As People Continue to Use Drugs More Areas Than Just Reward Pathways Are Affected

Our flourishing knowledge of the brain is in large part the product of research on addiction. Identifying what happens in the brain when a drug is inhaled, injected, or eaten, why it leads to compulsive drug seeking, and learning how to disrupt that process has seemed like the last best hope for a permanent fix for addiction. Which is why, according to Alan Leshner, director of the National Institute on Drug Abuse (NIDA), researchers know more about drugs in the brain than they know about anything else in the brain.

Among the revelations: addiction is now seen to be a brain disease triggered by frequent use of drugs that change the biochemistry and anatomy of neurons and alter the way they work. Scientists have developed a basic model of addiction that presents these changes as the desperate attempt of the brain to carry on business-as-usual—to make neurons less responsive to the drugs and so restore homeostasis—while under extreme chemical siege.

But the adaptations the drugs force on the brain can be long term or even permanent. With sustained drug use, the brain adapts to this saturation bombardment, and giving up drugs leaves it bereft and demanding a return to the new homeostasis. Thus, even the brains of people who have quit using drugs and urgently wish to stay clean remain vulnerable to relapse. Deprived addicts are no longer seeking to get high, they just want to feel normal.

Genetic factors, environmental factors, and—most important—the intricate and still mysterious interaction of the two are assumed to be fundamental to the addiction process. But a great many critical details are emerging from studies of events in the brain.

The common pathway

The most compelling revelation about addiction and the brain may even deserve that tattered encomium "breakthrough." The discovery that startled the scientists? Although each drug employs it in a somewhat different way, addictions center around alterations in a single pathway in the brain: the "reward" circuit whose chief centers of action lie in the ancient part of the brain known as the limbic system.

This pathway is involved in drug addictions of all kinds—not just addiction to illegal drugs such as heroin and cocaine, but also addiction to alcohol, tobacco, and even caffeine. Marijuana appears to employ this pathway too. And perhaps—a big perhaps because addiction experts are divided on this point—the pathway also figures in "addictions" that do not involve drugs, for example, the compulsive and destructive pursuit of eating, exercise, gambling, or sex.

The addiction pathway is the brain system that governs motivated behavior. When the pathway was first discovered, almost a half-century ago, people called it the pleasure center. Scientists now call it the brain reward region and have confirmed its role as the addiction pathway in countless animal studies (mostly with rats and mice) and many brain-imaging studies of human addicts.

The pathway is hidden deep within the brain (see illustration page 514). It begins at the ventral tegmental area in the midbrain, which sits on top of the brainstem. In evolutionary terms, this region is very old; it began with the vertebrates, which appeared 500 million years or so ago. The pathway extends to the nucleus accumbens, toward the front of the brain. This area is a traffic hub for signals to and from the addiction pathway and other parts of the brain. The nucleus accumbens is centrally located at the intersection of the stria-turn (where motion is begun and controlled) and the limbic system.

The limbic system is a collection of primeval brain structures that form a ring around the brain stem. Among those structures are the hippocampus, the brain's center of learning and memory, and the amygdala, the postulated site of, among other things, our emotional responses to experience. These are ancient centers of cognitive processing, but they still guide our behavior, sometimes to our woe. They long antedate the neocortex, where (among other tasks) rational thought processes are believed to take place. The limbic system is also closely connected to the hypothalamus, a tiny area in the center of the brain that controls many hormones, and with them, hunger, thirst, and sexual desire.

In short, the addiction pathway has been around a lot longer than humanity and is situated within easy reach of ancient brain centers that control many basic functions, most of them unconscious, that people share with other animals.

Drugs and the dopamine path

Chemicals called neurotransmitters pass messages from one neuron to another across the gaps (synapses) that divide them. Dopamine is among the most common of the more than 100 neurotransmitters that have been identified so far, although it is made in perhaps fewer than 100,000 nerve cells out of the brain's 100 billion. Dopamine is also the chief neuro-transmitter in the brain reward pathway. From cell bodies in the ventral tegmentum, electric commands go out, leaping along the cells' cablelike axons to their terminals in the nucleus accumbens, where dopamine is ejaculated into the synapses.

