Assessing brain function in stressed healthy individuals following the use of a combination of green tea, Rhodiola, magnesium, and B vitamins: an fMRI study.

Introduction: This randomized, controlled, single-blinded trial assessed the effect of magnesium (Mg)-Teadiola (Mg, vitamins B6, B9, B12, Rhodiola, and green tea/L-theanine) versus placebo on the brain response to stressful thermal stimulus in chronically stressed, but otherwise healthy subjects. Impacts on stress-related quality-of-life parameters (depression, anxiety, sleep, and perception of pain) were also explored. Methods: The study recruited a total of 40 adults (20 per group), suffering from stress for more than 1 month and scaling ≥14 points on the Depression Anxiety Stress Scale (DASS)-42 questionnaire at the time of inclusion. Individuals received oral Mg-Teadiola or placebo for 28 days (D). fMRI analysis was used to visualize the interplay between stress and pain cerebral matrices, using thermal stress model, at baseline (D0) and after D28. Results: Based on blood-oxygen-level-dependent (BOLD) signal variations during the stress stimulation (before pain perception), a significantly increased activation between D0 and D28 was observed for left and right frontal area (p = 0.001 and p = 0.002, respectively), left and right anterior cingulate cortex (ACC) (p = 0.035 and p = 0.04, respectively), and left and right insula (p = 0.034 and p = 0.0402, respectively) in Mg-Teadiola versus placebo group. During thermal pain stimulation, a significantly diminished activation of the pain matrix was observed between D0 and D28, for left and right prefrontal area (both p = 0.001), left and right insula (p = 0.008 and p = 0.019, respectively), and left and right ventral striatum (both p = 0.001) was observed in Mg-Teadiola versus placebo group. These results reinforce the clinical observations, showing a perceived benefit of Mg-Teadiola on several parameters. After 1 month of treatment, DASS-42 stress score significantly decreased in Mg-Teadiola group [effect size (ES) -0.46 (-0.91; -0.01), p = 0.048]. Similar reductions were observed on D14 (p = 0.011) and D56 (p = 0.008). Sensitivity to cold also improved from D0 to D28 for Mg-Teadiola versus placebo [ES 0.47 (0.02; 0.92) p = 0.042]. Conclusion: Supplementation with Mg-Teadiola reduced stress on D28 in chronically stressed but otherwise healthy individuals and modulated the stress and pain cerebral matrices during stressful thermal stimulus.

Assessment of Initial Depressive State and Pain Relief With Ketamine in Patients With Chronic Refractory Pain.

Importance: Repeated ketamine administration is common in treatment-refractory chronic pain, but ketamine analgesic and antidepressant effects are poorly understood in patients with chronic pain with depression symptoms. Objective: To determine clinical pain trajectories with repeated ketamine administrations, exploring whether ketamine dose and/or pretreatment depressive and/or anxiety symptoms may mediate pain relief. Design, Setting, and Participants: This nationwide, multicenter, prospective cohort study included patients in France with treatment-refractory chronic pain who received repeated ketamine administration, over 1 year, according to ketamine use in their pain clinic. Data were collected from July 7, 2016, through September 21, 2017. Linear mixed models for repeated data, trajectory analysis, and mediation analysis were performed from November 15 to December 31, 2022. Interventions: Ketamine administration in cumulative dose (milligrams) over 1 year. Main Outcomes and Measures: Primary outcome was mean pain intensity (0-10 on the Numerical Pain Rating Scale [NPRS]), assessed every month for 1 year by telephone, after inclusion in the hospital. Depression and anxiety (Hospital Anxiety and Depression Scale [HADS]), quality of life (12-item Short Form Health Survey [SF-12]), cumulative ketamine dose, adverse effects, and concomitant treatments were secondary outcomes. Results: A total of 329 patients (mean [SD] age, 51.4 [11.0] years; 249 women [75.7%] and 80 men [24.3%]) were enrolled. Repeated ketamine administration was associated with a decrease of NPRS (effect size = -0.52 [95% CI, -0.62 to -0.41]; P < .001) and an increase of SF-12 mental health (39.7 [10.9] to 42.2 [11.1]; P < .001) and physical health (28.5 [7.9] to 29.5 [9.2]; P = .02) dimension scores over 1 year. Adverse effects were in the normal range. There was a significant difference between patients without and with depressive symptoms in pain diminution (regression coefficient, -0.04 [95% CI, -0.06 to -0.01]; omnibus P = .002 for interaction of time × baseline depression [HADS score ≤7 or >7]). The mediation model showed that ketamine dose was not associated with pain diminution (r = 0.01; P = .61) and not correlated with depression (r = -0.06; P = .32), and that depression was associated with pain diminution (regression coefficient, 0.03 [95% CI, 0.01-0.04]; P < .001), whereas ketamine dose was not (regression coefficient, 0.00 [95% CI, -0.01 to 0.01]; P = .67). The proportion of reduction of pain mediated by baseline depression was 64.6%. Conclusions and Relevance: The findings of this cohort study on chronic refractory pain suggest that depression (and not ketamine dose or anxiety) was the mediator of the association of ketamine with pain diminution. This finding provides radically new insights on how ketamine reduces pain primarily by dampening depression. This reinforces the need for systematic holistic assessment of patients with chronic pain to diagnose severe depressive symptoms where ketamine would be a very valuable therapeutic option.

