- Catecholamines and Environmental Stress
- Chapter Contents
- Catecholamines and Health
- Methodological Considerations
- Gender Differences
- Relevance for Allostasis
- Catecholamine blood test
- Test ID: CATU Catecholamine Fractionation, Free, 24 Hour, Urine
- Catecholamines — Blood
- Catecholamines Kick Out the Demons of Depression
Catecholamines and Environmental Stress
Summary prepared by Ulf Lundberg, Department of Psychology and Centre for Health Equity Studies (CHESS), Stockholm University, for the Allostatic Load notebook. Last revised November, 2008.
- Catecholamines and Health
- Methodological Considerations
- Gender Differences
- Relevance for Allostasis
Research on the sympathetic adrenal-medullary (SAM) system has its roots in the work of Walter B. Cannon from the beginning of the 20th century (Cannon, 1914). On the basis of animal experiments, he described the fight-or-flight response, or the emergency function of the adrenal medulla. The SAM system is activated when an individual is challenged in his/her control over the environment (Henry, 1992). Via the hypothalamus and the sympathetic nervous system, psychological stress stimulates the adrenal medulla to secrete the two catecholamines, epinephrine (adrenaline) and norepinephrine (noradrenaline), into the bloodstream. This rapid defence reaction (occurring in less than a minute) prepares the body for battle.
The cardiovascular and neuroendocrine functions activated by the SAM system are aimed at mobilizing energy to the muscles, brain and heart and, at the same time, reducing blood flow to the internal organs, skin and gastro-intestinal system. In response to physical threat, this is an efficient means of survival as it increases the organism’s capacity for fight or flight. Today, however, the SAM system is more often challenged by threats of a social or mental nature rather than a physical one. Elevated blood pressure and heart rate and the release of glucose and free fatty acids into the bloodstream in mentally stressful but sedentary work will be harmful to the body, particularly the cardiovascular system. However, short-term activation of this system is often necessary for adequate coping with environmental demands and for the protection of the body, whereas intense, repeated and/or sustained activation of this psychobiological program in response to psychosocial demands may cause stress-related disorders and is relevant for allostasis.
Numerous studies based on laboratory experiments as well as various natural settings illustrate the sensitivity of the SAM system to various psychosocial conditions, such as daily stress at work, home, school, day care centres or hospitals, on commuter trains or buses, etc. (see reviews by Mason, 1968; Levi, 1972; Henry & Stephens, 1977; Ursin et al., 1978; Frankenhaeuser 1971; 1983; Usdin et al., 1980; Lundberg, 1984, 2005).
Catecholamines and Health
The catecholamines and their concomitant effects on other physiological functions, such as blood pressure, heart rate and lipolysis, may serve as objective indicators of the stress an individual is exposed to. However, these bodily effects are also assumed to link psychosocial stress to increased health risks. Long-lasting elevated catecholamine levels are thought to contribute to the development of atherosclerosis and to predispose to myocardial ischemia (Karasek et al., 1982; Krantz & Manuck, 1984; Rozanski et al., 1988; Yusuf et a., 2004). The elevated catecholamine levels also make the blood more prone to clotting, thus reducing the risk of heavy bleeding in case of tissue damage but, at the same time, increasing the risk of arterial obstruction and myocardial infarction.
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Less is known about the role of the catecholamines in other health problems. However, in the study of psychosocial aspects of musculoskeletal disorders (e.g., Moon & Sauter, 1996), it is generally assumed that psychological stress plays an important role by influencing various bodily functions including muscle tension and, thus, forms a link to neck, shoulder and back pain problems (Lundberg & Melin, 2002). For example, Schleifer & Ley (1994) have suggested that stress contributes to hyperventilation, reduced end-tidal PCO2, increased blood pH level and muscle tension and makes the muscles more sensitive to catecholamines. In keeping with this, jobs with a high prevalence of musculoskeletal disorders, such as repetitive assembly-line work, are characterized by elevated sympathetic arousal (cf. Table 3) and slow unwinding after work (Johansson et al., 1978; Melin et al., 1999). In addition, in laboratory experiments (Lundberg et al., 1994; Krantz et al., 2004), positive correlations have been found between blood pressure, norepinephrine and mentally induced EMG activity of the trapezius muscle. A link between high epinephrine levels and low socioeconomic status has recently been demonstrated by Cohen et al. (2005).
A small but relatively constant fraction of the circulating levels of epinephrine and norepinephrine in the blood is excreted into the urine (Frankenhaeuser, 1971; Levi, 1972). Consequently, assessment can be made using blood (usually plasma) as well as urine. However, whereas epinephrine is mainly produced by the adrenal medulla, the major part of the circulating norepinephrine is produced by sympathetic nerve endings. Studies comparing urinary levels with corresponding hormone determinations in plasma are scarce, but available data indicate a significant positive relationship between changes in urinary and plasma catecholamines (Åkerstedt et al., 1983; Steptoe, 1985).
