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Psychostimulant drug effects on glutamate, Glx, and creatine in the anterior cingulate cortex and subjective response in healthy humans.
White, TL, Monnig, MA, Walsh, EG, Nitenson, AZ, Harris, AD, Cohen, RA, Porges, EC, Woods, AJ, Lamb, DG, Boyd, CA, et al
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. 2018;(7):1498-1509
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Abstract
Prescription psychostimulants produce rapid changes in mood, energy, and attention. These drugs are widely used and abused. However, their effects in human neocortex on glutamate and glutamine (pooled as Glx), and key neurometabolites such as N-acetylaspartate (tNAA), creatine (tCr), choline (Cho), and myo-inositol (Ins) are poorly understood. Changes in these compounds could inform the mechanism of action of psychostimulant drugs and their abuse potential in humans. We investigated the acute impact of two FDA-approved psychostimulant drugs on neurometabolites using magnetic resonance spectroscopy (1H MRS). Single clinically relevant doses of d-amphetamine (AMP, 20 mg oral), methamphetamine (MA, 20 mg oral; Desoxyn®), or placebo were administered to healthy participants (n = 26) on three separate test days in a placebo-controlled, double-blinded, within-subjects crossover design. Each participant experienced all three conditions and thus served as his/her own control. 1H MRS was conducted in the dorsal anterior cingulate cortex (dACC), an integrative neocortical hub, during the peak period of drug responses (140-150 m post ingestion). D-amphetamine increased the level of Glu (p = .0001), Glx (p = .003), and tCr (p = .0067) in the dACC. Methamphetamine increased Glu in females, producing a significant crossover interaction pattern with gender (p = .02). Drug effects on Glu, tCr, and Glx were positively correlated with subjective drug responses, predicting both the duration of AMP liking (Glu: r = +.49, p = .02; tCr: r = +.41, p = .047) and the magnitude of peak drug high to MA (Glu: r = +.52, p = .016; Glx: r = +.42, p = .049). Neither drug affected the levels of tNAA, Cho, or Ins after correction for multiple comparisons. We conclude that d-amphetamine increased the concentration of glutamate, Glx, and tCr in the dACC in male and female volunteers 21/2 hours after drug consumption. There was evidence that methamphetamine differentially affects dACC Glu levels in women and men. These findings provide the first experimental evidence that specific psychostimulants increase the level of glutamatergic compounds in the human brain, and that glutamatergic changes predict the extent and magnitude of subjective responses to psychostimulants.
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Supplementation with Qter® and Creatine improves functional performance in COPD patients on long term oxygen therapy.
De Benedetto, F, Pastorelli, R, Ferrario, M, de Blasio, F, Marinari, S, Brunelli, L, Wouters, EFM, Polverino, F, Celli, BR, ,
Respiratory medicine. 2018;:86-93
Abstract
BACKGROUND Skeletal muscle dysfunction and poor functional capacity are important extra-pulmonary manifestations of chronic obstructive pulmonary disease (COPD), especially in COPD patients on long-term O2 therapy (LTOT). Beside the role of pulmonary rehabilitation, the effect of nutritional interventions is still controversial, and there are knowledge gaps on the effective role of nutraceutical supplementation on hard endpoints. The aim of this study was to investigate the effects of nutritional supplementation with Coenzyme Q10 (QTer®) - a powerful antioxidant with the potential to reduce oxidative stress and improve mitochondrial function - and Creatine on functional, nutritional, and metabolomic profile in COPD patients on long-term O2 therapy. METHODS One-hundred and eight patients with COPD from 9 Italian hospitals were enrolled in this double-blinded randomized placebo-controlled clinical study. At baseline and after 2 months of therapy, the patients underwent spirometry, 6-minute walk test (6MWT), bioelectrical impedance analysis, and activities of daily living questionnaire (ADL). Also, dyspnea scores and BODE index were calculated. At both time points, plasma concentration of CoQ10 and metabolomic profiling were measured. FINDINGS Ninety patients, who randomly received supplementation with QTer® and Creatine or placebo, completed the study. Compared with placebo, supplemented patients showed improvements in 6MWT (51 ± 69 versus 15 ± 91 m, p < 0.05), body cell mass and phase angle, sodium/potassium ratio, dyspnea indices and ADL score. The CoQ10 plasma concentration increased in the supplementation group whereas it did not change in the placebo group. The metabolomics profile also differed between groups. Adverse events were similar in both groups. INTERPRETATION These results show that in patients with COPD, dietary supplementation with CoQ10 and Creatine improves functional performance, body composition and perception of dyspnea. A systemic increase in some anti-inflammatory metabolites supports a pathobiological mechanism as a reason for these benefits. Further trials should help clarifying the role of QTer® and Creatine supplementation in patients with COPD.
