Cognition. Dr Edna Yamasaki Patrikiou, MD, PhD Department t of Life and Health Sciences University of Nicosia - Cyprus

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1 Caffeine and Cognition Dr Edna Yamasaki Patrikiou, MD, PhD Department t of Life and Health Sciences University of Nicosia - Cyprus

2 Caffeine Most widely used psychoactive substance, y py, and been considered as a drug of abuse.

3 Is Caffeine a drug of abuse? Classic drugs of abuse increases cerebral functional activity and dopamine release in the shell of the nucleus accumbens (the key neural structure for reward, motivation, and addiction). Caffeine - does NOT induce a release of dopamine in the shell of the nucleus accumbens, BUT leads to a release of dopamine in the prefrontal cortex (reinforcing properties). High doses - Increased glucose utilization in the shell of the nucleus accumbens, nonspecific stimulation brain structures.

4 So... Although caffeine fulfills some criteria for drug dependence and shares with amphetamine and cocaine a certain specificity of action on the cerebral dopaminergic system, Caffeine does not act on the dopaminergic structures related to reward, motivation, and addiction.

5 Caudate nucleus, and neural structures regulating sleep-wake cycle

6 Pharmacology of Caffeine 1,3,7-trimethylxanthine Following oral ingestion peaks at plasma in 30-75min Metabolized by liver and excreted in urine through demethylation and oxidation to paraxanthine, theobromine and theophylline

7 Pharmacology of Caffeine Plasma levels Between 2-6mg/L after consumption up to about 6 cups of coffee per day Half-life 3-7 hours - Increased in women during the later stages of pregnancy, long-term use of oral contraceptive steroids. - Increased with impaired liver function and in early infancy The rate of elimination varies by individual due to both genetic and environmental factors. The metabolism of methylxanthines is influenced by the presence of other agents or specific diseases Increased clearance: cigarette smoking and oral contraceptives Increased half life: hepatic cirrhosis, congestive heart failure, or acute pulmonary congestion.

8 Behavioral effects of caffeine Mental stimulation Systemic catecholamine release and Sympathetic neural stimulation increase in blood pressure and lipolysis increase in plasma free fatty acid concentrations Faster reaction times Higher overall arousal level More profound processing of both attended and unattended information, Acceleration of motor processes No effects in memory Higher doses negative effects (anxiety, restlessness, insomnia, and tachycardia)

9 Effects of Caffeine Caffeine - blocks adenosine e A1 and A2a receptors relatively low concentrations, which is the equivalent of 1-3 cups of coffee. Adenosine actions - decrease neuronal activity - inhibit synaptic transmission and release of most neurotransmitters. Caffeine - increases turnover of neurotransmitters (monoamines and acetylcholine). Adenosine A1 receptors - hippocampus, cerebral and cerebellar cortex, and thalamus Adenosine A2a receptors - striatum, nucleus accumbens, and olfactory tubercle.

10 Caffeine and Dopamine? Caffeine blocks Adenosine receptors Adenosine receptors interact in the central Adenosine receptors interact in the central nervous system with Dopamine receptors

11 Caffeine and Cognition Cognition Higher levels of human mental activity, such as self- awareness, mental imagery, and language. Capacity for processing information, applying knowledge, and changing preferences. It involves memory, attention, executive functions, perception, language, and psychomotor functions. Is caffeine a cognitive enhancer?

12 Is Caffeine a cognitive enhancer? Caffeine cannot be considered a pure cognitive enhancer. The indirect action of caffeine on arousal, mood and concentration contributes in large parttoits cognitive enhancing properties. Nehlig (2010)

13 Caffeine effects on cognitive tasks - Does NOT affect performance in learning and memory tasks, -May have facilitatory or inhibitory effects on memory and learning. - Facilitates learning in tasks in which information is presented passively; NO effect in tasks in which material is learned intentionally. - Facilitates performance in tasks involving working memory to a limited extent, but hinders performance in tasks that heavily depend on working memory, - Appears to improve memory performance under suboptimal alertness conditions.

14 Caffeine effects on cognitive tasks - At low doses, caffeine improves hedonic tone and reduces anxiety - At high doses there is an increase in tense arousal, including anxiety, nervousness, jitteriness. - Caffeine has also been reported to prevent cognitive decline in healthy subjects but results are heterogeneous, some finding no age-related effected while others reported effects only in one sex and mainly in the oldest population.