For obvious reasons, plasma reflects short-term and acute stress responses more readily than urinary measurements do. Urinary values provide integrated measurements for extended periods of time (usually an hour or more), which is an advantage in the study of long-term (chronic) psychosocial stress (Baum et al., 1985). Additional advantages of urinary measurements in the study of psychosocial stress are that urine samples are relatively easy to collect, and in field studies they do not interfere with the subject’s normal habits and environment and cause no harm or pain. The characteristics of plasma and urine measurements are summarized in Table 1.
Table 1. Characteristics of Catecholamine Assessment in Urine and Blood (Plasma)
| Urinary measurements
|Summary of advantages (+) and disadvantages (-) in different types of studies|
| Acute stress
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The amount of urinary catecholamines excreted during a particular period of time can be determined from the concentration in the sample, multiplied by total urine volume, or by relating the concentration to a reference substance such as creatinine excretion. Provided that reliable measurements are obtained and the subject is able to empty his/her bladder completely, the results from the different methods are almost identical. The catecholamines can be determined using high performance liquid chromatography with electrochemical detection (Lundberg et al., 1988; Hjemdahl et al., 1989).
The catecholamines have a pronounced diurnal pattern, which has to be considered in the assessment of the stress response. Under normal sleep/wake conditions, the catecholamines peak in the middle of the day and reach their lowest levels during night sleep. Epinephrine has an endogenous pattern that remains relatively stable, even during several nights of sleep deprivation (Åkerstedt, 1979), whereas norepinephrine is more influenced by physical activity. Consistent changes in the sleep/wake pattern, e.g., habitual night work, will completely reverse the circadian rhythm of the catecholamines in about a week. Other non-psychological factors influencing catecholamine secretion are the intake of caffeine (coffee), alcohol and nicotine (cigarette smoking), medication (beta blockers, diuretics, etc.) and heavy physical exercise (Table 2).
Table 2. Non-psychological Factors Influencing Catecholamine Levels
| Of great importance
|| Of some importance
The increase in catecholamine levels in the blood occurs within minutes in response to an acute stressor and may vary considerably depending on the mental and physical load on the individual. Individual variations in baseline levels are also pronounced. The highest epinephrine level in a random sample of individuals may be ten times greater than the lowest. However, individual catecholamine levels are relatively stable over time (Forsman & Lundberg, 1982). During mild stress, epinephrine output increases to about 2-3 times the resting level, whereas during more severe stress, e.g., childbirth (Alehagen et al., 2005), mean epinephrine levels rise to 8-10 times the corresponding level of a day during pregnancy, or much more in individual cases. There are no “normal” catecholamine levels, although pathological levels can be found in association with adrenal tumours, for example.
In order to reduce the influence of circadian rhythms and individual differences in baseline levels, it is recommended to express individual responses to stress in relation to a person’s corresponding baseline level obtained during relaxation at the same time of the day on another day. Thus, percent change from baseline is usually a more relevant measure than absolute levels.
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In stress research, like in many other research areas, most studies have been performed on men. However, in the early 1970s, investigators in Marianne Frankenhaeuser’s group in Stockholm started to compare stress responses of males and females. In these early studies of sex differences in psychophysiological stress responses, it was consistently found that women were less reactive than men in terms of epinephrine secretion during experimental stress (e.g., Frankenhaeuser, Dunne & Lundberg, 1976; Johansson, 1972). Although women performed as well or usually even better than men on the various stress tests, they did not increase their epinephrine secretion much. However, during more intense stress such as a stressful examination (Frankenhaeuser, Rauste von Wright et al., 1978), female students were found to increase their epinephrine output significantly but, still, to a lesser extent than male students did.
A possible explanation for these sex differences is that performance stress is less challenging to women than to men. Emotional stress, for example induced in parents when accompanying their child to a health check-up at the hospital, has been found to have a more pronounced effect on catecholamine levels in women (mothers) than men (fathers) (Lundberg, de Château, Winberg & Frankenhaeuser, 1981). In addition, women in less traditional roles, for example female students in male-dominated lines of education, seem to respond to performance stress with the same epinephrine output as their male colleagues do (Collins & Frankenhaeuser, 1978). Studies comparing men and women matched for education and occupational level show that women may respond with as much epinephrine output at work and during experimental stress as men do (Lundberg, 2005). However, women’s stress levels, but not men’s, have been found to remain elevated even after work (Frankenhaeuser et al., 1989; Lundberg & Frankenhaeuser, 1999).