Circulating Human Metabolites Resulting from TOTUM-070 Absorption (a Plant-Based, Polyphenol-Rich Ingredient) Improve Lipid Metabolism in Human Hepatocytes: Lessons from an Original Ex Vivo Clinical Trial.

TOTUM-070 is a patented polyphenol-rich blend of five different plant extracts showing separately a latent effect on lipid metabolism and potential synergistic properties. In this study, we investigated the health benefit of such a formula. Using a preclinical model of high fat diet, TOTUM-070 (3 g/kg of body weight) limited the HFD-induced hyperlipemia with a reduction in triglyceride (-32% after 6 weeks; -20.3% after 12 weeks) and non-HDL cholesterol levels (-21% after 6 weeks; -38.4% after 12 weeks). To further investigate such a benefit and its underlying mechanisms in humans, we designed an ex vivo clinical approach to collect the circulating bioactives resulting from TOTUM-070 ingestion and to determine their biological activities on human hepatocytes. Human serum was obtained from healthy subjects before and after intake of TOTUM-070 (4995 mg). The presence of circulating metabolites was assessed by UPLC-MS/MS. Serum containing metabolites was further incubated with hepatocytes cultured in a lipotoxic environment (palmitate, 250 µM). RNA sequencing analyses show that lipid metabolism was one of the most impacted processes. Using histologic, proteomic, and enzymatic assays, the effects of human TOTUM-070 bioactives on hepatocyte metabolism were characterized by (1) the inhibition of lipid storage, including both (2) triglycerides (-41%, p < 0.001) and (3) cholesterol (-50%, p < 0.001) intracellular content, (4) a reduced de novo cholesterol synthesis (HMG-CoA reductase activity -44%, p < 0.001), and (5) a lowered fatty acid synthase protein level (p < 0.001). Altogether, these data support the beneficial impact of TOTUM-070 on lipid metabolism and provide new biochemical insights in human mechanisms occurring in liver cells.

Effect of a Combination of Magnesium, B Vitamins, Rhodiola, and Green Tea (L-Theanine) on Chronically Stressed Healthy Individuals-A Randomized, Placebo-Controlled Study.

