Reader's Digest (Canada) - - Front Page - BY ROBERT ANTHONY SIEGEL FROM SMITH­SO­NIAN

“HERE THEY ARE,” John Kel­ley said, tak­ing a pa­per bag off his desk and pulling out a big am­ber pill bot­tle. In­side were the cap­sules we’d de­signed: a mag­i­cal con­coc­tion to treat my chronic writer’s block and the panic at­tacks and in­som­nia that al­ways come along with it.

I’ve known Kel­ley since we were un­der­grads at Har­vard in the early 1980s. Now he’s a psy­chol­ogy pro­fes­sor at Endi­cott Col­lege in Mas­sachusetts and the deputy di­rec­tor of PiPS, Har­vard’s Pro­gram in Placebo Stud­ies & Ther­a­peu­tic En­counter. Launched in 2011, it’s the first pro­gram in the world de­voted to the in­ter­dis­ci­plinary study of the placebo ef­fect.

The term placebo refers to a dummy pill passed off as a gen­uine phar­ma­ceu­ti­cal or, more broadly, any sham treat­ment pre­sented as a real one. By def­i­ni­tion, a placebo is a de­cep­tion, a lie. But doc­tors have been hand­ing them out for cen­turies, and pa­tients have been get­ting bet­ter—whether through the power of be­lief or sug­ges­tion, no one’s ex­actly sure. Even to­day, when the use of placebos is con­sid­ered un­eth­i­cal by many med­i­cal pro­fes­sion­als, a 2008 sur­vey of 679 Amer­i­can doc­tors showed that about half of them pre­scribe med­i­ca­tions such as vi­ta­mins and over-the-counter painkillers pri­mar­ily for their placebo value.

In­ter­est­ingly, the PiPS re­searchers have dis­cov­ered that placebos seem to work well even when a prac­ti­tioner doesn’t try to trick a pa­tient. These are called open-la­bel placebos—fakes ex­plic­itly pre­scribed as such.

So in 2015, I had turned to my old friend for help with my writer’s block. “I think we can de­sign a pill for that,” he’d told me ini­tially. “We’ll fine-tune it for max­i­mum ef­fec­tive­ness, colour, shape, size, dosage and time be­fore work­ing. What colour do you as­so­ciate with writ­ing well?”

I closed my eyes. “Gold.”

“I’m not sure the phar­ma­cist can do metal­lic. It may have to be yel­low.”

Over the next few weeks, we dis­cussed my treat­ment in greater de­tail. Kel­ley sug­gested cap­sules rather than pills, as they would look more sci­en­tific and there­fore have a stronger ef­fect. He also made them short act­ing: he be­lieved a two-hour time limit would cut down on my ten­dency to pro­cras­ti­nate. We com­posed a set of in­struc­tions that cov­ered not only how to take them but also what they were go­ing to do. Fi­nally, we or­dered 100 cap­sules, which cost a hefty $405, though they con­tained noth­ing but cel­lu­lose. Placebos are not cov­ered by in­sur­ance.

Kel­ley re­as­sured me: “The price in­creases the sense of value. It will make them work bet­ter.”

I called the phar­macy to pay with my credit card. After the trans­ac­tion, the phar­ma­cist said to me, “I’m sup­posed to coun­sel cus­tomers on the cor­rect way to take their med­i­ca­tions,

but hon­estly, I don’t know what to tell you about these.”

“My guess is that I can’t over­dose.” “That’s true.”

“But do you think there’s a chance I could get ad­dicted?”

“Ah, well, now that’s a re­ally in­ter­est­ing ques­tion.”

We laughed, but I felt un­easy. Open la­bel had started to feel like one of those post­mod­ern magic shows in which the ma­gi­cian ex­plains the il­lu­sion even as they per­form the trick—ex­cept there was no ma­gi­cian. Ev­ery­one was mak­ing it up as they went along.

