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Caffeine: A positive addition to a healthy lifestyle?

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2 Caffeine: A positive addition to a healthy lifestyle?
Ross Grant PhD Australasian Research Institute

3 “ Coffee-drinking is used for social engagement, leisure, enhancement of work performance and well-being.” “Unlike other [functional foods]….the wide use of coffee-drinking impacts a broad demographic (from children to elderly), with a wide spectrum of health benefits. Dorea J.G. etal. Br J Nutr (2005), 93:

4 “Tea acts as a stimulant and, to a certain extent, produces intoxication. The action of coffee and many other popular drinks is similar. The first effect is exhilarating. The nerves of the stomach are excited; these convey irritation to the brain, and this in turn is aroused to impart increased action to the heart and short-lived energy to the entire system. Fatigue is forgotten; the strength seems to be increased. The intellect is aroused, the imagination becomes more vivid. “Because of these results, many suppose that their tea or coffee is doing them great good. But this is a mistake. Tea and coffee do not nourish the system. “The continued use of these nerve irritants is followed by headache, wakefulness, palpitation of the heart, indigestion, trembling, and many other evils; for they wear away the life forces. Tired nerves need rest and quiet instead of stimulation”. Ministry of Healing p326

5 Caffeine Use by Age and Sex Australia & New Zealand SDA 2001

6 The issue: In recent times the ingestion of tea and coffee has become a topic of debate within the Adventist community.                                              

7 The issue: Is the introduction of caffeine into the SDA diet a beneficial adjunct to an already well-balanced lifestyle?

8 Background: origins and sources of caffeine
Molecular structure of caffeine identified by German chemist Runge in 1918

9 Background: origins and sources of caffeine
Coffee drinking in the middle east is traceable to the 15th century Sufi monks drank coffee to stay awake during prayers (Yemen, Arabia) By 1510 coffee was widely used in all levels of Arab society from Cairo to Mecca

10 Background: origins and sources of caffeine
Tea was consumed in China from at least the 6th century AD Olmec’s (ancient American civilization) may have used cacao pods for making chocolate drinks from 400BC Carbonated beverages containing caffeine were introduced by Coco-Cola in 1866 in Atlanta Georgia, USA. It is generally assumed that tea originated in China, although history indicates that tea was regarded as an exotic drink when introduced into China and documents indicating the exact origin have been lost. However, it can be assumed that tea was consumed in Chinese culture many centuries before the introduction of coffee into Arabia, as every Chinese dictionary published after the sixth century B.C. included the word for ‘tea’ (Weinberg and Bealer, 2001b).

11 Common dietary sources of caffeine
Food/Beverage Caffeine content Instant coffee (1 tsp) 60-80 mg/250 mL Percolated coffee mg/250 mL Instant decaffeinated 2 mg/250 mL cup Tea 10-50 mg/250 mL Tea decaffeinated 1 mg/250 mL cup Coca-Cola 36-50 mg/375 mL Milk Chocolate 20 mg/100g* bar Energy Drinks (R.Bull) 80 mg/250mL can Caffeine is also available over-the-counter in tablet form marketed as an alertness aid, (e.g. NoDoz contains 100 mg caffeine). Caffeine is included in amounts ranging from 32 to 140 mg in various medications such as analgesics, cold remedies, appetite suppressants, diuretics, and other prescription medications. Table 1: Caffeine content of selected foods (source: ANZFA caffeine report, 2001 and Choice Magazine online (Sept, 2001)). *An average sized Mars bar weighs 80g

12 Common dietary sources of caffeine Guarana
Guarana is a woody climbing plant that is native to the Amazon basin Guarana seeds contain more than 4% caffeine by weight, in comparison with coffee beans which may contain up to 2.2% by weight depending on the variety Caffeine is also available over-the-counter in tablet form marketed as an alertness aid, (e.g. NoDoz contains 100 mg caffeine). Caffeine is included in amounts ranging from 32 to 140 mg in various medications such as analgesics, cold remedies, appetite suppressants, diuretics, and other prescription medications.

