Sixty years of intermittent worry and warnings about the deleterious effects of coffee have had some effect on consumption. Over the last 30 years, Americans have drunk less and less, and over the last ten years, decaffeinated coffee has taken an ever greater share of the market. Doctors treating hypertension routinely recommend that their patients cut down on or cut out coffee. And faced with complaints of sleeplessness or general irritability, doctors immediately ask what role coffee plays in the patient's life-style.

Until very recently, though, the decision about how much coffee to drink was based on common sense and guesswork, not reasoned argument. Even pharmacologists and biochemists had little to support their suspicions that any stimulant as potent as caffeine was likely to have drastic negative effects. Beginning around the mid-80s, enough had been learned about coffee's wide-ranging yet subtle impact on the nervous system to make even the most devoted cappuccino drinker think again about this popular and public addiction. If the scientists are right, that morning (and/or mid-morning, afternoon, after-dinner) cuppa is doing you more harm than good in the very area in which it's supposed to be helping you out.

To a chemist, caffeine is a purine--one of a family of hundreds of organic compounds built around a basic structure of two interconnected "rings" of alternating carbon and nitrogen atoms. Purine compounds are found in all life forms: two varieties are integral components of the DNA genetic code, while a third, uric acid, is a principal waste product in animal metabolism.

More strictly defined, caffeine is one of a subvariety of purine compounds called xanthines, in which a pair of oxygen atoms is tightly bound to the hexagonal component of the basic purine ring structure. Xanthines turn up often in vegetable tissues, including seeds and berries. They seem to correspond to uric acid in animals: metabolic end products that play no further active role in the plant's life cycle. But many xanthines become chemically active if ingested by an animal. Some are potent poisons; most are diuretics, encouraging excretion; in higher animals, many also cause temporary relaxation of the circulatory system, lowering blood pressure by enlarging vessel capacity.

Xanthines also have a definite but strikingly ill defined stimulating effect on the nervous system. A laboratory mouse slipped a dose of pure caffeine in its water will temporarily be much more active than the undosed, genetically identical mouse in the cage next door. Experiments with mice also demonstrate clearly that the stimulation produced by caffeine is highly sensitive to the dosage. Below a certain level, caffeine has no effect at all on behavior; above a certain level, dosage and level of stimulation proceed in parallel for a while. Above another, higher level--50 milligrams of caffeine per kilogram of body weight--increasing the dosage has no further effect on behavior.

Though researchers could measure the level of stimulation induced by caffeine, they had no idea what produced it. But as early as 1970, there was speculation that caffeine might affect the nervous system by interfering with neurotransmitters--newly discovered chemicals that, when released by one set of nerve cells, affected the rapidity or strength of operation of other sets, thereby adjusting the overall operation of the nervous system. And caffeine, unlike most chemicals, has no trouble slipping past the so-called blood-brain barriers that protect the nervous system from most environmental effects.

The breakthrough into understanding how caffeine works came in the early 1980s. Pharmacologists working with rats and mice proved that caffeine linked up with brain-cell receptors sensitive to the compound adenosine, thereby blocking their normal functioning. This was an illuminating discovery, because, although adenosine is one of the most prevalent chemicals in the animal cell and has dozens of functions, as a neurotransmitter it clearly had a sedative effect: reducing the rate of nerve-cell firing, dulling pain response, slowing reaction time, lowering attention span, and reducing appetite--in general, turning down the thermostat on all life processes governed by the nervous system.

Over the next few years, scientists refined their observations, discovering that adenosine receptors in different portions of the nervous system produced quite different effects. Whereas activating most receptors reduces, decreases, or sedates the activity of the nervous system, other receptors, primarily in the striatum or basal ganglia of the brainstem, when activated control the organization of movement, while still others, located in the olfactory tubercle, help to maintain the organism's emotional state. Caffeine, by interfering with the body's natural balancing act between stimulation and sedation and by preventing cool-out messages from getting to their destination, shifted the whole mechanism--mood, physical activity, and overall excitability--into higher gear.

As soon as caffeine's modus operandi was understood, pharmacologists and biochemists knew where to look for its possible downside. The neurotransmitter mechanism is extremely complex, the supply of each compound affecting the production of many others. By temporarily blocking adenosine receptors and raising the system's general level of stimulation, caffeine set off a chain reaction throughout the system, inducing the body to produce more adenosine, individual cells to produce more receptors, or both, in order to bring the thermostat back into balance.