Although the possible influence of biological factors such as steroid sex hormones on catecholamine responses cannot be excluded (Wasilewska, Kobus and Bargiel, 1980; Tersman, Collins and Eneroth, 1991), it seems as if psychological factors and gender role patterns are more important than biological factors for the sex differences in catecholamine responses. For example, oestrogen replacement therapy did not significantly influence catecholamine responses in women during experimental stress (Collins et al., 1982), and women with elevated testosterone levels did not differ in catecholamine responses from women with normal levels (Lundberg et al., 1983).
In men, a significant positive correlation is usually found between perceived stress and physiological responses at work (e.g., Lundberg, Granqvist, Hansson, Magnusson & Wallin, 1989; Frankenhaeuser et al., 1962; Frankenhaeuser et al., 1989). However, in women, physiological stress levels at work seem to spill over into non-work situations (Rissler, 1977; Frankenhaeuser et al., 1989; Lundberg, 1996; Lundberg & Frankenhaeuser, 1999). This interaction between stress from paid employment and unpaid work at home is important to consider in the study of women’s stress.
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Relevance for Allostasis
Epinephrine levels are significantly elevated by overstimulation as well as understimulation, compared to more optimal environmental conditions (Frankenhaeuser et al., 1971; Levi, 1972; Frankenhaeuser & Gardell, 1976). Work overload, a very fast work pace, too much responsibility and role conflicts as well as simple, monotonous and repetitive jobs or a lack of meaningful activities (e.g., unemployment) may contribute to elevated epinephrine levels.
The acute response (“phasic” elevation, according to Ursin et al., 1978) to a novel environmental situation diminishes as the individual habituates but, in contrast to cortisol levels which seem to return to baseline (Pollard, 1995), catecholamine levels remain chronically elevated during normal work conditions also (“tonic” elevation, according to Ursin et al., 1978).
One example of an adequate or economic response to mental stress is presented in Fig. 1 (Forsman, 1983), which shows the epinephrine changes of healthy male students during successive periods of experimental stress and rest in the laboratory. The subjects were able to return to their baseline level each time the stress exposure ended.
Fig. 1. Epinephrine output (pmol/min) during successive periods of rest and experimental stress (based on Forsman, 1983).
Another example is shown in Fig. 2, illustrating the epinephrine output of 50 women giving birth to their first child (Alehagen et al., 2001). Despite a more than 500 percent increase during labour and pushing, the epinephrine levels had returned to the pregnancy levels after a couple of days.
Fig. 2. Epinephrine output of 50 women giving birth to their first child (Alehagen et al., 2001).
Lack of unwinding (norepinephrine) among female managers after a day at work compared to their male colleagues, has been found in two studies (Frankenhaeuser et al., 1989; Lundberg & Frankenhaeuser, 1999). This gender difference was found mainly in women with children at home, whereas in men the presence of children at home did not influence their stress hormone levels. Fig. 3 shows positive correlations between catecholamine levels at work and at home in women but not in men (Frankenhaeuser et al., 1989).
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Fig. 3. Correlation between catecholamine levels at work and in the evening at home in women and men (based on Frankenhaeuser et al., 1989).
Rissler (1977) found that a period of overtime (on Saturdays) at work during a period of several weeks influenced the epinephrine levels in the evening (measured on Wednesdays) in female white-collar workers. Lundberg and Palm (1989) found that overtime at work was correlated with epinephrine output during the weekend at home in full-time employed mothers, but not fathers, of preschool children. It is of interest to note that Alfredsson et al. (1985) found that overtime at work was associated with an elevated risk of myocardial infarction in women but not in men.
Whereas epinephrine output is influenced mainly by mental stress, norepinephrine is more sensitive to physical activity and body posture. Comparisons of work stress in blue and white-collar workers are consistent with experimental findings as shown in Table 3, where data from a series of real-life studies are summarized. It is shown that male and female managers, and male and female clerical workers, increase their epinephrine but not their norepinephrine levels at work, whereas assembly workers and supermarket cashiers increase both their epinephrine and norepinephrine levels compared to their normal resting levels (=100). The physical activity of the white-collar workers is probably too low to influence norepinephrine output.
Table 3. Catecholamine Responses in Different Occupations (Increase from Non-work Level)
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Considering the various cardiovascular and metabolic functions influenced by the catecholamines, this means that blue-collar workers in general are exposed to a greater total physiological load than white-collar workers are. In addition, workers in repetitive jobs seem to have difficulties unwinding after work, i.e., their physiological arousal remains elevated at least one to two hours after work compared to the rapid unwinding of workers in more flexible jobs (Johansson et al., 1978; Lundberg et al., 1993; Melin et al., 1999). This means that workers in simple, monotonous and repetitive jobs not only have to pay a greater physiological toll at work but also have less chance for relaxation and recovery off the job (Melin & Lundberg, 1997). Physical stressors at work such as noise may further contribute to the total load on blue-collar workers (Glass & Singer, 1972). This pattern of catecholamine responses is also consistent with the association between low SES and high catecholamine levels reported by Cohen et al. (2005).
