Pubdate: May 1999 Source: Harper's Magazine (US) Copyright: 1999 Harper's Magazine Foundation Contact: 666 Broadway, New York, New York, 10012 Fax: : (212) 228-5889 Website: http://www.harpers.org/ Contact: Joshua Wolf Shenk Note: Joshua Wolf Shenk is a former editor of The Washington Monthly who writes frequently on drug policy, pharmacology, and mental illness. He lives in New York City. AMERICA'S ALTERED STATES Part II In 1912, Merck Pharmaceuticals in Germany synthesized a type of amphetamine, methyllenedioxymethamphetamine, or MDMA. It remained largely unused until 1976, when a biochemist at the University of California named Alexander Shulgin, curious about reports from his students, produced and swallowed 120 milligrams of the compound. The result, he wrote soon afterward, was "an easily controlled altered state of consciousness with emotional and sensual overtones." Shulgin's immediate thought was that the drug might be useful in psychotherapy the way LSD had been. In the two decades after its mind-altering properties were discovered in 1943 by a chemist for Sandoz Laboratories, LSD was widely used as an experimental treatment for alcoholism, depression, and various clinical neuroses. More than a thousand clinical papers discussed the use of LSD among an estimated 40,000 people, and research studies of the drug led to some extraordinary advances including the discovery of the serotonin system. When LSD experiments were restricted in 1962 and again in 1965, Senator Robert Kennedy held a congressional hearing. "If they were worthwhile six months ago, why aren't they worthwhile now?" he asked officials of the Food and Drug Administration and the National Institute of Mental Health. "Perhaps to some extent we have lost sight of the fact that [LSD] can be very, very helpful in our society if used properly." The answer to Kennedy's question was that LSD had leaked out of the universities and clinics and into the hands of "recreational users." It had crossed the line that separates good drugs from bad. LSD was outlawed three years later. In 1970, when a new law devised five categories, or "schedules," of controlled substances, LSD was placed in Schedule I, along with heroin and marijuana. This is the designation for drugs with no accepted medical use and a "high potential for abuse." In 1986, MDMA would be added to that list of demon drugs. The question is: How does a substance get assigned to that category? What separates the good drugs from the bad? In the nineteenth century, now-illegal substances were commonly used in medicine, tonics, and consumer products. (The Illinois asylum that housed Mary Todd Lincoln in the 1870s offered its patients morphine, cannabis, whiskey, beer, and ale. Sigmund Freud treated himself with cocaine-and, for a time at least, praised it effusively-as did William McKinley and Thomas Edison.) A new era began with the federal Pure Food and Drug Act of 1906, which required the listing of ingredients in medical products. Then, the 1914 Harrison Narcotic Act, ostensibly a tax measure, asserted legal control over distributors and users of opium and cocaine. On the surface, this might seem progressive, the story of a still-young nation establishing commercial and medical standards. And there was genuine uneasiness about drugs that were intoxicating or that produced dependence; with the disclosure required by the 1906 act, sales of patent medicines containing opium dropped by a third. But the movement for prohibition drew much of its power from a far less savory motive. "Cocaine," warned Theodore Roosevelt's drug adviser, "is often a direct incentive to the crime of rape by the Negroes." (6) As David Musto reports in The American Disease, the prohibitions of the early part of the century were all, in part, a reaction to inflamed fears of foreigners or minority groups. Opium was associated with the Chinese. In 1937, the Marihuana Tax Act targeted Mexican immigrants. "I wish I could show you what a small marijuana cigarette can do to one of our degenerate Spanish-speaking residents, a Colorado newspaper editor wrote to federal officials in 1936. Even the prohibition of alcohol was underlined by fears of immigrants and exaggerations of the effects of drinking. On the eve of its ban in 1919, a radio preacher told his audience, "The reign of tears is over. The slums will soon be a memory. We will turn our prisons into factories, our jails into storehouses and corncribs. Men will walk upright now, women will smile and the children will laugh. Hell will be forever for rent." But the federal authorities, temperance advocates, and bigots had reached too far. Whereas alcohol (like coffee and tobacco) has been a demon drug in other cultures, in Western societies its use in medicine, recreation, and religious ceremonies stretches back thousands of years. Most Americans had personal experience with drink and could measure the benefits of Prohibition against the violence (by gangsters and by Prohibition agents, who, according to one estimate, killed 1,000 Americans between 1920 and 1930) and the deaths by "overdose." (7) After Franklin Roosevelt lifted