Addictions center around alterations in the brain's mesolimbic dopamine pathway, also known as the reward circuit, which begins in the ventral tegmental area (VTA) above the brain stem. Cell bodies of dopamine neurons arise in the VTA, and their axons extend to the nucleus accumbens. This centrally located hub connects with many other brain structures, such as the limbic system (the so-called emotional brain, in evolutionary terms very old). Some dopamine fibers also project to a much newer structure, the prefontal cortex, which is involved in cognitive tasks such as memory, planning, attention, and social behavior. Illustration courtesy of the National Institute on Drug Abuse, National Institutes of Health.

Once in the synapse, neurotransmitters swim across it and attach themselves to receptors on the surface of the receiving (postsynaptic) cell. Depending on the neurotrans-mitter, the attachment commands the postsynaptic cell to either do something or not do something. (The nature of the "something" also depends on the neurotransmitter.) Once it has carried out its task, the neurotransmitter is broken up by enzymes or vacuumed up by a transporter molecule and stored for reuse by the presynaptic cell that released it.

After dopamine has been ejected into a synapse, it normally doesn't remain there long; the presynaptic neuron's transporter sucks it right back up. But addictive drugs interfere with normal dopamine handling, prolonging its sojourn in the synapses and so its agreeable sensations. Some drugs do this by forcing the presynaptic cell to release more than the usual amounts of dopamine, others by preventing re-uptake by the transporter; some may even do a little of both. Cocaine, for example, imitates dopamine so well that it can bind to the transporter and block dopamine re-uptake. Amphetamines reverse the transporter's normal function, preventing re-uptake while also using the transporter to pump additional dopamine into the synapse from the presynaptic cell.

As with the other substances in its chemistry set, the brain usually keeps strict control over supplies of dopamine. Too little, and people will develop the tremors and characteristic stoop of Parkinson's disease. Too much may be responsible for the visions and delusions of schizophrenia. But the right amount of dopamine, scientists think, creates our subjective feelings of enjoyment, delight, even rapture—not just from drugs, but when we are eating ice cream, or making love, or getting a compliment. Defined biochemically, bliss is what we experience when that bolt of dopamine lightning strikes in the nucleus accumbens.

Addictive drugs share one pivotal characteristic: they all increase brain levels of dopamine. Many of the effects of the stimulants amphetamine and cocaine can be explained by their ability to elevate synaptic levels of dopamine and block the dopamine transporter, observes Marina Wolf, who studies addiction in rats at the Chicago Medical School in North Chicago. "So it was logical to go from the importance of dopamine systems in the acute actions of these drugs to proposing that the adaptations that occur when the drugs are given chronically—from the cellular level all the way up to a behavioral level—might be attributable to changes within the dopamine system," she says.

Opioids also stimulate release of abnormally large amounts of dopamine, employing one of nature's intricate juryrigged contraptions. Dopaminergic neurons in the ventral tegmentum are regulated by other neurons that keep them from releasing too much dopamine. Those regulatory neurons are studded with opioid receptors; when drugs such as morphine lock on to those receptors, they inhibit the inhibitory neurons. That is, they prevent the neurons from doing their normal job of holding down dopamine production, resulting in the release of large amounts of dopamine.

Nicotine probably activates both the dopamine and opioid overproduction systems, but the details are not yet clear. Ethanol, too, appears to employ the opioid method of disinhibiting dopamine neurons (in addition to its many other activities), but also increases their firing rate in the ventral tegmentum.

In short, each drug makes use of the dopamine pathway in a different way and recruits other brain chemicals (including other neurotransmitters) to help. What follows is a selective and much-simplified account of some consequences of the dizzyingly complicated process of addiction.

The evolution of motivation

Researchers have amassed a mountain of reasons to explain drug use. Leshner says that 72 "risk factors" have been defined, from the street price of a drug to the drug habits of the people one hangs out with. But the basic reason people use drugs isn't complicated or mysterious. They like the way drugs make them feel.

Scientists believe, however, that the reward pathway exists for reasons more fundamental than fun. It does, after all, contain receptors, transporters, and other molecules that normally hitch up not with drugs but with the chemicals that evolution has designed for them. Scientists have known that the brain produces these "natural" psychoactive drugs since the 1970s, when the enkephalins, the first of the opioid peptides, were discovered. Since then, researchers have identified the natural brain analogs of all of the major drugs of abuse.

Scientists believe activation of the reward pathway is an essential spur to motivation, an incentive to learn and repeat adaptive behavior that they call reinforcement. Eating may be pleasurable, but its underlying purpose is to sustain life; the pleasure that accompanies delightful flavors and full bellies is an enticement that encourages creatures to make a habit of it.