In view of traditional gender differences in responsibility for unpaid work at home (Hall, 1990; Kahn, 1991; Lundberg et al., 1994), the long-term health risks for women in repetitive work seem to be of particular importance (Repetti et al., 1989; Rodin & Ickovics, 1990; Frankenhaeuser et al., 1991; Lundberg 2005).
Catecholamine responses are strongly related to the intensity of mental stress regardless of its emotional valence. This was demonstrated in early experiments by Levi (1965), in which participants were exposed to films with contrasting emotional content, and by Lundberg et al. (1991/92) who found elevated epinephrine levels in five-year-old preschool children watching funny movies at their day care centre. Thus, elevated catecholamine levels reflect negative stress as well as strong positive emotions.
Urinary catecholamines are particularly useful in the study of occupational psychosocial stress as they reflect the mean stress levels for longer periods of time and do not cause pain or discomfort to the participants. In addition, catecholamines are linked to certain health problems such as cardiovascular disorders.
Axelrod, J., and Reisine, T.D. (1984). Stress hormones: Their interaction and regulation. Science, 224.
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Cannon, W.B. (1914) The emergency function of the adrenal medulla in pain and the major emotions. American Journal of Physiology 33: 356-372.
Cohen, S., Doyle, W.J., & Baum, A. (2006). Socioeconomic status is associated with stress hormones. Psychosomatic Medicine, 68, 414-420.
Forsman, L. (1983). Individual and group differences in psychophysiological responses to stress – with emphasis on sympathetic-adrenal medullary and pituitary-adrenal cortical responses. Doctoral Dissertation, Department of Psychology, Stockholm University.
Frankenhaeuser, M., Gardell, B. (1976) Underload and overload in working life: Outline of a multidisciplinary approach. Journal of Human Stress 2: 35-46.
Frankenhaeuser, M., Lundberg, U. & Chesney, M. (1991). Women, work and health. Stress and opportunities, New York: Plenum Press.
Frankenhaeuser, M. (1971) Behavior and circulating catecholamines. Brain Research, 31: 241-262.
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Glass, D.C., & Singer, J.E. (1972). Urban Stress. New York: Academic Press.
Hall, E. M. (1990). Womens work: an inquiry into the health effects of invisible and visible labour. Doctoral Dissertation, Karolinska Institute, Stockholm.
Henry, J.P. (1992) Biological basis of the stress response. Integrative Physiological and Behavioral Science, 1: 66-83.
Johansson, G. (1972) Sex differences in the catecholamine output of children. Acta Physiologica Scandinavica 86: 569-572.
Krantz, G., Forsman, M., & Lundberg, U. (2004). Consistency in physiological stress responses and electromyographic activity during induced stress exposure in women and men. Integrative Physiology and Behavioral Science 39, 105-118.
Levi, L. (1965). The urinary output of adrenaline and noradrenaline during pleasant and unpleasant emotional states. Psychosomatic Medicine, 27, 80-85.
Levi, L. (1972) Stress and distress in reponse to psychosocial stimuli. Acta Medica Scandinavica, Suppl. 528.
Lundberg, U. (1984) Human psychobiology in Scandinavia: II Psychoneuro-endocrinology human stress and coping processes. Scandinavian Journal of Psychology 25: 214-226.
Lundberg, U. (1996). The influence of paid and unpaid work on psychophysiological stress responses of men and women. Journal of Occupational Health Psychology, 1, 117-130.
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Lundberg, U., & Palm, K. (1989). Workload and catecholamine excretion of in parents of preschool children. Work and
Mason, J.W. (1968). A review of psychoendocrine research on the sympathetic-adrenal medullary system. Psychosomatic Medicine 30: 631-653.
Melin, B. and Lundberg, U. (1997). A psychobiological approach to work-stress and musculoskeletal disorders. Journal of Psychophysiology.
Melin, B., Lundberg, U., Söderlund, J., and Granqvist, M. (1999). Psychological and physiological stress reactions of male and female assembly workers: A comparison between two different forms of work organization. Journal of Organizational Behavior, 20, 47-61.
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Moon, S.D. & Sauter, S.L. (Eds.), (1996). Psychosocial Aspects of Musculoskeletal Disorders in Office Work. Taylor & Francis, London.
Pollard, T. M. (1995). Use of cortisol as a stress marker: practical and theoretical problems. American Journal of Human Biology.
Rissler, A. (1977) Stress reactions at work and after work during a period of quantitative overload. Ergonomics 20: 13-16.
Steptoe, A. (1985) Assessment of sympathetic nervous function in human stress research. Discussion meeting held at the Ciba Foundation, London.
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Catecholamine blood test
You will likely be told not to eat anything (fast) for 10 hours before the test. You may be allowed to drink water during this time.
