Prevention (USA) - - SCIENCE -

there was a cheap, drug-free, zero-side­ef­fect treat­ment to heal what ailed you? You’d prob­a­bly be skep­ti­cal yet cu­ri­ous, right? Well, such a thing may al­ready ex­ist—the placebo ef­fect, which is when a pa­tient in a lab set­ting feels bet­ter af­ter re­ceiv­ing treat­ment (such as a non­medic­i­nal pill) he or she be­lieves to be medicine. Sci­en­tists are ea­ger to un­der­stand how this phe­nom­e­non works so they can one day harness its power.

And that day may not be too far off: In the not-so-dis­tant fu­ture, we could see the placebo ef­fect put to use in doc­tor’s of­fices and phar­ma­cies. A grow­ing body of re­search is be­gin­ning to dis­pel its bad rap—that you’re stupid or gullible for be­liev­ing a “fake” drug works or, worse yet, that if it helps, you were never re­ally sick at all. “For a long time, placebos were stig­ma­tized be­cause they were thought to ‘work’ by trick­ing pa­tients into be­liev­ing they were re­ceiv­ing some­thing real,” says Anne Harrington, Ph.D., a pro­fes­sor of the his­tory of sci­ence at Har­vard Univer­sity and au­thor of

The Cure Within: A His­tory of MindBody Medicine. “It was even sug­gested that peo­ple who re­acted to them might be un­usu­ally sub­mis­sive to author­ity or less in­tel­li­gent than the rest of us.” That’s no longer the case, thanks to sci­en­tific ad­vance­ments like brain imag­ing and study af­ter study show­ing that there are real phys­i­cal and psy­cho­log­i­cal re­sponses in­volved in why pa­tients re­spond. Here’s what we know so far, and what it could mean for the fu­ture of medicine.


The placebo ef­fect first re­vealed it­self in the mid­dle of the 20th cen­tury, when placebos started be­ing used in all clin­i­cal drug tri­als—any new med­i­ca­tion needed to out­per­form the placebo to prove that it worked and was worth of­fer­ing to pa­tients. But it soon be­came ob­vi­ous that the placebos them­selves were hav­ing quite an im­pact on par­tic­i­pants. “When one looked at the data, it was ap­par­ent

that peo­ple tak­ing the sugar pill were some­times get­ting bet­ter too,” says Va­nia Ap­kar­ian, Ph.D., a pro­fes­sor at North­west­ern Univer­sity’s Fein­berg School of Medicine. Once sci­en­tists be­gan dig­ging, it be­came clear that there wasn’t just one un­der­ly­ing rea­son. Con­di­tion­ing (be­ing told con­tin­u­ously and re­peat­edly that some­thing helps you ac­tu­ally trains your brain to be­lieve it does) and sug­ges­tion (when sim­ply hear­ing that a shot is filled with drugs eases your pain de­spite the fact that there isn’t a drop of med­i­ca­tion in it) can change your brain, which changes how it re­sponds to pain.


Con­di­tion­ing, the field of neu­ro­science tells us, shifts the way neu­ro­trans­mit­ters com­mu­ni­cate with one an­other. “Ev­ery time you’ve been treated in the past and it worked, your brain cre­ated neu­ral path­ways as­so­ci­at­ing the treat­ment with feel­ing bet­ter,” says Tor Wager, Ph.D, a pro­fes­sor of psy­chol­ogy and neuro

sci­ence at the Univer­sity of Colorado in Boul­der. You’ve likely ex­pe­ri­enced this even if you’ve never been part of a re­search study: If you’ve ever taken an un­proven home rem­edy and felt bet­ter, then the next time you tried it, it prob­a­bly worked again, most likely be­cause your brain re­mem­bered and told you it should. Other fac­tors can strengthen this con­di­tion­ing and the re­sult­ing ex­pec­ta­tions that lead to im­prove­ment. “If you are given a treat­ment and told that it might help, the sug­ges­tion alone can make you more open to pos­i­tive changes and al­ter the nar­ra­tive you tell your­self about your symp­toms,” Wager adds. So if you tell your­self you’re feel­ing pretty good, that fur­ther re­in­forces how your brain re­sponds.

