Don’t Mess With Dopamine: The Truth About The “Happiness Hormone”

Martha Saraska
Posted on October 11, 2022

Google the word “dopamine” and you’ll learn that its nicknames are the “happiness hormone” and the “pleasure molecule” and that it’s one of the most important chemicals in our brain. With The Guardian’s branding as “Kim Kardashian the neurotransmitter,” dopamine has become a true darling of pop science — people around the world have tried to improve their mood with dopamine fasting and dopamine dressing.

A century ago, however, the newly discovered dopamine was considered an uninspiring chemical, nothing more than a precursor to norepinephrine. It took some persistent and diligent scientists to change this view.

Levodopa: An indifferent precursor

When Casimir Funk, a Polish biochemist and discoverer of vitamins, first synthesized the dopamine precursor levodopa in 1911, little did he know how important the molecule would prove to be in pharmacology and neurobiology. Neither was Markus Guggenheim, a Swiss biochemist who isolated levodopa from the seeds of a broad bean, Vicia faba, in 1913. Guggenheim administered 1 g of levodopa to a rabbit with no apparent ill effects. He then prepared a larger dose (2.5g) and tested it on himself. “Ten minutes after taking it, I felt very nauseous and vomited twice,” he wrote in his paper. In the body, levodopa is converted to dopamine, which can act as an emetic—an effect Guggenheim didn’t understand. He simply broke off his studies on humans and, based on his animal experiments, wrongly concluded that levodopa was “rather pharmacologically indifferent”.

Around the same time, several scientists across Europe were successfully synthesizing dopamine, but these discoveries were shelved with little fanfare. Over the next three decades, dopamine and levodopa were relegated to academic obscurity. Just before World War II, a group of German scientists showed that levodopa is metabolized to dopamine in the body, while another German researcher, Hermann Blaschko, discovered that dopamine is a mediator in the synthesis of norepinephrine. However, these findings were not immediately accepted either.

The dopamine story picked up steam in the post-war years when the hormone was observed to be present in various tissues and bodily fluids, though nowhere more abundant than in the central nervous system. Intrigued was Blaschko, who (after fleeing Nazi Germany, changing his name to Hugh and beginning his work at Oxford University) hypothesized that dopamine could not be an inconspicuous precursor to norepinephrine—it must have some physiological functions of its own . He asked his postdoc Oheh Hornykiewicz to test some ideas. Hornykiewicz soon confirmed that dopamine lowered blood pressure in guinea pigs, proving that dopamine did indeed have a physiological activity independent of other catecholamines.

reserpine and rabbit ears

While Blaschko and Hornykiewicz puzzled over the physiological role of dopamine in the body, across the ocean at the National Heart Institute in Maryland, pharmacologist Bernard Brodie and colleagues were laying the groundwork for the discovery of dopamine’s primary role in the brain.

Spoiler alert: Brodie’s work showed that a new psychiatric drug called reserpine was able to block the serotonin and ? of paramount importance, as it turned out – mimicking the neuromuscular symptoms typical of Parkinson’s disease. The connection to dopamine would be made by new lab colleague Arvid Carlsson, who would go on to win a Nobel Prize.

Derived from Rauwolfia serpentina (a plant used in India for centuries to treat mental illness, insomnia, and snakebite), reserpine was introduced to the West to treat schizophrenia.

It has worked wonders. In 1954, the press praised the “dramatic” and seemingly “incredible” results in treating “hopelessly insane patients.” However, reserpine had a downside. Reports of the drug’s severe side effects soon changed tone, including headaches, dizziness, vomiting and, far more disturbingly, symptoms mimicking Parkinson’s disease, ranging from muscle stiffness to tremors.

Brodie observed that the animals became completely immobile after the injection of reserpine. Serotonin almost disappeared from their brains, but oddly, drugs that boost serotonin production couldn’t reverse the rabbits’ immobility.

