Three articles on the Drug Problem

From the Economist May 15 -21, 1993

In 1883, Benjamin Ward Richardson, a distinguished British doctor, denounced the evils of drinking tea. He said it caused an "extremely nervous semi-hysterical condition". In 1936, an article in the American Journal of Nursing claimed that a marijuana taker "will suddenly turn with murderous violence upon whomever is nearest to him". Tea and marijuana have three things in common: they alter the moods of those who take them, they are regarded as tolerable safe, and they are addictive.

Attitudes to addiction are complicated and often contradictory. Tea and marijuana are in themselves fairly harmless, yet tea is generally legal and marijuana is not. Tobacco and cocaine are harmful but, again, tobacco is almost universally allowed, whereas most readers of The Economist live in countries which may imprison you for possessing cocaine.

Throw in the joker of addictions which come not in syringes or cigarettes, but in casinos and computer cartridges, and you have a fine arena for combat between libertarians and puritans.

This battle, always lively, has just become hotter. On April 28th Bill Clinton appointed Lee Brown, a former policeman, as America's new "drug tsar", and thus leader of the worlds toughest prohibition programme. Ten days before, Italians had voted to move in the other direction by scrapping the harshest measures of their drug laws.

Such boldness is rare. The attitude of most electorates and governments is to deplore the problems that the illegal drug trade brings, view the whole matter with distaste, and sit on the status quo--a policy of sweeping prohibition. Yet the problems cannot be ignored. The crime to which some addicts resort to finance their habits, and in which the suppliers of illegal drugs habitually engage, exacts its price in victims' lives, not just money. The illegal trade in drugs supports organised crime the world over. It pulls drug-takers into a world of filthy needles, poisoned doses and pushers bent upon selling them more addictive and dangerous fixes.

Yet most people still balk at exploring ways in which a legal regime might undermine such effects. Their refusal owes something to a distaste for addiction in itself. This is an argument shot through with inconsistency. The strongest disapproval often comes from those who scream about liberties if their own particular indulgences--for assault rifles, say--are attacked. Addiction to cigarettes is reckoned to be the chief avoidable cause of death in the world. Alcohol deprives boozers of their livers and their memories, and ends the lives of all too many innocents who get smashed on the roads by the inebriated. Yet here the idea of dissuasion within the law is broadly accepted.

A much sounder basis for doubt is the worry that legalisation would increase drug-taking, and that rising consumption and addiction would overwhelm the gains to be had from getting drugs within the law. Yet legalisation should not be taken to mean a lawless free-for-all, with no restraint on the supply or use of drugs. Done properly, it would allow governments to take control of the distribution and quality of these substances away from the criminals. Quality control is decisive, because much of the damage done by drugs bought on street corners is caused by adulterated products; in much the same way, carelessly distilled hooch can cause blindness.

Supply would be regulated by a system of government licences analogous to those already in force for tobacco and alcohol (and which would serve, among other things, to keep drugs out of the hands of children), backed by strict policing and heavy penalties. The toughness of the regime would rise with the addictiveness of the drug in question--a light touch for marijuana, an extremely dissuasive one for heroin.Such legalisation would not magically dispense with the need for policemen, but it would make the needed policing more manageable.

Particularly in the business of softer drugs, where the taxes can be lower and the restrictions less onerous, and where the first trial steps towards legalisation should take place, it would undermine the "risk premium" that provides drug cartels with their profits. Taxes raised on what is reckoned to be the world's largest untaxed industry would help governments spend money on treatment and education, which would do more good than the billions currently spent on attempting to throttle the criminal supply of drugs of all sorts.

The Quest for Soma

There is another consideration, one for the future. The illegality of drugs, coupled with distaste for pleasurable addiction, is skewing research. Progress is being made by scientists in understanding both what causes the pleasure of drugs and what makes the pleasure so hard to give up. Currently such research is obliged to have only one aim--unhooking existing addicts.