13 Absorption of Caffeine into the body
Caffeine is metabolized in the liver by CYP1A2 and is converted into the three products paraxanthine, theobromine and theophylline each of these have physiological effects on the body. Peak caffeine blood levels reached in minutes typical half-life of between 4-6 hours Once caffeine is absorbed, it is able to enter all body tissues and easily crosses the blood-brain, placental and blood-testicular barriers Broc, Brussel sprouts, tobacco smoke – induce Ciprofloxacin - inhibitis

14 Action of Caffeine on the body
FIG. 1. Effect of caffeine on different biochemical targets in relation to its levels in humans. Note that caffeine is able to significantly block adenosine effects on A2A (most potent) and A1 receptors already at the low concentrations achieved after a single cup of coffee. To inhibit cyclic nucleotide breakdown via inhibition of phosphodiesterase, 20 times higher concentrations are required; to block GABAA receptors, 40 times higher concentrations; and to mobilize intracellular calcium depots, concentrations of 100 times higher are needed. These latter levels are unlikely to be reached in humans by any form of normal use of caffeine containing beverages (modified from Fredholm, 1980). PHARMACOLOGICAL REVIEWS Vol. 51, No

15 Action of Caffeine on the body
Principle action of caffeine is thought to be through blocking adenosine receptors on nerve tissue. The principal action of caffeine is thought to be by blocking (antagonism) of predominantly adenosine A1 and also A2a receptors. Adenosine A1 receptors are found all over the brain and spinal cord, but adenosine A2 receptors are present in high amounts only in the dopamine-rich areas of the brain (Daly, 2004). In the body, adenosine receptors are located at various sites including the kidneys, digestive system, bronchial tree, heart and peripheral vasculature (Smith, 2004). Neurotransmitters are characterized as either small-molecule (e.g. adenosine and ATP) or neuropeptides (e.g. oxytocin). The widespread prevalence of caffeine-sensitive (adenosine) receptors in the body suggests the likelihood of multi-organ involvement following caffeine consumption. Caffeine Serotonin

16 Function of Adenosine receptors
Adenosine levels are raised whenever there is an increase in the amount of energy (ATP) consumption compared to energy (ATP) synthesis. Activation of adenosine receptors in various tissues allow the body to modulate cellular activity in response to decreasing energy (ATP) levels.

17 Distribution of Adenosine receptors in the body
Brain Lymphocytes Lung Muscle Heart Liver Stomach Pancreas Fat tissue human-body.jpg

18 Action of Caffeine on the body
Receptor subtype HEART CNS KIDNEY OTHER A1 Heart rhythm Decrease heart rate & force of atrial contraction & responsiveness to adrenaline Wakefulness-decrease in electrical excitability and inhibition of excitatory amino acid (EAA) release Antidiuresis Anti-lipolytic insulin enhancer Anti hypertensive Wound healing Hair growth A2A Regulates blood vessel tone-dilation of the coronary arteries supplying blood to heart and muscle Anti-inflammatory – increases cerebral blood flow Anti – aggregation of platelets Increases gastric mucosal blood flow (ethanol) The principal action of caffeine is thought to be by blocking (antagonism) of predominantly adenosine A1 and also A2a receptors. Adenosine A1 receptors are found all over the brain and spinal cord, but adenosine A2 receptors are present in high amounts only in the dopamine-rich areas of the brain (Daly, 2004). In the body, adenosine receptors are located at various sites including the kidneys, digestive system, bronchial tree, heart and peripheral vasculature (Smith, 2004). Neurotransmitters are characterized as either small-molecule (e.g. adenosine and ATP) or neuropeptides (e.g. oxytocin). Ethanol in the stomach stimulates increased blood flow to gut via vasodialtion mediated by A2 receptors (Nagata etal. Americal Journalof physiology Gastroenterinal liver physiology 271:G1028-G1033, 1996 The widespread prevalence of caffeine-sensitive (adenosine) receptors in the body suggests the likelihood of multi-organ involvement following caffeine consumption.

19 Action of Caffeine on the body
The widespread prevalence of caffeine-sensitive (adenosine) receptors in the body suggests the likelihood of multi-organ involvement following caffeine consumption.

