JOM Volume 27, Number 4, 2012 Review Article 177

Nutritional Brain Energy Enhancement for Reducing Mental Fatigue and Improving Mood and Cognition

Benjamin I. Brown, ND1 1 Nutri Ltd United Kingdom, British College of Nutritional Health, email: [email protected]

Abstract De!cits in mental energy negatively impact mood, motivation and cognition, and may signi!cantly a"ect quality of life in a large portion of the general population. Central to the mainte- nance of optimal mental energy is the role of the mitochondria in energy metabolism. #e mitochon- dria play a fundamental role in maintaining neuropsychiatric function with evidence suggesting a relationship between impaired mitochondrial function and de!cits in mood, cognition and men- tal vitality. #e enhancement of brain energy metabolism with nutritional factors such as creatine, acetyl-l-carnitine, multivitamins and polyphenol rich diets may be a novel strategy for reducing mental fatigue and improving mood and cognition, having wider relevance to neuropsychiatric and neurodegenerative illness, such as major depression and Alzheimer’s disease.

De!nition and Prevalence of Mental such as depression, cognitive dysfunction Energy De!cit and chronic fatigue, and are associated with Mental energy has been de!ned as a considerable morbidity. three-dimensional construct consisting of Major Depressive Disorder (MDD) is mood (transient feelings about the presence one of the most common psychiatric illness- of fatigue or energy), motivation (determi- es with a lifetime prevalence rate of 16.2%.3 nation and enthusiasm), and cognition (sus- #e diagnosis of MDD requires the presence 1 tained attention and vigilance). Optimal of symptoms that fall within the construct of mental energy, as re"ected by such features low mental energy including loss of interest, as an enthusiastic outlook, abundant energy, depressed mood, loss of energy and concen- clear thinking and a sharp memory, could be tration di$culties.4 #us, MDD could be considered features of good mental health viewed as a common and pathological ex- 2 and healthy brain aging. ample of low mental energy. It is conceivable that de!cits in mental Low mental energy in the cognitive do- energy in this context would have subtle, mains of memory and attention is frequently but important relationships to work perfor- found in the general population. Age-related mance, social relationships, and quality of cognitive dysfunction occurs across a gradual life in relatively healthy individuals although continuum of preclinical cognitive decline this has not been adequately investigated. (PCD), mild cognitive impairment (MCI) However, features of low mental energy in and Alzheimer’s disease (AD).5 PCD pre- the dimensions of mood, motivation and cedes MCI and AD by several years and be- cognition are common features of prevalent gins at least as early as 45 years of age.6 #e mental health disorders and chronic illness prevalence of MCI is 10% at 70-79 years and 178 Journal of Orthomolecular Medicine Vol 27, No 4, 2012

