Manufacturing depression

by Gary Greenberg

  Hofmann proceeded the old-fashioned way used by Paul Ehrlich and William Perkin before him—tweaking the compound, mixing together this and that to make new molecules and then seeing if they did something promising in the test tube or to an animal. He eventually invented a way to assay ergot’s presence in animal tissue, discovered its active ingredient, and synthesized it and a series of variations, but no clinical applications emerged. In 1938, he thought he’d found a drug, Lysergsaüre-diäthylamid (lysergic acid diethylamide), or LSD, that would be a good stimulant, but the guys in pharmacology concluded that it had no clinical promise. Five years later, Hofmann wanted to take another crack at convincing them. He whipped up a batch and suddenly found himself feeling unsteady and weak. He thought he was coming down with a cold, so he went home and got into bed, whereupon, as he put it in his report to his boss, he experienced “an uninterrupted stream of fantastic images of extraordinary plasticity and vividness accompanied by an intense kaleidoscopic play of colors.”

  That was on Friday. By Monday, Hofmann had determined a course of action. “I decided to conduct some experiments to find out what was the reason for that extraordinary condition I had experienced,” Hofmann told an interviewer fifty years later. Perhaps because it had been a “not-unpleasant” experience (certainly more pleasant than John Hunter’s self-inoculation with syphilis), he decided to run the experiment on himself.

  At first, he suspected that he had inhaled the solvent he’d used at the end of the synthesis. But when he tried directly exposing himself to it, nothing happened. Then he turned to the LSD. “I was open to the fact that, maybe, some trace of the substance had in some way passed into my body. That, maybe, a drop of the solution had come onto my fingertips and, when I rubbed my eyes, it got into the conjunctival sacs. But, if this compound was the reason for this strange experience I had, then it had to be very, very active.” He decided to proceed with “extreme caution” by taking what he thought was only a tiny dose—a quarter of a milligram.

  Hofmann quickly discovered that he had underestimated LSD. Within forty minutes of swallowing it, he could no longer write in his notebook. (“Beginning dizziness, feeling of anxiety, visual distortions, symptoms of paralysis, desire to laugh” was the last entry he managed to make.) That’s when he decided to go home—by bicycle, because the war was restricting the use of cars. It was a terrifying trip—“Everything in my field of vision wavered and was distorted as if seen in a curved mirror. I also had the sensation of being unable to move from the spot. Nevertheless, my assistant later told me that we had traveled very rapidly”—but that was nothing compared to what happened when he arrived home.

  Every exertion of my will, every attempt to put an end to the disintegration of the outer world and the dissolution of my ego, seemed to be wasted effort. A demon had invaded me, had taken possession of my body, mind, and soul. I jumped up and screamed, trying to free myself from him, but then sank down again and lay helpless on the sofa. The substance, with which I had wanted to experiment, had vanquished me. It was the demon that scornfully triumphed over my will. I was seized by the dreadful fear of going insane. I was taken to another world, another place, another time. My body seemed to be without sensation, lifeless, strange. Was I dying? Was this the transition?

  Hofmann didn’t die. Nor did he go insane, at least not permanently. He did call a doctor, but by the time he arrived, “the horror softened and gave way to a feeling of good fortune and gratitude,” and Hofmann began “to enjoy the unprecedented colors and plays of shapes that persisted behind my closed eyes.” After a few hours, he fell asleep, and the next day awoke

  refreshed, with a clear head, though still somewhat tired physically. A sensation of well-being and renewed life flowed through me. Breakfast tasted delicious and gave me extraordinary pleasure. When I later walked out into the garden, in which the sun shone now after a spring rain, everything glistened and sparkled in a fresh light. The world was as if newly created.

  It didn’t take long for Hofmann’s story, which he wrote up in a report to his boss, to filter back to his colleagues. They were incredulous at Hofmann’s tale, particularly about the possibility that 250 millionths of a gram of anything could wreak such havoc, but then they helped themselves to some LSD. “The effects were still extremely impressive, and quite fantastic,” Hofmann wrote. “All doubts about the statements in my report were eliminated.”