Prohibition, subsequent generations knew that the drug, though often abused and often implicated in crimes, violence, and accidents, differs in its effects depending on the person using it. With outlawed drugs, no such reality check is available. People who use illegal drugs without great harm generally stay quiet. Alcohol also can be legally used in medicines, such as Nyquil, or used medicinally in a casual way-say, to calm shattered nerves. Demon drugs, on the other hand, are prohibited or seriously limited even in cases of exceptional need. Forty percent of pain specialists admit that they undermedicate patients to avoid the suspicion of the Drug Enforcement Administration. Their fear is justified: every year about 100 doctors who prescribe narcotics lose their licenses, including, in 1996, Dr. William Hurwitz, a Virginia internist whose more than 200 patients were left with no one to treat them. One of these patients committed suicide, saying in a videotaped message, "Dr. Hurwitz isn't the only doctor that can help. He's the only doctor that will help." Chronic pain, mind you, doesn't mean dull throbbing. "I can't shower," one patient explained to U.S. News & World Report, "because the water feels like molten lava. Every time someone turns on a ceiling fan, it feels like razor blades are cutting through my legs." To ease such pain can require massive doses of narcotics. This is what Hurwitz prescribed. This is why he lost his license. But at least narcotics are acknowledged as a legitimate medical tool. Marijuana is not, despite overwhelming evidence that smoking the cannabis plant is a powerful treatment for glaucoma and seizures, mollifies the effects of AIDS or cancer chemotherapy, and eases anxiety. The editors of The New England Journal of Medicine, the American Bar Association, the Institute of Medicine of the National Academy of Sciences, and the majority of voters in California and six other states (plus the District of Columbia) are among those who believe that these uses of marijuana are legitimate. So does the eminent geologist Stephen Jay Gould. He developed abdominal cancer in the 1980s and suffered such intense nausea from intravenous chemotherapy that he came to dread it with an "almost perverse intensity." "The treatment," he remembers, "seem[ed] worse than the disease itself." Gould was reluctant to smoke marijuana, which, as thousands of cancer patients have found, is a powerful antiemetic. When he did, he found it "the greatest boost I received in all my years of treatment." "It is beyond my comprehension," Gould concluded, "and I fancy myself able to comprehend a lot, including much nonsense-that any humane person would withhold such a beneficial substance from people in such great need simply because others use it for different purposes." This distinction between "people in great need" and those with "different purposes" is crucial to the argument for the medical use of marijuana. (8) Like Gould, many who use marijuana for medical reasons dislike the "high." Many others don't even feel it. But it is a mistake to think that the reason these people can't legally use marijuana is simply that other people use it for purposes other than traditional medical need. Because the very idea of "medical need" is constantly shifting beneath our feet. I do not have cancer or epilepsy, or a disabling mental disorder such as schizophrenia. The "other purposes" Gould refers to are, in many ways, mine. The qualities of my suffering are (to simplify) anxiety, numbness, and anhedonia. If these were relieved by a legal drug-in other words, if a pharmaceutical helped me relax, feel more alive, have fun-I would be firmly in the mainstream of American medicine. This is my strong preference. But when I returned to see Donald Klein this past summer, hoping that new medications might have emerged in the last five years, he told me that "there are lots of things to try but there's only marginal evidence that any of them would do any good." He also made it clear that I shouldn't get my hopes up. "What you have," he said, "is not a common condition, and it's almost impossible [for pharmaceutical companies] to do a systematic study, let alone make money, on a condition that's not common." And so, yes, I turn sometimes to marijuana and other illicit substances for the (limited) relief they offer. I don't merely feel justified in doing so; I feel entitled, particularly since, every year, the pharmaceutical industry rolls out new products for pleasure, vanity, convenience. When Viagra emerged, it was not frowned upon by the authorities that lead the drug wars. Instead, President Clinton ordered Medicaid to cover the drug, and the Pentagon budgeted $50 million for fiscal 1999 to supply it to soldiers, veterans, and civilian employees. Pfizer hired Bob Dole to instruct the nation that "it may take a little courage" to use Viagra. This is a medicine whose sole purpose is to allow for sexual pleasure; it was embraced by the black market and is easily available from doctors, including some who perform liexaminations" via a three-question form on the Internet. But Viagra's