syndrome.
Xie, Y, Zhou, G, Xu, Y, He, B, Wang, Y, Ma, R, Chang, Y, He, D, Xu, C, Xiao, Z
Pain research & management. 2019;2019:7890461
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The causes of irritable bowel syndrome (IBS) are complex and not fully understood, yet the occurrence of migraine has been linked with this disease. As they have an association, therapies used for either disorder may have a direct impact on both. Food sensitivities have been shown to affect both migraines and IBS and the elimination of foods may be of benefit to both disorders. This randomised cross-over trial of 60 individuals with migraine and IBS assessed immune reactions to certain foods and aimed to determine the effect of eliminating these foods and the addition of probiotics on individuals with IBS and migraine. The results showed that after 14 weeks of treatment, only elimination diet combined with probiotics improved migraine and IBS symptoms, resulting in a decrease in the use of medications. Individuals treated with elimination diet or probiotics only did show an improvement in comparison to the start of the trial, however not when compared to the combination treatment It was concluded that elimination diet in combination with probiotics may be of benefit to relieve symptoms of migraine and IBS. This study could be used by healthcare professionals to understand possible causes of IBS and migraines, and that treatments may involve targeting both illnesses.
Abstract
Several research studies have revealed that migraine has a solid link with gastrointestinal diseases especially irritable bowel syndrome (IBS). This study was carried out to investigate therapeutic potential of diet based on IgG elimination combined with probiotics on migraine plus irritable bowel syndrome. A total of 60 patients diagnosed with migraine plus IBS were recruited for the study. IgG antibodies against 266 food varieties were detected by ELISA. Then, the subjects were randomized into three groups for treatment of IgG elimination diet or probiotics or diet combined with probiotics. Migraine symptom, gut function score, medication use, and serum serotonin level were measured at baseline, 7 weeks, and 14 weeks. Improvement of migraine and gut symptom was achieved at a certain time point. Reduced use of over-the-counter- (OTC-) analgesics was seen in all groups. However, use of triptans did not show significant difference. An increased serum serotonin level was seen in subjects treated with elimination diet and elimination diet combined with probiotics. IgG elimination diet combined with probiotics may be beneficial to migraine plus IBS. It may provide new insight by understanding the intricate relationship between migraine and gastrointestinal diseases.
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A Randomized Double-Blind, Cross-Over Trial of very Low-Calorie Diet in Overweight Migraine Patients: A Possible Role for Ketones?
Di Lorenzo, C, Pinto, A, Ienca, R, Coppola, G, Sirianni, G, Di Lorenzo, G, Parisi, V, Serrao, M, Spagnoli, A, Vestri, A, et al
Nutrients. 2019;11(8)
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The ketogenic diet (KD) constitutes high-fat, adequate protein, and low-carbohydrate, and has been proven to be efficacious for the treatment of drug-resistant epilepsy. Recently, KD showed promising results for treating other neurological conditions. The aim of this study was to analyse the effects of very low-calorie ketogenic diets (VLCKDs) in overweight episodic migraine patients during a weight-loss intervention. This study is a double-blind cross-over design randomised trial (of five phases). Participants eligible for trial participation were overweight/obese adults, aged 18 to 65 years, who had at least 12 months’ history of migraines with or without aura. Subjects alternated randomly between a very low-calorie ketogenic diet and a very low-calorie non-ketogenic diet (VLCnKD) each for one month. Results indicate that a 4-week period VLCKD, despite inducing similar weight loss and glycaemic profile, was significantly more effective than VLCnKD in preventing migraine attacks, as evidenced by a decrease in the frequency of migraine days and attacks, and a greater than 50% response rate. Authors conclude that VLCKD is effective for rapid, short-term improvement of migraines in overweight patients, while VLCnKD is not.
