XIM Time Off What tO watch, read, ロ Botox Gets a Face-Lift see and dO The company that makes Botox 4 幻 HBO's The owns 800 patents for the drug—and u れ g 0 〃 e banishingwrinkles isjust one of 4 引 Movies: them. See how doctors are using HiddenFigures and Botox to treat all kinds of medical AMonster Calls conditions, from migraines and depression tO sweatypalms and 4 引 Rachel Cusk's Transit, plus new overactive bladder January books ByAIexandra SifferIin 34 47 ー Susanna Russian Spy Story Schrobsdorffon the mother-daughter What a report onthe Kremlin's bond meddling inthe U. S. presidential election means for the Putin-Trump 48 巨 0 Que stions relationship for conservative broadcaster Glenn ByMassimo Calabresi18 Beck PhiIippine Drug War TIME shows the toll ofPresident R0drigo Duterte's bloody campaign against illegal drugs and those ONTHE COVER. who use themphotographs 妙 lllustration 妙れ MetzforTIME JamesNachtwey 24 TIME ASla is pu sh TIME ASla ( Hor Kong) Limited. TIME publishes eght double issues. Each counts as two of 52 issues in an annual subscription. TIME may a 0 publish occasional extra issues. ◎ 2017 Time Asia (Hong Kong) l-imited. AllriÜ1ts reserved. ReprOductlOn in whOle in 代 w 曲 0 糶 en is prohibited. TlMEand the Border Design are protectedthrough trademark registration inthe し S. and magazinecirculates. Bureau Of CirculatiOns. ー′ 5 : げ物 e g.X)S ねーⅳ ces a に usthatyourmagazine is undeliverable, 、肥 have nofurtherobligation unless 、給78ei肥 acMrected addresswithin twoyears. CUSTOMERSERVICEANDSUBSCRIPTIONS F 24 / 7 ′ⅵ , 加 le 新 n れーー , ー、物忙れ / / “物ー浦一一物 .9 / 、・・ You may 引 email OJStomer ces center at 市ーー . ー 0 「旧 852 ) 312 & 5688 , orwrite Time Asia (Hong Kong.) 37 / 0 対 0 「 d 979 Kings RO , Quarry Bay, HO Kong 旧」 apan,these aree れ 4 ⅵ′れれ 0 1 研 012066 & 236 旧 Dial) 0r2-51-27FAt 0 , MinatO-ku. TO 0 1056227. A t 回一 : For information and rates• Hong KongTelephone: ( 852 ) 312 & 5169. Orvisit: 物ー .9 / ー航 . た旧 fO 「 ma も on is available at 物ー . ” / ーー一区 TO requestcustom reprints,visitü1E ′ . mm. M 胸セ、 make a 代 ion Ofou 「 mailing listavailable tO reputable firms. lfyou 、い u 旧 prefer 物物 0 目ⅳ your name, please contact ou 「 customer services center. TIME Asia is in Hong Kong and printed in and HO Kong. MCI (P) NO. 07 〃 08 / 2015. Malaysia KKDN no. PPS 676 / 03 / 201 022933 ). 0 The View 2 ー Conversation 引 For the kecord ldeas, OP 加 ion, innovations TheBrief 1 引 The dish on News 庁 0 t わ e し S. and food fraud, and around the world how mislabeled 引 The future of products make it tO Obamacare supermarket shelve s 引 French law 15 lls any one year protects workers more important who don'treply to than another? omce emails after hours 1 引 lnside the European Union's 8 ー Remembering new headquarters in Carrie Fisher (Star Brussels Wars), Debbie Reynolds (Singin' ユ引 AdmiralJames ⅲ the ⅲれ ) and Stavridis 0 Ⅱ why pop star George the U. S. should Michael bolster ties with lsrael 10 llstanbul mourns after a nightclub 1 引 Amne sty terrorist attack on lnternational's New Year's Eve AnnaNeistat on Russia's human- 12 llan Bremmer's rights abuses risk report for 2017 The Feature s A victim 可 0 summary executton な found the . Ⅳ avotas area onNO 既 30 Photograph 妙 James Nachtwey forTIME ノ 9d1 い「 1( 、おダ 1

Conversation the President and Congress THE VALUE OF FREEDOM are exempt from laws RE "STYLE OVER criminalizing conflicts Of Substance: Why Fidel interest by federal workers. ” Castro's Revolutionary Chic Trump should recover some Was a Fraud ” [Dec. 12 ] : Joe of the goodwill that he lost Klein writes , “ There has during the presidential tO be a balance between campaign and move swiftly freedom and equality, but t0 separate himself from his freedom iS always more business interests. important. " But freedom FIDEL NigeI Wade, from oppression and CASTRO inequality is what the ILFORD, ENGLAND majority ofCubans fought for in the 1950S. lfthe U. S. HOMECOMING had allowed Cuba greater RE "BRINGING A HERO Home ” [Dec. 12 ] : Wars freedom from oppressive begin with the cause 0f his behavior so far, Trump improve tax compliance, sanctions, its population justice but Often end with a shows that he cares most resulting in greater could almost certainly have grief-stricken family. Mark about staying newsworthy. transparency in lndia's enjoyed more individual He'll allow himself to be Thompson's article depicts financial system. True, freedom. When people and the ideal and the real among guided by his team, then farmers, urban poor and states feel threatened, they a nation, a family and the stand by his actions even sometimes d0 bad things, the middle class have been soldier himself. I was le 仕 if his justifications are as the U. S. knows too well. put t0 temporary hardship with mixed emotions Of petty and put out via an However, the U. S. could do by the sudden contraction sadness, solemnity and untrustworthy social-media 0f money supply, but the much tO end injustice and maltreatment Of prisoners in poignant joy, though I vehicle. We 'd learn a lot if we same iS inevitable in any knew whom he's governing found relief in knowing that Cuba tomorrow by closing reform intended to plug a for. We'II judge by his Major Troy Gilbert's body leaking monetary system. Guantanamo. Steve Hopkins, behavior, not his tweets. returned home. However, I doubt that lndia's A れ to ⅲ 0 H. Terada, Terry 0 0 れ lo れ , black wealth can be tackled ECCLES, ENGLAND without radical structural OSAKA, JAPAN CLEVELAND, AUSTRALIA and tax reforms. Modi's war CONFLICTS OF INTEREST RE "CAN TRUMP CLEAN UP on black money has j ust TIME W にし TELL ROOT OF THE PROBLEM His Messy WorId of trimmed its branches while RE "INDIA PAYS STEEP RE "TRUMP TAKES OVER' Conflicts? ” [Dec. 12 ] : [NOV. 28—Dec. 引 : If there's Price for Cash Withdrawal ” itS roots continue tO flourish President-elect Donald one thing that's been made [Nov. 28—Dec. 引 : WhiIe in illicit money stashed Trump will need to build a very clear since the election, lndian Prime Minister abroad by wealthy lndians. firewall between his business it's that what Donald Trump Narendra Modi's de- Ka れ ga. ア am . Narasimhan, interests and political duties said during the campaign monetization has created CHENNAI, INDIA t0 avoid the possibility of was what he expected would a serious cash crunch, it creating an international get him elected. NO one has given a severe jOlt tO financial oligarchy having knows what he believes in. fake currency, cross-border an undemocratic influence Now that he's going to be insurgency, black money on political decisionmaking. President, he'll approach and the growing corruption I was surprised tO learn that everything anew. From in the country. lt will also SETTING THE RECORD STRAIGHT ln "The Person ofthe Year" (Dec. 19 ) , we incorrectly de- scribed Mike Pence as the former ln- diana governor. His term ends Jan. 9. TALK TO US SEND AN EMAIL: letters@timemagazine.com Please dO not send attachments Send 0 r : Letters to the Editor must include writer'sfull name, address 0 〃 d home telephone, may be editedfor purposes ofclarity or space, 0 れ d should be addressed the nearest ofice: HONG KONG - TIME Magazine 社 ers , 37 / F , Ox House, Taikoo P1ace, 979 King's Road, Quarry Bay, Hong Kong;L JAPAN - TIME Magazine ers , 2- 1-27F Atago, Tokyo 1056227 , Japan; PIease recycle EUROPE - TIME Magazine 社 ers , PO Box 63444 London, SEIP 5 日 , UK; this magazine a れ 2m0 e inserts AUSTRALIA - TIME Magazine Letters, GPO Box 3873 , sydney, NSW 2001 , Austra1ia; and samples NEW ZEALAND - TIME Magazine 地 ers , PO Box 198 ,. Sho and st. , Auck1and, 1140 , New Zealand recycling FOLLO 、 US: facebook.com/time @ti me (Twitter and lnstagram) TIME January 16 , 2017 2