25% at 80-89 years of age.7 #e frequency neurological processes including the main- of AD is also high with prevalence rates in tenance of neuronal electrical potential, neu- people over 60 years of age in North Ameri- rotransmitter release in the synapse, the ex- can and Western European populations es- pression of cell receptors, cell signaling and timated at 6.4% and 5.4% respectively.8 #e gene expression. Accordingly, reductions in clinical characteristics of PCD and MCI are mitochondrial ATP production may result de!cits in memory with more advanced cog- in rapid synaptic fatigue.16 nitive impairment in AD.9 Neuroplasticity is a broad term that en- Fatigue is also a very common com- compasses adaptive structural and functional plaint, in one large survey amongst general changes that occur in the in practices in the United Kingdom some 38% response to physiological or pathological per- of respondents reported substantial physi- turbations. #ese changes include the gen- cal and mental fatigue and 18.3% reported eration of new (neurogenesis) and that their fatigue had lasted six months or the formation of synapses. #e mitochondria longer.10 Population estimates of chronic fa- are known to move dynamically along axons tigue syndrome (CFS), an illness character- and dendrites where they provide energy ized by severe debilitating physical and men- and play a fundamental regulatory role in tal fatigue and cognitive dysfunction range processes related to neuroplasticity.17 from 1.85% to 11.3%.11 Fatigue is frequently Calcium is a leading secondary messenger a non-speci!c symptom, and although often in the brain and calcium signaling is critical to accompanies lifestyle issues, physical illness neurotransmission and neuroplasticity. In neu- and mental disorders, the cause cannot be rotransmission, calcium releases into the syn- identi!ed in one-third of cases.12 Interest- apse following release and ingly, there is evidence to suggest that men- signals synaptic activity to the . Calcium tal fatigue may be central to the experience signaling is a highly energy dependent process of peripheral fatigue symptoms.13 and requires ATP to restore intracellular cal- Considerable clinical overlap exists be- cium levels. As a primary source of energy for tween symptoms of depression, cognitive maintaining calcium homoeostasis, the mi- dysfunction and fatigue. For example, up tochondria play an important role in calcium to 57% of CFS su%erers may have MDD mediated neurological processes.18 disorder.14 #erefore, it is conceivable that Cellular energy metabolism requires oxy- a de!cit in metabolic energy metabolism gen consumption, and consequently, the mito- might be the biological explanation for the chondria are a major source of oxidant stress. clinical symptoms of low mental energy #e mitochondria also play a critical role in across seemingly disparate illnesses. Central maintaining redox balance through the gener- to energy metabolism throughout the cen- ation of antioxidant defenses.19 Mitochondrial tral nervous system are the mitochondria, energy metabolism usually generates low-level organelles that generate the majority of en- oxidant production, but this can be up-regulat- ergy in the form of adenosine triphosphate ed in pathological states.20 Low-level oxidative (ATP). De!cits in mitochondrial function stress plays an important role in neurological have been implicated in several neurop- functions such as neurotransmission and neu- sychiatric disorders characterized by low roplasticity; however, excessive production of mental energy, including several mood and reactive oxygen species and/or reduced antioxi- cognitive disorders.15 dant defenses can result in neurotoxicity and cellular dysfunction.21 For example, mitochon- Neurological Roles of the Mitochondria drial reactive oxygen species have been shown #e brain consumes approximately 20% to inactivate neuronal nicotinic acetylcholine of the body’s energy although it only rep- receptors (important for cognitive functions) resents 2% of absolute body mass. Energy and reduce synaptic transmission in a dose de- in the form of ATP is essential to several pendant fashion.22 Nutritional Brain Energy Enhancement, Mental Fatigue, Mood and Cognition 179

Mitochondrial Dysfunction, Mood, of fatigue.30 #e severity of mitochondrial Cognition and Fatigue dysfunction in CFS has been shown to cor- Several lines of evidence including exper- relate with symptom severity, suggesting a imental studies, brain autopsy investigations primary role of impaired energy production and functional assessment of mitochondrial in the peripheral and mental fatigue of this activity and brain energy metabolism sug- illness.31 Mitochondrial dysfunction has also gest that there are important behavioral and been suggested to play a role in age-related cognitive consequences of mitochondrial cognitive fatigue.32 Also, in a group of vol- dysfunction that are expressed as clinical unteers a mentally fatiguing task was found symptoms of low mental energy. to reduce brain phosphocreatine, a substrate A number of post mortem studies of pa- for ATP production; suggesting, that the ex- tients with depression have found evidence of perience of mental fatigue may be related to mitochondrial dysfunction in various regions a reduction in brain energy metabolism even of the brain involved in regulation of mood in healthy individuals.33 and cognitive function, such as the prefron- tal cortex.23 Low levels of respiratory chain Orthomolecular Restoration of Brain enzyme ratios and ATP production and in- Energy creased mitochondrial gene deletions have #ere is increasing interest in the use of been found in the peripheral muscle tissue nutrients known to improve the structure of patients with chronic depression.24 Inter- and function of mitochondria as a means to estingly, in these patients symptoms related treat and prevent behavioral and cognitive to muscular dysfunction and mental fatigue illness as well as enhancing mental function predicted muscle ATP production rates sug- in healthy individuals.34-37 #e term “mito- gesting that a sub-group of depression may chondrial nutrients” was coined to catego- be due to mitochondrial dysfunction.25 #ere rize nutritional compounds that enter the is even experimental evidence suggesting cells and mitochondria following exogenous that common anti-depressant drugs may be administration, and protect the mitochon- working at least in part by improving brain dria from oxidative damage and improve mitochondrial metabolism.26 mitochondrial function.38 Mitochondrial Reductions in brain glucose metabo- nutrients have been shown to have a number lism have been consistently documented of important e%ects including, reducing oxi- and are characteristic of cognitive decline dative stress, enhancing energy metabolism, with age. Impaired glucose metabolism can and increasing mitochondrial biogenesis.39 be detected in earlier stages of AD includ- Examples of mitochondrial nutrients ing MCI and have been found to predate with established e%ects on mitochondrial clinical symptoms by decades in individuals function with the potential to improve mood, genetically susceptible to AD. Changes in cognition and reduce mental fatigue include brain glucose metabolism could be explained creatine, carnitine, coenzyme Q10 (CoQ10) by underlying mitochondrial dysfunction.27 and lipoic acid. In addition, nutraceuticals A study of the brains in patients with au- containing combinations of mitochondrial topsy con!rmed AD found that alterations nutrients, as well as multivitamin and miner- in citric acid cycle enzymes of the mitochon- als have shown evidence of bene!t. #is re- dria signi!cantly correlated with ratings of view will focus on creatine, acetyl-l-carnitine clinical disability.28 Further, a study in mice and multivitamins. with reduced mitochondrial gene expression indicated that normal mitochondrial energy Creatine production is essential for the retention and Creatine is a dietary nutrient that direct- consolidation of memory.29 ly in"uences phosphocreatine reserves in the Deceased brain energy metabolism brain.40 Phosphocreatine plays an important has been suggested to be a central feature role in energy homoeostasis by storing and 180 Journal of Orthomolecular Medicine Vol 27, No 4, 2012