Abstract
Here we aimed at determining the therapeutic effect of a very low-calorie diet in overweight episodic migraine patients during a weight-loss intervention in which subjects alternated randomly between a very low-calorie ketogenic diet (VLCKD) and a very low-calorie non-ketogenic diet (VLCnKD) each for one month. In a nutritional program, 35 overweight obese migraine sufferers were allocated blindly to 1-month successive VLCKD or VLCnKD in random order (VLCKD-VLCnKD or VLCnKD-VLCD). The primary outcome measure was the reduction of migraine days each month compared to a 1-month pre-diet baseline. Secondary outcome measures were 50% responder rate for migraine days, reduction of monthly migraine attacks, abortive drug intake and body mass index (BMI) change. Only data from the intention-to-treat cohort (n = 35) will be presented. Patients who dropped out (n = 6) were considered as treatment failures. Regarding the primary outcome, during the VLCKD patients experienced -3.73 (95% CI: -5.31, -2.15) migraine days respect to VLCnKD (p < 0.0001). The 50% responder rate for migraine days was 74.28% (26/35 patients) during the VLCKD period, but only 8.57% (3/35 patients) during VLCnKD. Migraine attacks decreased by -3.02 (95% CI: -4.15, -1.88) during VLCKD respect to VLCnKD (p < 0.00001). There were no differences in the change of acute anti-migraine drug consumption (p = 0.112) and BMI (p = 0.354) between the 2 diets. A VLCKD has a preventive effect in overweight episodic migraine patients that appears within 1 month, suggesting that ketogenesis may be a useful therapeutic strategy for migraines.
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A Mediterranean-style dietary intervention supplemented with fish oil improves diet quality and mental health in people with depression: A randomized controlled trial (HELFIMED).
Parletta, N, Zarnowiecki, D, Cho, J, Wilson, A, Bogomolova, S, Villani, A, Itsiopoulos, C, Niyonsenga, T, Blunden, S, Meyer, B, et al
Nutritional neuroscience. 2019;22(7):474-487
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Observational studies have shown that a healthy diet is associated with a reduced risk for depression. This study investigated whether a Mediterranean-style diet supplemented with fish oil can improve mental health in adults suffering depression. Adults with self-reported depression were randomised to receive fortnightly food hampers and Mediterranean diet cooking workshops for 3 months and fish oil supplements for 6 months, or attend social groups fortnightly for 3 months. Assessments at baseline, 3 and 6 months included mental health, quality of life and dietary questionnaires, and blood samples for fatty acid analysis. Both groups experienced in improvements in their mental health. The Mediterranean diet group had greater reduction in depression and improved mental health quality of life scores at 3 months and 6 months. Reduced depression was correlated with an increased Mediterranean diet score, nuts and vegetable diversity. Other mental health improvements were associated with increased vegetable diversity and legumes. There were some correlations between increased omega-3, decreased omega-6 and improved mental health. The authors suggest that getting back to basics by promoting cooking skills and family/group meals could be a simple yet powerful and empowering approach to healthcare and prevention.
Abstract
OBJECTIVES We investigated whether a Mediterranean-style diet (MedDiet) supplemented with fish oil can improve mental health in adults suffering depression. METHODS Adults with self-reported depression were randomized to receive fortnightly food hampers and MedDiet cooking workshops for 3 months and fish oil supplements for 6 months, or attend social groups fortnightly for 3 months. Assessments at baseline, 3 and 6 months included mental health, quality of life (QoL) and dietary questionnaires, and blood samples for erythrocyte fatty acid analysis. RESULTS n = 152 eligible adults aged 18-65 were recruited (n = 95 completed 3-month and n = 85 completed 6-month assessments). At 3 months, the MedDiet group had a higher MedDiet score (t = 3.95, P < 0.01), consumed more vegetables (t = 3.95, P < 0.01), fruit (t = 2.10, P = 0.04), nuts (t = 2.29, P = 0.02), legumes (t = 2.41, P = 0.02) wholegrains (t = 2.63, P = 0.01), and vegetable diversity (t = 3.27, P < 0.01); less unhealthy snacks (t = -2.10, P = 0.04) and red meat/chicken (t = -2.13, P = 0.04). The MedDiet group had greater reduction in depression (t = -2.24, P = 0.03) and improved mental health QoL scores (t = 2.10, P = 0.04) at 3 months. Improved diet and mental health were sustained at 6 months. Reduced depression was correlated with an increased MedDiet score (r = -0.298, P = 0.01), nuts (r = -0.264, P = 0.01), and vegetable diversity (r = -0.303, P = 0.01). Other mental health improvements had similar correlations, most notably for increased vegetable diversity and legumes. There were some correlations between increased omega-3, decreased omega-6 and improved mental health. DISCUSSION This is one of the first randomized controlled trials to show that healthy dietary changes are achievable and, supplemented with fish oil, can improve mental health in people with depression.