The effect of a combination of magnesium, vitamins B6, B9, B12, rhodiola and green tea/L-theanine (Mg-Teadiola) on stress was evaluated in chronically stressed, otherwise healthy individuals. Effects on stress-related quality-of-life parameters (sleep and perception of pain) were also explored. Adults with stress for ≥1 month, scoring ≥14 points on the Depression Anxiety Stress Scale (DASS)-42 questionnaire, were randomized (1:1) to receive oral Mg-Teadiola (n = 49) or a placebo (n = 51), for 28 days, with a follow-up assessment on Day 56 (NCT04391452). The primary endpoint was the change in the DASS-42 stress score from baseline to Day 28 with Mg-Teadiola versus placebo. The DASS-42 stress scores significantly decreased from baseline to Day 28 with Mg-Teadiola versus placebo (effect size, 0.29; 95% CI [0.01, 0.57]; p = 0.04). Similar reductions were observed on Day 14 (p = 0.006) and Day 56 (p = 0.02). A significant reduction in sensitivity to cold pain (p = 0.01) and a trend for lower sensitivity to warm pain was observed (p = 0.06) on Day 28. Improvements in daytime dysfunction due to sleepiness (Pittsburgh Sleep Quality Index-7 component score) were reported on Day 28, and were significant on Day 56 (p < 0.001). Mg-Teadiola is effective in managing stress in otherwise healthy individuals. Its beneficial effects on sleep and pain perception need further investigation.

Short-Term Magnesium Therapy Alleviates Moderate Stress in Patients with Fibromyalgia: A Randomized Double-Blind Clinical Trial.

Patients suffering from fibromyalgia often report stress and pain, with both often refractory to usual drug treatment. Magnesium supplementation seems to improve fibromyalgia symptoms, but the level of evidence is still poor. This study is a randomized, controlled, double-blind trial in fibromyalgia patients that compared once a day oral magnesium 100 mg (Chronomag®, magnesium chloride technology formula) to placebo, for 1 month. The primary endpoint was the level of stress on the DASS-42 scale, and secondary endpoints were pain, sleep, quality of life, fatigue, catastrophism, social vulnerability, and magnesium blood concentrations. After 1 month of treatment, the DASS-42 score decreased in the magnesium and placebo groups but not significantly (21.8 ± 9.6 vs. 21.6 ± 10.8, respectively, p = 0.930). Magnesium supplementation significantly reduced the mild/moderate stress subgroup (DASS-42 stress score: 22.1 ± 2.8 to 12.3 ± 7.0 in magnesium vs. 21.9 ± 11.9 to 22.9 ± 11.9 in placebo, p = 0.003). Pain severity diminished significantly (p = 0.029) with magnesium while the other parameters were not significantly different between both groups. These findings show, for the first time, that magnesium improves mild/moderate stress and reduces the pain experience in fibromyalgia patients. This suggests that daily magnesium could be a useful treatment to improve the burden of disease of fibromyalgia patients and calls for a larger clinical trial.

Circulating Human Serum Metabolites Derived from the Intake of a Saffron Extract (Safr'InsideTM) Protect Neurons from Oxidative Stress: Consideration for Depressive Disorders.

Increases in oxidative stress have been reported to play a central role in the vulnerability to depression, and antidepressant drugs may reduce increased oxidative stress in patients. Among the plants exerting anti-inflammatory and anti-oxidant properties, saffron, a spice derived from the flower of Crocus sativus, is also known for its positive effects on depression, potentially through its SSRI-like properties. However, the molecular mechanisms underlying these effects and their health benefits for humans are currently unclear. Using an original ex vivo clinical approach, we demonstrated for the first time that the circulating human metabolites produced following saffron intake (Safr'InsideTM) protect human neurons from oxidative-stress-induced neurotoxicity by preserving cell viability and increasing BNDF production. In particular, the metabolites significantly stimulated both dopamine and serotonin release. In addition, the saffron's metabolites were also able to protect serotonergic tone by inhibiting the expression of the serotonin transporter SERT and down-regulating serotonin metabolism. Altogether, these data provide new biochemical insights into the mechanisms underlying the beneficial impact of saffron on neuronal viability and activity in humans, in the context of oxidative stress related to depression.

Self-Healing: A Concept for Musculoskeletal Body Pain Management - Scientific Evidence and Mode of Action.