donating phosphate for ATP synthesis and creatine on mood in non-depressed individu- regeneration. #e importance of creatine in als. Also, no studies have investigated creatine maintaining energy homeostasis in the brain in dementia despite evidence that brain cre- is underappreciated.41 Creatine supplemen- atine is particularly low in those at high ge- 56 tation is safe, well tolerated and has shown netic risk. promise for neurological disorders with de!- Acetyl-l-carnitine cits in energy metabolism including neuro- degenerative, mood and anxiety disorders.42 Acetyl-l-carnitine (ALC) is a natural es- A number of short-term studies have ter of the amino acid carnitine, is responsible investigated the ability of supplemental cre- for the transport of acetyl CoA into the mi- atine to enhance mood (Table 1, below) and tochondria during fatty acid oxidation, and cognitive function (Table 2, p.181), particu- is thus crucial for cellular energy production. larly under conditions of high demand such ALC is known to enhance neuronal energy as sleep deprivation or stress. Collectively, the metabolism although this is not necessarily current evidence suggests a promising role for its primary mechanism of action; ALC has creatine supplementation as a means of en- several other established neurological e%ects, hancing brain energy metabolism and im- notably the enhancement of cholinergic proving mood and cognitive function.55 #ere neurotransmission through the donation of are no studies that have assessed the e%ects of the acetyl moiety to the production of ace-

Table 1. Studies of Creatine on Mood

Reference Study group Intervention Results

43 Women with 5 grams of creatine Significantly improved major depressive per day for 8 weeks depressive symptoms disorder

44 Female adolescents 4 grams of creatine Reduced depressive with SSRI-resistant for 8 weeks symptoms and major depressive increased brain disorder phosphocreatine

45 Unipolar and bipolar 3-5 g creatine per Patients with unipolar patients with treatment- day for 4 weeks (but not bipolar) resistant depression depression improved

46 Case report of a 3-5 g creatine per Improved depressive patient with day for 8 weeks symptoms fibromyalgia and depression

47 Patients with treatment- Dose and duration Improved symptoms; resistant posttraumatic unknown greatest benefit in stress disorder in patients diagnosed with comorbid depression Nutritional Brain Energy Enhancement, Mental Fatigue, Mood and Cognition 181

tylcholine, which is involved in cognition mild cognitive impairment (MCI) and mild and mood.57 (early) AD found a bene!cial e%ect of ALC on #ere is experimental data to show that both the clinical scales and the psychometric supplemental ALC can enhance brain en- tests with bene!ts observed in memory, cog- ergy metabolism. Chronic feeding of ALC nitive function, and mood. Doses were mostly to healthy mice for example was able to 1,500-2,000 mg daily, and bene!ts were no- improve brain glucose metabolism, increase ticed within three months and increased over metabolites involved in energy metabolism time.59 Brain imaging has revealed that ALC (adenosine nucleotides) and increase brain treatment in subjects with AD improves energy stores (phosphocreatine).58 A num- high-energy phosphate levels.60 ber of human studies have also indicated More recently ALC was shown to ben- bene!cial e%ects of ALC on brain energy e!t age-related fatigue and functional im- metabolism, mood, and cognitive function. pairment. Elderly subjects supplemented A meta-analysis of 21 studies of ALC for with ALC (2000 mg twice daily) had a sig-