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Acetyl-L-carnitine for the treatment of diabetic peripheral neuropathy.
Rolim, LC, da Silva, EM, Flumignan, RL, Abreu, MM, Dib, SA
The Cochrane database of systematic reviews. 2019;6:CD011265
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Diabetic patients are at an increased risk of diabetic peripheral neuropathy (DPN), which affects around 50% of diabetic patients. Pain that worsens at night is characteristic of DPN. Prolonged hyperglycaemia and metabolic disturbances increase the risk of developing DPN. Acetyl-L-carnitine (ALC) is an amino acid with antioxidant and neuroprotective properties. ALC is often found depleted in the peripheral nerves of patients with DPN. This meta-analysis included four randomised controlled trials to evaluate the therapeutic potential of ALC in reducing the symptoms of DPN, especially pain. The trials included different dosages of ALC ranging from 1500 mg/day to 3000 mg/day. Based on their findings, the researchers concluded that they are uncertain about the benefits of ALC for reducing pain related to DPN, neurophysiological improvements, and the safety of the supplement. Healthcare professionals must exercise caution when considering ALC as a therapeutic agent in treating DNP-related complications, even though dosages above 1500 mg/day of ALC reduced pain in DNP patients after taking the supplements for 6 to 12 months. Further robust long-term research is required as the current evidence is limited and uncertain to determine the clinical utility of ALC.
Abstract
BACKGROUND Diabetic peripheral neuropathy (DPN) is a common and severe complication that affects 50% of people with diabetes. Painful DPN is reported to occur in 16% to 24% of people with diabetes. A complete and comprehensive management strategy for the prevention and treatment of DPN, whether painful or not, has not yet been defined.Research into treatment for DPN has been characterised by a series of failed clinical trials, with few noteworthy advances. Strategies that support peripheral nerve regeneration and restore neurological function in people with painful or painless DPN are needed. The amino acid acetyl-L-carnitine (ALC) plays a role in the transfer of long-chain fatty acids into mitochondria for β-oxidation. ALC supplementation also induces neuroprotective and neurotrophic effects in the peripheral nervous system. Therefore, ALC supplementation targets several mechanisms relevant to potential nerve repair and regeneration, and could have clinical therapeutic potential. There is a need for a systematic review of the evidence from clinical trials. OBJECTIVES To assess the effects of ALC for the treatment of DPN. SEARCH METHODS On 2 July 2018, we searched the Cochrane Neuromuscular Specialised Register, CENTRAL, MEDLINE, Embase, LILACS, ClinicalTrials.gov, and the World Health Organization International Clinical Trials Registry Platform. We checked references, searched citations, and contacted study authors to identify additional studies. SELECTION CRITERIA We included randomised controlled trials (RCTs) and quasi-RCTs of ALC compared with placebo, other therapy, or no intervention in the treatment of DPN. Participants could be of any sex and age, and have type 1 or type 2 diabetes mellitus, of any severity, with painful or painless DPN. We accepted any definition of minimum criteria for DPN, in accordance with the Toronto Consensus. We imposed no language restriction.Pain was the primary outcome, measured as the proportion of participants with at least 30% (moderate) or 50% (substantial) decrease in pain over baseline, or as the score on a visual analogue scale (VAS) or Likert scale for pain. DATA COLLECTION AND ANALYSIS We followed standard Cochrane methods. MAIN RESULTS We included four studies with 907 participants, which were reported in three publications. Three trials studied ALC versus placebo (675 participants); in one trial the dose of ALC was 2000 mg/day, and in the other two trials, it was 1500 mg/day or 3000 mg/day. The fourth trial studied ALC 1500 mg/day versus methylcobalamin 1.5 mg/day (232 participants). The risk of bias was high in both trials of different ALC doses and low in the other two trials.No included trial measured the proportion of participants with at least moderate (30%) or substantial (50%) pain relief. ALC reduced pain more than placebo, measured on a 0- to 100-mm VAS (MD -9.16, 95% CI -16.76 to -1.57; three studies; 540 participants; P = 0.02; I² = 56%; random-effects; very low-certainty evidence; a higher score indicating more pain). At doses of 1500 mg/day or less, the VAS score after ALC treatment was little different from