20 Immediate effects of Caffeine Positive:
Caffeine can increase serotonin and dopamine release in the brain; somewhat mimicking the effect caused by antidepressants. (Casas, 2004) Elevated Mood; including increased; Feeling of wellbeing Alertness Energy Sociability The principal action of caffeine is thought to be by blocking (antagonism) of predominantly adenosine A1 and also A2a receptors. Adenosine A1 receptors are found all over the brain and spinal cord, but adenosine A2 receptors are present in high amounts only in the dopamine-rich areas of the brain (Daly, 2004). In the body, adenosine receptors are located at various sites including the kidneys, digestive system, bronchial tree, heart and peripheral vasculature (Smith, 2004). Neurotransmitters are characterized as either small-molecule (e.g. adenosine and ATP) or neuropeptides (e.g. oxytocin). The widespread prevalence of caffeine-sensitive (adenosine) receptors in the body suggests the likelihood of multi-organ involvement following caffeine consumption. Caffeine can increase serotonin release in limbic areas of the brain and dopamine release in the prefrontal cortex, which is the effect caused by antidepressants.

21 Immediate effects of Caffeine Positive:
Studies indicate that: Caffeine decreases reaction times and improves vigilance, sustained attention and selective attention (Smith, 2004). Tasks requiring speed are more sensitive to caffeine’s benefits than tasks involving intellectual power (Snel, 2004). NOTE: Caffeine seems to have either no effect or a negative effect on memory (Smith, 2004). The principal action of caffeine is thought to be by blocking (antagonism) of predominantly adenosine A1 and also A2a receptors. Adenosine A1 receptors are found all over the brain and spinal cord, but adenosine A2 receptors are present in high amounts only in the dopamine-rich areas of the brain (Daly, 2004). In the body, adenosine receptors are located at various sites including the kidneys, digestive system, bronchial tree, heart and peripheral vasculature (Smith, 2004). Neurotransmitters are characterized as either small-molecule (e.g. adenosine and ATP) or neuropeptides (e.g. oxytocin). The widespread prevalence of caffeine-sensitive (adenosine) receptors in the body suggests the likelihood of multi-organ involvement following caffeine consumption.

22 Immediate effects of Caffeine Negative:
Studies indicate that: Higher doses of caffeine produce: Anxiety Jitteriness Upset stomach (Juliano and Griffiths, 2004)

23 Immediate effects of Caffeine Negative:
Studies indicate that: caffeine can exaggerate the body’s response to stress by increasing heart rate and blood pressure (Lane et al., 2002) It is possible that caffeine alone may induce an adrenocortical stress response during rest and in the absence of explicit stressful challenge (al'Absi and Lovallo, 2004) The adrenal cortex releases adrenaline, which results in an increased heart rate, increased blood flow to the muscles and elevated blood sugar. These effects are known as the ‘fight or flight response’, and this response would probably be detrimental in the long term to a person sitting working at a desk, not running or fighting; a situation in which coffee is often consumed. Because a low dose of caffeine is not potent enough to produce consistent adrenocortical effects (al'Absi and Lovallo, 2004), various individuals may experience differing effects.

24 Longer-term effects of Caffeine Negative: cardiovascular
James (2004) suggests that population studies of BP indicate that caffeine use could account for: 14% of premature deaths due to coronary heart disease, and 20% due to stroke. Does caffeine predispose to disease or protect against it? Scientific research indicates that caffeine consumption increases the likelihood of some diseases. On the other hand, caffeine may provide a protective effect against the development of other diseases. This review does not comprehensively assess all available studies in each area, but highlights relevant findings.

25 Longer-term effects of Caffeine Negative: cardiovascular
A prospective study of 1971 middle-aged men, showed that heavy coffee consumption (814 mL or more/day), increased the risk of acute myocardial infarction or coronary death by up to 75% compared to non- coffee drinkers (Happonen et al., 2004). Caffeine has been shown to, dose dependently, increase serum homocysteine levels (Verhof et al., 2002, Panagiotakos et al., 2004) Increased serum cholesterol and urinary excretion of 8-hydroxy-2-deoxguanosine in rats (Sakamoto et al., 2005) Although increased caffeine consumption is an observed risk factor for myocardial infarction, as stated above, a recent article takes the view that coffee drinking does not pose a significant health hazard. These authors state that stronger risk factors such as lack of exercise, cigarette smoking, saturated fat intake and insufficient consumption of vegetables should be focused on in the reduction of cardiovascular disease (Dorea and da Costa, 2005). As the SDA lifestyle already precludes these risk factors, consumption of caffeine is unlikely to produce any health benefit.

