The Promise and Perils of Brain Research

Scientific expertise should determine the direction of brain research.

Posted June 3, 2026 | Reviewed by Monica Vilhauer Ph.D.

A common theme traceable back at least 2,000 years holds that neuropsychiatric illnesses are the result of an excess of substances (humors) within the body. Black bile was considered responsible for melancholia ( depression ); yellow bile produced a choleric explosive temperament; excess of blood led to a sanguineous confident disposition; and phlegm induced inactivity and passivity. This humeral theory was responsible for various diagnoses and treatments (like bloodletting) up until the mid-nineteenth century.

With the advent of early medications aimed at various symptoms and signs of mental illness ( psychopharmacology ), belief in the causative effects of substances in the body as the cause of various mental illnesses waned. Fortunately, it persisted long enough to stimulate the discovery of one of the most powerful psychotropic agents in history.

The Discovery of Lithium for Bipolar Disorder

The lithium story started in the late 1940s when an Australian psychiatrist, John Cade, formulated a hypothesis about manic depression , an illness that we now refer to as bipolar disorder, typically marked by periods of depression alternating with episodes of mania . Cade believed in the existence of a “toxin” circulating in the blood of patients suffering from the manic phase of bipolar disorder. Secondary to his belief, he hit upon the idea of injecting urine from manic patients into guinea pigs. He postulated that the toxin circulating within the manic patient and then excreted in the urine would have deadly consequences if the urine from the manic patient were injected into a test animal. Cade’s hunch seemed to bear fruit. While concentrated urine from any source would kill a guinea pig if given in sufficient quantities, the urine from a manic patient killed more quickly and at about one-third of the dose.

One of Cade’s findings was that uric acid, a component of urine, exerted an enhancing effect on the toxic action of another component of urine, urea. In order to study this further, Cade came up with a solution containing lithium that could dissolve the uric acid crystals. When the guinea pigs were injected with lithium citrate or carbonate, the toxicity was reduced. Intrigued, Cade shifted his attention to lithium.

“It appeared that the lithium ion may have been exerting a protective effect,” he wrote at the time.

Cade’s idea was bizarre and seemed unlikely, since lithium is present in the universe in only small quantities in comparison with its chemical relatives, sodium, potassium, magnesium and calcium. From the viewpoint of pure probability, therefore, lithium seemed an unlikely candidate for altering the toxicity of the alleged agent in the blood, which Cade believed was responsible for the mood alterations of manic patients.

When he injected large doses of pure lithium carbonate into the guinea pigs, he observed that instead of exhibiting their usual frantic behavior, they “merely lay there and gazed placidly back at the experimenter.” At this point, Cade medicated himself with lithium carbonate, thus determining that it did not exert any harmful effects on humans. He then tried it on several manic patients whose responses exceeded Cade’s grandest expectations. By the fifth day of treatment, a 51-year-old man confined for 5 years while suffering from chronic manic excitement became calmer. Within weeks, he was well enough to be discharged from the psychiatric hospital.

Micro Doses of Lithium

In the second decade of the twenty-first century, lithium at much smaller doses than employed by Cade is proving a promising element in mental and cognitive health. Although most of us have only encountered lithium in school as a component of the periodic table, trace amounts can be found in groundwater and plant foods such as legumes, leafy greens, and root vegetables.

Intriguingly, the rejuvenating spas and miracle springs of the nineteenth century, attended by wealthy health enthusiasts, contained generous amounts of lithium. The beneficial effects of lithium on the general population were scientifically confirmed in 2026, when higher naturally occurring lithium concentrations in local drinking water were found to correlate with significantly lower suicide rates.

Equally fascinating are recent findings that among people with mild cognitive impairment , the administration of low doses of lithium slows the decline in verbal memory , decreases brain inflammation, and increases synaptic integrity. When lithium is administered in trace nutritional doses, the structural integrity of neurons and their supporting layers are preserved.

If we think of lithium as promoting brain integrity at the macromolecular level—the manic patient composed of billions of molecules—a similar effect is happening much further down at the micromolecular level of the brain cell “Lithium can be more fully understood not simply as a pharmacologic agent, but as a biologically relevant regulator of the neuroimmune and metabolic systems that underpin cognitive stability and long-term brain resilience ” according to James M. Greenblatt , one of the current proponents of lithium as a key element in the ongoing paradigm shift within neuropsychiatry towards the brain’s microenvironment.

Lessons From the History of Lithium in Psychiatry

Lithium’s bimodal rise in eminence (1940s and 2020s) among mind-altering substances illustrates two principles in brain research:

Solid research findings can emerge even when based on mistaken initial assumptions. Neither Cade nor anyone before or after him has ever demonstrated a toxin in the blood of bipolar patients responsible for their illness. From a literal perspective, therefore, Cade was engaged on a fool’s errand when he made his paradigm-shattering discovery.
The reasoning underlying research pathways—even those based on an incorrect initial premise—can ricochet like a pinball striking random and unpredictable targets, as illustrated by John Cade’s research.

Unfortunately, current proposals about federal research grants for current and future research are out of sync with how scientific research is actually conducted. Just this week, the Office of Management and Budget (OMB) proposed that research proposals be reviewed by “senior political appointees” (not scientists or researchers) in order to “ensure grant awards conformed to administrative priorities and executive orders”.

If such a proposed rule existed at the time of John Cade, the efficacy of lithium would never have been discovered.

As illustrated by John Cade’s scientific discovery of lithium’s powerful effects, research sometimes progresses along inscrutable pathways, bringing beneficial results that are not always anticipatable.

Richard M. Restak, M.D.

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Richard Restak, MD , is Clinical Professor of Neurology at George Washington University School of Medicine and Health Sciences, and the author of The 21st Century Brain.

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This article is part of the Bringwise Psychology Journal — daily insights on human behavior, mental health, and personal growth.