Traditionally, musculoskeletal pain management has focused on the use of conventional treatments to relieve pain. However, multi-modal integrative medicine including alternative/complementary treatments is becoming more widely used and integrated into treatment guidelines around the world. The uptake of this approach varies according to country, with generally a higher uptake in developed countries and in females aged more than 40 years. Integral to the concept described here, is that the body has an innate ability to self-heal, which can be optimized by the use of integrative medical strategies. Stress triggers for acute or recurring musculoskeletal pain are diverse and can range from physical to psychological. The mechanism by which the body responds to triggers and initiates the self-healing processes is complex, but five body networks or processes are thought to be integral: the nervous system, microcirculation/vasodilation, immune modulation, muscular relaxation/contraction and psychological balance. Multi-modal integrative medicine approaches include nutritional/dietary modification, postural/muscular training exercises, and cognitive behavioral mind/body techniques. This article will review the self-healing concept and provide plausible scientific evidence where available.

Metabolic and Anti-Inflammatory Protective Properties of Human Enriched Serum Following Artichoke Leaf Extract Absorption: Results from an Innovative Ex Vivo Clinical Trial.

The aging of our population is accompanied by an increased prevalence of chronic diseases. Among those, liver, joint and adipose tissue-related pathologies have a major socio-economic impact. They share common origins as they result from a dysregulation of the inflammatory and metabolic status. Plant-derived nutrients and especially polyphenols, exert a large range of beneficial effects in the prevention of chronic diseases but require clinically validated approaches for optimized care management. In this study, we designed an innovative clinical approach considering the metabolites produced by the digestive tract following the ingestion of an artichoke leaf extract. Human serum, enriched with metabolites deriving from the extract, was collected and incubated with human hepatocytes, human primary chondrocytes and adipocytes to determine the biological activity of the extract. Changes in cellular behavior demonstrated that the artichoke leaf extract protects hepatocytes from lipotoxic stress, prevents adipocytes differentiation and hyperplasia, and exerts chondroprotective properties in an inflammatory context. These data validate the beneficial health properties of an artichoke leaf extract at the clinical level and provide both insights and further evidence that plant-derived nutrients and especially polyphenols from artichoke may represent a relevant alternative for nutritional strategies addressing chronic disease issues.

Effects of Totum-63 on glucose homeostasis and postprandial glycemia: a translational study.

Global prevalence of type 2 diabetes (T2D) is rising and may affect 700 million people by 2045. Totum-63 is a polyphenol-rich natural composition developed to reduce the risk of T2D. We first investigated the effects of Totum-63 supplementation in high-fat diet (HFD)-fed mice for up to 16 wk and thereafter assessed its safety and efficacy (2.5 g or 5 g per day) in 14 overweight men [mean age 51.5 yr, body mass index (BMI) 27.6 kg·m-2] for 4 wk. In HFD-fed mice, Totum-63 reduced body weight and fat mass gain, whereas lean mass was unchanged. Moreover, fecal energy excretion was higher in Totum-63-supplemented mice, suggesting a reduction of calorie absorption in the digestive tract. In the gut, metagenomic analyses of fecal microbiota revealed a partial restoration of HFD-induced microbial imbalance, as shown by principal coordinate analysis of microbiota composition. HFD-induced increase in HOMA-IR score was delayed in supplemented mice, and insulin response to an oral glucose tolerance test was significantly reduced, suggesting that Totum-63 may prevent HFD-related impairments in glucose homeostasis. Interestingly, these improvements could be linked to restored insulin signaling in subcutaneous adipose tissue and soleus muscle. In the liver, HFD-induced steatosis was reduced by 40% (as shown by triglyceride content). In the subsequent study in men, Totum-63 (5 g·day-1) improved glucose and insulin responses to a high-carbohydrate breakfast test (84% kcal carbohydrates). It was well tolerated, with no clinically significant adverse events reported. Collectively, these data suggest that Totum-63 could improve glucose homeostasis in both HFD-fed mice and overweight individuals, presumably through a multitargeted action on different metabolic organs.NEW & NOTEWORTHY Totum-63 is a novel polyphenol-rich natural composition developed to reduce the risk of T2D. Totum-63 showed beneficial effects on glucose homeostasis in HFD-fed mice, presumably through a multitargeted action on different metabolic organs. Totum-63 was well tolerated in humans and improved postprandial glucose and insulin responses to a high-carbohydrate breakfast test.