26 Longer-term effects of Caffeine Negative: osteoporosis
Basic science experiments show that caffeine increases calcium excretion in the urine In a prospective study of ~ women followed for 6.5 years a weak association of highest caffeine intake (>6 cups daily) was observed with osteoporosis (Hansen et al., 2000). In another well-designed study, investigators from the Study of Osteoporotic Fractures Research Group followed nearly 10,000 white women 65 years and older, for an average of 4.1 years (Cummings et al., 1995). In these women, who had no previous fractures, a number of important risk factors for hip fracture, other than low bone mineral density (BMD), were demonstrated. Heavy caffeine use was among the potentially reversible factors. However another study that had less subjects (672 subjects), and is therefore more open to confounding factors, did not show an association (Albrand et al., 2003). Overall, these studies seem to indicate an association between osteoporosis and heavy caffeine usage.

27 Longer-term effects of Caffeine Negative: Urinary
A high caffeine intake (>400 mg/d) was associated with urinary urge incontinence in a study of almost 260 women (overall risk, 2.4%; 95% CI, ), Note: This is similar to the likelihood of urinary stress incontinence of a vaginal delivery compared with caesarean delivery (2.4%; 95% CI, ) (Arya et al., 2000; Rortveit et al., 2003; Holroyd-Leduc and Straus, 2004). Note: although larger studies are required to determine if the relationship is causal. This is similar to the likelihood of urinary stress incontinence of a vaginal delivery compared with caesarean delivery (OR, 2.4; 95% CI, ) (Arya et al., 2000; Rortveit et al., 2003; Holroyd-Leduc and Straus, 2004).

28 Longer-term effects of Caffeine Negative: Brain
Headache Caffeine is considered a modest risk factor in chronic daily headache, (Gadoth and Hering-Hanit, 2005). Caffeine withdrawal headache, (beginning 1 to 2 days following cessation of regular caffeine use), can last up to a week (van Dusseldorp and Katan, 1990). Caffeine may disrupt sleep or aggravate mood, both of which may exacerbate headache (van Dusseldorp and Katan, 1990).

29 Longer-term effects of Caffeine Negative: Behavioural
Dependence Caffeine exhibits physical dependence in up to 30% of consumers (Griffiths and Chausmer, 2000) Some caffeine users may also demonstrate clinical dependence (Strain et al., 1994). Withdrawal symptoms (start 12-24hr–last 2-9 days) Headache, fatigue, depressed mood, irritability, nausea, vomiting muscle pain/stiffness Clinical dependence is observed in cases where individuals become dependent on caffeine and are unable to stop using the drug despite medical problems being exacerbated by its use.

30 Longer-term effects of Caffeine Negative: Behavioural
Sleep Sleep is one of the physiological functions most sensitive to the effect of caffeine in humans 200mg caffeine will: Prolong sleep latency Increase initial light sleep Decrease later deep sleep Increase shifts between sleep stages Decrease in subjective sleep quality Increased time taken to reach REM sleep Clinical dependence is observed in cases where individuals become dependent on caffeine and are unable to stop using the drug despite medical problems being exacerbated by its use.