The brain contains other circuits that interact with the reward pathway to encourage adaptation and survival, circuits that deal with emotion and learning. These circuits assign significance and meaning to experience—to individuals, things, and events in the world. Doing so requires calculating, for example, whether something is hazardous, or edible, or sexy, and then adjusting brain function to generate adaptive tactics, such as flight, approach, or courtship.

Using PET (positron emission tomography) scanning, researchers at the National Institute on Drug Abuse detected the activation of brain regions implicated in certain forms of memory when human volunteers who abuse cocaine were exposed to drug-related cues (drug paraphernalia and a videotape of cocaine users). Brain activation (increased neural activity) was detected as an increase in glucose metabolism, as indicated by the color scale at the lower right. The drug-related cues did not produce brain activation in control subjects (scans not shown), but volunteers who experienced a high level of cue-induced cocaine craving showed brain activation in the dorso-lateral prefrontal cortex (DL; upper scans), which is important in short-term memory, and in the amygdala (AM; lower scans), which is implicated in emotional influences on memory. When these volunteers were exposed to neutral (non-drug related) cues, this activation was not seen (scans at left). Image republished with permission from Grant S, et al. 1996. Proceedings of the National Academy of Sciences USA 93: 12040-12045.

Assigning significance and meaning to experience also requires storing memories of those tactics—successful and unsuccessful—as a guide to adaptive behavior in the future. In short, it requires learning. As an aid to this learning, the brain links experiences with emotions; we tend to remember best the experiences that are accompanied by strong sensations such as the euphoric rush from that dopamine zap in the nucleus accumbens. In fact, researchers now think that dopamine's chief role may be less to produce pleasure directly than to focus attention on events that portend reward (such as the dinner bell) or perhaps even distress (such as nausea) to facilitate learning and remembering.

The anatomy of addiction

With enough reinforcement, drug users move on to the stages of addiction known as craving and dependence. Dependence is an ambiguous word, sometimes used to mean physical and sometimes psychological dependence. Yet these are very different states, and—perhaps not surprisingly—they employ different parts of the brain.

Drugs can cause a host of changes to parts of the brain that control body functions, especially the brain stem and spinal cord. These alterations produce physical dependence on the drug. When the drug supply stops, the result can be a sickness called withdrawal. Withdrawal from heroin is a ghastly experience, and alcohol withdrawal can actually be fatal.

A natural brain compound called BDNF (brain-derived neurotrophic factor) can "rescue" dopamine-producing neurons from alteration by morphine. At left is a normal dopamine-producing neuron in the ventral tegmental area of a rat's brain. Repeated administration of morphine shrinks the neuron perceptibly (center). However, when BDNF is administered along with morphine, no shrinkage occurs (right). Photos: Eric Nestler.

Historically, withdrawal illness has been regarded as the telltale sign of an addictive drug. Many researchers, however, now reject physical withdrawal symptoms as a defining characteristic of addiction because it turns out that a drug can be powerfully addictive without causing serious withdrawal sicknesses. Two such drugs much in evidence today are crack cocaine and methamphetamine.

All addictive drugs alter neurons. Some of these changes appear to contribute to signs of psychological dependence when the drug is stopped, such as depression and craving. These two sensations in particular are now believed to spur addicts on in their compulsive pursuit of drugs. This irresistible desire has replaced withdrawal symptoms as the new hallmark of addiction.

Addiction and dopamine receptors

Studies of dopamine receptors are helping to shed light on the physiology of craving. There are two major classes of dopamine receptors, according to David Self, of Yale University. He calls them Dl-like and D2-like. Self and his colleagues, who study addiction in rats, report that the two receptor types have certain structural similarities and that their within-cell signaling systems are similar, but they have different anatomical profiles: They tend to be in the same brain regions, but sometimes on different cell types.

Self and his colleagues have found evidence that these two classes of dopamine receptors also function differently in addiction in rats. Craving and relapse seem to involve D2 activation almost exclusively, although both receptors are activated during reinforcement. Self hypothesizes that each receptor is involved in a different motivational phase of the reinforcement process, which he calls appetitive (D2) and consumatory (Dl). "I like to use the terms 'seeking' and 'having.' You can think of D2 receptors as stimulating seeking, whereas Dl receptors stimulate having," he says.