The accuracy of the test can be affected by certain foods and medicines. Foods that can increase catecholamine levels include:
- Citrus fruits
You should not eat these foods for several days before the test. This is especially true if both blood and urine catecholamines are to be measured.
You should also avoid stressful situations and vigorous exercise. Both can affect the accuracy of the test results.
Medicines and substances that can increase catecholamine measurements include:
- Calcium channel blockers
- Nicotinic acid (large doses)
- Tricyclic antidepressants
Medicines that can decrease catecholamine measurements include:
- MAO inhibitors
If you take any of the above medicines, check with your health care provider before the blood test about whether you should stop taking your medicine.
Test ID: CATU Catecholamine Fractionation, Free, 24 Hour, Urine
Many alterations in physiologic and pathologic states can profoundly affect catecholamine concentrations.
Any environmental factors that may increase endogenous catecholamine production should be avoided. These include noise, stress, discomfort, body position, and the consumption of food, caffeinated beverages, and nicotine. Caffeine and nicotine effects are short term, a few minutes to hours only.
Other substances and drugs that may affect the results include:
Substances that result in increased release or diminished metabolism of endogenous catecholamines:
-Monamine oxidase inhibitors (MOIs): a class of anti-depressants with marked effects on catecholamine levels, particularly if the patient consumes tyrosine rich foods, such as nuts, bananas, or cheese
-Catecholamine reuptake inhibitors including cocaine and synthetic cocaine derivatives, such as many local anesthetics, which also can be antiarrhythmic drugs (eg, lidocaine)
-Some anesthetic gases, particularly halothane
-Withdrawal from sedative drugs, medical or recreational, in particular alcohol, benzodiazepines (eg, Valium), opioids, and some central acting antihypertensive drugs, particularly Clonidine, but, generally not cannabis or other hallucinogens such as lysergic acid diethylamide (LSD), mescal, or peyote
-Vasodilating drugs (eg, calcium antagonists, alpha-blockers)
-Tricyclic antidepressants usually exert a negligible effect
Substances that reduce or increase plasma volume acutely (eg, diuretics, radiographic contrast media, synthetic antidiuretic hormone )
Historically, a third category of potentially interfering substances was represented by molecules that are either similar in chemical structure, antibody epitopes, or chromatographic migration pattern to the catecholamines, or have metabolites that can be mistaken for the catecholamines. Our current HPLC-based assay is not subject to any significant direct interference of this kind. In most cases, the following drugs do not cause problems with the current assay that cannot be resolved: acetaminophen, allopurinol, amphetamines and its derivatives (methamphetamine, methylphenidate , fenfluramine, methylenedioxymethamphetamine ), atropine, beta blockers (atenolol, labetalol, metoprolol, sotalol), buspirone, butalbital, carbamazepine, clorazepate, chlordiazepoxide, chlorpromazine, chlorothiazide, chlorthalidone, clonidine, codeine, diazepam, digoxin, dimethindene, diphenhydramine, diphenoxylate, dobutamine, doxycycline, ephedrine and pseudoephedrine, fludrocortisone, flurazepam, guanethidine, hydralazine, hydrochlorothiazide, hydroflumethiazide, indomethacin, insulin, isoprenaline, isosorbide dinitrate, L-Dopa, methenamine mandelate (mandelic acid), methyldopa, methylprednisolone, nitrofurantoin, nitroglycerine, oxazepam, entazocine, phenacetin, phenformin, phenobarbital, phenytoin, prednisone, probenecid, progesterone, propoxyphene, propranolol, quinidine, spironolactone, tetracycline, thyroxine, and tripelennamine.
On occasion, when interference cannot be resolved, an interference comment will be reported.
The variability associated with age, gender, and renal failure is uncertain.
Catecholamines — Blood
Catecholamines are hormones produced by the adrenal glands, which are found on top of the kidneys. They are released into the blood during times of physical or emotional stress. The major catecholamines are dopamine, norepinephrine, and epinephrine (which used to be called adrenalin).
This article discusses the test to check the level of catecholamines in a sample of blood.
Catecholamines are more often measured with a urine test than with a blood test. See: Catecholamines – urine
Norepinephrine – blood; Epinephrine – blood; Adrenalin – blood; Dopamine – blood
How the test is performed
Blood is typically drawn from a vein, usually from the inside of the elbow or the back of the hand. The site is cleaned with germ-killing medicine (antiseptic). The health care provider wraps an elastic band around the upper arm to apply pressure to the area and make the vein swell with blood.
Next, the health care provider gently inserts a needle into the vein. The blood collects into an airtight vial or tube attached to the needle. The elastic band is removed from your arm.
Once the blood has been collected, the needle is removed, and the puncture site is covered to stop any bleeding.