15 Caffeine and Alzheimer s Disease The equivalent amount of daily caffeine intake required for human therapeutic benefit against AD is approximately 500mg. The average US intake is only around 150mg/day and decreases during aging. Caffeine protects against and minimizes brain cognitive impairment, such as that due to brain Aβ accumulation/aggregation in AD

16 Coffee and Caffeine Coffee Type Arabica Caffeine content mg/cup Caffeine source Coffee mg/150mL Robusta mg/cup Tea 32-42mg/150mL Country USA & Canada Sweden and Finland Average Caffeine consumption 76mg/person/day mg/person/day gp >400mg/person/day Source % from coffee UK >400mg/person/day /d 72% from tea Cola Cocoa 32-70mg/330mL 4mg/150mL

17 Caffeine and Alzheimer s Disease Protective/treatment effects of caffeine intake on AB production/aggregation and memory in AD transgenic mice (Tg) mice when caffeine consumption is started during young adulthood (life-long caffeine) or after development of AD pathology/memory impairment. Arendash and Cao, Caffeine and Coffee as therapeutics against AD.

18 Caffeinated but not de-caffeinated coffee suppresses plasma Aβ levels

19 Caffeine and Alzheimer s Disease Caffeine reduces expression of and secretase protein expression which is involved in the production of A protein has anti-inflammatory effects has anti-oxidant actions mitochondrial activator stimulates neuronal activity and glucose utilization block disruptions of the blood-brain-barrier antagonizes A1 and/or A2a adenosine receptors Arendash and Cao, Caffeine and Coffee as therapeutics against AD. J Alzheimer s Disease 20(2010) S117-S126.

20 Caffeine and Dementia and Alzheimer s Disease Midlife coffee and tea drinking and the risk of late-life dementia: a population-based CAIDE (cardiovascular risk factors, aging and dementia) study. Eskelinen et al., Finland 1500 individuals (62% women, 38% men, seen at mean age 50.4 and then 71.3) Coffee drinkers at midlife had lower risk of dementia and AD later in life compared with those drinking no or only little coffee Adjusted for demographic, lifestyle and vascular factors, apolipoprotein E e4 allele and depressive symptoms. The lowest risk (65% decreased) was found in people who drank 3-5 cups/day. Tea drinking was not associated with dementia/ad. Caffeine as a protective factor in Dementia and Alzheimer s Disease. Eskelinen and Kivipelto, 2010

21 Caffeine and Dementia and Alzheimer s Disease Caffeine as a protective factor in Dementia and Alzheimer s Disease. Eskelinen and Kivipelto 2010.

22 Caffeine and Dementia and Alzheimer s Disease Caffeine as a protective factor in Dementia and Alzheimer s Disease. Eskelinen and Kivipelto 2010.

23 Caffeine and Dementia Caffeine intake and dementia: systematic review and meta- analysis. Santos et al. (2010) trend towards protective effect of caffeine Caffeine, cognitive functioning, and white matter lesions in the elderly: establishing causality from epidemiological evidence. Ritchie et al., elderly l (324 women, 317 men) in France Association between caffeine consumption and lower cognitive change over time to be statistically significant for women only, independent of confounders (education, depression, cardiovascular disease, body mass index, diabetes, cholesterol levels, anticholinergic medication, disability and alcohol use), dose-dependent and temporarily related (caffeine consumption precedes cognitive change) Caffeine intake is associated with a lower risk of cognitive decline: a cohort study from Portugal. Santos et al., caffeine intake associated with lower risk of cognitive decline in women

24 Caffeine and Parkinson s Disease Caffeine exposure and the risk of Parkinson s s Disease: a systematic review and meta-analysis of observational studies. Costa et al., studies were included. Outcome: confirmed inverse association between caffeine intake and the risk of PD.

25 Caffeine and Parkinson s s Disease Effects of Caffeine in Parkinson s s Disease: from neuroprotection to the management of motor and non-motor symptoms. Prediger, 2010 Epidemiological and pre-clinical data Neuroprotection against dopaminergic neuron degeneration, and influence the onset and progression of PD. Cafffeine can improve the motor deficits of PD Adenosine A2a receptor antagonists reduces OFF time and dyskinesia associated with standard dopamine replacement treatments. Potential of caffeine in the management of non-motor symptoms of PD. Caffeine - promising therapeutic tool. First compound to restore both motor and non-motor early symptoms of PD, together with its neuroprotective potential.