I wor­ried that my anx­i­eties about the pills not work­ing

might ul­ti­mately pre­vent them from work­ing.

ONE OF THE KEY el­e­ments of the placebo ef­fect is the way our ex­pec­ta­tions shape our ex­pe­ri­ence. As Kel­ley handed over the pills, he wanted to heighten my ex­pectancy, as psy­chol­o­gists call it, as much as pos­si­ble. He showed me the of­fi­cial-look­ing stuff that came with the yel­low cap­sules: the pill bot­tle, the la­bel, the pre­scrip­tion, the re­ceipt from the phar­macy and the in­struc­tion sheet we’d writ­ten to­gether, which he read to me out loud. Then he asked me whether I had any ques­tions.

Sud­denly we were in the midst of an earnest con­ver­sa­tion about my fear of fail­ure as a writer. There was some­thing sooth­ing about hear­ing Kel­ley re­spond, about his gen­tle man­ner. As it turns out, that’s an­other key el­e­ment of the placebo ef­fect: an em­pa­thetic care­giver. The heal­ing force, or what­ever you want to call it, passes into you from the placebo, but it helps if it starts with some­one who wants you to get bet­ter.

Back home, I sat down at the din­ing room table with a glass of wa­ter and a note­book. Take two cap­sules with wa­ter 10 min­utes be­fore writ­ing, said the la­bel. Be­low that: placebo, no re­fills.

I un­folded the direc­tions: “This placebo has been de­signed es­pe­cially for you, to help you write with greater free­dom and more spon­ta­neous and nat­u­ral feel­ing. It is meant to help elim­i­nate the anx­i­ety and self­doubt that can some­times act as a drag on your cre­ative self-ex­pres­sion. Pos­i­tive ex­pec­ta­tions are help­ful but not es­sen­tial: it is nat­u­ral to have doubts. Nev­er­the­less, it is im­por­tant to take the cap­sules faith­fully and as di­rected be­cause pre­vi­ous stud­ies have shown that ad­her­ence to the treat­ment reg­i­men in­creases placebo ef­fects.”

I swal­lowed two cap­sules and, per the in­struc­tions, closed my eyes and tried to imag­ine the pills do­ing what I wanted them to do. But still, I wor­ried

that my anx­i­eties about their not work­ing might pre­vent them from work­ing.

Over the next few days, I felt my anx­i­ety level soar while at work and when fill­ing out the self-re­port sheets. “On a scale of zero to 10, where zero is no anx­i­ety and 10 is the worst anx­i­ety you have ever ex­pe­ri­enced, please rate how you felt dur­ing the ses­sion to­day,” one sec­tion read. I was giv­ing my­self eights out of a mis­placed sense of re­straint, though I wanted to give 10s.

Then, one night in bed, my eyes opened. My heart was pound­ing. The clock said 3 a.m. I got up and sat in an arm­chair and, since my pill bot­tle was there on the desk, took two cap­sules, just to calm down. They made me feel a lit­tle bet­ter, but I didn’t ac­tu­ally get to writ­ing. In the morn­ing, I emailed Kel­ley, who wrote back say­ing that, like any med­i­ca­tion, the placebo might take a cou­ple of weeks to build up to a ther­a­peu­tic dose.

TED KAPTCHUK, Kel­ley’s boss and the founder and di­rec­tor of PiPS, has trav­elled an ec­cen­tric path. He be­came em­broiled in rad­i­cal pol­i­tics in the 1960s and stud­ied Chi­nese medicine in Ma­cau. After re­turn­ing to the United States, he prac­tised acupunc­ture in Cam­bridge, Mass., and ran a pain clinic be­fore be­ing hired at Har­vard Med­i­cal School. But he’s not a doc­tor, and the de­gree he earned in Ma­cau isn’t rec­og­nized here.