Result? Patient once again feels logy, drowsy, out of touch. Treatment? Another cup of coffee. And another. And another.

Quentin Regestein of the sleep clinic of Harvard's Brigham and Women's Hospital in Boston wonders whether using coffee may not, in the long run, paradoxically make people sleepier. "A pharmacologist here, Avram Goldstein, did a survey in a married students dormitory, asking questions about general life-styles, and he found that people who drank coffee generally described themselves as sleepy in the mornings. That could be why they drink coffee, of course, but in fact what we find here is that when people stop using coffee, morning sleepiness doesn't get worse, it goes away. Ordinarily, people who give up coffee say that the clear stimulus they used to feel for an hour, hour and a half in the morning is no longer there, but that the average productivity of their day improves.

"Some people, not just coffee drinkers, have the very devil of a time getting up in the morning," Regestein continues. "A person's natural circadian rhythm is often longer than 24 hours. Some people may have started drinking coffee in an attempt to 'reset' their body clocks each morning. But the net effect may simply be to make going to bed on time harder, which in turn makes getting up harder and using coffee to get going in the morning all that much more necessary."

"Caffeine is a compound handled by a process we call first-order metabolism," says John Carney, a caffeine researcher at the University of Kentucky. "No matter how much is there to start with, after a given amount of time, a certain percentage of what was there will be gone. In the case of caffeine--which pervades the whole body, is broken down in the liver, and is excreted through the kidneys--the half-life in the system is about four hours."

Someone who drinks two or three cups of coffee in the morning and no more for the day, then, would have essentially eliminated all but a good-sized sip's worth of caffeine from the system by wake-up time 24 hours later. People who keep on topping off their caffeine reserves throughout the day, however, will always have a substantial reservoir of the chemical in their bloodstreams: a prime condition for the body to redress its biochemical imbalance by boosting production of counter-caffeine chemicals. To put it briefly, coffee drinkers can't win the battle with their own biochemical natures. But in trying to, they can push the biochemical balance so far to one side that any interruption in the caffeine supply can have severe and debilitating side effects: violent headaches, uncombatable drowsiness, and frequently depression.

The problem with making flat statements of this kind is that for some people they just don't apply. "Caffeine has a tremendously wide variation in action," Regestein admits. "The people who say 'I can drink a cup of coffee right before I go to bed and go right to sleep' aren't lying." Hard biochemical research confirms the fact. Carney describes "one common strain of laboratory mouse, Jackson's Lab's SWR strain, inbred since the 1920s, who is just totally immune to the effect of caffeine: there's no dose that will excite him--not 100 milligrams per kilogram, which would be equivalent to 100 cups of coffee in a human.

"But take that mouse and breed him with another strain called CBA, who's essentially the great-great-great-grandson of the common European white mouse. The first generation of offspring will all look like the CBA mouse and show his caffeine sensitivity, which means that the caffeine resistance of the SWR mouse is genetically recessive. Then take those first-generation mice and cross them among themselves, and you get offspring spread right across a bell curve: mice who are significantly less active than the SWR mouse, who are actively depressed by caffeine in fact, all the way across the activity spectrum to mice a good three standard deviations above the activity norm, mice that are rocketing right off the walls of their cages. Caffeine sensitivity is obviously not a simple genetic either-or: at least two genes are involved, and probably more, to get that kind of result."

But though people who say they can drink coffee at any hour and still go to sleep aren't kidding, they may be kidding themselves. For one thing, their ability to go right off to sleep may just mean that their tolerance of caffeine has grown to the point where an incremental dose has no further effect.

Coffee's effects can be insidious, too. "Lab studies show that middle-aged coffee drinkers tend to sleep less soundly overall than middle-aged nondrinkers, and in middle age we tend to sleep less soundly anyhow," says Regestein. "That's why a lot of people start cutting back their coffee consumption as they get older, without any advice from their doctor. They just find they feel generally better drinking less." Regestein also cites studies of hospital patients that suggest that for people who are already ill, "drinking coffee makes their ills more symptomatic"--reasonable enough now that it's known that caffeine is an antagonist of adenosine, one of the body's own antipain chemicals.