Effect of magnesium and vitamin B6 supplementation on mental health and quality of life in stressed healthy adults: Post-hoc analysis of a randomised controlled trial.

Magnesium status and vitamin B6 intake have been linked to mental health and/or quality of life (QoL). In an 8-week Phase IV randomised controlled study in individuals with low magnesemia and severe/extremely severe stress but who were otherwise healthy, greater stress reduction was achieved with magnesium combined with vitamin B6 than with magnesium alone. We present a previously unreported secondary analysis of the effect of magnesium, with and without vitamin B6, on depression, anxiety, and QoL. Adults with Depression Anxiety Stress Scales (DASS-42) stress subscale score >18 were randomised 1:1 to magnesium + vitamin B6 combination (Magne B6® ; daily dose 300 and 30 mg, respectively) or magnesium alone (Magnespasmyl® ; daily dose 300 mg). Outcomes included changes from baseline in DASS-42 depression and anxiety scores, and QoL (Short Form-36 Health Survey). DASS-42 anxiety and depression scores significantly improved from baseline to week 8 with both treatments, particularly during the first 4 weeks. Improvement in QoL continued over 8 weeks. Participants' perceived capacity for physical activity in daily life showed greater improvement with magnesium + vitamin B6 than magnesium alone (Week 4). In conclusion, magnesium supplementation, with or without vitamin B6, could provide a meaningful clinical benefit in daily life for individuals with stress and low magnesemia.

Magnesium level correlation with clinical status and quality of life in women with hormone related conditions and pregnancy based on real world data.

This study was aimed to assess the effectiveness of magnesium (Mg)-vitamin B 6 replenishment and its correlation with clinical status in pregnant women (PW), and quality of life in women with hormone-related conditions (HRCW) and hypomagnesemia (HME). Data collected in four observational studies were pooled and analysed. All women received Mg supplementation for 4 weeks. The proportion of women with normalized Mg level, and the correlation between serum Mg dynamics and number of symptoms/complaints (PW) or changes in World Health Organization quality of life questionnaire scores (WHOQOL; HRCW) were evaluated. 869 PW and 957 HRCW were included in the study. Normalization of serum Mg level to ≥ 0.66 mmol/L occurred in 92.1% of PW and 78.4% of HRCW, and to ≥ 0.8 mmol/L in 73.8% and 58.9%, respectively. Mg normalization was accompanied by a median decrease of 1 symptom and 1 complaint in PW. Serum Mg level increase by 0.1 mmol/L was associated to significant changes in the WHOQOL scores in HRCW. Treatment of HME with the Mg for approximately 4 weeks provided a high response rate of Mg serum level, was associated with an improvement in symptom severity and complaints in PW, and WHOQOL score in HRCW. A 0.8 mmol/L cut-off appeared to be more relevant in terms of patient-reported outcomes.

Magnesium Status and Stress: The Vicious Circle Concept Revisited.

Magnesium deficiency and stress are both common conditions among the general population, which, over time, can increase the risk of health consequences. Numerous studies, both in pre-clinical and clinical settings, have investigated the interaction of magnesium with key mediators of the physiological stress response, and demonstrated that magnesium plays an inhibitory key role in the regulation and neurotransmission of the normal stress response. Furthermore, low magnesium status has been reported in several studies assessing nutritional aspects in subjects suffering from psychological stress or associated symptoms. This overlap in the results suggests that stress could increase magnesium loss, causing a deficiency; and in turn, magnesium deficiency could enhance the body's susceptibility to stress, resulting in a magnesium and stress vicious circle. This review revisits the magnesium and stress vicious circle concept, first introduced in the early 1990s, in light of recent available data.

Impact of magnesium supplementation, in combination with vitamin B6, on stress and magnesium status: secondary data from a randomized controlled trial.