31 Longer-term effects of Caffeine Negative: Brain
Can precipitate the onset and/or exacerbation symptoms of anxiety disorders, including panic disorder and obsessive-compulsive disorder, (Smith, 2004). Caffeine can interfere with the action of medication used to treat anxiety disorders and depression (Greden et al., 1981; Jefferson, 1988). Long term caffeine use affects serotonin metabolism in the brain of rats: implications for depression (Haider etal 1998, Haleem etal 1995) Caffeine can increase serotonin release in limbic areas of the brain and dopamine release in the prefrontal cortex, which is the effect caused by antidepressants. This may be why more studies have found positive mood lifting effects of caffeine. However, very high caffeine doses can exacerbate mood disorders (Casas, 2004). 24h withdrawal following repeated administration of caffeine attenuates brain serotonin but not tryptophan in rat brain: implications for caffeine-induced depression. Life Sci. 1995;57(19):PL Haleem DJ, Yasmeen A, Haleem MA, Zafar A. Caffeine injected at doses of 20, 40 and 80 mg/kg increased brain levels of tryptophan, 5-hydroxytryptamine (5-HT) and 5-hydroxyindole acetic acid (5-HIAA) in rat brain. In view of a possible role of 5-HT in caffeine-induced depression the effects of repeated administration of high doses of caffeine on brain 5-HT metabolism are investigated in rats. Caffeine was injected at doses of 80 mg/kg daily for five days. Control animals were injected with saline daily for five days. On the 6th day caffeine (80 mg/kg) injected to 5 day saline injected rats increased brain levels of tryptophan, 5-HT and 5-HIAA. Plasma total tryptophan levels were not affected and free tryptophan increased. Brain levels of 5-HT and 5-HIAA but not tryptophan decreased in 5 day caffeine injected rats injected with saline on the 6th day. Plasma total and free tryptophan were not altered in these rats. Caffeine-induced increases of brain tryptophan but not 5-HT and 5-HIAA were greater in 5 day caffeine than 5 day saline injected rats. The findings are discussed as repeated caffeine administration producing adaptive changes in the serotonergic neurons to decrease the conversion of tryptophan to 5-HT and this may precipitate depression particularly in conditions of caffeine withdrawal Pak J Pharm Sci Jul;11(2):55-60. Related Articles, Links Neurochemical and behavioural effects of long term intake of tea. Haider S, Yasmeen A, Parveen T, Haleem DJ. Pak J Pharm Sci Jul;11(2):55-60. Department of Biochemistry, University of Karachi, Karachi-75270, Pakistan. Tea consumption in many cases is the main source of caffeine intake in humans. In the present study neurochemical and behavioural effects of long-term tea intake are monitored in rats. Long-term tea administration did not alter plasma tryptophan (TRP) but significantly attenuated brain TRP and 5-hydroxytryptamine (5-HT, serotonin) levels. Brain 5-hydroxyindole acetic acid (5-HIAA) was comparable in both tea-treated and control rats. An increase in home cage activity was observed after one week in rats taking tea as sole source of liquid, whereas no change on the activity was observed in an open field. Caffeinism has been associated with depression. The decreases of brain monoamine metabolism observed in present study are discussed as lowering of mood observed in tea or coffee consumers.

32 Longer-term effects of Caffeine Negative: pregnancy/foetus
Caffeine is cleared at a slower rate from the pregnant woman and foetus (t1/2 18hrs) Caffeine readily crosses the placenta into the foetus Metabolising enzymes not present in foetus or placenta (Grosso and Bracken, 2005). Foetus therefore exposed to caffeine and its metabolites for a prolonged periods of intra-uterine life. A reduction in the enzyme that processes caffeine, CYP1A2 has been noted in pregnant women, and this is neither foetus nor placenta possess the enzyme necessary to metabolize caffeine and it must be excreted via the kidneys (Grosso and Bracken, 2005). Thus the foetus is exposed to caffeine and its metabolites for a prolonged period of intra-uterine life.

33 Longer-term effects of Caffeine Negative: pregnancy/foetus
Conflicting reports - foetal development Increased caffeine use may cause spontaneous abortion A decrease in intervillous placental blood flow has been documented after maternal ingestion of just 200 mg of caffeine (Kirkinen et al., 1983). May effect foetal oxygenation and nutrition (Ghidini, 1996) After reviewing several animal studies, Nakamoto (2004) suggests that caffeine may affect neurodevelopment; further human studies required A reduction in the enzyme that processes caffeine, CYP1A2 has been noted in pregnant women, and this is neither foetus nor placenta possess the enzyme necessary to metabolize caffeine and it must be excreted via the kidneys (Grosso and Bracken, 2005). Thus the foetus is exposed to caffeine and its metabolites for a prolonged period of intra-uterine life.

34 Longer-term effects of Caffeine Negative: Child
Insufficient research precludes a definite conclusion as to whether caffeine consumption during pregnancy leads to mood disorders in children. However, cortisol, which is increased by caffeine, may influence the foetal hypothalamic-pituitary-adrenal axis which controls the stress response Prenatal stress has been linked to interference in neuron development in the serotonergic system in late gestation (Linnet et al., 2003; Lovallo et al., 2005).

35 Longer-term effects of Caffeine Negative: Adolescence
Significantly higher anxiety scores were observed in caffeine dependent year-olds (13.7 ± 7.7) compared with the non-dependent group (7.5 ± 5.9) (Bernstein et al., 2002). It would be useful to study more about how much caffeine children consume, and how this may affect them as adolescents are currently exposed to the opportunity to consume large amounts of caffeine due to the introduction of energy drinks, and frequenting of coffee lounges.