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Effects of Creatine and Carbohydrate Loading on Cycling Time Trial Performance.
Tomcik, KA, Camera, DM, Bone, JL, Ross, ML, Jeacocke, NA, Tachtsis, B, Senden, J, VAN Loon, LJC, Hawley, JA, Burke, LM
Medicine and science in sports and exercise. 2018;(1):141-150
Abstract
INTRODUCTION Creatine (Cr) and carbohydrate loadings are dietary strategies used to enhance exercise capacity. This study examined the metabolic and performance effects of a combined CR and CHO loading regiment on time trial (TT) cycling bouts. METHODS Eighteen well-trained (~65 mL·kg·min V˙O2peak) men completed three performance trials (PT) that comprised a 120-km cycling TT interspersed with alternating 1- and 4-km sprints (six sprints each) performed every 10 km followed by an inclined ride to fatigue (~90% V˙O2peak). Subjects were pair matched into either CR-loaded (20 g·d for 5 d + 3 g·d for 9 d) or placebo (PLA) groups (n = 9) after the completion of PT1. All subjects undertook a crossover application of the carbohydrate interventions, consuming either moderate (6 g·kg body mass (BM) per day; MOD) or CHO-loaded (12 g·kg BM·d; LOAD) diets before PT2 and PT3. Muscle biopsies were taken before PT1, 18 h after PT1, and before both PT2 and PT3. RESULTS No significant differences in overall TT or inclined ride times were observed between intervention groups. PLA + LOAD improved power above baseline (P < 0.05) during the final 1-km sprint, whereas CR + MOD and CR + LOAD improved power (P < 0.05) during the final 4-km sprint. Greater power was achieved with MOD and LOAD compared with baseline with PLA (P < 0.05). CR increased pre-PT BM compared with PLA (+1.54% vs +0.99% from baseline). CR + LOAD facilitated greater [total CR] (P < 0.05 vs baseline) and muscle [glycogen] (P < 0.01 vs baseline and MOD) compared with PLA + LOAD. Mechanistic target of rapamycin decreased from baseline after glycogen depletion (~30%; P < 0.05). CONCLUSIONS Power output in the closing sprints of exhaustive TT cycling increased with CR ingestion despite a CR-mediated increase in weight. CR cosupplemented with carbohydrates may therefore be beneficial strategy for late-stage breakaway moments in endurance events.
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Effects of creatine supplementation on cognitive function of healthy individuals: A systematic review of randomized controlled trials.