TheBrief THE RISK REPORT The top global risks for 201 a year Of geopolitical recesslon TICKER ・ Swarm' ofquakes ⅲ Cal(fornia More than 250 small earthquakes shOOk BrawIey, a city in Southern California, on New Year'S Eve, experts say. There were no in, 」 uries 0 「 damages from the series Of weak temblors. Gambia setfor clash 0 工 leaders Gambia President- elect Adama Barrow says he is planning a 」 an. 19 inauguration even though the defeated incumbent, Yahya 」 ammeh, has rejected the result Of December's electiom Unrest could follow if longtime ruler 」 ammeh attempts tO block the handover Of power. Cheetahs race toward extinction The cheetah faces "extreme challenges" to its survival and should be classified as endangered by ・ conservationists, a new study has concluded. There are about 7 , 000 cheetahs 代 in the world, mainly in South and EastAfrica. New theory claims fire sank Titanic The Titanic's hull was fatally weakened by a fire in the boiler 「 00E before it hit an iceberg, according tO a new documentary. lrish journalist Senan MoIony spent 30 years researching the 1912 maritime disaster that killed more than 1 , 500 people. By lan Bremmer The lnauguration of Donald Trump onJan. 20 is set tO bring tO an end the 70-year era ofPaxAmericana, when U. S. hegemony in security, trade and the promotion ofvalues provided stability for the global economy. ln its absence, the world will fall into a deep geopolitical downturn. With that as abackdrop, here are my top eight political risks for the commg year: 1. UNPREDICTABLE AMERICAThe world's SOle superpower IS now a Wild card. 5. TECHNOLOGY DISRUPTING THE MIDDLE EAST Technological change is further president Trump will use U. S. power weakening an already fragmenting re- primarily tO advance U. S. intere sts , gion. The revolution in energy produc- forging a more hawkish, and less pre- tion undermine s state s still dependent dictable, foreign policy. Allies ⅲ Europe on 0i1 and gas exports for revenue, while and Asia will hedge. Rivals like China new communication technologies en- and Russia will probe for weakness. hance the ability ofangry citizens to find like minds and to organize. 2. CHINA OVERREACTING The sheer num- ber ofplaces where U. S. -China tensions might play out—North Korea, Taiwan, 6. CENTRAL BANKERS GET POLITICAL Hong Kong, the East and South China Trump may use the Federal Reserve as seas—・ make 2017 a dangerous year for a political scapegoat, piling pressure on China, and all who depend on it for future decisions. This isn'tjust a U. S. risk. Britain's Theresa May has blamed growth and stability. the Bank of EngIand for exacerbating income inequality, and German Finance 3. A POWER VACUUM 粮 EUROPE Minister Wolfgang SchäubIe says low Though Angela Merkel is likely t0 win re-election as Germany's Chancellor interest rates have acted as a disincen- in 2017 , she'll emerge as a weakened tive for reform among E. U. states. figure. This will leave Europe with no strong leadership at all, at a time when 7. THE WHITE HOUSE VS. SILICON VALLEY strong leaders are badly needed. When it comes tO technology, Trump wants security, control and new jObS. The tech giants want freedom, privacy 4. A PAUSE Ⅲ ECONOMIC PROGRESS Don't expect a surge in needed eco- and more automation. There will be nomic reforms in 2017. lndia and Mex- plenty in 2017 for them t0 fight over. ico have accomplished as much as they can for now. ln France and Germany, 8. TURKEY'S ONGOING CRACKDOWN reform will wait until after coming elec- President Recep Tayyip Erdogan will tions, and China faces an all-consuming likely use a referendum to formalize his leadership transition in the fall. ln Bra- powers, and tighten his hold on the ju- zil, Nigeria and Saudi Arabia, ambi- diciary, bureaucracy, media and eve n tious plans will advance but fall short of business sector. ThiS Will exacerbate what's needed. the country's economic problems and worsen relations With Europe. Theyear 2017 will be pivotalfor Chinese PresidentXiJinping M A R K S C エ一 E F E L B E 一 N ー A P ロ