It might have another. In many areas of pharmacology, researchers are exploring the idea of "designer drugs", chemicals tailored to fit harmlessly into human biochemistry. Addiction research should be encouraged to do the same: to move beyond devising better therapies for those who wish to kick the drug habit, into the invention of safer, more effective and less habit-forming highs. At the moment it cannot, for a safe drug equals a "substance abuse" equals a crime.

The fact remains that any legal regime which lowers the economic incentive for drugs-crime will surely boost drug consumption. The question is by how much. One possible pointer is that, when asked, people say it will not rise a lot. In opinion polls, Americans generally insist that they would not be persuaded by legalisation to try drugs they are not taking now. There is some reason to believe them, despite the first instinct to be sceptical, since they already have access to plenty of mindbending substances, from alcohol and tobacco to diet pills.

Then there is reassurance from experiments. The American states that decriminalised marijuana during the 1970s saw no divergence in the consumption of the drug from that in neighbouring states which continued to prohibit it. Extensive experience with decriminalisation in Holland shows that not only is there no accompanying surge in consumption--allowing for the inrush of addicts from more restrictive countries--but related crime falls when drugs are legalised.

One further argument is used by defenders of the status quo. They say that, even if the case for exploring legalisation were conceded by governments, public resistance would doom the idea. This is hardly surprising, given the way governments the would over have for decades hammered home the dogma of prohibition. A more rational discussion could do much to change public opinion. Only a few years before alcohol prohibition was repealed in the United States in 1933, public sentiment was similarly dominated by the opinions of the country's prohibitionist leaders.

There are signs that public instincts are changing. In recent months a growing number of federal judges and lawyers have voiced their exasperation with America's approach to drugs. Their objections led politicians in Washington to hold a meeting earlier this month to rethink the country's failed drugs policies. Janet Reno, the attorney-general, started the day be describing her doubts about America's current approach. It ended, significantly, with a discussion of the merits of legalisation. Neither Mr. Brown nor Ms. Reno, and certainly not their boss Mr. Clinton, has so far supported legalisation. But they have done what no American administration has dared do in living memory--set the scene for a proper debate.

Drugs policy: The enemy within

A quiet revolt has been taking place in courtrooms across America. It has been led by judges disillusioned with the country's war on drugs. On April 29th Harold Greene, a prominent federal judge in Washington, ruled that important elements of the mandatory sentencing laws for drugs offenders were unconstitutional. Less than two weeks earlier, two senior federal judges, Jack Weinstein, and Whitman Knapp, of New York, had announced that they would no longer preside over drugs cases. In recent months, a number of federal judges have taken such a stance. It might be a sign, much further down the road, of a change in policy. Lee Brown, the former New York police chief who was appointed as "drug tsar" by Bill Clinton on April 28th, is thought to be a good appointment. Apart from that, Mr Clinton has not done much with drugs policy. Granted, he has been in office a short while, and has had much to occupy him. But his drug-policy staff has been cut, and the budget request he has sent to Congress looks just like the one sent by George Bush. He has asked for much the same amount of money, divided up in the same way: two-thirds of the money to criminal-enforcement efforts, one-third to treatment.

Some had hoped for a change of emphasis. Although the "war on drugs" was first promoted by Richard Nixon in 1972, it was not until George Bush's term that the war began in earnest. Mr Bush appointed though-talking drug tsars and spent $40 billion to attack traffickers abroad and punish pushers and users at home. The result has been disappointing. cocaine is available about as freely and cheaply today as in 1989. Drug-related violence in the cities is still high.The most praiseworthy part of the Bush policy was a drop in overall cocaine-taking. But hard-core addicts, who account for four-fifths of all consumption, are taking as much as ever. Mark Kleiman, of Harvard University, argues that Mr Bush's policies, put in place soon after the peak in cocaine's popularity, did little to affect a decline already under way. Changing fashion (including the recent surge in heroin-taking) probably deserves the credit for that.