Avgerinos, KI, Spyrou, N, Bougioukas, KI, Kapogiannis, D
Experimental gerontology. 2018;:166-173
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Abstract
BACKGROUND AND AIMS Creatine is a supplement used by sportsmen to increase athletic performance by improving energy supply to muscle tissues. It is also an essential brain compound and some hypothesize that it aids cognition by improving energy supply and neuroprotection. The aim of this systematic review is to investigate the effects of oral creatine administration on cognitive function in healthy individuals. METHODS A search of multiple electronic databases was performed for the identification of randomized clinical trials (RCTs) examining the cognitive effects of oral creatine supplementation in healthy individuals. RESULTS Six studies (281 individuals) met our inclusion criteria. Generally, there was evidence that short term memory and intelligence/reasoning may be improved by creatine administration. Regarding other cognitive domains, such as long-term memory, spatial memory, memory scanning, attention, executive function, response inhibition, word fluency, reaction time and mental fatigue, the results were conflicting. Performance on cognitive tasks stayed unchanged in young individuals. Vegetarians responded better than meat-eaters in memory tasks but for other cognitive domains no differences were observed. CONCLUSIONS Oral creatine administration may improve short-term memory and intelligence/reasoning of healthy individuals but its effect on other cognitive domains remains unclear. Findings suggest potential benefit for aging and stressed individuals. Since creatine is safe, future studies should include larger sample sizes. It is imperative that creatine should be tested on patients with dementias or cognitive impairment.
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Influence of Creatine Supplementation on Apoptosis Markers After Downhill Running in Middle-Aged Men: A Crossover Randomized, Double-Blind, and Placebo-Controlled Study.
Sheikholeslami-Vatani, D, Faraji, H
American journal of physical medicine & rehabilitation. 2018;(11):825-831
Abstract
OBJECTIVE Strenuous exercise can induce apoptosis in a variety of tissues. We investigated the effects of creatine loading on apoptosis markers after downhill running. DESIGN Twenty-two middle-aged men were randomly assigned to either a creatine or a placebo group. Crossover design, double-blind controlled supplementation was performed using 20 g/d(-1) of creatine or maltodextrin for 7 days. Downhill running (12% incline) at 70% of heart rate maximum for 40 mins was performed on the eighth day. Blood samples were taken on the day before supplementation, after supplementation and after running. RESULTS There were no significant changes in the caspase-3, caspase-9, p53, Bax, and IGF-1 concentrations from presupplementation to postsupplementation in both groups of creatine and placebo (P > 0.05). There were significant increases (P < 0.05) in serum caspase-3, caspase-9, p53, and Bax after running in the placebo group. These markers were not noticeably changed in the creatine group (P > 0.05). Bcl-2 was unchanged in the placebo group but substantially increased (P < 0.05) in the creatine group. No significant changes were observed in IGF-1 concentration after running comparing to prerunning in both groups (P > 0.05). Lactate levels increased similarly in both groups (P < 0.05). CONCLUSIONS The findings indicate that creatine supplementation could prevent exercise-induced apoptotic markers.
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Effects of Protein, Essential Amino Acids, B-Hydroxy B-Methylbutyrate, Creatine, Dehydroepiandrosterone and Fatty Acid Supplementation on Muscle Mass, Muscle Strength and Physical Performance in Older People Aged 60 Years and Over. A Systematic Review on the Literature.
Beaudart, C, Rabenda, V, Simmons, M, Geerinck, A, Araujo De Carvalho, I, Reginster, JY, Amuthavalli Thiyagarajan, J, Bruyère, O
The journal of nutrition, health & aging. 2018;(1):117-130
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Abstract
OBJECTIVES The objective of this study was to perform a systematic review to investigate the effects protein, essential amino acids (EAA), β-hydroxy β-methylbutyrate (HMB), creatine, dehydroepiandrosterone (DHEA) and fatty acid supplementation on muscle mass, muscle strength and physical performance of elderly subjects. METHODS Using the electronic databases MEDLINE and EMBASE we identified RCTs published until February 2016 which assessed the effects of these nutrient supplementation on muscle strength, muscle mass or physical performance. Study selection and data extraction were performed by two independent reviewers. RESULTS Search strategy allowed us to identify 23 RCTs. Among them, four used proteins as nutritional supplement, seven EAAs, six creatine, four DHEA and finally, two HMB. From our systematic review, it seems that the effects of these supplementations on muscle health are rather limited. Only consistent effects of EAA supplementation on physical performance (3 out of the 4 RCTs using EAA supplementation found significant effect of this supplementation on physical performance) and HMB supplementation on muscle mass (all the 2 identified RCTs using HMB supplementation found significant effect of this supplementation on muscle mass) have been found across studies. No consistent effects were found for the other types of dietary supplementation. Because of the important limitations in study design, inconsistency and lack of directness, the overall quality of the evidence was judged to be low or very low using the GRADE system. CONCLUSION This systematic review showed a limited effect of nutritional supplementation on muscle mass, muscle power and physical function. Inconsistent positive effects were observed for some specific supplementations but the results only concerned one aspect of the muscle. Well designed and appropriately powered RCTs are needed to provide evidence for appropriate clinical recommendations.