Primary findings from a recent study reported that magnesium supplementation significantly reduced stress in severely stressed subjects with low magnesemia, and additional vitamin B6 enhanced this effect. The mechanism by which combining magnesium and vitamin B6 leads to reduced stress in these subjects remains to be elucidated. This secondary analysis investigated the impact of magnesium and vitamin B6 supplementation and perceived stress on erythrocyte magnesium levels, as a marker of body magnesium status. This was a secondary analysis from an 8-week randomized controlled trial comparing oral magnesium (300 mg) and magnesium-vitamin B6 (300 mg + 30 mg) supplementation. Stress level and erythrocyte magnesium level at baseline, and change in erythrocyte magnesium and serum vitamin B6 levels at weeks 4 and 8, were analyzed. Overall, 264 subjects were randomized to treatment and had evaluable Depression Anxiety Stress Scale scores (132 in each treatment arm). At baseline, stress scores, and mean serum magnesium, erythrocyte magnesium, and serum vitamin B6 concentrations were similar between arms. Although not significant between groups, a significant increase over time in erythrocyte magnesium levels was observed in the subgroup of subjects with low baseline erythrocyte magnesium levels (<1.6 mmol/L) following treatment with magnesium and magnesium-vitamin B6 (week 4:0.21 mmol/L [95% confidence interval (CI), 0.10 to 0.31], p = 0.0003; and 0.13 mmol/L [95% CI, 0.02 to 0.23], p = 0.0233, respectively). Change from baseline in circulating vitamin B6 levels at weeks 4 and 8 in the magnesium-vitamin B6 supplemented group (314.96 nmol/L [95%CI, 294.61 to 335.31]) was significantly different (p < 0.0001) compared with the magnesium supplemented group (-0.39 nmol/L [95% CI, -20.73 to 19.94]). Magnesium alone and magnesium-vitamin B6 provided statistically significant increases in erythrocyte magnesium in subjects with low magnesium status (<1.6mmol/L). Vitamin B6 supplementation did not further increase magnesium levels.

Headaches and Magnesium: Mechanisms, Bioavailability, Therapeutic Efficacy and Potential Advantage of Magnesium Pidolate.

Magnesium deficiency may occur for several reasons, such as inadequate intake or increased gastrointestinal or renal loss. A large body of literature suggests a relationship between magnesium deficiency and mild and moderate tension-type headaches and migraines. A number of double-blind randomized placebo-controlled trials have shown that magnesium is efficacious in relieving headaches and have led to the recommendation of oral magnesium for headache relief in several national and international guidelines. Among several magnesium salts available to treat magnesium deficiency, magnesium pidolate may have high bioavailability and good penetration at the intracellular level. Here, we discuss the cellular and molecular effects of magnesium deficiency in the brain and the clinical evidence supporting the use of magnesium for the treatment of headaches and migraines.

Topical Treatment of Localized Neuropathic Pain in the Elderly.

The prevalence of neuropathic pain in the older population has been reported to be very high and is most commonly localized to a circumscribed area. Treatment failure is frequent in neuropathic pain and is accompanied by central side effects with recommended oral drugs acting on the central nervous system. A number of topical pharmaceuticals are available on prescription and also sold over the counter. This review in persons aged older than 60 years shows the efficacy of lidocaine 5% and capsaicin 8% for localized neuropathic pain while results with other pharmaceuticals are rather inconsistent. Local application of drugs has a very limited systemic effect and the pharmacological advantages of local over systemic treatment are particularly interesting in older persons who often have comorbidities and take multiple medications. However, more information is needed on the efficacy and safety of lidocaine 5% and capsaicin 8% in older old persons and on the long-term effects of these pharmaceuticals. These studies should also pave the way for research and development in the field of topical analgesics with a satisfactory level of evidence-based medicine.

Magnesium for the Management of Chronic Noncancer Pain in Adults: Protocol for a Systematic Review.

