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Placebos Can Treat Depression. So Why Don’t We Use Them More Often?

Fake drugs have been shown to be at least as effective as antidepressants at treating mental illness, so why does your prescription still say ‘Prozac’?

Katie Peabody held the glistening, impossibly airy Entenmann’s chocolate donut up to her mouth knowing one of two things were about to happen: Either she’d finish it and go about her day like nothing ever happened, or the chocolate in its sticky, mud-brown frosting would make her go blind.

A doctor had warned her about the possibility of this side effect early on. It was 1988, and she was a research subject in his Columbia University clinical trial for an exciting new antidepressant he’d touted as the “next Prozac” (though she doesn’t now remember the name of the exact drug). Severely depressed, socially isolated and living a life she describes as “completely devoid of pleasure,” she’d jumped at the opportunity to enroll — she desperately wanted to change herself, and a new pill seemed like a promising solution.

There was just one problem. As the doctor had explained, there was a 50 percent chance she’d be taking a placebo, an inert substance with no physiological effect. And because the trial was double-blind, she’d have to wait until afterward to find out whether the vial of pills he’d given her was filled with active drugs or total fakes. Just to be safe, he advised her to stay far, far away from chocolate — he didn’t want her to go blind in case she was taking the real thing.

In her mind, too, there was no doubt — of course, she was taking the real thing. Within a few hours of popping one of the little white pills, almost every symptom of her debilitating depression had lifted as it were no heavier than a bedsheet. “Almost instantaneously, I felt like a totally different person,” she says. “Every aspect of my life changed.” Not only did she become more social and present than she’d been in years, she also started to enjoy the things she’d lost interest in. She even rode the roller coaster at Coney Island with her boyfriend, something she’d never have done before.

Still, something inside her ached to know who was truly in the driver’s seat — was her life turning around because of her, or because of a drug?

Good thing there was a certain chocolate-flavored litmus test she could use. She sank her teeth into the donut and awaited her fate. Within a few minutes, her vision faded entirely to black. Once everything had gone dark, her boyfriend helped her into bed, where she sobbed uncontrollably as she envisioned how her life was about to change. But when she woke up two hours later, her vision had returned. She was shook up, but a part of her felt satisfied knowing she was taking the real drug. She was actually getting the help she needed, after all.

A few weeks later, Peabody returned to Columbia for her final appointment with the test’s administrator. When their session was over, he asked her if she wanted to know whether she’d been taking a placebo or the real drug. To her utter surprise, she’d been taking the placebo the entire time. Her improved mood, social life and relationships hadn’t been the result of some newfangled pharmaceutical — they’d been caused entirely by her.

“I was totally wowed,” Peabody, who is now 66 and a creative director, copywriter and storyteller, tells me. “On one hand, I felt disappointed, like I’d been conned. But on the other, I realized I’d done all this for myself. I was suddenly overwhelmed, and even a little scared by how powerful my mind could be.” After that, something shifted in her for good — she still had bad days every now and then, but she never felt “plagued” by depression again.

According to Luana Colloca, a placebo expert at the University of Maryland, reactions like Peabody’s aren’t uncommon in depressed patients who are randomly assigned placebos in clinical drug trials — though they’re taking a fake drug, their depression will often improve and their good mood will last. In fact, according to a 2008 meta-analysis published in the journal PLoS Med, placebos have been shown to be at least as effective as antidepressants (if not more so) in treating cases of mild to moderate depression. They can help with major depression like Peabody’s, too; while real drugs are often more effective in these cases, research from University of Utah psychiatrist Jon-Kar Zubieta found that placebo was a productive treatment for 45 to 50 percent of severely depressed participants. They’ve even been shown to significantly improve symptoms of Parkinson’s disease, irritable bowel syndrome, allergies and a laundry list of other conditions.

But how is it possible that an inert substance like a sugar pill could not only alleviate depression, but cause bona-fide side effects like blindness as well? More importantly, is it possible to harness that power to treat our own feelings of sadness and despair?

If you’re Zubieta, Colloca or any of the other placebo researchers who have spent the last 150 years studying how mere thoughts can impact physical and mental health, the answer is a resounding “yes.” But to understand why, we first have to understand how.

Sugar is a Hell of a Drug

According to Colloca, placebos work for the simple reason that we expect them to. “If an intervention is believed to be effective, it often will be,” she says. “Your brain can convince your body a fake treatment is real.” This, she explains, is because expectancy can create actual physiological changes.

These changes vary depending on the condition the placebo is supposed to target, but in depressed people, they often take place in the brain’s endogenous opioid system, a neural network that controls pain, reward and emotions. In depression, this system is often “quieter,” meaning the neurons in it don’t fire properly or release as many pain-killing neurotransmitters as a less depressed brain would. Active drugs like antidepressants work by causing this area to light up, but a placebo can have the same effect. According to Zubieta, administering a fake drug to depressed patients can cause a natural release of opioids, cannabinoids and dopamine, all of which can improve mood and reduce both physical and psychological pain.

The same thing can happen in other areas of the brain that regulate mood as well. One study found that placebos can improve depression by altering brainwave activity in the prefrontal cortex, while another found that they increase activity and dopamine release in the midbrain’s periaqueductal gray. That barely begins to cover it, though; a 2009 meta-analysis by Zubieta found that there’s a vast, complex network of neurons and neurotransmitters that respond to placebo. This suggests that the brain is loaded with its own self-healing mechanisms that are capable of banishing depression on their own — they just need the power of positive expectation to activate.

