Manufacturing depression (24 page)

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.

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.