If casual consumption of cocaine is down, it may well be the result of education and treatment programmes rather than criminal enforcement. But enforcement has been, and remains, the core of American policy. Presidents, naturally, do not want to be seen to condone the taking of drugs; the public temper is for stiff penalties and the locking up of offenders, not tender care. But the effect of the policy, as the American Bar Association pointed out in a recent report, is that the country's prisons are filled not only with drug-handlers but also with drug-takers, and cannot cope with the numbers. Neal Sonnett, the head of the ABA's criminal-justice section, notes with particular alarm the sharp rise in incarceration of low-level drug offenders, which has hindered efforts to fight more serious, and violent, crime. He thinks the criminal-justice system may be "on the point of collapse". If it is, it will be for reasons to do with overall levels of sentencing for many sorts of crimes, not merely those related to drugs. But such arguments livened up a drugs meeting held in Washington on May 7th to rethink America's policies. At the start of the day Janet Reno, the attorney-general, admitted dissatisfaction with the present emphasis on enforcement efforts, and suggested the mandatory sentencing guidelines might be reviewed. The speech confirmed hints from Mr. Clinton that, despite his status-quo budget, he plants to cut back on enforcement efforts, especially overseas, in favour of trying to reduce demand at home. Another significant aspect of the meeting was the openness of debate. Prohibition was not unquestioningly supported. Ethan Nadelmann, a drugs expert who heads the Princeton Working Group, which is developing alternative ideas to prohibition, notes that legalisation of drugs was given a serious hearing. The way forward, he believes, is towards "harm reduction". Such efforts, like the one supported by Kurt Schmoke, the mayor of Baltimore, build on programmes from parts of Europe and Australia which treat drug-taking not as a criminal matter, but more as an issue of personal choice and public health.

A small chorus has applauded such a shift in resources, arguing that prohibition of drugs will always fail so long as Americans remain so determined to get hold of them. Mr. Clinton, who got himself in plenty of trouble during the campaign for not inhaling marijuana, is unlikely to go that far.

High and hooked

A better understanding of how addictions work could provide benefits for science, for medicine and for recreation

In 1964 Aryeh Routtenberg stuck electrodes into the brains of his experimental rats. The electrodes were so positioned that current flowing though them caused a particular pleasure. For one hour a day, each rat could control this current by means of a lever in its cage. Another lever, which also worked for just that one hour, controlled the food supply. There was no contest between the levers. The rats, too busy mainlining current to stop for food, wasted away to ecstatic death.

The link between pleasure and addiction is not always so extreme, but more mundane addictions have brought about millions of less dramatic deaths outside the laboratory, and caused untold misery and pain. The substances to which people get addicted, though, also bring great pleasure to billions--some addicted, some not. They are the basis of several multi-billion dollar industries around the world. Some 60m Americans smoke tobacco; three-quarters of West European adults drink alcohol; no one knows how many people around the world consume caffeine in tea, coffee or cola. Figures for illegal drugs are harder to come by, but around 2m Americans are thought to take cocaine, and many more than that have smokes marijuana.

Not all the people who indulge in these tastes are addicts--that is, they do not depend on their habit in a way that seems clearly abnormal to the bulk of people who do not share their tastes. Though almost everyone who smokes tobacco is hooked, drinkers are not necessarily alcoholics and not all heroin users are hopeless junkies. Pleasure and the addiction need not come together--either can be present without the other. yet the two are obviously connected. Neuroscientists are now using the tools of molecular biology to find the links between them, deep in the recesses of the brain.

The kick from cocaine

The cerebral nooks and crannies of interest are those between nerve cells--synapses. To jump over the gap between two cells, a nerve impulse has to be translated from electricity to chemicals and back. The first cell releases a chemical called a neurotransmitter into the synaptic gap. These molecules are then picked up by receptor proteins on the surface of the second cell. The neurotransmitter fits the receptor as a key fits a lock. The unlocking of the receptor leads to the creation or suppression of a nerve impulse in the second cell.

There are many different types of neurotransmitter, and thus of synapse; different pathways in the brain need their different properties. It is by subverting some of these synapses, and thus some of the brain's pathways, that drugs produce pleasure. it is through changing them in a more fundamental way that the drugs cause addiction.

