Health & Medicine / Nutrition

Like Kaplan, Popper gradually began giving the formula to bipolar patients who had not done well on psychotropic drugs. The supplement not only worked for 80 percent of the patients, it also took effect far more quickly than conventional drugs for many of them. After testing the supplement for six months and seeing improvements in some two dozen patients, Popper decided he had something noteworthy enough to share with colleagues. In 2001 he and Kaplan each published articles in The Journal of Clinical Psychiatry describing their findings and encouraging further research. “What if some psychiatric patients could be treated with inexpensive vitamins and minerals rather than expensive patented pharmaceuticals?” Popper wrote. It was a strikingly optimistic statement about a discredited idea. “I knew going public would raise a lot of eyebrows, that I was putting my career on the line,” Popper says. “But I was convinced.”

One reason that orthomolecular psychiatry was treated with such derision in the 1960s and early ’70s was that biologists had only a faint understanding of the physical effects that nutrients had on the brain. In the past two decades, however, researchers have begun to gain a better understanding of the brain’s biochemical machinery. Psychiatrists now know that nutrients are the brain’s backstage crew, endlessly constructing and maintaining cellular set designs, directing players to their marks. They also play important roles in the creation of chemical messengers thought to mediate mood, such as serotonin, dopamine, and norepinephrine. Zinc is a particularly versatile player, involved in more than 300 enzymatic reactions; when zinc goes missing, a cell’s DNA and its repair machinery can be damaged.

Neuroscientist Bryan Kolb, at the Canadian Centre for Behavioural Neuroscience in Lethbridge, Alberta, has explored how brain cells are affected by drugs, hormones, and injury. When Stephan and Hardy first approached him in 1997, he politely declined to start up a study. He had little psychiatric expertise, he explained, and his usual experimental subjects had four legs and long tails.

Two years ago, Kolb decided to take another look. In an effort to tease out a biochemical pathway that might account for the clinical effects that Kaplan, Popper, and others had described, he ran a series of rat studies. First, he inflicted injuries in two parts of infant rats’ brains: the frontal lobe, which controls motor function and the ability to plan and execute tasks, and the parietal lobe, which influences spatial functions. Half the group then got a diet spiked with a supplement similar to EMPowerplus and half got plain rat chow. When Kolb put them through a series of cognitive and spatial-ability tests, the vitamin-charged rats did markedly better than the control group.

Kolb noticed something else about the supplement-fed rats: “They were unbelievably calm.” Lab rats usually flinch and squeal when identification tags are stapled onto their ears, he says. “These rats acted like nothing had happened.” Kolb then autopsied the rats’ brains: The formula-fed rats had bigger brains than the chow-fed rats. In areas near where he’d inflicted lesions, the dendrites of the existing cells—the long, tentacled parts of neurons that conduct electrical impulses—had sprouted new branches, each ending with hundreds of new synapses. (In an earlier study, Kolb had found that the amino acid choline could also stimulate dendritic growth. But the results weren’t as pronounced.)

Kolb can’t say if such neural connections could alleviate  mental illness. Schizophrenia may be associated with structural abnormalities in the brain, but so far that’s not thought to be the case in mood disorders like depression or bipolar disorder. Whatever the mechanism, Kolb says, he’s persuaded that “the diet can clearly alter brain function.”

Of course, not everyone with a vitamin deficiency grows violent or sinks into a clinical depression. So why might a nutritional supplement help only some people? Kaplan has a possible explanation: Some of us have “inborn errors of metabolism.” We are born with unusual nutritional requirements that can affect our mental function. Mental illness appears to be partly heritable (bipolar disorder, for one, runs in families), yet no one has discovered a gene for the disease. Perhaps, Kaplan speculates, what’s passed down is a gene that affects the metabolic pathways influenced by various nutrients. Some people may simply inherit a metabolism that demands higher-than-normal amounts of vitamins and minerals. “What’s optimal for me may not be optimal for someone with a mental illness,” Kaplan said at a meeting of the American Psychiatric Association in 2003. “I’ve been blessed with a stable mood, and I could probably eat a terrible diet and not have any problems. Others may need additional supplementation.”

The next research step should be a controlled randomized trial of how bipolar patients taking supplements fare compared with those taking a placebo. Such studies are the gold standard for testing drugs and supplements. But Kaplan and Popper’s efforts have been stalled by controversy. The two scientists have been under attack by a group led by Terry Polevoy, a dermatologist in Kitchener, Ontario, who runs a Web site called HealthWatcher.net. A onetime devotee of holistic therapies, Polevoy now crusades against alternative treatments he considers scams. For the past four years, he and his colleagues have accused Stephan and Hardy of irresponsibly marketing an unproven remedy. The employees that take the company’s orders have no medical training, Polevoy points out, yet they’re told to encourage customers, many of them mentally ill, to stop using traditional medicines and rely exclusively on the supplement. “People have been injured by taking this stuff,” Polevoy says. In one well-publicized case, a schizophrenic man quit his medications in order to take the supplement and wound up psychotic, in jail, and facing assault charges.

Hardy and Stephan, in turn, accuse Polevoy of being a front man for the pharmaceutical industry, a charge Polevoy denies. “I may go to a few meetings a year hosted by pharmaceutical companies,” Polevoy says, “but I’m not paid.”

After Kaplan and Popper published accounts of their experiences with the formula, Polevoy charged the scientists with conducting experimental research on patients without proper institutional review. The allegations triggered lengthy investigations by the scientists’ academic institutions, as well as by Canadian and U.S. health authorities. Kaplan and Popper were ultimately cleared of any improprieties, but the ordeal left both so gun shy that they stopped talking publicly about the supplement. (Kaplan declined to be interviewed for this story. Neither she nor any of the other scientists mentioned in this story have any financial ties to the supplement.)

Both scientists have had a tough time securing government support for their psychiatric research. EMPowerplus has yet to be approved for sale in Canada, and Health Canada, the agency that regulates food and drugs in that country, has sued Truehope for advertising the product to Canadians who might wish to import it. “The manufacturer has not provided us with scientific evidence that the drug is safe and effective,” says Jirina Vlk, a spokeswoman for the agency. Hardy and Stephan, in turn, have sued Health Canada for blocking shipments at the border. Health Canada initially denied Kaplan permission to pursue a randomized study of the supplement in 100 bipolar patients, although Kaplan already had funding from the Alberta government. That decision was reversed in 2004, after the agency established a new division dedicated to overseeing supplements and natural health products.

Meanwhile in the United States, Popper and Kaplan recently secured approval from the Food and Drug Administration to conduct an even larger clinical study of the supplement. Other scientists think this is long overdue. “It’s something that needs to be investigated,” says L. Eugene Arnold, a psychiatrist at Ohio State University who plans to explore the use of zinc to treat ADHD. “There’s no point in people arguing about whether it works or not without getting some data to get the answer.” Arnold is no advocate of alternative treatments for mood disorders, but he thinks it’s reasonable to suspect that vitamins and minerals might have an effect. The standard treatment for bipolar disorder is lithium, he points out. “And what is that but a mineral?”

For Hardy and Stephan, the long wait for scientific validation has been frustrating. But they are patient. “It’s like any new discovery—acceptance is slow to come,” Stephan says. “But that will change. It will come.”