Table 2. Studies of Creatine on Cognition

Reference Study group Intervention Results

48 Healthy individuals 8 grams of creatine per Attenuated of mental fatigue subject to a repeated day for 5 days and increased oxygen mathematical utilization in the brain calculation

49 Healthy young adult 5 grams of creatine for Improved working memory vegetarians 6 weeks and intelligence

50 Healthy individuals 20 g creatine per day Supplementation had a subject to 24 hours for 7 days positive effect on mood state sleep deprivation and tasks that place a heavy stress on the prefrontal cortex

51 Healthy individuals 20 g creatine per day Improved performance of subject to 36 hours for 7 days complex central executive sleep deprivation tasks

52 Older age individuals 20 grams of creatine per Significantly improved day for 2 weeks cognitive function

53 Healthy young adults 0.03 grams creatine Supplementation did not (21±2 years) per kg body weight improve cognitive function per day for 6 weeks

54 Healthy individuals 5 grams of creatine per Improved cognitive functions subjected to cognitive day for 2 weeks including reaction times and assessment tasks memory 182 Journal of Orthomolecular Medicine Vol 27, No 4, 2012

ni!cant decrease in mental fatigue and im- and mineral formulations (multivitamins) provements in cognitive function. #ey also can improve cognitive function, mood and had signi!cant reductions in muscle pain, reduce mental fatigue.67 #e authors identi- general and physical fatigue, post-exercise !ed nine studies of which all but one report- fatigue, and sleep disorders.61 ed bene!ts from multivitamins on cognitive ALC may also be e%ective for depression. function. A number of these studies also Fourteen depressed elderly patients (between reported positive outcomes on subjective 70 and 80 years of age) were treated with measures of mental fatigue, mood, anxiety, 1,500 mg of ALC, while another fourteen and stress. In one such study a multivitamin received placebo. ALC reduced depression formula taken over 33 days was found to scores (in the Hamilton Rating Scale for De- improve ratings of stress, cognitive perfor- pression and Beck Depression Inventory) and mance and reduce mental fatigue in healthy behavioral aspects.62 A signi!cant antidepres- adult men.68 A similar study of a multivita- sant e%ect was similarly observed in an earlier min in women found that supplementation study of elderly depressed subjects.63 for nine weeks improved cognitive function #ere is also clinical evidence to show and reduced mental fatigue during a men- ALC can improve mood in patients with tally demanding task assessment.69 dysthymia.64 In one such report ALC was Extensive experimental evidence sug- compared to amisulpride for the treatment gests that one of the primary e%ects of low of dysthymia over 12 weeks and was found micronutrient intake is decreased ATP syn- to be as e%ective as the medication, but with thesis and increased oxidative stress in the superior tolerability.65 mitochondria, and that this can in-turn lead Supporting a central role of enchant- to accelerated cognitive dysfunction and ment in brain energy metabolism by ALC, chronic disease.70 Multivitamin supplemen- a study in elderly patients with depression tation may therefore be a means of improv- demonstrated a signi!cant increase in brain ing mitochondrial function, brain energy phosphocreatine with treatment that directly metabolism and enhancing neurological correlated with symptomatic improvement health.71 “Tuning up your metabolism” with in depressive symptoms.66 a multivitamin has been proposed as a safe, Overall, ALC appears to improve brain cheap and important way to enhance micro- energy metabolism, cognitive function, and nutrient intake, improve metabolic function mood and reduce mental fatigue although and optimize wellbeing.72 most studies are limited to older age indi- viduals with mild AD, unipolar depression Dietary Enhancement of Brain Energy or dysthymia. Metabolism A traditional dietary pattern character- Multivitamins ized by foods that re"ect those consumed by Vitamin and mineral intake is frequently humans throughout the majority of recent de!cient in modern diets, and due to the im- evolutionary history (e.g. fruits, vegetables, portance of micronutrients for neurological herbs, spices, nuts, seeds, lean meats and function, the restoration of optimal nutrition- seafood) has shown promise for enhancing al status with dietary supplements has been mental health while modern dietary patterns explored as an avenue for improving mood, (e.g. soda, sweetened desserts, fried food, pro- cognition and reducing mental fatigue. cessed meat, re!ned grains and high-fat dairy A recent review of the evidence for ben- products) may negatively impact neurological e!t from vitamin supplementation on cogni- function and are related to mental illness. tive function found that while interventions With regards to depression a “processed using one or only a few vitamins have largely food” dietary pattern was found to strongly demonstrated little bene!t, there is relatively predict the development of depression with- consistent evidence to suggest multivitamin in !ve years, while a “whole food” pattern Nutritional Brain Energy Enhancement, Mental Fatigue, Mood and Cognition 183