The first evidence for this is almost 20 years old. Recently it has started to pile up quite quickly. In 1975 Solomon Snyder, at Johns Hopkins University in Baltimore, Hans Kosterlitz of the University of Aberdeen in Scotland and John Hughes of Parke-Davis, and English pharmaceuticals company, found out how heroin, then drug-du-jour for worried policy-makers, works. Dr. Snyder discovered there was a receptor protein in mammalian brains which heroin would stick to. Dr. Kosterlitz and Dr. Hughes reasoned that nature was unlikely to have produced such a lock without also evolving a key.

Working independently, they found a chemical in the body that fitted into the same receptor as heroin; Dr. Kosterlitz named it "endorphin". This type of neurotransmitter (there are, it turns out, at least three different endorphins) damps down pain by suppressing the signals which transmit it; it also provides feelings of well-being. heroin acts as an ill-fitting key which can open the lock but cannot then be withdrawn. The synapse is over-stimulated. Unusually pleasurable sensations result.

If you replace heroin and endorphins with nicotine and the neurotransmitter acetylcholine, or with caffeine and adenosine, or Valium and gamma-amino butyric acid, or marijuana and anadamide, the same story can be told. Other drugs work in slightly more subtle ways. Alcohol does not mimic a neurotransmitter, but at least some of its effects come from messing up the same synapses that heroin works on. Cocaine, which has replaced heroin as the drug of concern in America, and has thus been extensively researched, works on nerves that use the neurotransmitter dopamine. These nerves are found in, among other places, the mesolimbic system--the part of the brain which seems to generate emotion. Cocaine subverts the pathway not by binding to dopamine receptors, but by sticking to a molecule called, inelegantly, the dopamine re-uptake transporter.

Nerve cells, canny little things, recycle their neurtransmitters. Receptor molecules spit out their neurotransmitters once they have served their purpose, and the cell whence they came mops them up for reuse. Block this re-uptake, and the transmitters will just sit in the synaptic gap, stimulating the receptors again and again and again. Another strategy is to jam the re-uptake system open, so that dopamine flows though it the wrong way all the time, keeping the gap suffused with the neurotransmitter. That is what amphetamines do.

The fact that amphetamines and cocaine work in similar ways will come as no surprise to anyone who has tried both. The nature of the high a drug provides depends on the type of neurotransmitter it interferes with. but the brain is a complex place; the separate systems within it that use different neurotransmitters all interact. A drug acting on one set of synapses can have secondary and tertiary effects all over the place. That is why drug experiences are so varied. The range of things that can be addictive, though, is wider even than the range of available drugs. Foreign bodies in the synapses are not an absolute prerequisite for an addiction. Something as straightforward as healthy exercise can, in the extreme, hook. In the case of exercise it appears that the body becomes addicted to the endorphins it produces to ameliorate the pain and stress.

Other behaviours that carry an intensity with them--and thus presumable overstimulate some parts of the brain's wiring--can produce similar effects, though the synapses involved have yet to be charted. Gambling has many of the characteristics of drug taking--a euphoric high, and a craving in the addict. Some people believe themselves addicted to sex; lawyers in England recently convinced a jury that a teenage hacker was addicted to computing.

It is easy to see some such "addictions" as excuses, especially as the term resists strict definition. But addiction to chemicals is clearly real, and there seems no reason to believe that compulsive chemical-taking is necessarily in a different class from other acquired compulsive habits. Anyway, chemical dependency is easier to study than other sorts. That is why it has been possible to locate the roots of pleasure in the synapses--and why it has been possible to find the roots of withdrawal there, too.

Cold turkey

Clinically, addiction can be characterised by two things: craving and withdrawal. Craving is still the subject of a certain amount of scientific handwaving. The best the psychologists can do is describe the process as one of positive reinforcement--which means that if you like something, you will tend to do it again. Having their receptors overstimulated is something people tend to like a lot. How this "liking" translates into neural circuitry is not yet clear.