BACKGROUND: Chronic pain is a highly prevalent and complex health problem that is associated with a severe symptom burden, as well as substantial economic and social impact. Many patients with chronic pain still suffer from unrelieved or undertreated pain due to the incomplete efficacy and dose-limiting adverse effects of current therapies. Long-term and high-dose opioid use has considerably increased in the past 20 years despite limited evidence supporting its effectiveness in several chronic pain conditions, and serious concerns have emerged regarding adverse effects and potential misuse. Until recently, the steady increase in opioid prescribing rates has been associated with rising opioid-related mortality and other serious problems, emphasizing the need for better nonopioid therapies. Emerging evidence supports the safe use of magnesium in controlling chronic pain, but its overall efficacy and safety is still unclear. OBJECTIVE: This paper aims to assess the efficacy and safety of magnesium compared with a placebo for the treatment of chronic noncancer pain. METHODS: We will conduct a detailed search on Cochrane Central Register of Controlled Trials, MEDLINE, and EMBASE from their inception until the date the searches are run to identify relevant randomized controlled trials. The reference lists of retrieved studies as well as Web-based trial registries will also be searched. We will include randomized double-blind trials comparing magnesium (at any dose, frequency, or route of administration) with placebo using participant-reported pain assessment. Two reviewers will independently evaluate studies for eligibility, extract data, and assess trial quality and potential bias. Risk of bias will be assessed using criteria outlined in the Cochrane Handbook for Systematic Review of Interventions. Primary outcomes for this review will include any validated measure of pain intensity or pain relief. Dichotomous data will be used to calculate the risk ratio and number needed to treat or harm. The quality of evidence will be assessed using the Grading of Recommendations Assessment, Development and Evaluation approach. RESULTS: This protocol is grant-funded and has undergone a peer-review process through the Queen's University Department of Anesthesiology and Perioperative Medicine Vandewater Endowed Studentship. This project is also supported, in part, by the Chronic Pain Network of the Canadian Institutes of Health Research Strategy for Patient-Oriented Research. The electronic database search strategies are currently being developed and modified. The entire review is expected to be completed by January 1, 2019. CONCLUSIONS: The completion of this review is expected to identify available high-quality evidence describing the efficacy and safety of magnesium for the treatment of chronic noncancer pain. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/11654.

Superiority of magnesium and vitamin B6 over magnesium alone on severe stress in healthy adults with low magnesemia: A randomized, single-blind clinical trial.

INTRODUCTION: Animal and clinical studies suggest complementary effects of magnesium and high-dose pyridoxine (vitamin B6) on stress reduction. This is the first randomized trial evaluating the effects of combined magnesium and vitamin B6 supplementation on stress in a stressed population with low magnesemia using a validated measure of perceived stress. METHODS: In this Phase IV, investigator-blinded trial (EudraCT: 2015-003749-24), healthy adults with Depression Anxiety Stress Scales (DASS-42) stress subscale score >18 and serum magnesium concentration 0.45 mmol/L-0.85 mmol/L, were randomized 1:1 to magnesium-vitamin B6 combination (Magne B6 [Mg-vitamin B6]; daily dose 300 mg and 30 mg, respectively) or magnesium alone (Magnespasmyl [Mg]; daily dose 300 mg). Outcomes included change in DASS-42 stress subscale score from baseline to Week 8 (primary endpoint) and Week 4, and incidence of adverse events (AEs). RESULTS: In the modified intention-to-treat analysis (N = 264 subjects), both treatment arms substantially reduced DASS-42 stress subscale score from baseline to Week 8 (Mg-vitamin B6, 44.9%; Mg 42.4%); no statistical difference between arms was observed (p>0.05). An interaction (p = 0.0097) between baseline stress level and treatment warranted subgroup analysis (as per statistical plan); adults with severe/extremely severe stress (DASS-42 stress subscale score ≥25; N = 162) had a 24% greater improvement with Mg-vitamin B6 versus Mg at Week 8 (3.16 points, 95% CI 0.50 to 5.82, p = 0.0203). Consistent results were observed in the per protocol analysis and at Week 4. Overall, 12.1% of Mg-vitamin B6 treated and 17.4% of Mg-treated subjects experienced AEs potentially treatment related. CONCLUSIONS: These findings suggest oral Mg supplementation alleviated stress in healthy adults with low magnesemia and the addition of vitamin B6 to Mg was not superior to Mg supplementation alone. With regard to subjects with severe/extremely severe stress, this study provides clinical support for greater benefit of Mg combined with vitamin B6.