Kaptchuk’s out­sider sta­tus has given him an un­usual amount of in­tel­lec­tual free­dom. In the in­tensely spe­cial­ized world of aca­demic medicine, he rou­tinely crosses the lines be­tween clin­i­cal re­search, med­i­cal his­tory, an­thro­pol­ogy and bioethics. “They orig­i­nally hired me at Har­vard to do re­search in Chi­nese medicine,” he told me. His in­ter­ests shifted when he tried to rec­on­cile his own suc­cesses as an acupuncturist with his col­leagues’ com­plaints about the lack of hard sci­en­tific ev­i­dence. “At some point in my re­search, I asked my­self, If the med­i­cal com­mu­nity as­sumes that Chi­nese medicine is just a placebo, why don’t we ex­am­ine this phe­nom­e­non more deeply?”

Some stud­ies have found that when acupunc­ture is per­formed with re­tractable nee­dles or lasers, or when the pricks are made in the wrong spots, the treat­ment still works. By con­ven­tional stan­dards, this would make acupunc­ture a sham. If a drug doesn’t out­per­form a placebo, it’s con­sid­ered in­ef­fec­tive. But in the acupunc­ture stud­ies, Kaptchuk was struck by the fact that pa­tients in the sham treat­ment group were ac­tu­ally get­ting bet­ter. He points out that the same is true of many phar­ma­ceu­ti­cals. In ex­per­i­ments with post-op­er­a­tive pa­tients, for ex­am­ple, pre­scrip­tion pain med­i­ca­tions lost up to half their ef­fec­tive­ness when the pa­tient did not know they had just been given a painkiller. A study of the mi­graine drug riza­trip­tan found no sta­tis­ti­cal dif­fer­ence be­tween a placebo la­belled riza­trip­tan and ac­tual riza­trip­tan la­belled placebo.

What Kaptchuk found was some­thing akin to a blank spot on the map. “In med­i­cal re­search, ev­ery­one is al­ways ask­ing, ‘Does it work bet­ter than a placebo?’ So I asked the ob­vi­ous ques­tion that no­body was ask­ing: ‘What is a placebo?’ And I re­al­ized that no­body ever talked about that.”

Work­ing with Kel­ley and other col­leagues, he’s found that the placebo ef­fect is not a sin­gle phe­nom­e­non but rather a group of in­ter­re­lated mech­a­nisms. It’s trig­gered not just by fake drugs but by the sym­bols and ri­tu­als of health care it­self—ev­ery­thing from the prick of an in­jec­tion to the sight of a per­son in a lab coat.

And the ef­fects aren’t just imag­i­nary, as was once as­sumed. Func­tional mag­netic res­o­nance imag­ing, which maps brain ac­tiv­ity by de­tect­ing small changes in blood flow, shows that placebos, like real phar­ma­ceu­ti­cals,

ac­tu­ally trig­ger neu­ro­chem­i­cals such as en­dor­phins and dopamine and ac­ti­vate ar­eas of the brain as­so­ci­ated with anal­ge­sia and other forms of symp­to­matic re­lief.

“No­body would be­lieve my re­search with­out the neu­ro­science,” Kaptchuk told me. “Peo­ple ask, ‘How does a placebo work?’ I want to say by ri­tu­als and sym­bols, but they say, ‘No, how does it re­ally work?’ and I say, ‘Oh, you know, dopamine,’ and then they feel bet­ter.”

To gain a greater un­der­stand­ing of the phys­i­ol­ogy, PiPS has be­gun spon­sor­ing re­search into the ge­net­ics of placebo re­sponse. After meet­ing with Kaptchuk, I vis­ited the Divi­sion of Pre­ven­tive Medicine at Brigham and Women’s Hos­pi­tal to see Kathryn Tayo Hall, a ge­neti­cist. She stud­ies the gene for cat­e­chol-O-methyl­trans­ferase (also called COMT), an en­zyme that me­tab­o­lizes dopamine. In one study, Hall found that the type of COMT en­zyme pa­tients pos­sessed seemed to de­ter­mine whether a placebo would work for them.