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Changing to a vegetarian diet reduces the body creatine pool in omnivorous women, but appears not to affect carnitine and carnosine homeostasis: a randomised trial.
Blancquaert, L, Baguet, A, Bex, T, Volkaert, A, Everaert, I, Delanghe, J, Petrovic, M, Vervaet, C, De Henauw, S, Constantin-Teodosiu, D, et al
The British journal of nutrition. 2018;(7):759-770
Abstract
Balanced vegetarian diets are popular, although they are nearly absent in creatine and carnosine and contain considerably less carnitine than non-vegetarian diets. Few longitudinal intervention studies investigating the effect of a vegetarian diet on the availability of these compounds currently exist. We aimed to investigate the effect of transiently switching omnivores onto a vegetarian diet for 6 months on muscle and plasma creatine, carnitine and carnosine homeostasis. In a 6-month intervention, forty omnivorous women were ascribed to three groups: continued omnivorous diet (control, n 10), vegetarian diet without supplementation (Veg+Pla, n 15) and vegetarian diet combined with daily β-alanine (0·8-0·4 g/d) and creatine supplementation (1 g creatine monohydrate/d) (Veg+Suppl, n 15). Before (0 months; 0M), after 3 months (3M) and 6 months (6M), a fasted venous blood sample and 24-h urine was collected, and muscle carnosine content was determined by proton magnetic resonance spectroscopy (1H-MRS). Muscle biopsies were obtained at 0M and 3M. Plasma creatine and muscle total creatine content declined from 0M to 3M in Veg+Pla (P=0·013 and P=0·009, respectively), whereas plasma creatine increased from 0M in Veg+Suppl (P=0·004). None of the carnitine-related compounds in plasma or muscle showed a significant time×group interaction effect. 1H-MRS-determined muscle carnosine content was unchanged over 6M in control and Veg+Pla, but increased in Veg+Suppl in soleus (P<0·001) and gastrocnemius (P=0·001) muscle. To conclude, the body creatine pool declined over a 3-month vegetarian diet in omnivorous women, which was ameliorated when accompanied by low-dose dietary creatine supplementation. Carnitine and carnosine homeostasis was unaffected by a 3- or 6-month vegetarian diet, respectively.
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No effect of creatine monohydrate supplementation on inflammatory and cartilage degradation biomarkers in individuals with knee osteoarthritis.
Cornish, SM, Peeler, JD
Nutrition research (New York, N.Y.). 2018;:57-66
Abstract
The study purpose was to evaluate the effectiveness of creatine monohydrate supplementation (20 grams/day for 1 week and then 5 grams/day for 11 weeks) on inflammation (C-reactive protein, interleukin-1β, interleukin-6, s100 A8/A9, and tumor necrosis factor-α) and cartilage degradation (serum cartilage oligomeric matrix protein) in patients with knee osteoarthritis. We hypothesized that supplementing with creatine monohydrate for 12 weeks would lower biomarkers of inflammation and cartilage degradation in patients with knee osteoarthritis when compared to placebo. A total of 18 patients with mild to moderate knee osteoarthritis were recruited and randomized in a double blind fashion to either a creatine supplementation group (N = 9) or a placebo (N = 9). At baseline and after 12 weeks of supplementation patients had inflammatory and cartilage degradation biomarkers measured in the systemic blood. Further, patients completed the Knee injury and Osteoarthritis Outcome (KOOS) questionnaire as well as had their isometric thigh strength evaluated using an isokinetic dynamometer at both time points. Results indicated that there was no difference between the creatine and placebo groups at 12 week follow up in the inflammatory biomarkers measured nor was there any difference between the groups for cartilage degradation (all P>.05). No statistical differences were noted for the KOOS questionnaire subscales or total score (all P>.05). Muscle strength testing indicated a main effect of time for both groups where isometric thigh strength at 0° of knee flexion was lowered significantly (P=.047). No other significant differences were found in the strength data. We conclude that 12 weeks of supplementation with creatine monohydrate does not affect inflammatory biomarkers, cartilage degradation, KOOS scores, or muscle strength in patients with mild to moderate knee osteoarthritis.