legitimacy was never questioned, because it treats a disease-erectile dysfunction. Before Viagra, when the only treatment options were less-effective pills and awkward injection-based therapies, this condition was referred to as impotence. The change in language is interesting. The "dys" sits on the front of dysfunction like a streak of dirt on a pane of glass. At a level more primal than cognitive, we want it removed. This is what we do with dysfunctions: we fix them. Impotence, on the other hand, meaning "weakness" or "helplessness," is something we all experience at one time or another. Applied to men "incapable of sexual intercourse, often because of an inability to achieve or sustain an erection," the word carries a sense of something unfortunate but part of living, and particularly of growing older. Thus the advent of Viagra does not simply treat a disease. It changes our conception of disease. This paradigm shift is a common occurrence but is below our radar. Hair loss becomes a disease, not a fact of life. Acid indigestion becomes a disease, not a matter of eating poorly. If these examples seem to make light of the broadening of disease, the ascent of psychopharmaceuticals makes the issue urgent. Outside the realm of the tangibly physical, the power of drugs and drugmakers is far greater. What we now know as "anxiety disorder," for example, existed only in theory from Freud's time through World War II. In the early 1950s, a drug company polled doctors and found that most had no interest in a medication that treated anxiety. But by 1970, one woman in five and one man in thirteen were using a tranquilizer or sedative, and anxiety was a mainstay of psychiatry. The change could be directly attributed to two drugs, Miltown and Valium, which were released in 1955 and 1963, respectively. The successor to these drugs, Xanax, introduced in 1981, virtually created a disease itself. Donald Klein had already proposed the existence of something called "panic disorder," as opposed to generalized anxiety, some twenty years before. But his theory was widely refuted, and in practice panic anxiety was treated only in the context of a larger problem. Xanax changed that. "With a convenient, effective drug available," writes Peter Kramer, "doctors saw panic anxiety everywhere." Xanax has also become the litmus test for generalized anxiety disorder. "If Xanax doesn't work, instructs The Essential Guide to Psychiatric Drugs, "usually the original diagnosis was wrong." (9) This is not to say that all specific disorders are arbitrary, just that there is a delicate line to be drawn. "The term 'disease'-and the border between health and disease-is a social construct," says Steven Hyman, director of the National Institute of Mental Health. "There are some things we would never argue about, like cancer. But do we call it a disease if you have a few foci of abnormal cells in your body, something that you could live with without any problem? There is a gray zone. With behavior and the brain, the gray zone is much larger." To Hyman's observation, it must be added that, whereas vague dissatisfactions make money for psychic hot lines and interior decorators, diseases make money for pharmaceutical companies. What Peter Kramer calls psychiatric diagnostic creep is not an accident of history but a movement engineered for profit. We have only begun to grapple with the consequences. The example of Prozac has been chewed over, but it's worth chewing still more because it is so typical of a new generation of drugs, which are being used to treat debilitating conditions and also by people with far less serious problems. With Lauren Slater, author of the fine memoir Prozac Diary, we have a case anyone would regard as serious. Suffering from obsessivecompulsive disorder, severe depression, and anorexia, she had been hospitalized five times, attempted suicide twice, and cut herself with razors. Prescribed Prozac in 1988, she found the drug a reprieve from a lifetime sentence of serious illness-"a blessing, pure and simple," she writes. The patients described in Peter Kramer's Listening to Prozac are quite unlike Lauren Slater. They share, he writes, "something very much like 'neurosis,' psychoanalysis's umbrella term for the mildly disturbed, the near-normal, and those with very little wrong at all." The use of Prozac for these patients is not incidental; they make up a large portion, probably a wide majority, of people on the drug. (One good indication is that only 31 percent of antidepressant prescriptions are written by psychiatrists.) Throughout his book, Kramer flirts with "unsettling" comparisons between Prozac and illegal drugs. Since Prozac can "lend social ease, command, even brilliance," for example, he wonders how its use for this purpose can "be distinguished from, say, the street use of amphetamine as a way of overcoming inhibitions and inspiring zest." The better comparison, I suggested in a conversation with Kramer, is between Prozac and MDMA. Both drugs work by increasing the presence of serotonin in the brain. (Whereas Prozac inhibits serotonin's reuptake, MDMA stimulates its