Carlsson realized that other catecholamines must be involved in reserpine’s side effects, and he began looking for the culprits. He moved back to his native Sweden and ordered a spectrophotofluorimeter. In one of his experiments, Carlsson injected a pair of rabbits with reserpine, causing the animals to become catatonic with flattened ears. After the researchers injected the animals with levodopa over a period of 15 minutes, the rabbits hopped around, ears proudly pricked up. “We were just as excited as the rabbits,” Carlsson later recalled in a 2016 interview. Carlsson realized that dopamine depletion must have been directly responsible for the motor inhibitory effects of reserpine since norepinephrine was not present in the rabbits’ brains.

Skeptics are silenced

In 1960, however, the medical community wasn’t ready to accept that dopamine was anything but a boring intermediate between levodopa and norepinephrine. At a prestigious London symposium, Carlsson and his two colleagues presented their hypothesis that dopamine might be a neurotransmitter, linking it to Parkinson’s disease. They met with harsh criticism. Some of the experts said levodopa is nothing more than a poison. Carlsson later recalled that he faced “a deep and almost unanimous skepticism about our positions”.

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That would change soon. Hornykiewicz, the biochemist who previously discovered dopamine’s blood pressure-lowering effects, tested Carlsson’s ideas on the postmortem brains of Parkinson’s patients. Carlsson seemed right: Unlike healthy brains, the striatum of patients with Parkinson’s disease contained almost no dopamine. Beginning in 1961, Hornykiewicz, in collaboration with neurologist Walther Birkmayer, injected levodopa into 20 patients with Parkinson’s disease and observed a “miraculous” (albeit temporary) improvement in stiffness, immobility, and speechlessness.

In the late 1960s, levodopa and dopamine made headlines. A 1969 New York Times article described similar amazing improvements in patients with Parkinson’s disease who were treated with levodopa. A patient arriving at a hospital unable to speak, with clenched hands and a frozen expression, was suddenly able to stride to his doctor’s office and even jog around. “I could say I’m human,” he told reporters. Although the treatment was expensive — the equivalent of $210 in 2022 — doctors were inundated with requests for “dopa.” To date, levodopa remains a gold standard in the treatment of Parkinson’s disease.

Still misunderstood

However, the history of dopamine does not only affect Parkinson’s disease, but also extends to the treatment of schizophrenia and addiction. When a French military surgeon began giving soldiers undergoing surgery a new antihistamine, promethazine, to prevent shock in the 1940s, he noticed a bizarre side effect: the soldiers became euphoric and strangely calm at the same time.

After the drug was modified by adding a chlorine atom and renamed chlorpromazine, it quickly became a popular treatment for psychosis. Back then, nobody made the connection to dopamine. Contemporary doctors believed that it calmed people down by lowering body temperature (common treatments for mental illness at the time included wrapping patients in cold, wet sheets). However, just like reserpine, chlorpromazine produced a number of unpleasant side effects that were very similar to Parkinson’s disease. This led a Dutch pharmacologist, Jacques van Rossum, to hypothesize that dopamine receptor blockade might explain the antipsychotic effects of chlorpromazine—an idea that is still widely accepted today.

In the 1970s, research in rodents linked dopamine to addiction, and this novel idea captured people’s imaginations for decades to come. A story about dopamine entitled “How We Get Addicted” made the cover of Time in 1997.

But as the connection between dopamine and addiction became widespread, it also became oversimplified. According to a 2015 article in Nature Reviews Neuroscience, a wave of low-quality research — unreplicated, inadequate — followed, leading the authors to conclude that we are “addicted to the dopamine theory of addiction.” Almost every pleasure under the sun has been attributed to dopamine, from eating delicious food and playing computer games to sex, music and hot showers. However, as recent science shows, dopamine isn’t just about pleasure—it’s about reward prediction, response to stress, memory, learning, and even immune system function. Since it was first synthesized in the early 20th century, dopamine has often been misunderstood and oversimplified—and it seems like history is now repeating itself.

In one of his last interviews, Carlsson, who died in 2018 at the age of 95, warned against messing around with dopamine and in particular prescribing drugs that act as an inhibitor to this neurotransmitter. “Dopamine is involved in everything that happens in our brain — all of its important functions,” he said.

We should be careful how we deal with such a delicate and still little known system.

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