Self's animal studies have gotten confirmation of a sort from studies on humans by Margaret Haney and her colleagues at Columbia University. Looking for possible treatments for addiction, they found that pergolide, which occupies both kinds of receptors, reduced a dozen heavy coke users' subjective experiences of being high and even their heart rates, but it had no effect on self-administration of cocaine and actually increased craving. The group also studied ABT-431, another possible therapeutic agent, which selectively occupies the Dl receptor. This drug also significantly reduced feelings of being high in nine cocaine smokers and had no effect on self-administration. But its effect on craving was more ambiguous. There was a trend for ABT-431 to decrease cocaine craving, although it failed to achieve statistical significance.

"Thus, D2 activation increased drug craving while Dl activation did not," Haney acknowledges. She is not, however, convinced that Self's hypothesis is correct because she suspects that, at the low doses she used, pergolide acted selectively at the D2 receptor, yet, like ABT-431, it did not affect self-administration.

But Self says Haney's findings fit the hypothesis that the two receptors, although they seem to be doing similar things in stimulant and reinforcing effects, are doing opposite things with regard to appetitive versus consumatory behavior. "I think it is useful to make a distinction between reinforcement and reward, appetitive versus consumatory behavior. Those terms are often interchanged, and they shouldn't be," he says.

Addiction and the dopamine transporter

Although the details may have been disputed, the central role of dopamine in addiction nevertheless seemed firmly established. And then last May came research that appeared at first glance to contradict the notion that dopamine underlies addiction. "The leading hypothesis for how cocaine works in the brain appears to be wrong," said The New York Times. The headline in Nature Neuroscience asked: "Hard knocks for the dopamine hypothesis?"

Marc Caron, of Duke University Medical Center, and his colleagues had genetically engineered mice that completely lack the transporter for clearing dopamine out of its synapses and thus have perpetual high levels of extracellular dopamine. These knockout mice should not have been interested in cocaine. But they were; the researchers were able to teach the mice to self-administer the drug, Caron's group suggested that cocaine interacts with targets other than the dopamine transporter, and that the serotonin transporter could possibly initiate and sustain cocaine self-administration in the mice.

Caron points out that pharmacologists have known for a number of years that many psychostimulants are capable of blocking not only the ability of the dopamine transporter to re-uptake dopamine and therefore increase extracellular dopamine concentration, but also the ability of the norepinephrine transporter to re-uptake norepinephrine and the ability of the serotonin transporter to re-uptake serotonin. Previously, the effects on other neurotransmitter systems were not thought to be important because many of the reward mechanisms can be blocked by blocking the dopamine system.

What the study suggests, Caron says, is that addiction does not depend solely on the ability of cocaine to raise the concentration of dopamine. "It's probably much more that cocaine interacts with many other systems," he says, noting the possibility that norepinephrine might also be involved.

In normal mice, Caron says, cocaine probably also raises levels of serotonin, which in some way is capable of modulating the dopaminergic responses. The genetically engineered mice are allowing researchers to tease out the contribution of the serotonin system to the regulation of the dopamine system. Pharmacologic studies, which are often plagued by a drug's lack of selectivity, have yielded ambiguous results on how—or even whether—serotonin interacts with the dopamine system. By contrast, Caron notes, one of the advantages of genetic manipulation is that it permits researchers to be highly selective in the effects that they choose to investigate.

Of the dopamine transporter knockouts, Haney observes, "I don't think the Caron study alone negates the dopamine theory of addiction; there are too many data supporting it. It seems possible to me that knockout mice have different brains—different neuronal adaptations have taken place to compensate for what is missing." She points out that most of the data implicating other neurotransmitters and neuromodulators in the addiction story, including glutamate, GABA (gamma-amino-butyric acid), and endogenous cannabinoids, still support the notion that these substances exert their effects via the dopamine system.

Addiction and glutamate

However glutamate exerts its effects, it is playing an increasingly prominent role in the addiction story. Addictive drugs commandeer cells in the amygdala and hippocampus to construct intense emotional memories of drug experiences. These memories link the powerful pleasures of drug highs to the people, places, and paraphernalia associated with them. Thereafter these associations can by themselves trigger cravings. Indeed, one way in which alcohol and drug treatment programs help users abstain is by trying to sever these associations, creating a fresh social circle and new friends, supportive and abstinent, as a substitute for their former drinking buddies or fellow drug users.