was protective.73 Adhering to a traditional role in preserving neurological function and Mediterranean style diet also prevented de- protecting against cognitive decline.81 pression over a 4-year prospective study.74 Several neuroprotective activities of A “traditional” dietary pattern (mostly veg- polyphenols have been identi!ed including etables, fruit, grass fed meat, !sh, and whole the ability to increase cellular detoxi!cation grains) was associated with lower odds for enzymes, enhance the production of neu- major depression or dysthymia and for anxi- rotrophic factors involved in nerve cell func- ety disorders compared to a “western” diet of tion and growth, and enhance levels of proteins processed or fried foods, re!ned grains, sug- that protect neurons and prevent cell death.82 ary products, and beer.75 A traditional diet providing a high concentra- #ere is also increasing evidence to sug- tion of polyphenol rich foods may therefore gest that a traditional diet can preserve or stimulate genes involved in enhancement of improve cognitive function with age. In par- neurological energy metabolism and function ticular, the traditional Mediterranean-type and improve cognition and mood. diet has been well studied with experimen- tal, epidemiological and prospective data Discussion suggesting strong cognitive bene!ts.76 Healthy mood, cognitive vitality and Few, if any, controlled intervention stud- minimal mental fatigue are undoubtedly de- ies have investigated the e%ects of a tradi- sirable aspects of good mental health. One tional diet in subjects with depression or potential way to enhance mental energy is cognitive impairment. An important inter- the use of targeted mitochondrial nutrients vention study, however, did investigate the such as creatine and carnitine, particularly in e%ect of a short-term (10-day) dietary inter- people with functional or clinical evidence of vention on mood and cognition in healthy, impaired mitochondrial metabolism. More young women.77 #e subjects who followed a broadly, the use of a multivitamin may help nutrient-dense Mediterranean diet showed optimize the daily supply of micronutrients signi!cant improvements in self-rated vigor, important for brain energy metabolism and alertness and contentment compared to a cognitive health in people exposed to modern, control group. Cognitive function was also processed diets. Furthermore consumption of assessed with evidence of small, but non- a phytonutrient dense traditional diet appears signi!cant improvements. to augment brain energy metabolism and im- #e reasons for the bene!ts of a tradi- prove neurological function with clinical ben- tional dietary pattern on mental health are e!ts noted in a matter of days and protective likely diverse, but do seem to be in part due bene!ts extending over many years. to higher concentrations of phytochemicals, Beyond enhancing mental energy in in particular polyphenols. For example, a otherwise healthy individuals there is con- strong relationship between the polyphenol siderable evidence to suggest that augment- rich foods typical of the traditional Mediter- ing brain mitochondrial energy metabolism ranean diet (olive oil, walnuts, co%ee, wine may have important therapeutic e%ects on and total urinary polyphenols) and measures mood and behavioral disorders. “Mitochon- of memory and cognitive function has been drial psychiatry,” as it has been coined, may detected.78 therefore emerge as a method of addressing Polyphenols trigger mild cellular stress, wider mental illness.83 such as a free radical production and in- It is also intriguing to note that wider creased energy demands, which cause the cell lifestyle changes associated with improved to activate an adaptive response ultimately re- mental health have also been observed to ducing oxidative stress and improving energy in"uence brain energy metabolism. Stress metabolism.79 #is occurs via a group of genes management may be bene!cial because known as the vitagenes.80 In the central ner- chronic stress has been shown to impair vous system the vitagenes play an important mitochondrial structure and function in the 184 Journal of Orthomolecular Medicine Vol 27, No 4, 2012

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