Is the COMT gene “the placebo gene”? Hall was quick to put her find­ings into con­text. “The ex­pec­ta­tion is that the placebo ef­fect is a knot in­volv­ing many genes and bioso­cial fac­tors,” she told me, not just COMT.

There’s an­other layer: wor­ri­ers— peo­ple who have higher dopamine lev­els—can ex­hibit greater lev­els of at­ten­tion and mem­ory but also greater lev­els of anx­i­ety, and they deal poorly with stress. War­riors—peo­ple with lower dopamine lev­els—can show lesser lev­els of at­ten­tion and mem­ory un­der nor­mal con­di­tions, but their abil­i­ties in­crease un­der stress. The placebo com­po­nent thus fits into the wor­rier/ war­rior per­son­al­ity types as one might ex­pect: wor­ri­ers tend to be more sen­si­tive to placebos; war­riors tend to be less sen­si­tive.

I told Hall, a lit­tle sheep­ishly, about my one-man placebo trial, not sure how she would re­act. “Bril­liant,” she said, and showed me a box of home­o­pathic pills she used to take to help with pain in her arm from an old in­jury. “My placebo. The only thing that helped.”

WHAT MIGHT THE FU­TURE of placebos look like? Kaptchuk imag­ines doc­tors one day pre­scrib­ing open-la­bels to their pa­tients as a way of treat­ing cer­tain symp­toms with­out the costs and side ef­fects that can come with real phar­ma­ceu­ti­cals. Other re­searchers are fo­cus­ing on placebos’ abil­ity to help pa­tients with hard-to-treat symp­toms such as nau­sea and chronic pain. Still oth­ers talk about mak­ing con­ven­tional med­i­cal treat­ments even more ef­fec­tive by us­ing the sym­bols and ri­tu­als of health care (such as get­ting an in­jec­tion from some­one in a white lab coat) to add a placebo ef­fect.

Hall would like to see placebo re­search lead to more in­di­vid­u­al­ized

medicine; she posits that iso­lat­ing a ge­netic marker could al­low doc­tors to tai­lor treat­ment to a pa­tient’s in­di­vid­ual level of placebo sen­si­tiv­ity. Cit­ing the re­search show­ing that an em­pa­thetic care­giver is key, Kel­ley also hopes to re­fo­cus our at­ten­tion on the re­la­tion­ship be­tween pa­tient and care­giver, re­mind­ing us all of the heal­ing power of kind­ness and com­pas­sion.

I’d been tak­ing my writ­ing cap­sules for two weeks when I be­gan to feel an ef­fect. My sen­tences were awk­ward and slow, and I dis­liked them as much as ever, but I didn’t throw them out: I didn’t want to ad­mit to that in the self-re­ports I was keep­ing, sheets full of notes such as “Bit fin­ger in­stead of eras­ing.” When the urge to delete my work be­came over­whelm­ing, I would swal­low a cou­ple of ex­tra cap­sules (I was way, way over my dosage—had in fact reached Val­ley of the Dolls lev­els of ex­cess). “I don’t have to be­lieve in you,” I told them, “be­cause you’re go­ing to work any­way.”

One night, my 12-year-old daugh­ter was hav­ing trou­ble sleep­ing. She was up­set about a sit­u­a­tion with the other kids in school; we were talk­ing about it, try­ing to fig­ure out how best to help, but in the mean­time, she needed to get some rest.

“Would you like a placebo?” I asked. She seemed in­ter­ested. “Like the ones you take?”

I got my bot­tle and did what John Kel­ley had done for me in his of­fice, ex­plain­ing the sci­en­tific ev­i­dence and show­ing her the im­pres­sive la­bel. “Placebos help many peo­ple. It helped me, and it will help you.” She took two of the shiny yel­low cap­sules and within min­utes was deeply asleep.

Stand­ing in the door­way, I shook a cou­ple more cap­sules into the palm of my hand. I popped them into my mouth and went back to work.

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