Withdrawal, the physical and mental turmoil that follows when an addiction is interrupted, is proving more tractable to experimental analysis. A suggestive picture of how it works can be pieced together, as long as you do not mind taking the pieces from different studies of different drugs: work on cocaine by Nora Volcow at Brookhaven National Laboratory, among others; on cocaine and amphetamines by Bruce Cohen of McLean Hospital in Boston; on heroin by Zvi Vogel at the Weizmann Institute in Rehovot in Israel and Antol Shofelmeer at the Free University in Amsterdam; an on benzodiazepines (such as Valium) by Erick Sigel at the University of Berne.

Again, the synapse is the scene of the action. Most biological systems have feedback mechanisms that help smooth out the little fluctuations that life throws at them. Synapses are no exception. The receiving cell can adjust itself to changes in the behaviour of the transmitting cell in two ways. It can finetune the signal the receptors pass on, and it can change the number of receptors. The receptor molecules are conduits for information, with one end outside the cell and the other inside. When a neurotransmitter attaches itself outside, the part on the inside changes its shape. In this new shape, it can accommodate molecules called G-proteins, which hang around inside the cell. These G-proteins are, themselves, also shape-changers. Interacting with the receptor activates the G-proteins; these then head off to spread the word via yet more molecules, called second messengers.

the second messengers tell the cell about the signal from the neurotransmitters. One part of the cell that listens is the system which sends out and suppresses nerve impulses. Another avid audience is made up of the enzymes which add phosphate groups to proteins, some of which help in the production of impulses. More messages make them more active, and more likely to add phosphate to receptor molecules. A phosphorylated receptor is an unhappy receptor. It is reluctant to accommodate G-proteins and thus to bring information in from the outside. The nucleus, which controls the production of proteins, and also listens to the second messengers. Lots of chatter from them suggests to the nucleus that there are too many receptors at the synapse, so it brings their manufacture to a halt. Insert an addictive drug into the system and the din from the second messengers becomes deafening. The result is fewer receptor molecules. Both the phosphorylation of receptors and their absence means that it takes more of the drug to obtain the same effect. Those high doses, in turn, lead to even less sensitive synapses. And they also lead to synapses that can no longer function without the drug. The cell gets used to damming the flood of drug-induced noise in order to be able to deal with the faint whispers of reality that float on top of it. Remove the drug, and the normal signals can no longer get over the barrier that has been erected. The system goes from getting too much of the neurotransmitter's effects to not enough; heaven turns to hell.

Put this way, the molecular picture seems obvious. It fits with a common experience of addiction, that of needing to do more and more of the drug just to keep from feeling bad. Of course, it cannot be that simple--after all drugs that work on the same neurotransmitter may vary in their addictiveness. And people vary, too, in their susceptibility to addiction. Then again, addictions to substances that affect different types of synapse can be quite similar--and some people seem to be prone to addiction per se, rather than just to have a weakness for a particular substance. And the fact that addiction remains after withdrawal has ended--a fact attested to at Alcoholics Anonymous every day--suggests there is a more general problem to look at.

Dopamine heads

For more evidence that addictions have something in common in the way they act on the brain as a whole, no matter which pathways they stimulate, look at the pictures on this page.

Edythe London, who works at America's National Institute on Drug Abuse, studies glucose metabolism in the brains of people with addictions. Glucose is the body's principal fuel, so its use is a good index of how active an area is. Dr London's pictures show that, in certain parts of the brain, addicts use less glucose than non-addicts do. The difference applies regardless of what drug is being used, and it is still visible when they are not under the influence.

Other clues to a general theory of addiction have led researchers to focus on the dopamine system--even when looking at drugs which do not affect dopamine receptors. There is evidence that many, and possibly all, addictions affect the dopamine cells in the brain's mesolimbic system. In the case of cocaine this effect is direct, which may account for the drug's peculiar potency. for other drugs it seems to be indirect, brought about by connections between the dopamine system and the other neurotransmitter systems.