release.) Both can be helpful to the seriously ill as well as to people with more common problems. Most of the objections to MDMA-that it distorts "real" personality, that it rids people of anxiety that may be personally or socially useful, that it induces more pleasure than is natural have also been marshaled against Prozac. Both these drugs challenge our definitions of normalcy and of the legitimate uses of a mind-altering substance. Yet Kramer rejects the comparison. "The distinction we make," he told me, "is between drugs that give pleasure directly and the drugs that give people the ability to function in society, which can indirectly lead to pleasure. If the medication can make you work well or parent well, and then through your work or parenting you get pleasure, that's fine. But if the drug gives you pleasure by taking it directly, that's not a legitimate use." (Viagra, because it allows men to experience sexual pleasure, falls on the side of legitimacy. But, Kramer said, a drug that directly induced an orgasm would not.) The line between therapeutic and hedonistic pleasure, however, is awfully hard To draw. I think of a friend of mine who uses MDMA a few times a month. His is a textbook case of "recreational" use. He takes MDMA on weekends, in clubs, for fun. He is not ill and is not in psychotherapy. But he will live for the rest of his life in the shadow of a traumatic experience, which is that for more than two decades he hid his homosexuality. Some might say the drug is an unhealthy escape from "the real world, that the relaxation and intimacy he experiences are illusory. But these experiences give him a point of reference he can use in a "sober" state. His pleasure from the drug is entirely social-being and sharing and loving with other people. Is this hedonistic? "I found it astonishing," Kramer writes of Prozac, "that a pill could do in a matter of days what psychiatrists hope, and often fail, to accomplish by other means over a course of years: to restore to a person robbed of it in childhood the capacity to play." Perhaps I would find restrictions on MDMA more reasonable if they at least carved out an exception for therapeutic use. Keep in mind, that's where this drug started. After Shulgin's experiment word spread, and thousands of doses were taken in a clinical setting. As with LSD, MDMA was seen not as a medicine but as a catalyst to be taken just a few times-or perhaps only once-in the presence of a therapist or "guide." The effects were impressive. Many users found their artifice and defenses stripped away and long-buried emotions rising to the surface. The drug also had the unusual effect of increasing empathy, which helped users trust their therapists crucial characteristic of effective healing-and also made it useful in couples therapy. In a collection of first-person accounts of therapeutic MDMA use, Through the Gateway of the Heart, published in 1985, a rape victim described working through her fears. Another woman described revelations about her son, her weight problems, and "why angry men are attracted to me." I can hear the skeptics shuffling their feet, wanting data from double-blind controlled trials. But MDMA research never reached that stage. Mindful of what had happened with LSD, the therapists, scientists, and other adults experimenting with MDMA tried to keep it quiet. Inevitably, though, word spread, and a new mode of use sprang up at raves, in dance clubs, in dorm rooms. An astute distributor of the drug renamed it Ecstasy to emphasize its pleasurable effects. ("'Empathy' would be more appropriate," he said later. "But how many people know what that means?") ? (10) As the DEA moved to restrict MDMA, advocates of its medical use flooded the agency with testimony, pleading for a chance to subject the drug to methodical study. The agency's administrative-law judge, Francis Young, saw merit in this argument. In a ninety-page decision handed down in 1986, he recommended that the drug be placed in Schedule III, which would allow for it to be prescribed by doctors and tested further. Young cited its history of "currently accepted medical use in treatment in the United States" and argued that "the evidence of record does not establish that ... MDMA has a 'high potential' for abuse." DEA officials overruled Young and placed MDMA in Schedule I, with the assurance that its decision would be self-fulfilling. A Schedule I substance cannot be used clinically and can be studied only with great difficulty. So medical use is essentially forever impossible. That leaves illicit use, which, by one common definition, is the abuse for which Schedule I drugs have a "high potential." Since then, government-funded researchers have sought to document MDMA's dangers. Here we come to the truth about the line and how it is maintained. With rare exceptions, everything we know about legal drugs comes from research sponsored by the pharmaceutical industry. Naturally, this work emphasizes the benefits and downplays the accompanying risks. On the other hand, the National Institute on Drug Abuse, which funds more than 85 percent of the world's health research