Interestingly, the physiological effects of placebo can swing the other way, as well — often called the “evil twin of placebo,” the nocebo effect occurs when someone gets the side effects of a drug without actually taking one. Temporary, chocolate-based blindness would be a perfect example.

Both placebo and nocebo are strengthened by what’s called “reward learning,” which refers to the process of learning to associate a placebo with a positive effect over time. “If you get a placebo and you get better, and then you get it again and continue to improve, your brain will remember that positive effect and begin to associate the placebo with the benefit,” explains Zubieta. “That strengthens the neural systems associated with the improvement, which increases the strength and duration of the positive effect.”

This is a major reason why Peabody’s depression stayed manageable after her drug trial ended — because of her high expectations and her strong belief that she was getting the help she needed, she’d effectively conditioned her brain to respond in the way she thought it was supposed to.

However, not everyone has such strong reactions to placebo, or any reaction at all, for that matter. “For reasons we still don’t entirely understand, some people respond much better to placebo than others,” Colloca says. Researchers are still trying to determine what genetic, psychological and environmental factors differentiate these people from the rest of the pack, but she suspects it has to do with how strong their expectation of improvement is. The stronger that expectation is, she says, the more likely they are to either benefit from a placebo or suffer from a nocebo.

In his best-selling book You Are the Placebo, neuroscientist and placebo researcher Joe Dispenza explains that the meaning a placebo is given can determine how strong of an effect it has — the more knowledge and context researchers give participants about the effect a drug is supposed to have, the more they tend to react to it. For example, in a 2008 study, a group of hotel maids were told that their daily duties of making beds, washing tubs and vacuuming carpets counted as a healthy daily dose of exercise. This group of maids lost weight and achieved better physical health than a control group of maids who weren’t given that information at all. Nothing changed in what either group was doing; it was just that the maids who were downloaded about the benefits of cleaning as exercise attached meaning to that knowledge, which influenced how their bodies responded.

The environment in which a placebo is given also matters a great deal. How trustworthy a clinician seems, how reputable a research institution is or how well other patients are responding to a treatment can make or break someone’s expectation that a treatment will work.

Peabody tells me that it was the prestige of Columbia University that did it for her — while she didn’t know much about the program, the fact that it was being conducted by white-jacketed clinicians within the hallowed walls of such a renowned laboratory made the whole thing seem convincingly trustworthy. That, and they told her there was “much excitement” about the drug, planting an expectation to, well, increase her expectation.

And while Zubieta cautions that there’s too much variability to the placebo effect to give it credit as a panacea for depression, he says stories like Peabody’s still suggest that the mind might be more equipped to heal the body than we think. This is an especially important realization in the context of the opioid epidemic and the current culture of antidepressant overprescription. That is, in a world where more people die from prescription drug overdoses than any other accident and half of people taking antidepressants aren’t even depressed, it might not hurt to consider that for some people, the mind can be its own, pill-free pharmacy.

But if people like Peabody can rebound from severe depression by thought alone — and if placebos are so effective in clinical trials — why aren’t doctors handing out placebo prescriptions to their depressed patients left and right?

Your Own Personal Placebo

In some countries like Germany, they are. There, more than half of doctors prescribe them for everything from upset stomachs to — you guessed it — depression, the latter of which they seem to treat effectively about a third of the time. (Fun fact: Placebos are more effective in the U.S., where our pill-hungry populace has been conditioned to believe in the power of pharmaceuticals with the same fervency they believe in the Second Amendment.)

Stateside, we’re not quite at German levels, but we’re not far behind either. The American Medical Association supports the use of placebos when the doctor tells the patient they’re taking a placebo, obtains their consent to administer one and avoids prescribing them merely to mollify a difficult patient. Interestingly, some research has shown that placebos can work for depression even when the patient knows they’re taking a fake drug, which means, in some cases, clinicians don’t even need to deceive patients for the placebo to work.

That said, it’s still uncommon for American doctors to prescribe placebos to treat depression. While they show a remarkable amount of promise in research settings, Colloca says it’s not always ethical to give a depressed patient a fake drug in clinical practice, even if they know they’re taking one. “With depression, where the risk of suicide is high and the quality of life can be so low, it’s generally safer to give someone a real treatment,” she explains. “For that reason, placebos make much better interventions for more minor conditions like IBS or [allergies] that don’t carry such grave risks.”

However, that doesn’t mean depressed people shouldn’t try to employ the power of the mind-body connection for their own use in conjunction with regular clinical treatment or supervision. “It would benefit all patients to know how powerful their minds were in changing how they feel,” says Zubieta. “If they can harness that feeling and realize they can change themselves, that’s going to help, even if what they’re using to accomplish that isn’t necessarily an effective pharmacological agent.”

Taking vitamins, supplements or homeopathics is a good way to start. None of these have been shown to be superior to placebo in most conditions, yet they’re almost always marketed to consumers using a certain magical, dramatic anticipation of health (which can go a long way toward increasing expectancy). Practicing self-help methods like eating right, exercising or meditating can work, too. “The bottom line is, if you think something works, it’s probably going to,” says Zubieta.

That’s exactly how Peabody has been able to keep her depression at bay all these years. By getting regular exercise and creating a meticulous daily schedule, she’s been able to reinforce the fateful revelation she had during the placebo trial — that she is control of her depression. “The mind really does have an incredible power over the body,” she says. “Once I began to understand that my brain was just as powerful as any drug, I never looked back.”