In infants or young children, a sharp tool called a lancet may be used to puncture the skin and make it bleed. The blood collects into a small glass tube called a pipette, or onto a slide or test strip. A bandage may be placed over the area if there is any bleeding.
How to prepare for the test
The accuracy of the test can be affected by certain foods and drugs, as well as physical activity and stress.
Foods that can increase catecholamine levels include:
- Citrus fruits
You should avoid these foods for several days prior to the test, particularly if both blood and urine catecholamines are to be measured.
You should also avoid stressful situations and vigorous exercise, which can both interfere with test results.
Drugs that can increase catecholamine measurements include:
- Chloral hydrate
- Nicotinic acid (large doses)
Drugs that can decrease catecholamine measurements include:
- MAO inhibitors
Never stop taking any medication without first talking to your doctor.
How the test will feel
Some people feel discomfort when the needle is inserted. Others may notice only a prick or stinging sensation. Afterward, there may be some throbbing.
Why the test is performed
This test is used to diagnose or rule out a pheochromocytoma or neuroblastoma. It may also be done in patients with those conditions to determine if treatment is working.
Epinephrine: 0-900 picograms/milliliter (pg/ml)
Norepinephrine: 0-600 pg/ml
Note: Normal value ranges may vary slightly among different laboratories. Talk to your doctor about the meaning of your specific test results.
The examples above show the common measurements for results for these tests. Some laboratories use different measurements or may test different specimens.
What abnormal results mean
Higher-than-normal levels of blood catecholamines may suggest:
- Acute anxiety
- Ganglioblastoma (very rare)
- Ganglioneuroma (very rare)
- Neuroblastoma (rare)
- Pheochromocytoma (rare)
- Severe stress
Additional conditions under which the test may be performed include Shy-Drager syndrome.
What the risks are
There is very little risk involved with having your blood taken. Veins and arteries vary in size from one patient to another and from one side of the body to the other. Taking blood from some people may be more difficult than from others.
Other risks associated with having blood drawn are slight but may include:
- Excessive bleeding
- Fainting or feeling light-headed
- Hematoma (blood accumulating under the skin)
- Infection (a slight risk any time the skin is broken)
Guber HA, Farag AF, Lo J, Sharp J. Evaluation of endocrine function. In: McPherson RA, Pincus MR, eds. Henry’s Clinical Diagnosis and Management by Laboratory Methods. 21st ed. Philadelphia, Pa: Saunders Elsevier; 2006:chap 24.
Review Date: 2/1/2011
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Catecholamines Kick Out the Demons of Depression
Phenylalanine May Also Help with Weight Loss
neurotransmitters dopamine and noradrenaline
This article originally appeared in the July 1999 issue of Life Enhancement. Its reappearance is timely because there is a renewed interest in the amino acid phenylalanine, a precursor to the neurotransmitter molecules dopamine and noradrenaline. Although it is well known that boosting the synaptic levels of these neurotransmitters can help alleviate depression, it is not so well known that phenylalanine can help reduce food intake through its ability to stimulate release of the satiety hormone CCK.
I would scarcely kick to come to the top.
— John Keats
Metabolic pathway of phenylalanine, tyrosine, and the catecholamines.
Despair and hopelessness, so characteristic of serious depression, had engulfed the poet John Keats when he wrote to a friend in 1818. He could not have known that a chemical compound called phenylalanine (which had not yet been discovered) might provide a helpful “kick” for his own soul as well as for many other depressed souls in their struggle to remain afloat.
The demons of depression exact a terrible toll on human happiness and productivity—even on life itself. But scientists’ quest to understand the origins of this affliction, and to ameliorate it, continues to bear fruit. A recent study at the Yale University School of Medicine has shown a strong link between depression and low levels of compounds called catecholamines (cat-eh-coal-ah-meens´) in our bodies.1
That in itself is not news, but there is an intriguing twist. It was found that people who suffer from bouts of clinical depression are biochemically different from those who are normal and healthy. This is true even when the depression-prone individuals are in remission and appear to be normal and healthy. They are, in a sense, biochemical time bombs ready to go off into another depressive episode.
But what lights the fuse? Perhaps a better question is: is there a way to dampen the fuse so it fizzles before anything goes boom? Neither question has a simple answer, but much research points to the catecholamines.
What Are Catecholamines?
Catecholamines are biologically active compounds that play key roles in metabolism and cardiovascular function. These simple, structurally similar organic compounds also play vital roles in regulating the function of our nervous systems, both central and peripheral. Without them, our bodies would be like the Internet if all the transmission lines failed—dead. One catecholamine in particular, noradrenaline, is involved in mood regulation.
Catecholamines are obtained exclusively by synthesis from nutrient molecules—mainly the amino acids phenylalanine and tyrosine—in our foods. In normal metabolism, phenylalanine converts to tyrosine, which converts via dopa to the catecholamine dopamine; dopamine is the immediate precursor of noradrenaline, which converts to adrenaline.