Who you are also mat­ters. Peo­ple who ex­pe­ri­ence the big­gest placebo ef­fect tend to be more aware of their own bod­ies and emo­tions, have low anx­i­ety and high op­ti­mism, and con­sider them­selves open to the power of sug­ges­tion. Cer­tain genes may also af­fect how in­di­vid­ual brains re­spond, thus hav­ing an im­pact on sus­cep­ti­bil­ity to placebos.


So far, health is­sues re­lated to brain cir­cuitry are emerg­ing as the most promis­ing ar­eas for placebo ap­pli­ca­tion. “It can work on pain, de­pres­sion, and some symp­toms as­so­ci­ated with Parkin­son’s dis­ease, be­cause in those cases the mind is an adapt­able and pow­er­ful con­troller of moods and emo­tions,” says Ap­kar­ian. But when it comes to things like in­fec­tions and can­cer, a sugar pill won’t re­place peni­cillin or chemo.

Con­sider pain re­lief, for in­stance: Tak­ing a placebo of­ten works on pain be­cause it ac­ti­vates the opi­ate path­ways in the brain, which are the same ones used to dull the ouch. But if you get in the way of those path­ways (say, by giv­ing a placebo-pop­ping pa­tient an opi­oid-block­ing drug), the placebo no longer has a phys­i­cal ef­fect and stops work­ing. And in the area of men­tal


health, brain imag­ing has shown that placebos can in­ter­fere with neu­ral path­ways in­volved in pro­duc­ing feel­ings of emo­tional dis­tress: In one study, af­ter be­ing told a nasal spray re­duced emo­tional pain, peo­ple looked at a photo of an ex who’d re­cently bro­ken up with them; even though the spray was a placebo, they re­ported feel­ing less sad. In an­other, sub­jects who were told that the color green was calm­ing and then looked at the color green re­ported feel­ing calmer, likely be­cause of sug­gestibil­ity.


As promis­ing as this un­der­stand­ing is, ev­ery study that re­veals some­thing new tends to raise more ques­tions. This isn’t nec­es­sar­ily a bad thing, since the more we know, the more so­phis­ti­cated treat­ments may even­tu­ally be­come. Th­ese ques­tions in­clude Can you com­bine a placebo with a tra­di­tional drug and get even bet­ter re­sults? and Are there ways to boost the placebo re­sponse? And then there’s prob­a­bly the big­gest mys­tery re­searchers are try­ing to solve: why some peo­ple re­spond to placebos while oth­ers don’t. “Who will show a re­sponse and how it can be pre­dicted ahead of time are mil­lion-dol­lar ques­tions,” says Wager. “And some­one might re­spond in one sit­u­a­tion, but not in an­other. Why?” As an­swers start to trickle in, the hope is that doc­tors will be able to pre­dict who will re­spond and per­haps turn a per­son who doesn’t into one who does, ex­pand­ing the po­ten­tial placebos hold.


The lat­est phase of re­search in­volves “open-la­bel,” or “hon­est,” placebo tri­als, in which pa­tients are told out­right that they’re re­ceiv­ing a drug-free treat­ment. This is, among other things, an at­tempt to erase the eth­i­cal dilemma of de­ceiv­ing pa­tients in or­der to find out whether a drug is ef­fec­tive. For ex­am­ple, one study on IBS and an­other on mi­graine pa­tients have seen suc­cess­ful re­sults; par­tic­i­pants were told from the get-go that their treat­ment had no medicine, but they still felt bet­ter. Th­ese kinds of stud­ies will pro­vide doc­tors with the clin­i­cal data they need to show their pa­tients that the placebo ef­fect is real and al­low them to of­fer a drug-free op­tion if a per­son is in­ter­ested in it. “It’s very ex­cit­ing to see ev­i­dence that open-la­bel placebos work,” says Ap­kar­ian. “We are still at the be­gin­ning of know­ing how to use them, but the im­pli­ca­tion is re­ally big.”

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