  Sandoz had no idea how LSD worked and no immediately obvious commercial application for it. But by 1947, perhaps because the son of Hofmann’s boss, a psychiatrist, had started experimenting with the drug on himself and his patients, the company saw enough potential to give it a name—Delysid. Psychiatrists soon began receiving samples from Sandoz. Enclosed was a note suggesting that they use it as a psychotomimetic—a drug that would induce “model psychoses” and thus allow firsthand study of the “pathogenesis of mental illness.”

  The recipients wasted no time in investigating LSD. They had all sorts of ideas. They gave it to therapy patients in lower and higher doses and found that a single dose could bring about “spectacular, and almost unbelievable results,” according to one enthusiastic review, “in which an individual comes to experience himself in a totally new way.” They gave it to psychotic people, who didn’t like it much. They gave it to normal people to see if they really became psychotic. Which they did, in a manner of speaking, but not in a way that was terribly helpful to investigators like Max Rinkel, who complained that “subjects appeared more interested in their own feelings and inner experiences than in interacting with the examiner.”

  Rinkel got some of his research money from the CIA, which, upon hearing of LSD had tried to buy up Sandoz’s entire supply—twenty pounds by the agency’s estimate. By then, the suggested dose was around one hundred micrograms, which meant that the CIA thought Sandoz had enough LSD to turn on the entire population of the United States at least once. That wasn’t what the CIA had in mind, of course. They were more interested in driving the entire Soviet Union crazy, or maybe in loosening up captured spies, but in any event, the agents whom they dispatched to Sandoz headquarters in Basel with $240,000 in cash quickly discovered that intelligence estimates about this weapon of mass destruction had been faulty. Sandoz only had 40 grams on hand—a mere 400,000 doses. Not to be deterred, the CIA prevailed upon Indianapolis-based Eli Lilly to provide a homegrown version of LSD, which they provided to experimenters like Rinkel. The Company also funded the dosing of unsuspecting soldiers (one of whom flung himself out a window when he thought he’d gone permanently nuts) and even paid prostitutes to give it to their johns so that agents could observe the results.

  LSD was a failure as a research drug, largely because its effects were so dependent on circumstances. It turned out that patients tripping in hospital beds, surrounded by men in white coats asking them questions and taking notes didn’t have a very good time of it. They failed to achieve the “happy and dreamy feeling of ecstasy” or “seeing something of extraordinary beauty, as it was stated in early reports.” Even worse, “subjects became hostile when treated in a cold, investigative, unsupportive or hostile manner”—in other words, when they were treated as subjects.

  But in the meantime, many doctors were taking Sandoz up on another suggestion the company had sent with the free samples: “By taking Delysid himself, the psychiatrist is able to gain an insight into the world of ideas and sensations of mental patients.” The result wasn’t exactly what Sandoz had in mind. Doctors glimpsed the inner world all right—not their patients’, but their own. And not only doctors. By 1955, LSD had found its way to literary figures like Aldous Huxley, who was so impressed by LSD (and by the mescaline he’d recently taken) that he proposed that it belonged to a new class of drugs. He even suggested a name for it, based on the Greek for “making the soul visible” and announced it in a couplet sent to Humphrey Osmond, a British psychiatrist who was among the first to use LSD therapeutically:

  To make the trivial world sublime />
  Take half a gramme of phanerothyme

  Osmond responded with his own coinage. “To fathom hell or soar angelic,” he wrote back, “take a pinch of psychedelic”—a word that drew on a more familiar Greek word for soul, one that, thanks to psychoanalysis, was much more doctor friendly.