on illegal drugs, emphasizes the dangers and all but ignores potential benefits. One recent NIDA-funded study on MDMA was widely reported last fall. Dr. George Ricaurte found, in fourteen men and women who had used MDMA 70 to 400 times in the previous six years, "long-lasting nerve cell damage in the brain." Specifically, Ricaurte found decreases in the number of serotonin-reuptake sites. The study begs three major questions. First, do its conclusions really reflect the experience of heavy MDMA users? British physician Karl Jansen reports that he referred MDMA users who had taken more than 1,000 doses and that "they were told by Ricaurte that they had a clean bill of health" but were excluded from his study. Second, should the brain changes Ricaurte found be called "damage," given that a number of psychiatric medications, Prozac and Zoloft among them, decrease the number of serotonin receptors by blockading them? As psychopharmacologist Julie Holland writes, "This could be interpreted as an adaptive response as opposed to a toxic or 'damaged' response." Third, do Ricaurte's findings have any bearing on the use of MDMA in therapy, which calls for a handful of doses over many months? In this climate, it's hard to know. Charles Grob, a psychiatrist at Harbor-UCLA Medical Center in Los Angeles, has been trying to restart MDMA research for eight years. He received FDA approval to conduct Phase I trials on human volunteers, to see if MDMA is safe enough to be used as a medicine. But even with his impeccable credentials, the backing of a prestigious research hospital, and an extremely conservative protocot-involving terminal patient, Grob has faced a seemingly interminable wait for permission to begin Phase II, in which he would study efficacy. Grob's struggle explains why he has little company in the research community. "When you have a drug that's popular among young people," Grob says, "that's the kiss of death when it comes to exploring its potential utility in a medical context." There is another "kiss of death": lack of interest from industry. I asked Lester Grinspoon, a professor of psychiatry at Harvard Medical School, who led the legal challenge to the DEA's scheduling decision, whether he had approached drug companies about supporting the effort. "We didn't even consider it," he said. "No drug company is going to be interested in a drug that's therapeutically useful only once or twice a year. That's a no-brainer for them." When you see the feelgood ads from the Pharmaceutical Research and Manufacturer's Association with the tag line "Leading the way in the search for cures," keep in mind that cures-conditions in which medication is no longer required-are not particularly high on the pharmaceutical companies' priority list. Market potential isn't the only factor explaining the status of drugs, but its power shouldn't be underestimated. The principal psychoactive ingredient of marijuana, THC, is available in pill form and can be legally prescribed as Marinol. A "new" creation, it was patented by Unimed Pharmaceutical and is sold for about $15 per 10-mg pill. Marinol is considered by patients to be a poor substitute for marijuana, because doses cannot be titrated as precisely and because THC is only one of 460 known compounds in cannabis smoke, among other reasons. But Marinol's profit potential-necessary to justify the up-front research and testing, which can cost upward of $500 million per medication-brought it to market. Opponents of medical marijuana claim that they simply want all medicines to be approved by the FDA, but they know that drug companies have little incentive to overcome the regulatory and financial obstacles for a plant that can't be patented. The FDA is the tail, not the dog. The market must be taken seriously as an explanation of drugs' status. The reason is that the explanations usually given fall so far short. Take the idea "Bad drugs induce violence." First, violence is demonstrably not a pharmacological effect of marijuana, heroin, and the psychedelics. Of cocaine, in some cases. (Of alcohol, in many.) But if it was violence we feared, then wouldn't we punish that act with the greatest severity? Drug sellers, even people marginally involved in a "conspiracy to distribute," consistently receive longer sentences than rapists and murderers. Nor can the explanation be the danger of illegal drugs. Marijuana, though not harmless, has never been shown to have caused a single death. Heroin, in long-term "maintenance" use, is safer than habitual heavy drinking. Of course, illegal drugs can do the body great harm. All drugs have some risk, including many legal ones. Because of Viagra's novelty, the 130 deaths it has caused (as of last November) have received a fair amount of attention. But each year, anti-inflammatory agents such as Advil, Tylenol, and aspirin cause an estimated 7,000 deaths and 70,000 hospitalizations. Legal medications are the principal cause of between 45,000 and 200,000 American deaths each year, between I and 5.5 million hospitalizations. It is telling that we have only estimates. As Thomas J. Moore notes in Prescription