36 Longer-term effects of Caffeine Positive:
Diabetes Coffee drinkers in the highest category (≥6 or ≥7 cups/day) showed a relative risk of 0.65. (4-6 cups/day) had a relative risk of 0.72 compared with the lowest category (0 or ≥2 cups/day). Two reasons were suggested for the apparent protective effect of caffeine against diabetes: 1. Coffee contributes antioxidants to the diet (Pulido et al., 2003; Svilaas et al., 2004). 2. Caffeine ingestion can acutely reduce glucose storage (Greer et al., 2001). However, authors don’t recommend increasing coffee consumption as other health effects should first be considered (van Dam and Hu, 2005). ed Fifteen epidemiological studies were synthesized and habitual coffee consumption and relative risk of developing type 2 diabetes calculated (van Dam and Hu, 2005).

37 Longer-term effects of Caffeine Positive:
Gallstones Leitzmann et al., ( 1999) reported that 4 cups of coffee per day showed a relative risk of gallstone formation of 0.55, This indicates a 45% reduction in the risk of forming gallstones in moderately heavy coffee drinkers. Colon Cancer Case-control studies seem to indicate a lower risk of colon cancer associated with coffee drinking, but cohort study results are less clear (Tavani and La Vecchia, 2004).

38 Longer-term effects of Caffeine Positive:
Parkinson’s disease A 5-fold lower risk of developing PD was observed in those who drank over 4 medium cups of coffee per day. This protection was not seen in decaffeinated coffee (Xu et al., 2005). Animal experiments also show that caffeine directly protects against the death of neurons in Parkinson’s disease (Xu et al., 2005). Only one paper thus far has looked at the possibility that a vegan diet may reduce Parkinson’s disease (McCarty, 2001). McCarty suggests that groups that consume a vegan or quasi-vegan diet such as rural Chinese and Japanese enjoy substantially lower rates of this disease. This paper notes there are currently no published reports available regarding the prevalence of Parkinson’s disease in SDA’s. It would be interesting to investigate this question with regard to vegetarian diet and caffeine intake

39 CONCLUSIONS Almost 2000 research papers have been published that included caffeine as a research variable in the title in the last 10 years Almost universal use of caffeine throughout the world have made well controlled studies difficult Almost 2000 (1984) publications with caffeine in in the title in the last 10 years As caffeine is a drug, its most important effects on the body are due to its amplification of physiological processes through a specific receptor activation system The presence of either antioxidants or toxins in the coffee bean or tealeaf is not relevant to the action of the drug caffeine, and has therefore not been covered in this review.

40 CONCLUSIONS Caffeine is a drug that blocks activation of a specific nerve receptor system Benefits observed include reduced risk of Parkinson’s disease, type 2 diabetes, colon cancer and gallstones These are offset by negative biological effects; physical dependence, exacerbation of anxiety increased blood pressure & cardiac fatality risk osteoporosis, urge incontinence, potential harm to the foetus. Almost 2000 (1984) publications with caffeine in in the title in the last 10 years As caffeine is a drug, its most important effects on the body are due to its amplification of physiological processes through a specific receptor activation system The presence of either antioxidants or toxins in the coffee bean or tealeaf is not relevant to the action of the drug caffeine, and has therefore not been covered in this review. The collection of negative effects impact on the quality of life in the community.

41 CONCLUSIONS A lifestyle with moderate energy intake, exercise and a diet high in fruit and vegetables would not appear to benefit from the inclusion of caffeine; but would rather result in the addition of unnecessary negative physiological stressors.

42 “Tea acts as a stimulant and, to a certain extent, produces intoxication. The action of coffee and many other popular drinks is similar. The first effect is exhilarating. The nerves of the stomach are excited; these convey irritation to the brain, and this in turn is aroused to impart increased action to the heart and short-lived energy to the entire system. Fatigue is forgotten; the strength seems to be increased. The intellect is aroused, the imagination becomes more vivid. “Because of these results, many suppose that their tea or coffee is doing them great good. But this is a mistake. Tea and coffee do not nourish the system. “The continued use of these nerve irritants is followed by headache, wakefulness, palpitation of the heart, indigestion, trembling, and many other evils; for they wear away the life forces. Tired nerves need rest and quiet instead of stimulation”. Ministry of Healing p326


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