One way to ensure adequate levels of these essential compounds is by consuming their nutrient precursors via supplementation. Phenylalanine can be taken as a supplement; tyrosine can too, but it does not provide the same uplifting benefits as phenylalanine, because the latter is required for the production of a metabolite, phenylethylamine, whose mood-elevating properties augment those of noradrenaline.
The “Big Three” Catecholamines
The best-known catecholamines are dopamine, noradrenaline, and adrenaline. (Scientists prefer the terms norepinephrine and epinephrine for noradrenaline and adrenaline, but the latter terms are still being used.) Dopamine and noradrenaline are neurotransmitters—compounds that mediate the flow of impulses between neurons. Adrenaline is a stress hormone responsible for the well-known “fight or flight” response, which prepares the body to cope with crises.
Dopamine deficiency is implicated in some forms of depression and in Parkinson’s disease; conversely, excessive dopamine levels are implicated in some forms of psychosis, such as schizophrenia. Noradrenaline is prevalent in the peripheral nervous system but is also found, in much lower concentrations, in the brain (adrenaline is found in the brain too, at lower concentrations still). In some types of depression, there is a noradrenaline deficit in certain regions of the brain, and some antidepressants drugs are designed to boost these levels by interfering with the mechanism that keeps them down.
Catecholamine Deficiency Leads to Depression in Depression-Prone Patients
In the Yale study mentioned above (a randomized, placebo-controlled, double-blind, crossover trial), Dr. R. M. Berman and his colleagues administered a compound, alpha-methylparatyrosine, that inhibits the synthesis of catecholamines from their chemical precursors. The subjects had a history of clinical depression and had been in remission and medication-free for at least three months.
Quick: what do rabbits, pigs, monkeys, and humans have in common? A lot, actually, but one thing is that they (and other species as well) have all been shown to eat less when injected with a polypeptide hormone called cholecystokinin (CCK). It’s not that CCK makes them sick, but rather that it induces a feeling of satiety, or fullness. And even if you’re a pig (a real pig), you tend to stop eating when your stomach feels full.
How CCK accomplishes this trick is not clear, but some evidence points to a direct action on the pyloric sphincter (the valve between the stomach and the duodenum), causing a delay in the gradual, hours-long process of releasing the stomach’s contents to the intestines. That would send a message to the brain saying, “Hey, I’m getting full! Make this guy stop eating!”
Be that as it may, few people would want to try to lose weight by getting daily injections of CCK, even if they could afford it. A better way would be to stimulate the body’s own production of CCK, which, as it happens, is produced naturally by the small intestine in response to the presence of fats. This causes the gallbladder to contract, releasing bile into the intestine to help digest the fats. The presence of CCK in the bloodstream (which it enters via the intestinal wall) also causes the secretion of digestive enzymes from the pancreas, as well as insulin and glucagon.
Those are useful functions, obviously, but it’s CCK’s satiety effect that is of interest here. Which brings us back to the question of how to stimulate this effect. It has long been known that phenylalanine is a potent releaser of CCK, but experiments in the 1980s to cause a suppression of food intake with phenylalanine doses of as much as 10 g failed to show any such effect.
CCK Levels Increase 5-Fold in 20 Minutes
In 1994, two British researchers tried again, this time being careful to ascertain both the degree to which phenylalanine caused blood levels of CCK to increase and the precise time at which the levels peaked.1 In preliminary experiments, they found that oral administration of 10 g of phenylalanine in human test subjects caused a 5-fold increase in CCK levels, peaking 20 minutes after the supplement was taken. That, they concluded, was the correct time at which to give the subjects a meal to see what effect the enhanced CCK levels might have.
The subjects were six healthy, not overweight adults (four men and two women, average age 30). After an 8-hour fast starting at midday, they were given the phenylalanine at 8 P.M., followed 20 minutes later by a buffet-style supper at which they could choose freely and eat and drink whatever they liked. The caloric content of all the foods was known, and the subjects’ intakes were measured, as were their CCK levels before the meal. (As in the preliminary experiments, there was a 5-fold increase in CCK during the 20-minute period.)
The study was placebo-controlled, with each subject acting as his or her own control via phenylalanine and placebo trials that were conducted in identical fashion at least seven days apart. The trial was single-blind—the researchers knew who was getting what in each session, but the subjects did not.
Caloric Intake Drops About 30%
The results showed a significant satiety effect with phenylalanine: the subjects consumed an average of 1587 kilocalories (1 kilocalorie = 1000 calories = 1 Calorie) after taking placebo, but only 1089 kilocalories after taking phenylalanine—a 31% reduction in caloric intake. (If you count the 42 kilocalories contributed by the 10 g of phenylalanine, their intake was really 1131 kilocalories, a 29% reduction.) There were no reports of any side effects.