The latest brain-imaging techniques offer visual evidence of why recovering addicts may need this sort of behavior modification to replace old habits with new ones. PET (positron emission tomography) studies by researchers at NIDA's intramural research program in Baltimore reveal that when cocaine addicts watch videos of coke users, not only do they feel craving for the drug, but also the parts of their brains that light up are those involved in memory, including the dorsolateral prefrontal cortex (probably the site of "working" memory) and the amygdala. This finding suggests, the researchers say, "that a distributed neural network, which integrates emotional and cognitive aspects of memory, links environmental cues with cocaine craving."

Because craving and reinforcement are aspects of learning, it is not surprising that addiction researchers are interested in glutamate, the neurotransmitter most associated with the learning process. Indeed, as the chief agent of fast neuron stimulation, glutamate is at the core of nearly all brain physiology and biochemistry and is central to the most sophisticated cortical processes. Glutamate receptors in the hippocampus appear to trigger the complex cascade of biochemical reactions that convert short-term memories into permanent ones, a process called long-term potentiation.

Wolf thinks that the introduction of glutamate as a player in addiction is logical, not just because glutamate underlies learning, but also because the dopamine system is regulated by glutamate-containing neurons. "Forget about drugs of abuse and just think of the dopamine neurons in the ventral tegmental area. One very important way that they get excitatory drive is through glutamate-containing nerve terminals that synapse on them. So on that end glutamate is very important in driving the cells," she says.

On the other end of the dopamine pathway, dopamine terminals center in the nucleus accumbens. "And the other major synaptic input that those accumbens cells get is glutamatergic. There are a lot of transmitters in the accumbens, but two of the major transmitters determining the output of the accumbens are dopamine and glutamate," Wolf points out. "The glutamate connection makes very good anatomical sense because it's working together with dopamine at the level of the accumbens to determine what the response to dopamine really is."

In the last decade, Wolf and her colleagues have shown that glutamate receptors participate in behavioral sensitization, the frenetic activity seen in lab animals that researchers accept as a model of drug craving. Long-term changes that occur with chronic drug administration, she says, seem to be dependent on glutamate systems, although each drug interacts with glutamate in a different way.

Despite her concentration on glutamate, Wolf says, "I don't think that anybody would suggest that we abandon the idea that the dopamine cells are the core of the reward pathway. I wouldn't move to describing glutamate as the primary transmitter, I would stick with dopamine." She also points out that research on the role of glutamate in addiction is still in its early stages.

There is, she says, a growing consensus that addiction is simply another form of neural plasticity. "Glutamate seems to be important in just about every form of neural plasticity, but in each case its specific role is a little bit different, and I'm sure that's going to be the case for drug addiction too."

In fact, glutamate may be just as central to learning to become drug free as it is to becoming a user. Self and his colleagues have recently found that addicted rats that are no longer given drugs and eventually abandon their search for them, a phenomenon known as extinction, show changes in glutamate receptors in the nucleus accumbens. The subsequent brain changes, Self says, are not caused by the fact that the rats have been cocaine users, because the researchers don't see those changes in rats that continue to use cocaine. And the changes are not caused by withdrawal from cocaine because they are not seen in rats that have gone through withdrawal but not the extinction process.

His conclusion? "[The brain changes are] caused by the experience of extinction," he says. "This is another type of neural adaptation. There are changes in the brain that are direct pharmacological effects of the drug. There are other changes in the brain that are the result of experience. Learning, in short. And these interact."

Indeed, Peter Kalivas and his colleagues at Washington State University at Pullman have proposed that whereas pharmacology is largely responsible for producing paranoia in cocaine users, craving and relapse are mostly the result of learning.

"It's sort of a circular thing," Self says. "Taking drugs changes the brain through both learning and direct pharmacological effects. How then do those changes affect motivation for subsequent drug taking or, in the absence of the drug, drug seeking and drug craving?"

Addiction inside neurons

Some researchers hope that knowledge about the interaction of pharmacology and learning will emerge by paying less attention to what goes on between brain cells and more to what goes on inside them. The newest frontier in addiction research is, therefore, signal transduction: the process by which events on the outside of a postsynaptic neuron influence events inside it. Binding to a dopamine receptor, for example, unleashes a chain of events in the cell that culminate in an order to a cell's genes to modify what they're doing.