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The Combination of Physical Exercise with Muscle-Directed Antioxidants to Counteract Sarcopenia: A Biomedical Rationale for Pleiotropic Treatment with Creatine and Coenzyme Q10.
Guescini, M, Tiano, L, Genova, ML, Polidori, E, Silvestri, S, Orlando, P, Fimognari, C, Calcabrini, C, Stocchi, V, Sestili, P
Oxidative medicine and cellular longevity. 2017;:7083049
Abstract
Sarcopenia represents an increasing public health risk due to the rapid aging of the world's population. It is characterized by both low muscle mass and function and is associated with mobility disorders, increased risk of falls and fractures, loss of independence, disabilities, and increased risk of death. Despite the urgency of the problem, the development of treatments for sarcopenia has lagged. Increased reactive oxygen species (ROS) production and decreased antioxidant (AO) defences seem to be important factors contributing to muscle impairment. Studies have been conducted to verify whether physical exercise and/or AOs could prevent and/or delay sarcopenia through a normalization of the etiologically relevant ROS imbalance. Despite the strong rationale, the results obtained were contradictory, particularly with regard to the effects of the tested AOs. A possible explanation might be that not all the agents included in the general heading of "AOs" could fulfill the requisites to counteract the complex series of events causing/accelerating sarcopenia: the combination of the muscle-directed antioxidants creatine and coenzyme Q10 with physical exercise as a biomedical rationale for pleiotropic prevention and/or treatment of sarcopenia is discussed.
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Cognitive effects of creatine monohydrate adjunctive therapy in patients with bipolar depression: Results from a randomized, double-blind, placebo-controlled trial.
Toniolo, RA, Fernandes, FBF, Silva, M, Dias, RDS, Lafer, B
Journal of affective disorders. 2017;:69-75
Abstract
BACKGROUND Depressive episodes and cognitive impairment are major causes of morbidity and dysfunction in individuals suffering from bipolar disorder (BD). Novel treatment approaches that target clinical and cognitive aspects of bipolar depression are needed, and research on pathophysiology suggests that mitochondrial modulators such as the nutraceutical creatine monohydrate might have a therapeutic role for this condition. METHODS Eighteen (N=18) patients with bipolar depression according to DSM-IV criteria who were enrollled in a 6-week, randomized, double-blind, placebo-controlled trial of creatine monohydrate 6g daily as adjunctive therapy were submitted to neuropsychological assessments (Wisconsin Card Sorting Test, Digit Span subtest of the Wechsler Adult Intelligence Scale-Third Edition, Stroop Color-Word Test, Rey-Osterrieth complex figure test, FAS Verbal Fluency Test) at baseline and week 6. RESULTS There was a statistically significant difference between the treatment groups of the change on the total scores after 6 weeks in the verbal fluency test, with improvement in the group receiving adjunctive treatment with creatine. We did not find significant differences between the groups of the changes on other neuropsychological tests. LIMITATIONS Small sample and lack of a control group of healthy subjects. CONCLUSIONS Our trial, which was the first to investigate the cognitive effects of creatine monohydrate on bipolar depression, indicates that supplementation with this nutraceutical for 6 weeks is associated with improvement in verbal fluency tests in patients with this condition.