  LSD turned out to be a little too doctor friendly, at least when it came to doctors like Timothy Leary and Richard Alpert, who, starting in the early 1960s, scandalized Harvard University by turning its psychology department into a psychedelic Animal House, terrified parents by urging their kids to “turn on, tune in, and drop out,” and eventually provoked the U.S. government into making LSD illegal, thus bringing scientific research into the drug to a near halt. But there was another, much less famous, doctor, a British pharmacologist named John Gaddum, who took the Delysid challenge. And while Gaddum’s acid trips don’t seem to have changed his life much, let alone the course of American popular culture, his effect on us was in a way more profound than Leary’s.

  If Humphrey Osmond thought that LSD could illuminate the soul, Gaddum had a different idea—that it could illuminate the flesh. Specifically, he thought it could shed light on what serotonin did to blood vessels and how. He wanted to use the drugs in the old-fashioned way: not as a therapy but as a means of investigating how biology works by treating tissue with a substance and watching what happened.

  Like Betty Twarog, Gaddum had gotten samples of serotonin to play with in the early 1950s. He knew about its effects on circulation, and to find out more about them he was introducing other chemicals to animal tissues in tandem with serotonin and comparing the result to what would have happened with serotonin alone. From this he could deduce the chemical properties of serotonin and get a clue about what was going on with blood pressure. Among the drugs he tried was LSD (Gaddum knew that ergot derivatives dampened vasoconstriction), and when he dosed rat uteri with both LSD and serotonin, he found that LSD almost completely blocked the effects of serotonin. It was, in other words, a serotonin antagonist.

  Gaddum wasn’t entirely uninterested in the effect of serotonin on the mind—or at least on the brain. Indeed, he found serotonin in the mammalian brain in May 1952, just a month after (and independently of) Twarog. And in 1953, he began giving LSD to cats and making behavioral observations. “The cats became for a time unreasonable and intolerant,” he wrote, but that wasn’t really the cats’ fault—their eight hundred microgram dose was, on a body weight basis, forty times even Hofmann’s initial huge dose. It was also more than three hundred times the dose Gaddum gave himself in the midst of the cat experiments, on Good Friday 1953. Not much happened, and when he reported on LSD and serotonin to Britain’s Physiological Society a week later, he didn’t mention his own experience. But he did point to a very intriguing convergence of data:

  Lysergic acid diethylamide has a powerful action of the brain…There is evidence that HT [Gaddum’s shorthand for serotonin’s chemical name, 5-hydroxytryptamine] is present in some parts of the brain. The molecular structures of these two substances are similar; lysergic acid contains tryptamine as part of its molecule. This last fact suggested that these two powerful drugs might interact.

  Gaddum wasn’t ready to connect the dots until, in the months after the meeting, he took more LSD, ramping up the dose, and adding a small dose of amphetamine, until he finally “experienced some of the known effects of this drug, such as a feeling of irresponsibility and euphoria.” Soon, he was ready to make quite a bit more of that convergence. If LSD changes the way the brain works and also blocks the action of serotonin, and if serotonin, which is chemically related to LSD, is present in the brain, then it is possible, Gaddum wrote in 1954, “that the mental effects of lysergic acid diethylamide are due to interference with the normal action of this HT.”

  Gaddum remained the careful scientist, letting hang in the air the obvious implication—that serotonin plays an important role in our mental lives. But a couple of his American colleagues, scientists at the Rockefeller Institute in New York whose LSD status is unknown, were less cautious. Gaddum’s work, they wrote in a note at the back of Science in 1954, suggested

  that the mental changes caused by the drugs are the result of a serotonin deficiency which they induce in the brain. If this be true, then the naturally occurring mental disorders—for example, schizophrenia—which are mimicked by these drugs, may be pictured as being the result of a cerebral serotonin deficiency arising from a metabolic failure rather than from drug action.