it's been proved tO work for that condition. Now, thanks in large p art to off-label use, Botox—the wrinkle smoother that ex- ploded as a cultural phenomenon and med- ical triumph—is increasingly being drafted for problems that go farbeyond the cosmetic. The depression suffered by Rosenthal's pa- tient is Just one example on a list that in- cludes everything from excessive sweating and neck spasms to leaky bladders, pre- mature ejaculation, migraines, cold hands and even the dangerous cardiac condition Of atrial fibrillation after heart surgery, among others. The range 0f conditions for which dOCtors are now using BOtOX iS dizzying, re- flecting the drug's unique characteristic s as much as the drug industry 's unique strate - gies for creating a blockbuster. Botox iS a neurotoxin derived from the bacterium Clostridium botulinum. lngested in contaminated fOOd, it can interfere with key muscles in the body, causing paralysis and even death. But when injected in tiny doses intO targeted areas, it can block signals be- tween nerves and muscles, causing the mus- cles tO relax. That's how it smooths wrinkles: when you immobilize the muscles that sur- round fine lines, those lines are less likely to move—making them less noticeable. lt's also why it's FDA-approved to treat an overactive bladder: Botox can prevent involuntary mus- cle contractions that can cause people to feel like they have to pee even when they don't. ln 2015 , B0tox, produced by pharmaceu- tical maker Allergan, generated global reve- nue of $ 2.45 billion—more than halfofwhich came from therapeutic rather than cosmetic uses. That noncosmetic revenue iS likely t0 balloon in the years ahead as doctors try out URING A RECENT THERAPY session, one Of Dr. Norman Rosenthal's regulars said he was consider- ing suicide. lt wasn't the first time the pa- tient had entertained the thought, and even thoughhe was 0 Ⅱ antidepressants and always kept up with his appointments, Rosenthal, a licensed psychiatrist with a private practice ⅲ North Bethesda, Md. , wanted to 0ffer his patient something else. "I think you should get B0tox; ” Rosenthal told him. "You should schedule an appoint- ment on your way home. lt was peculiar advice coming from a shrink, but not without precedent. ln 2014 , Rosenthal, a clinical professor ofpsychiatry at Georgetown University Sch001 0f Medi- cine, and Dr. EriC Finzi, an assistant pro- fessor 0f psychiatry at George Washington SchooI of Medicine , published a study show- ing that when people with maJ0r depression got B0tOX, they reported fewer symptoms six weeks later than people who had been given placebo injections. "l'm always on the 100k- out for things that are unusual and interest- ing for depression, ' says Rosenthal, wh0 is widely considered an expert on the condi- tion. "l've found B0tox t0 be helpful, but it's still not malnstream. lt's also not approved by the U. S. F00d and Drug Administration (FDA) for depres- sion, not that that stops doctors from pre- scribing it that way. Such off-label use 0f Botox, like that of any FDA-approved drug, is legal in the U. S. That's because once a drug has been approved by the FDA for a condi- tion, licensed physicians are legally allowed tO prescribe it for any medical issue they think it could benefit, regardless ofwhether ' 夏 meet w physicians 0 are 題取 g ま e toxin everywhere--— for diseases YO WO ー never 取 OW abo MIN DONG, Harvard Medical School BO を ox ド 0 BOtOX was invented as a drug tO treat crossed eyes. TOday it's used on a wide range of disorders—some approved, some not. Here's what tO know: WHAT ー 5 B010X ? Botox comes from a bacterium called Clostridium botulinum that can cause severe fOOd poisoning if eaten. When the drug is injected, it delivers a tiny dose Of toxin that blocks communication between nerves and muscles. 0 0 E S ー N 5 U R A N 0 E 0 0 E R 打 ? Not forwrinkles. Some companies will cover it for FDA-approved medicaluses if Other therapies have not worked. Out Of pocket, it can cost $ 350 to $ 500 per injection. MOSt treatments require multiple shOts. ー 5 IT SAFE? The FDA requires Botox to bear a black-box warning— an alertthat the drug may come with major risks—but most experts agree it's safe when used correctly for approved conditions. Still, serious Side effects have been reported. 引に感 200 リⅲ / ⅵ畆 36 TIME January 16 , 2017