for Disaster, the government calculates the annual deaths due to railway accidents and falls of less than one story, among hundreds of categories. But no federal agency collects information on deaths related to legal drugs. (The $30 million spent investigating the crash of TWA Flight 800, in which 230 people died, is six times larger than the FDA's budget for monitoring the safety of approved drugs.) Psychoactive drugs can be particularly toxic. In 1992, according to Moore, nearly 100,000 persons were diagnosed with "poisoning" by psychologically active drugs, 90 percent of the cases due to benzodiazepine tranquilizers and antidepressants. It is simply a myth that legal drugs have been proven "safe." According to one government estimate, 15 percent of children are on Ritalin. But the long-term effects of Ritalin-or antidepressants, which are also commonly prescribed-on young kids isn't known. "I feel in between a rock and a hard place," says NIMH director Hyman. "I know that untreated depression is bad and that we better not just let kids be depressed. But by the same token we don't know what the effects of antidepressants are on the developing brain.... We should have humility and be a bit frightened." These risks are striking, given that protecting children is the cornerstone of the drug wars. We forbid the use of medical marijuana worrying that it will send a bad message. What message is sent by the long row of pills laid out by the school nurse-or by "educational" visits to high schools by drugmakers? But, you might object, these are medicines-and illegal drug use is purely hedonistic. What, then, about illegal drug use that clearly falls under the category of self-medication? One physician I know who treats women heroin users tells me that each of them suffered sexual abuse as children. According to University of Texas pharmacologist Kathryn Cunningham, 40 to 70 percent of cocaine users have preexisting depressive conditions. This is not to suggest that depressed people should use cocaine. The risks of dependence and compulsive use, and the roller-coaster experience of cocaine highs and lows, make for a toxic combination with intense suffering. Given these risks, not to mention the risk of arrest, why wouldn't a depressed person opt for legal treatment? The most obvious answers are economic (many cocaine users lack access to health care) and chemical. Cocaine is a formidable mood elevator and acts immediately, as opposed to the two to four weeks of most prescription antidepressants. Perhaps the most important factor, though, is cultural. Using a "pleasure drug" like cocaine does not signal weakness or vulnerability. Self-medication can be a way of avoiding the stigma of admitting to oneself and others that there is a problem to be treated. Calling illegal drug use a disease is popular these days, and it is done, I believe, with a compassionate purpose: pushing treatment over incarceration. It also seems clear that drug abuse can be a distinct pathology. But isn't the "disease" whatever the drug users are trying to find relief from (or flee)? According to the Pharmaceutical Research and Manufacturer's Association, nineteen medications are in development for "substance use disorders." This includes six products for "smoking cessation" that contain nicotine. Are these treatments for a disease or competitors in the market for longterm nicotine maintenance? Perhaps the most damning charge against illegal drugs is that they're addictive. Again, the real story is considerably more complicated. Many illegal drugs, like marijuana and cocaine, do not produce physical dependence. Some, like heroin, do. In any case, the most important factor in destructive use is the craving people experience craving that leads them to continue a behavior despite serious adverse effects. Legal drugs preclude certain behaviors we associate with addictionlike stealing for dope money-but that doesn't mean people don't become addicted to them. By their own admissions, Betty Ford was addicted to Valium and William Rehnquist to the sleeping pill Placidyl, for nine years. Ritalin shares the addictive qualities of all the amphetamines. "For many people," says NIMH director Hyman, explaining why many psychiatrists will not prescribe one class of drugs, "stopping short-acting high-potency benzodiazepines, such as Xanax, is sheer hell. As they try to stop they develop rebound anxiety symptoms (or insomnia) that seem worse than the original symptoms they were treating." Even antidepressants, although they certainly don't produce the intense craving of classic addiction, can be habit forming. Lauren Slater was first made well by one pill per day, then required more to feel the same effect, then found that even three would not return her to the miraculous health that she had at first experienced. This is called tolerance. She has also been unable to stop taking the drug without "breaking up." This is called dependence. "'There are plenty of addicts who lead perfectly respectable lives, Slater's boyfriend tells her. To which she replies, "'An addict .... You think so?"' - --- MAP posted-by: Don Beck