placebo (MD -0.05, 95% CI -10.00 to 9.89; two studies; 159 participants; P = 0.99; I² = 0%), but at doses greater than 1500 mg/day, ALC reduced pain more than placebo (MD -14.93, 95% CI -19.16 to -10.70; three studies; 381 participants; P < 0.00001; I² = 0%). This subgroup analysis should be viewed with caution as the evidence was even less certain than the overall analysis, which was already of very low certainty.Two placebo-controlled studies reported that vibration perception improved after 12 months. We graded this evidence as very low certainty, due to inconsistency and a high risk of bias, as the trial authors did not provide any numerical data. The placebo-controlled studies did not measure functional impairment and disability scores. No study used validated symptom scales. One study performed sensory testing, but the evidence was very uncertain.The fourth included study compared ALC with methylcobalamin, but did not report effects on pain. There was a reduction from baseline to 24 weeks in functional impairment and disability, based on the change in mean Neuropathy Disability Score (NDS; scale from zero to 10), but there was no important difference between the ALC group (mean score 1.66 ± 1.90) and the methylcobalamin group (mean score 1.35 ± 1.65) groups (P = 0.23; low-certainty evidence).One placebo-controlled study reported that six of 147 participants in the ALC > 1500 mg/day group (4.1%) and two of 147 participants in the placebo group (1.4%) discontinued treatment because of adverse events (headache, facial paraesthesia, and gastrointestinal disorders) (P = 0.17). The other two placebo-controlled studies reported no dropouts due to adverse events, and more pain, paraesthesia, and hyperaesthesias in the placebo group than the 3000 mg/day ALC group, but provided no numerical data. The overall certainty of adverse event evidence for the comparison of ALC versus placebo was low.The study comparing ALC with methylcobalamin reported that 34/117 participants (29.1%) experienced adverse events in the ALC group versus 33/115 (28.7%) in the methylcobalamin group (P = 0.95). Nine participants discontinued treatment due to adverse events (ALC: 4 participants, methylcobalamin: 5 participants), which were most commonly gastrointestinal symptoms. The certainty of the adverse event evidence for ALC versus methylcobalamin was low.Two studies were funded by the manufacturer of ALC and the other two studies had at least one co-author who was a consultant for an ALC manufacturer. AUTHORS' CONCLUSIONS We are very uncertain whether ALC causes a reduction in pain after 6 to 12 months' treatment in people with DPN, when compared with placebo, as the evidence is sparse and of low certainty. Data on functional and sensory impairment and symptoms are lacking, or of very low certainty. The evidence on adverse events is too uncertain to make any judgements on safety.
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Taurine supplementation for prevention of stroke-like episodes in MELAS: a multicentre, open-label, 52-week phase III trial.
Ohsawa, Y, Hagiwara, H, Nishimatsu, SI, Hirakawa, A, Kamimura, N, Ohtsubo, H, Fukai, Y, Murakami, T, Koga, Y, Goto, YI, et al
Journal of neurology, neurosurgery, and psychiatry. 2019;90(5):529-536
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Mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) is a major clinical entity encompassing mitochondrial diseases resulting from mitochondrial dysfunction. Stroke-like episodes, the most critical symptom of MELAS, are characterised by an abrupt onset of cortical neurological deficits with typical MRI abnormalities not conforming to the distribution of main arteries. The aim of this study was to evaluate the efficacy and safety of high-dose taurine supplementation for prevention of stroke-like episodes. This study is a multicentre, open-label, phase III trial with a total of 291 patients with MELAS. Results show that oral supplementation with high-dose taurine was effective in preventing stroke-like episodes. Furthermore, the 50% responder rate reached 80%, and the annual relapse rate of stroke-like episodes significantly decreased with concomitant increases in blood and cerebrospinal fluid taurine levels. Adverse events associated with taurine were observed among the participants, but no serious adverse events associated with taurine supplementation were reported. Authors conclude that oral high-dose taurine supplementation was effective and safe for the prevention of stroke-like episodes in patients with MELAS by ameliorating the modification defect in the first anticodon nucleotide of mitochondrial tRNA [transfer RNA – a small RNA molecule].