Essay The Pursuit Of Happy-ish The unexpected benefits Of ending up at the back 0f the pack By Susanna Schrobsdorff IN LATE DECEMBER, I WENT FOR A HIKE WITH MY TWO daughters. And by hike I mean we walked, climbed and slid for five hours through a thick, wet mountainous patch 0f Costa Rican jungle to get to what promised to be a spectacular waterfall. lt felt like we were either clawing our way up at a 90-degree hillside or slipping uncontrollably down through red-clay mud toward hidden ravines rife with poison dart frogs and tiny, vicious biting ants. ln other words, it was like the rest Of 2016. My daughters are spry and strong. And I thought I was tOO. But it became pretty obvious as we went on that while we were all falling and covered with mud, laughing at the absurdity of it all, they got up quicker and kept up with our guide more easily. I was always the slowest and the sweatiest. They'd wait for me if I got too far back, watching as I picked my way toward them. lt reminded me 0f the first glimpses I had 0f my mom as someone weaker than I, like when she started t0 get out ofbreath walking across parking lOts. I remember reaching the doors Of a supermarket and looking back bewildered, because she was still barely out of the car. And then there was the year my sister and I started making most 0f Thanksgiving dinner. lt's a slow shift that happens in small jolts over decades, until one day you re your mother's mother making sure She eatS dinner. When we got back tO our vacation cottage and the lnternet, I read that Debbie Reyn01ds had died just a day after her daughter Carrie Fisher. Fisher's death was sobering. She wasn't that much older than me, and selfishly I wanted t0 hear what she'd have t0 say about life in her 60S. Surely she would have shown us hOW tO meet Old age with wit and hone sty. The death of the two, mother and daughter, a famously entwined pair, was ineffably sad and kind 0f amazing. As Carrie's brother T0dd Fisher put it, theirs was a beautiful love story. Unique in its intensity and extremes, but not SO different from most families in its shifting balances Of authority, wis dom and health. AS OU TRIBES expand and contract, we evolve tO fit the new paradigms. The oldest child gets bogged down with her own kids and abdicates her spot as leader, the baby steps up and takes over. There will inevitably be illness, which can shatter all the old dynamics. So can betrayal or bankruptcy. We have tO adapt, instead ofclinging tO stale expectations ofourselves or the people we love. There's probably nothing harder t0 d0 than that. A lifelong duet: Carrie Fisher 0 d Debbie ReynoIds onstage early in Fisher's career When the girls and I finally got to that waterfal it was indeed stunning: a 40- 代 . wall Of water crashing down with such fury that we had to shout above the noise. We peeled off a few soppy layers and jumped into the deep pool at the base. lt was shocking, not because of the blast of coolness in the jungle, but because of the force of the current. lt didn't lOOk swift, but underneath it was flowin so fast into the small river behind us that you could swim with all your strength and not get any nearer tO the waterfall. lt was like one ofthose home-exercise pools they sell on late-night TV. For a while we tried, the three of us kicking WIIdIy, tO see whO could move a fOOt closer only tO be dnverv back into the pack again. Then the youngest of u figured out how to navigate the sharp rock walls around the edges where the water was calmer and almost made it to the