Inside the dopamine system, the researchers' attention has lighted on D2. it should come as no surprise by now to hear that D2 is a protein found in synapses, one of the three different receptor proteins for dopamine. The detailed make-up of these proteins can vary from person to person--variation that comes from differences in the gene which describes the protein. So the different variants of D2 are inherited.

It was inheritance that led the researchers to D2. In the 1970s a series of Danish studies compared the children and step-children of alcoholic fathers. The former proved more likely to succumb to the same addiction. This, and the evidence that identical twins are more likely to share an alcoholic fate than are non-identical twins, suggested that genes were playing a role. In 1990, to great excitement, Kenneth Blum of the University of Texas at San Antonio, and Ernest Noble of the University of California, Los Angeles, announced that they had found a gene peculiarly common among alcoholics. It described a form of the D2 receptor known as A1.

This was challenged by several researchers, most notably Kenneth Kidd, of Yale. Dr. Kidd points out that different ethnic groups have different frequencies of A1, which could confuse the statistics. Others, convinced by Dr. Blum, Dr. Noble and subsequent work, have suggested that A1 frequencies may actually explain differences in alcoholism between ethnic groups, though this is far from certain. In 1992 George Uhl, of Johns Hopkins, found that a second variant of D2, known as B1, seemed peculiarly common in people addicted to tobacco, cocaine, heroin, tranquillizers, marijuana and amphetamines as well as alcohol--almost the whole list of commonly addictive substances. This is at least as controversial as the original finding; its meaning is not clear, nor is the nature of the difference between the different D2s.

To link small variations in a single protein with the existence of an all-purpose "addictive personality" is to go a long way too far. But there is evidence in one case for a link between personality and withdrawal symptoms--and to link withdrawal symptoms to specific molecules is not too farfetched. About 40% of people prescribed courses of benzodiazepines to treat anxiety or insomnia can suffer some withdrawal symptoms--souped-up versions of the symptoms the drugs are used to treat--after the course of medication is finished. Peter Tyrer, who worked at St. Charles' Hospital in London, has found that the people who suffer withdrawal share not a specific protein, but rather specific personality traits: insecurity, inability to make decisions, an over-reliance on the opinions of others. Spot them, and you can save people from withdrawal.

Better living through chemistry

The links between proteins, the lowly building blocks of the brain, and personalities, the high abstractions of the mind, are undoubtedly going to be convoluted--but evidence from both ends suggests they are there to be found. What are the pharmaceutical companies, to which this should be of interest, doing about it?

Some work is going into drugs to treat drug addiction. Naltrexone keeps heroin from activating endorphin receptors, without activating them itself. Methadone works in the same way as heroin, but less effectively; it thus provides a way off heroin that minimises withdrawal symptoms. Similar approaches to cocaine are being tried. Drugs which act on dopamine pathways in general may have widespread effects on addiction.

but drugs to defeat dependence are not the only possibilities. Some of the damage that comes from drug addiction, especially the physical damage, comes from secondary aspects of the drug. Lung cancer, for examples, is caused by the substances that accompany nicotine in tobacco smoke, not by nicotine itself. It might be possible to get rid of some of these problems without getting rid of the pleasure, even if it is not possible to get rid of the addictions. Another option is to develop tests which could tell people if they were at risk of falling under a particular spell so that they could choose their pleasures wisely.

Eventually, an understanding of neurotransmitters, receptors, G-proteins, and second messengers might allow pleasure and addiction to be decoupled--or at least allow withdrawal to be suppressed. Though, on the face of it, the effects that cause pleasure in the short term are those that cause addiction in the long term, there is a lot of variability in the system that might be exploited. Techniques like those used to target specific dopamine receptors in the treatment of Parkinson's disease, might, at least in principle, be used to fine tune a drug's effects at the synapse and produce low-addiction highs. And pure substances tailored to neurotransmitter sites would have a good chance of being free of unpleasant side effects elsewhere in the body. That would not create a brave new world; it might, perhaps, create a slightly happier one.