26 Caffeine in Neurologic Conditions Migraine i headaches h As a nonprescription combination of acetaminophen, aspirin, and caffeine (AAC), eg, Excedrin Migraine i from Bristol-Myers Squibb Company, is highly effective in treating the pain, disability, and migraines with and without association with menses. Post lumbar puncture headaches The characteristics of this headache are very distinct with typically orthostatic t ti symptoms, but the exact pathophysiology h remains poorly understood. Caffeine may lead to vasoconstriction by blocking the adenosine receptors.

27 Caffeine in Neurologic Conditions Caffeine and sleep Every single exposure to caffeine can produce cerebral stimulant effects. In humans, sleep seems to be the physiological function most sensitive to the effects of caffeine. More than 200 mg of caffeine is required to affect sleep significantly, ifi prolonging sleep latency and shortening total sleep duration with preservation of the dream phases of sleep. Tolerance develops but it seems to relate to differences in the rate of caffeine metabolism. Poor sleepers metabolize caffeine at a lower rate, and heavy coffee drinkers appear to be less sensitive to caffeine-induced induced sleep disturbances than light coffee drinkers.

28 Caffeine in Neurologic Conditions Tremors Caffeine and beta-adrenergic drugs are well-recognized drugs that can cause or worsen the underlying tremors. The severity may vary based upon the amount of caffeine consumed. Parkinson disease Reduced risk of Parkinson disease for coffee drinkers. Caffeine is an inhibitor of the adenosine A2 receptor and improves motor deficits in a mouse model of Parkinson disease. Since estrogen inhibits the caffeine metabolism by competitive mechanisms, its effect in women may vary with the use of estrogen replacement.

29 Caffeine and T2DM Isolated, caffeine increase daytime glucose concentrations and exaggerated post-prandial glucose responses Laboratory conditions might be different from those of long term habitual caffeine intake as part of coffee consumption. Effect could be due to other coffee components other than caffeine. Alone or though synergistic effects with caffeine, these compounds may affect T2DM risk though multiple mechanisms, including weight loss, thermogenesis, antioxidant effects, effects on the gut and the liver, and modulation of satiety. Incidence of Dementia in T2DM is increased by % relative to non-diabetic individuals

30 The Question of Dependence and Withdrawal Drug dependence is defined as a pattern of behavior focused on the repetitive and compulsive seeking and taking of a psychoactive drug.

31 The Question of Dependence and Withdrawal Characterization of withdrawal symptoms in humans The most often reported symptoms are headaches; fatigue; weakness; drowsiness; impaired concentration; work difficulty; depression; anxiety; irritability; increased muscle tension; and, occasionally, tremor, nausea, and vomiting. Withdrawal symptoms generally begin hours after sudden cessation of caffeine consumption and reach a peak after hours. And do not relate to the quantity of caffeine ingested daily. In the last decade, 2 studies suggested that caffeine withdrawal symptoms (but not caffeine abuse or dependence) should be added to the list of diagnoses recognized by the American Health System (ie, DSM-IV and International Classification of Diseases, 10th edition [ICD-10]).

32 My weekends...or life without coffee... Headache Sleepiness Irritability Lethargy Constipation Depression Muscle Pain/Stiffness Lack of Concentration Flu-like symptoms Insomnia

33 The Question of... Abstinence Relief of abstinence symptoms by caffeine Caffeine withdrawal symptoms disappear shortly after ingestion of caffeine. This effect is linked strongly to the psychological satisfaction related to the ingestion of caffeine; this is especially true for the first cup of the day. Caffeine content influences coffee consumption, and the beneficial effects of caffeine consumption on mood or alertness seem to encourage the consumption of coffee or caffeine-containing beverages. Heavy consumers of coffee show a preference for coffee containing caffeine, while those who typically drink decaffeinated coffee generally choose either decaffeinated or caffeine-containing coffee.