base of the falls. We gathered up our stuff, arguing over who would return with the heaviest pack. I did not get a pass due t0 age. Hadn't they seen me struggling back there ? lnstead I was accused of being "able-bodied. ” As we set off, back ⅲ formation, the girls climbed just ahead of me, talking intensely about something couldn't quite make out above the squawk and trill of the wildlife. ON CAN IMAGINE that ifFisher hadn't collapsed on that long London-t0-L. A. flight, her 84-year-old mother would have gone before her, as these things are supposed t0 go. I want t0 believe that Fisher would have been 0. K. , that she would have adapted, that with her family she would have found a way to keep the most pernicious aspects Ofher bipolar disorder in check without Reynolds' care. Ofcourse, that's what every generation hopes for the next—that they'll be able t0 take care ofeach other without you, that whe you slow down, they'll have each other. ロ 7

the poison. ln medicine, it'S used in such small amounts that most experts deem it safe. "lt's fascinating,' says Dong, the Harvard researcher. "These are the most toxic sub stances known tO man, and they are also the most useful toxins used in medicine right now. BOtox works by temporarily immobiliz- ing muscle activity. lt does this by block- ing nerve-muscle communication, WhiCh makes the injected muscles unable tO con- tract. Paralyzing muscle activity is hOW BOtOX can steady a straying gaze, eliminate an eye- lid spasm or stop signaling from nerves that stimulate sweat in a person S armpit. BOtOX has alSO been shown tO prevent chronic migraines, but there, it'S unclear exactly why B0t0X works. (For doctors, reaching a firm understanding 0f how BOtOX prevents migraines will be tricky, since they don't know for certain what causes the severe headaches in the first place. ) "There were multiple clinical trials for migraines, and most 0f them failed," says Dr. Mitchell Brin, senior vice president of drug development at Allergan and chief scientific Offcer for BOtOX. "lt tOOk a long time tO figure out where tO inject and hOW much. ” T0day people wh0 receive B0t0X for migraine prevention get 31 inJ ections lll different spots on their head and neck. The effects Of Botox can last about three tO six months depending on the condition. The use Of BOtox for migraines was, like many other new applications for the drug, a kind 0f happy accident. A Beverly Hills plastic surgeon observed that people wh0 got BOtOX for wrinkles were reporting fewer headaches, paving the way for studies about migraines. Similarly, doctors in Europe were intrigued when they noticed that their pa- tients whO got BOtOX for facial spasms were sweating less than usual. "lt's pure serendipity, ' says Brin. THOUGH P OP 0 T 地 N ASSOCIATE phar- maceutical discovery with giant industrial laboratories and expansive, rigorous clinical trials, the mission creep for Botox—as with many other drugs that have received govern- ment approval for one specific use—has been driven by off-label use. ln the case ofBotox, doctors whO experl- ment off-label say they do so because they're looking for better treatment options for their patients. "ln my 30 years ofmedical practice, BOtOX is one Ofthe most impactful treatments I had ever seen; ” says Dr. Linda Brubaker, 38 TIME January 16 , 2017 WHAT BOTOX 儁 USED ド OR Best known fO 「 reducing facial wrinkles, Botox is approved by the FDA fo 「 the conditions below. The drug now brings in significantly more revenue for itS noncosmetic uses. FDA-APPROVED Rigorous cllnical trials were required before Botox was determined tO be safe and effective fo 「 these uses: 第 Strabismus (crossed eyes) ・ BIepharospasm (eyelid spasms) ■ CervicaI dystonia (severe neck spasms) ■ Severe underarm sweati ng 第 Upper-Iimb spasticity 第 Chronic-migraine prevention ■ Overactive bladder ■ Lower-Iimb spasticity ・ Some facial wrinkles dean and chiefdiversity