Haldol was a wonder drug. Then doctors began to question its safety and efficacy.

From The Mind and the Moon by Daniel Bergner. Copyright © 2022 by Daniel Bergner. Adapted courtesy of Ecco, a division of HarperCollins Publishers.

American science, President John F. Kennedy announced in 1963, would take us to “the remote reaches of the mind” and would discover new ways to medicate our most troubling psychiatric conditions. Such patriotic optimism—and such a clear vision of the physically finite and conquerable nature of our psyches!

In the realm of psychosis, where the mind can be overtaken by alternate realities, by voices and visions and private fears, there seemed to be progress in the post-Kennedy ’60s. Haldol replaced Thorazine as a more potent antipsychotic. The chemical was discovered by Paul Janssen, a Belgian pharmacologist, whose company would soon be bought by Johnson & Johnson. Janssen had just developed an opioid painkiller and was looking for something even stronger. He employed a team of 50 chemists, most of them self-taught and low-paid, and directed them in a simple method: synthesize chemical offshoots of the original painkiller as quickly as possible, inject the new molecules into mice, and see what happens .

One of the molecules—the 45th in the series they concocted—had a curious effect. It didn’t seem to work as a painkiller. This Janssen could tell by measuring the pupils of his rodents when they were placed on a hot metal plate. But while the animals did register pain, they seemed paradoxically unconcerned about it. The chemical put them in a trancelike state, apparently unmotivated to lift their paws. Second after second went by—30 seconds or more ticked past—and the mice stayed where they were on the scorching surface.

The chemical intrigued the pharmacologist. He gave it to Belgian psychiatrists for trial-and-error experiments. It was injected into two alcoholics going through the hallucinations of delirium tremens and then into 18 psych ward patients. “We consider its hallucinolytic action”—its reduction of voices and visions—“to be greater than that of any other neuroleptic,” the psychiatrists wrote, referring to Thorazine and other antipsychotics. But they noted that with the new chemical “Parkinsonism is the norm.” Next, a French psychiatrist who had earlier developed Thorazine tested the new drug. He affirmed its effect on hallucinations but warned about frequent damage to the brain and nervous system. In a French journal, he urged that dosages be kept moderate to lessen the side-effects: a skewed gait, facial rigidity, drooling, torpor, and a range of often irreversible tics, from shoulder-rocking to tongue-thrusting.

If it was used judiciously, psychiatrists now had, it appeared, a better molecule to pit against psychosis. Gradually, though, it was not only the drug’s safety but its efficacy that was questioned. Much later, the Lancet, Britain’s premier medical journal, published an analysis spanning backward over more than half a century’s worth of studies assessing antipsychotics: Haldol didn’t do impressively well—even when its devastating side-effects were left out and the calculation included only addressing psychotic symptoms. And in America, a careful concern for Haldol’s side effects never did prevail. Before Haldol, when Thorazine was the star antipsychotic, Nathan Kline—a luminary in American biological psychiatry, who had won two Lasker Awards for public service in medicine—advised the field that only “massive doses” would bring about successful outcomes. US practitioners heeded his advice on Thorazine and kept right on once Haldol took over. Typical Haldol doses doubled between the mid-’70s and mid-’80s, climbing to levels many times higher than in Europe.

The reasons for this aren’t easy to pin down. Johnson & Johnson denied the dangers, and professional organizations did their part. Right after speaking on Oprah about the risks posed by Haldol, one psychiatrist found himself under investigation, fending off an attempt to revoke his medical license. And psychiatrists likely managed to deceive themselves. A potent medicine is a seductive thing to possess and prescribe. But corporate self-interest and practitioner self-deception aren’t limited to America; they are insufficient explanations for American dosages. Perhaps, then, American culture is especially prone to a faith in cures and a belief that aggressive methods will prove to be remedies, even panaceas.

By the ’90s, Haldol was supplanted by a new generation of antipsychotics, though it remains a drug of choice in emergency rooms, where it is injected involuntarily into agitated or threatening patients and tends to subdue them immediately. Studies have found the new generation of drugs to be only somewhat better than their predecessors, or no better at all. They are helpful for some, with severe side effects for many. There have been no great medical solutions, not for psychosis, not for our more common conditions like depression and anxiety.

Neuroscientist after neuroscientist told me that we have made little to no true progress in medicating our psyches for more than half a century. Eric Nestler, the director of the Friedman Brain Institute at the Icahn School of Medicine at Mount Sinai and one of our country’s preeminent psychiatric researchers, recalled being in medical school, four decades ago, and professors predicting imminent, precisely tailored cures for cancer. Choosing a career in psychiatry, he had felt equal optimism. “And cancer is so dumb-ass simple compared with disorders of the brain,” he said. “We were so naive.”

He talked about the reasons for psychiatry’s frustrated efforts, but one in particular struck me above all. Consider “what philosophers call emergent functions,” he said—“functions that arise as a whole that are not evident in the molecular and cellular constituents of the organ. This occurs only in the brain. In every other organ in the body, the function of the cells matches the function of the organ. Heart cells pump blood. Lung cells add oxygen and remove carbon dioxide. Kidney cells filter the blood. I can cut out a chunk of a kidney, put it in a petri dish, and show you that it does just what it does in the animal. I can show you a single heart cell pumping. The brain is the only organ where this is not so. And that’s what makes it really cool! Brain science is unique in medicine. We need to understand how circuits of cells give rise to a thought, an emotion, a behavior. And this will be extremely difficult to penetrate.”

I asked if it was even possible that we could solve this dilemma about ourselves. I asked if it was even possible to conceived crossing the chasm between the brain and the mind, between the activity of cells and our thoughts and feelings, between physical matter and consciousness, perceived reality, the self. “How do we bridge that divide?”

“That is the crux,” he said. “If I knew how to cross it, I’d be a very special person.”

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