An important feature of this experiment was that the phenylalanine was taken with 200 ml (7 fl oz) of water, which acted as a physical “load” on the stomach, causing some distension. The stimulation produced by such loading interacts with CCK’s biochemical action to reduce food intake. In other words, CCK works much better with a load than without one.
Thus, if these results are borne out, it may be possible to lose weight through the satiety effect by taking phenylalanine with a glass of water 20 minutes before a meal. The smaller the amount taken, the smaller the effect is likely to be, but there is some evidence that even very small amounts of supplemental phenylalanine (less than a gram) may influence appetite.2
- Ballinger AB, Clark ML. L-Phenylalanine releases cholecystokinin (CCK) and is associated with reduced food intake in humans: evidence for a physiological role of CCK in control of eating. Metabolism 1994 June; 43(6):735-8.
- Hall WL, Millward DJ, Rogers PJ, Morgan LM. Physiological mechanisms mediating aspartame-induced satiety. Physiol Behav 2003 Apr;78(4-5): 557-62.
The results were dramatic: depleting the catecholamines produced marked symptoms of depression in the experimental group, as measured by the Hamilton Depression Rating Scale. By contrast, the control group was almost totally unaffected. The authors concluded that “. . . catecholamine function may play a crucial role in mood regulation for subjects who are vulnerable to depression.”
Catecholamine Deficiency is Implicated in Age-Related Mental Problems
Several earlier short-term studies had shown that inhibition of catecholamine synthesis did not have any effect on the mood of normal, healthy people who had never suffered from clinical depression. They were clearly more resilient than those whose prior depression had made them vulnerable to a temporary depletion of these vital molecules.
This does not mean, however, that maintaining optimal levels of catecholamines is not important for normal, healthy people. Catecholamines are very important for good mental health, especially as we grow older and our output of these neurotransmitters gradually declines. Most of the mental failings that often accompany aging, such as loss of memory, loss of mental alertness and energy, tendency toward depression, vulnerability to stress, and Alzheimer’s and Parkinson’s diseases, are associated with reduced levels of noradrenaline or dopamine.
Phenylalanine Can Help Fight Depression and Sustain Mood
There is a growing body of both anecdotal evidence and clinical observations showing that phenylalanine supplements can alleviate the symptoms of some forms of depression. It can also boost various aspects of mental function in healthy people who wish to maximize their ability to stay that way.2 In one such clinical study published in 1984, the authors concluded that “The results support the view that the brain is able to use dietary amino acids to enhance production of brain neuroamines capable of sustaining mood.”3
The Orthomolecular Approach
The two main goals of nutritional intervention—to alleviate the symptoms of disease and to optimize a state of health—exemplify an approach to health care called orthomolecular medicine, or orthomolecular psychiatry when it’s aimed at mental disorders. (The prefix ortho is from the Greek orthos, meaning correct.)
The underlying idea is that many diseases or disorders result from imbalances in the concentrations of certain compounds normally found in the body, and that such conditions can best be treated by administering one or more of those compounds or their natural precursors (plus any relevant cofactors) so as to restore the correct balance and, therefore, good health. The optimal concentrations of the compounds in question may differ greatly from the concentrations actually provided by the person’s genetic makeup or normal diet—hence the need for nutrient supplementation.
The leading figure in the orthomolecular school of medicine was the late Linus Pauling, one of the greatest scientists who ever lived. Part of Pauling’s legacy is the increasing acceptance of his conviction that the orthomolecular approach to therapy, prophylaxis, and health optimization, particularly in cases of mental disorder, is generally the best. In his own words, “Significant improvement in the mental health of many persons might be achieved by the provision of the optimum molecular concentrations of substances normally present in the human body.”4
And remember: if you start feeling down or depressed, it may not be all in your head. You may be able to kick-start your mental energy again just by putting the correct molecules in your stomach.
- Berman RM, Narasimhan M, Miller HL, Anand A, Cappiello A, Oren DA, Heninger GR, Charney DS. Transient depressive relapse induced by catecholamine depletion: potential phenotype vulnerability marker? Arch Gen Psychiatry 1999 May;56(5):395-403.
- Hendler SS. The Doctors’ Vitamin and Mineral Encyclopedia. Simon & Schuster, New York, 1990, pp 225-8.
- Kravitz HM, Sabelli HC, Fawcett J. Dietary supplements of phenylalanine and other amino acid precursors of brain neuroamines in the treatment of depressive disorders. J Am Osteopath Assoc 1984;84/1 Suppl:119-23.
- Pauling L. Orthomolecular psychiatry: varying the concentrations of substances normally present in the human body may control mental disease. J Nutr Environ Med 1995;5/2:187-98.