offcer ofthe LOY01a University Chicago Stritch Sch0010f Medi- cine, wh0 independently studied B0t0X for overactive bladder before the FDA approved it for that condition in 2013. Many ofthe women she saw in her prac- tice didn't want t0 take drugs for the disor- der over the long term. Brubaker found that about 70 % ofwomen she treated with B0tox reported an average ofthree leaks a day, com- pared with the average of five leaks a day at the start Ofthe study. "lt's a very rewarding option for them,: ” she says. lt's true that BOtOX's ever expanding uses have been largely physician-driven. But drugmakers are also often aware ofoff-label uses long before those uses are offcially rec- ognized by the FDA; that's how B otox ended up being approved for wrinkles, after all. Some industry insiders say it's not un- usual, ifstill legally murky, for drug-company representatives and doctors tO share infor- mation with one another about the different ways an approved drug maybe used. lfa doc- tor notices that, say, a treatment for crossed eyes alSO "takes the lines out," he may men- tion it tO the representative from whom he buys the drugs. That rep may share that with another Ofhis clients, and so on. U. S. pharmaceutical companies are p rohibited from marketing a drug for un- approved purposes until they've submitted proofto the FDA ofits efflcacy and gotten the agency's green light. If they skip that step, they're breaking the law, and the penalties can be steep. ln 2010 , Allergan pleaded guilty and agreed to pay $ 600 million to resolve alle- gations that it unlawfully promoted Botox for conditions ー including headache s , p ain, sp asticity and juvenile cerebral palsy—that at the time were not approved by the FDA. ln one Ofthe complaints, prosecutors said that Allergan "illegally, vigo rously and without any thought to the possible negative health effects tO which it subjected patients, pro- moted off-label uses of Botox. ” The U. S. Department 0fJustice also argued that AI- lergan exploited on-label uses for cervical dystonia—a disorder characterized by ex- treme neck-muscle contractions—to grow off-label pain and headache sales. ” Prosecu- tors also argued that Allergan paid doctors tO give presentations and trainings tO other physicians about BOtOX uses that at the time were off-label. As part ofthe settlement, Allergan agreed tO plead guilty tO one criminal misdemeanor

B0tox for even more off-label uses and as AI- lergan conducts studies Of its own. "ln the majority of these cases, it's the doctors at the front line who start using B0tox off-label, and then we see the treat- ment ofthings we never expected the toxin tO work for," says Min Dong, a researcher at Harvard Medical School who studies botu- linum toxins in the lab and has no financial ties t0 Allergan. "I meet with physicians who are using the tOXin everywhere—for diseases you would never know about. The potential 0f the drug is enormous, but it isn't without risks. MOSt Of the experts I spoke with agree that in small doses, Botox is safe when administered by a licensed profes- sional, but not everyone agrees that its safety extends tO all Of its newer off-label uses. ln recent years, a number ofhigh-profile lawsuits have been brought against Aller- gan in which plaintiffs claimed that 0 label uses—for ailments including a child's cerebral-palsy symptoms, for instance, or an adult's hand tremors ー resulted ⅲ lasting del- eterious side effects. Still, the drug's accep- tance in a growing number ofdoctors' Offces worldwide , and its revenue growth show no signs of slowing. lt's a remarkable arc for a drug that only a few years ago was associated with H011y- WOOd cocktail parties where guests came for Bellinis and left with a forehead んⅡ of B0t0X injections. lt highlights the advances that can occur When physicians , seeking new therapies for their patients, explore creative new uses for 叩 proved