  It’s hard to overstate just how far out on a limb these scientists were climbing. They really had no idea what serotonin was doing in the brain; some researchers thought it was a waste product. Much more important, the idea that chemicals played a role in the central nervous system was complete heresy. It’s tempting to think that it was LSD itself that led to these bold insights. Gaddum is mostly mum on the subject, his notes about his trip mostly limited to accounts of what happened when he tried to dictate a passage from a book or touch his finger to his nose. (Although he does write—with impressively legible penmanship, given the circumstances—about the way that his hand looked “queer like a monstrous picture of a hand—that writhes about until I fix it with a look.”) But according to his daughter, his experiences were powerful enough to make him think that serotonin was the key to normal mental functioning. This world-in-a-grain-of-sand, everything-fits-together revelation is the signature of the LSD experience, and one researcher who worked with the drug——France’s Jean Thuillier, who administered the drug to patients and took it himself—left no doubt about what he thought inspired this theory:

  We have all had wonderful dreams. At one stroke we thought we knew everything…We had mental illness in microcrystals, delirium in homeopathic suspension. An active, calculated dose of a few hundred million LSD molecules, thrown at our fourteen billion nerve cells,* was the detonator…Surely, the mechanism would be found and dismantled. One day the action of LSD on the neuron was discovered, the next day the action on the barrier between the brain and the meninges, and the following week on nerve transmission…It was thought that everything had been demonstrated.

  On the other hand, all of my nerve cells once sang out in unison to me that I would like hockey. You have to be careful with drug-inspired revelation.

  CHAPTER 9

  GETTING HIGH AND MAKING MONEY

  This chapter is going to be full of words like catecholamine and iminodibenzyl and phenothiazine. I’m not exactly apologizing for this, but I am warning you: this might be a good time to take a stretch and get some coffee or whatever drug you use to stay alert. It will be worth it, because if you get through this stuff, you’ll be prepared when your doctor starts to tell you about your chemical imbalances. You’ll understand what he or she is talking about, where that idea came from, and what its strengths and weaknesses are. And you might even be able to respond to your doctor better than I did when George Papakostas and I talked about these things.

  I performed especially poorly when I told Papakostas about my adventures with mind-altering drugs. The topic came up three times. The second time was when he asked me if I’d had any prolonged remissions, periods when I just didn’t feel depressed. I recounted my MDMA experience and its aftermath. I left out the part about Angel and Grace. You have to know your audience, and I already knew that my Harvard doctor was no Timothy Leary.

  This had become clear in our first conversation on the subject, which took place in the first half hour of our first day together. Your drug-taking habits are an important part of a clinical trial intake interview. Partly that’s because of the possibility of interactions between the study drug and whatever drugs you might be taking on your own initiative. Serotonergic drugs like MDMA and Prozac, for instance, can on rare occasions add up to too much of a good thing, specifically to serotonin syndrome, a condition in which your brain loses control of vital functions like body temperature. You can die that way, and researchers don’t want your blood on their hands.


  But even more important to the clinicians taking your drug inventory is the question of just exactly how sick you are—and with what. The DSM offers them seventeen diagnostic categories to choose from, including substance-related disorders. That section, at 106 pages, is the longest in the 700-page book. That’s not because the doctors who wrote the DSM have something against drug use. Indeed, with substance use disorders as with all diagnoses, they have taken great care to maintain neutrality. For reasons that will become clear in chapter 12, they want to make sure that no one can say that they are pathologizing mere deviance, making value judgments about people’s behavior rather than identifying actual illness.

  In general, this means defining mental disorder as a condition that causes you clinically significant impairment or distress. For the most part, it’s up to you to decide if you are impaired or distressed; a mental illness is an illness only if it is a problem for you. It’s a strange way to think about disease. If a routine chest X-ray inadvertently turns up the fact that I have cancer, I’m still sick whether or not the condition was actually causing me problems before I heard about it; my distress may well begin with the diagnosis. On the other hand, ensuring that the disorder is a problem for you imposes an important safeguard: psychiatrists can’t become gulag commissars by making pathological what they (or their bosses) merely find distasteful or dangerous.