An Advanced Formulation of a Magnesium Dietary Supplement Adapted for a Long-Term Use Supplementation Improves Magnesium Bioavailability: In Vitro and Clinical Comparative Studies.

While general recommendations are for 300-mg magnesium intake a day, an advanced low-dose formulation of magnesium chloride, ChronoMag®, was designed to provide 100 mg of magnesium element, thus decreasing the risk of gastrointestinal side effects and allowing long-term supplementation in health conditions related to low magnesium levels. The present study aimed to compare magnesium release profile and bioavailability between this patented low-dose continuous-release magnesium chloride tablet (100 mg magnesium element) and a reference tablet at the usually prescribed dose (300 mg magnesium element). Magnesium release profile was determined by dissolving the tablets in solutions simulating the gastrointestinal tract environment. A randomized double-blind crossover controlled trial of ChronoMag® versus reference tablet (3 × 100 mg magnesium element tablets) in 12 normo-magnesemic healthy volunteers was conducted to evaluate the bioavailability of the patented magnesium chloride tablets (two 50 mg magnesium tablets, once-a-day intake). While the reference tablet released 100% of its magnesium within 1 h of dissolution, release from the magnesium chloride formulation was continuous for 6 h. Cumulative urinary magnesium levels compared to those with the reference tablet were 76% (0-5 h), 89% (0-10 h), and 87% (0-24 h). Elimination after 24 h was fairly similar with both supplements. Our results suggest that the new magnesium chloride formulation, providing continuous low-dose magnesium release throughout the gastrointestinal tract, improves absorption and bioavailability. This formulation conforms to the physiological mechanism of magnesium absorption throughout the digestive tract, allowing high absorption, and may improve gastrointestinal tolerance in long-term use.

Exploratory clinical trials: implementation modes & guidelines, scope and regulatory framework.

The working group focused on defining exploratory trials on medicinal products and developing recommendations for their implementation in France (notably concerning non-clinical requirements, the pharmaceutical quality of the investigational medical product and the conditions under which this type of clinical trial may be performed).To this end, the working group took account of existing guidelines (notably those in the USA and Belgium) and a draft revision of the ICH M3 guideline.Exploratory trials are clinical trials performed early in Phase I, prior to dose escalation and safety and tolerability trials. These trials are de facto first-in-man studies but lack a therapeutic or diagnostic goal and do not seek to establish the maximum tolerated dose (MTD). The objective is to answer precise questions which condition the continuation or suspension of the drug's development program. Exploratory trials include a small number of patients or healthy subjects and expose them (over a short period of time) to a low dose of an investigational medicinal product.The draft revision of M3 describes five approaches (two involving microdoses and three with pharmacological doses).The group's main recommendations can be summarized as follows:An exploratory trial may be performed when it is (i) justified, (ii) useful for product development and (iii) consistent with prerequisites. The pharmaceutical dossier should take account of the low quantity of product available, the short period of product administration and the low doses used. Good Manufacturing Practices can be adapted accordingly. The non-clinical dossier should also be adapted to suit the development phase and particular features of product use. In this respect, the group has commented on the recommendations in the draft revision of M3. The protocol must be designed to provide answers to a set of specific, pertinent questions concerning this administration phase - particularly on choice of the initial dose, the size of the dose escalation and the rules for subject withdrawal and trial suspension. In general, so-called "vulnerable" populations should not be involved in this type of trial, apart from duly justified exceptions. The group considered that approaches 3 to 5 should only apply to a medicinal product intended for treatment of a severe or rare disease or a condition with significant unmet medical needs. Pre-filing at the Afssaps (the French Agency for Healthcare Product Safety) is recommended, notably for approaches using pharmacological doses.