drugs—basically, real- world experiments that take place largelybe- yond the reach of federal regulators. That, in turn, raises questions about the risks Of deploying medicines in ways that have not been fullyvetted. But it happens all the time. THE DRUG HAS COME A LONG WAY since its ability to smooth facial wrinkles was first dis- covered, by accident. ln the 1970S , ophthal- mologist Dr. Alan B. SC0tt started studying the toxin as a therapy for people with a medi- cal condition that rendered them cross-eyed. "Some Of these patients that would come would kind ofjoke and say, ℃ h, Doctor, l've come t0 get the lines out. ' And I would laugh, but I really wasn't tuned ⅲ t0 the practical, and valuable, aspect ofthat; ” Scott told CBS in 2012. SCOtt named the drug Oculinum and formed a company Ofthe same name in 1978. ln 1989 he received FDA approval for the treatment ofstrabismus (the crossed-eye disorder) and abnormal eyelid spasms. BOTOX BY THE NUMBERS 旧 the 28 years since Botox was approved, the drug's popularity—and the number Of ailments it treats—has skyrocketed 2.2 billion Number of Botox doses administered in the past quarter-century 800 Number Of patents held by AIIergan for current and potential BOtOX applications 旧 1991 , AIlergan paid $9 million for a small company that made Botox 旧 1998 , Botox globalrevenue was S125 million By 2015 glObal $ 2.45 revenue b 一一 0 取 h its $2.45 billion Revenue 作 om Botox S13 million 1990 2000 SOURCE: ALLERGAN $2B 1 0 ' 10 ' 15 Two years later, Allergan bought Oculié num for $ 9 million and changed the drug's name tO BOtOX. At the time, Allergan was primarily an ocular-care company thai sold products like contact-lens cleaners and prescription solutions for dry eyes, bringing in about $ 500 million in annual sales. AIIergan says it saw Botox as a drug for a niche population: it's estimated that 4 % 0f people in the U,. S. have crossed eyes, for which the drug was initially approved, and Allergan made about $ 13 million in sales 朝 om the drug by the end of 1991. ln 1998 , David E. I. pyott became CEO Of Allergan. He was enthusiastic about BOtOX's wrinkle-reducing potential he says, and pushed the company t0 co duct a series Of studies on the matter. ln 2002 , B0tox earned FDA approval for so- called frown lines—wrinkles between eyebrows ー marking the first time a phar- maceutical drug was glven the gree n light for a strictly cosmetic purpose. ln 2001 , the year before Botox was approved for wrinkles, it generated about $ 310 million ⅲ sales. By 2013 , the year it was approved for overactive bladder, AIIergan reported nearly $ 2 billion in revenue from BOtox. lnjust over a decade, the number ofpeo- ple in the U. S. receivlng cosmetic botulinum toxin type A inJections—mostly 仕 om BOtOX but also from another brand called Dys; port, which commands less than 10 % ofthe market—exploded. From 2000 tO 2015 , use ofthe toxins for wrinkles increased 759 %. I became a cultural phenomenon tOO, spawn ing BOtOX parties, Simpsonsjokes, even greet ing cards. ln 2008 , Sex れ d the City character Samantha famously quipped, "I don't really believe in marriage. NOW BOtOX, on the Other hand, that works every time. ” But today it's the medical uses ofthe drug that are the great moneymaker, in part be- cause doctors are getting a better handle on hOW tO use it. Botulinum toxin type A is one Of seven neurotoxins produced from CIOS± tridium bO tulinum. Contracting botulism is bad news: it can cause blurred ViSion, sistent trouble swallowing and worse. ln one recent case, close tO 30 people were hospital- ized in Ohi0 in 2015 after attending a church potluck. One person died. The outbreakwas ultimately attributed tO a potato salad made from improperly home-canned potatoes that were harboring the bacteria. Given its level Of toxicity, some countries have even explored its potential use as a bioweapon. With Botox, however, the dose makes 37