Neuroscientists of all sorts have paid intense attention to a crucial link in this chain, an intracellular signaling chemical called cyclic adenosine monophosphate (cAMP), because it turns genes on and orders them to make some very consequential proteins. These are the proteins that help form new synaptic connections between neurons—the basis for long-term potentiation.

Addiction researchers have investigated cAMP's role in various regions of the brain, including the nucleus accumbens, where chronic exposure to morphine accelerates activity in the cAMP pathway. One outcome appears to be increased levels of a molecule nicknamed CREB (short for cAMP response element binding protein)—the molecular switch that governs production of synaptic proteins and so converts short-term into long-term memories. CREB and the cAMP pathway almost certainly play a role—perhaps a central role—in forming the memories that researchers suspect are fundamental to craving and relapse.

Eric Nestler and his colleagues at the Yale University School of Medicine have suggested that CREB-mediated gene transcription in the nucleus accumbens serves as a kind of drug reward rheostat. They showed that CREB regulates nucleus accumbens expression in vivo of the rat gene for dynorphin, an endogenous opiate, concluding that opiate receptors play a role in both cocaine reward and aversion to it. Repeated exposure to cocaine, they say, up-regulates dynorphin expression through the cAMP pathway—via the dopamine Dl-type receptors. Enhanced dynorphin release could eventually inhibit dopamine release via opioid receptors on the terminals of dopaminergic neurons. "Diminished release of dopamine in the nucleus accumbens may be aversive, or it may unmask other actions of cocaine that oppose drug reward," they say. This interpretation could explain why, over time, human addicts tend to find cocaine less rewarding and more likely to cause anxiety, irritability, and other unpleasantness.

Most of the neuronal adaptations generated by the drugs that have been studied so far have involved second-messenger systems, especially cAMP, but researchers are also investigating other ways that the brain remodels its ever-malleable neurons. This approach has led them to neurotrophic factors. Once thought to be active only during the earliest stages of nerve cell growth and development, neurotrophic factors are now believed to be essential to the adult brain as well, where they are involved in signal transduction and neuron growth and maintenance.

Neurotrophic factors might even be able to repair a drug-damaged brain. Nestler's lab has reported that chronic morphine administration reduces the size of dopamine-producing neurons in the rat ventral tegmentum by 25 percent on average while making no obvious changes in other kinds of neurons in that region. This shrinkage may be one way in which the rat brain tries to adjust its dopamine supply to a flood of opiates, Nestler suggests. But infusions of BDNF (brain-derived neurotrophic factor) into the ventral tegmentum not only prevent opiates from shriveling the dopamine neurons (perhaps by ratcheting down the speedup in the cAMP pathway that opiates induce), but can even restore those neurons to their former plump state.

The dopamine pathway is not the yellow brick road

Neuroscientists believe that their research is at last going to enable serious progress on this ancient human affliction. The common pathway was a benchmark revelation, in part because it offered a unified framework for studying what for a long time had seemed like a hodgepodge of unrelated behaviors.

Important though it may be for understanding addiction, the dopamine pathway itself does not seem likely to yield promising new medications or other treatments for addiction. The pathway is so essential to normal functioning, to the everyday pleasures of life, and perhaps to learning itself, that it may be nearly impossible to interfere with it successfully. "Whatever you do to the dopamine system, you always get more than you bargained for," Caron observes. "That's because of lack of selectivity and our lack of fundamental understanding of which protein of the dopamine system really mediates the addictive behavior."

And although genes seem more and more likely to play a key role in addiction, identifying these genes will not necessarily lead to treatments either. "There's not going to be a single gene that's defective in people that have more liability to become addicted. You probably can have many, many changes in the brain that will all eventually manifest themselves in addictive personalities," Caron says.

Researchers are hopeful that understanding the differences in the way the brain handles the various psychoactive agents will help them identify suitable points of attack. Leshner cautions audiences constantly against the hope of a magic bullet against addiction. But in the next few years, there may be real progress in treating and perhaps even preventing this peculiarly human affliction, one that is as old as the first Paleolithic brewers and as new as the latest mind-bending molecule from the designer druggist's clandestine chemistry lab.

Author notes

Science writer Tabitha M. Powledge is the author of Your Brain: How You Got It and How It Works (Scribner, 1995).

© 1999 American Institute of Biological Sciences.

© 1999 American Institute of Biological Sciences.

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Source: https://academic.oup.com/bioscience/article/49/7/513/236613

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