34 Tolerance to Caffeine? Tolerance to a drug refers to an acquired change in responsiveness after repeated exposure to the drug. Tolerance can be considered in 2 ways: The dose necessary to achieve the desired euphoric or reinforcing effects increases with time, thus encouraging increased consumption of the drug. Tolerance to the aversive effects of high doses of the drug may occur, also leading to increased consumption of the drug over time. In humans, the tolerance to some physiological actions of caffeine can occur. Effect of caffeine on blood pressure, heart rate, diuresis, plasma adrenaline and noradrenaline levels, and renin activity. Usually develops within a few days. Tolerance to some subjective effects of caffeine, such as tension-anxiety, jitteriness, nervousness, and the strength of drug effect, has been shown. Evidence of tolerance to caffeine-induced alertness and wakefulness is limited.

35 Is Caffeine safe? - No adverse effects on the cardiovascular system, bone status and calcium balance, or incidence of cancer - No significant associations between coffee consumption and the risk of coronary heart disease mg/day does not increase risk, frequency or severity of cardiac arrhythmias - Reduce the risk of type 2 Diabetes Mellitus by 35-79% - Reduce risk of Parkinson s Disease - Reduce risk of liver cirrhosis

36 Caffeine, diabetes, and cognition: five cups a day keeps dementia away? Although there is evidence to support this affirmative, recommendations for coffee consumption in individuals with T2DM or pre-diabetic stages or Parkinson s s Disease, Alzheimer s Disease or Dementia are difficult to establish.

Caffeine use in Children and Adolescents Caffeine use is on the rise among children and adolescents. Several points to be emphasized: Children and adolescents are not miniaturized adults.

Caffeine use disrupts sleep patterns, and the excess consumption of soda is associated with poor diet, excess weight and dental caries.

37 Caffeine use in Children and Adolescents Caffeine use is on the rise among children and adolescents. Several points to be emphasized: Children and adolescents are not miniaturized adults. Childhood and adolescence is a period of rapid growth and the final stage of brain development. In order to maximize growth and development, e e proper sleep seep and nutrition to are essential. Caffeine use disrupts sleep patterns, and the excess consumption of soda is associated with poor diet, excess weight and dental caries. Childhood and adolescence may be a critical period for the establishment of eating patterns and taste preferences. Caffeine can prime the brain to increase responding to subsequent drug exposure, thereby potentiating the reinforcing effects of drugs, and children and adolescents may be particularly vulnerable to these effects.

38 Caffeine use in Children and Adolescents Is it safe? Little empirical data exist on the physiological, psychological, or behavioral effects of habitual caffeine use among children. More research is needed to determine the long-term consequences of caffeine exposure during the critical period of development.

39 Cellular Basis for the Action of Caffeine (1) Translocations of intracellular calcium - increase in strength and duration of contraction in skeletal and cardiac muscles (high concentration mmol), - relaxation of vascular smooth muscle (0.2mmol or more) (2) increasing accumulation of cyclic nucleotides - does not seem to play a very important role

40 Cellular Basis for the Action of Caffeine (3) adenosine receptor blockade - predominant mode of action. - Methylxanthines act as competitive antagonists at adenosine receptors at concentrations well within the therapeutic range. - The effects of exogenous adenosine are frequently opposite to those of the methylxanthines. - Plasma concentrations of caffeine that raise blood pressure are within the range for antagonism of adenosine receptors. (4) other effects - potentiation of inhibitors of prostaglandin synthesis - possibility that methylxanthines reduce the uptake and/or metabolism of catecholamines in non-neuronal ltissues.

41 Caffeine content Varies according to: Where the coffee beans are grown, Different types of coffee preparation (percolation, filtration, boiling, instant, espresso), Quantity of beans employed, Degree of roasting, Fineness of grinding, Amount of water used for extraction, Length of time of extraction

42 Starbucks Caffeine content Beverage Caffeine (mg) short (8 oz) Tall (12 oz) Grande (16 oz) Venti (20-24 oz) Brewed coffee Brewed decaf coffee Cappucino Espresso 75 (solo) 150 (doppio) Hot chocolate

Addictive Properties of Caffeine. Roland R. Griffiths, Ph.D. Departments of Psychiatry and Neuroscience Johns Hopkins University School of Medicine

Addictive Properties of Caffeine Roland R. Griffiths, Ph.D. Departments of Psychiatry and Neuroscience Johns Hopkins University School of Medicine Caffeine Subjective Effects Reinforcing Effects (i.e.