Abstract
OBJECTIVE The aim of this study was to evaluate the efficacy and safety of high-dose taurine supplementation for prevention of stroke-like episodes of MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes), a rare genetic disorder caused by point mutations in the mitochondrial DNA that lead to a taurine modification defect at the first anticodon nucleotide of mitochondrial tRNALeu(UUR), resulting in failure to decode codons accurately. METHODS After the nationwide survey of MELAS, we conducted a multicentre, open-label, phase III trial in which 10 patients with recurrent stroke-like episodes received high-dose taurine (9 g or 12 g per day) for 52 weeks. The primary endpoint was the complete prevention of stroke-like episodes during the evaluation period. The taurine modification rate of mitochondrial tRNALeu(UUR) was measured before and after the trial. RESULTS The proportion of patients who reached the primary endpoint (100% responder rate) was 60% (95% CI 26.2% to 87.8%). The 50% responder rate, that is, the number of patients achieving a 50% or greater reduction in frequency of stroke-like episodes, was 80% (95% CI 44.4% to 97.5%). Taurine reduced the annual relapse rate of stroke-like episodes from 2.22 to 0.72 (P=0.001). Five patients showed a significant increase in the taurine modification of mitochondrial tRNALeu(UUR) from peripheral blood leukocytes (P<0.05). No severe adverse events were associated with taurine. CONCLUSIONS The current study demonstrates that oral taurine supplementation can effectively reduce the recurrence of stroke-like episodes and increase taurine modification in mitochondrial tRNALeu(UUR) in MELAS. TRIAL REGISTRATION NUMBER UMIN000011908.
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Cannabidiol in Anxiety and Sleep: A Large Case Series.
Shannon, S, Lewis, N, Lee, H, Hughes, S
The Permanente journal. 2019;23:18-041
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After the psychoactive tetrahydrocannabinol (THC), cannabidiol (CBD) is the second most abundant, and non-psychoactive, cannabinoid of the cannabis plant. CBD appears to have a calming effect on the central nervous system, however, clinical evidence for its use is limited. The purpose of the present study is to describe the effects of CBD on anxiety and sleep. A retrospective chart review of 72 adult patients with primary concerns of anxiety (47 patients) or poor sleep (25 patients) and treated with CBD for at least 1 month as an adjunct to usual treatment, was conducted at a large integrative psychiatric outpatient clinic. Nearly all patients were given CBD 25 mg/d in capsule form. If anxiety complaints predominated, the dosing was every morning, after breakfast. If sleep complaints predominated, the dosing was every evening, after dinner. Monthly visits included clinical evaluation and documentation of patients’ anxiety and sleep status. Whilst anxiety scores showed a rapid and sustained decrease over the three months study period, no sustained improvements in sleep was seen. The treatment with CBD was generally well accepted and tolerated. The authors conclude that these results support the existing scientific evidence, and that more clinical research is needed to provide better clinical guidance on the use of CBD.
Abstract
CONTEXT Cannabidiol (CBD) is one of many cannabinoid compounds found in cannabis. It does not appear to alter consciousness or trigger a "high." A recent surge in scientific publications has found preclinical and clinical evidence documenting value for CBD in some neuropsychiatric disorders, including epilepsy, anxiety, and schizophrenia. Evidence points toward a calming effect for CBD in the central nervous system. Interest in CBD as a treatment of a wide range of disorders has exploded, yet few clinical studies of CBD exist in the psychiatric literature. OBJECTIVE To determine whether CBD helps improve sleep and/or anxiety in a clinical population. DESIGN A large retrospective case series at a psychiatric clinic involving clinical application of CBD for anxiety and sleep complaints as an adjunct to usual treatment. The retrospective chart review included monthly documentation of anxiety and sleep quality in 103 adult patients. MAIN OUTCOME MEASURES Sleep and anxiety scores, using validated instruments, at baseline and after CBD treatment. RESULTS The final sample consisted of 72 adults presenting with primary concerns of anxiety (n = 47) or poor sleep (n = 25). Anxiety scores decreased within the first month in 57 patients (79.2%) and remained decreased during the study duration. Sleep scores improved within the first month in 48 patients (66.7%) but fluctuated over time. In this chart review, CBD was well tolerated in all but 3 patients. CONCLUSION Cannabidiol may hold benefit for anxiety-related disorders. Controlled clinical studies are needed.