Carney points out that if some individuals are not much affected by caffeine, others--some 5 to 10 percent of the population--are hypersensitive to its effects. These individuals are the most likely to succumb to a serious coffee habit, exhibit the greatest physical and personality effects from it, and have the greatest difficulty in finally kicking the habit.

David Calhoun, a maker and maintainer of harpsichords, is one person who had a "caffeine problem" and licked it. "I started drinking coffee in med school, for the usual reasons, to stay awake. When I dropped out of med school after three years, I was certainly a confirmed coffee drinker. I may even have already been carrying caffeine tablets around with me everywhere I went by then, and I think a good definition of addictive behavior is always making sure you know where your next dose is coming from.

"By 1977 I was dependent to the extent of being absolutely unable to wake up in the morning without my caffeine fix. I always put a cup of coffee by my bed before I went to sleep to drink before I got up--yep, cooold coffee--and then lie there 20 minutes more to begin to wake up. Associated behavior patterns? I became known over the years for my terrible temper. This was particularly a problem combined with alcohol. If I so much as had a sip of wine at lunch, I might have a panic attack or more likely a temper tantrum later in the afternoon. This became a problem when I found myself fighting with people I didn't want to fight with--banging somebody's car door in a temper and having to spend a bunch of money I didn't have to spare fixing their paint job. I finally stopped drinking entirely; couldn't trust it.

"Then falling asleep: drinking two, three cups of nice strong coffee in the morning, then one at mid-morning and another at lunch, two or three more by mid-afternoon and falling asleep over the last one--sleeping not 20 minutes but two hours or more, and waking up quite dopey--slugging down some more coffee to get me through the evening, then just folding up. I was never seen without a cup of coffee in my hand, half-drunk cups all over the house, in my workshop. Typical--filling up a cup in the morning, walking into the workshop, putting it on the lid of a harpsichord, and raising the lid: it was, after all, the first cup.

"When did I recognize I had . . ."a problem'? Staying with Dr. Regestein in Boston during the Boston Early Music Festival; Reg's wife is a well-known organist. He watched me stumble upstairs one morning with my cold cup of coffee in one hand and my bottle of caffeine tablets in the other and said, "Young man, you have a problem; let me explain it to you.' And he did, and since I already spoke medical language, what he said made sense. But it wasn't until a short while later that I made my move. I was in a doctor's office having my blood pressure taken, and it read 195 over 148. Well, chalk that up to doctor anxiety, take some deep breaths, relax, try again: no change. Now, I am not overweight and I don't smoke, and 120 over 80, 130 over 85 would have been normal for my age. One-ninety-five systole is heart-attack, stroke country; 148 diastole is kidney damage. My heart was hammering just to get the blood through my arteries. They were clenched. Tight."

Regestein had warned Calhoun not to cut his caffeine intake abruptly, something that can bring on blinding headaches, cold sweats, hot flashes--all the classic symptoms of going cold turkey. "So I decided to take it very slow and easy. I started out by simply making the same big pot of coffee in the morning, but cutting the number of beans in half. And slept through the month of July."

Calhoun spent the better part of the next two years gradually tapering off caffeine. "I kept on drinking as much: I just made it weaker and weaker, until it tasted so terrible it wasn't worth drinking. I also broke my caffeine tablets into smaller and smaller slivers. When I couldn't stand the taste of the coffee anymore I switched to tea, which I actively dislike. I'm now completely off the stuff. But I don't kid myself. It's really ironic sitting around with a beer with former alcoholic friends, craving a sip of their cup of coffee."

Very few people ever get as dependent on caffeine as David Calhoun, but most coffee drinkers are probably a lot more dependent than they think they are. For most, diminishing the dependence isn't terribly difficult. "Rodents develop tolerance to caffeine in just seven days, and it only takes them about another seven to adjust back after being deprived of it," says Carney. "Humans aren't rats, but most people seem to readapt after a very brief withdrawal period"--particularly if they avoid the temptation to go cold turkey.

"It's probably worth any coffee drinker's while to at least experiment with their intake," says Regestein. "Most people who do soon find they're feeling better. A few cups of coffee a day by themselves aren't going to kill you, but all coffee's for is to make you feel better. If it turns out it doesn't, what's the point?"