Nora Volkow Leads the World's Biggest Funder of Addiction Research, And

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THE SCIENTIST BATTLING THE ADDICTION CRISIS Nora Volkow leads the world’s biggest funder of addiction research, and now she’s facing her greatest test in the opioid crisis. By Emiliano Rodríguez Mega

n a cold Friday night in February 1995, for another few days and was sent home with comeback of cocaine and methamphetamine, addiction researcher Nora Volkow more. But she decided not to take it. She was and a two-decade-old opioid epidemic that has and her husband got into their car afraid — she knew many of her patients could devastated many parts of the country: opioid after a long day at Brookhaven not stop once they started. She would get overdoses have killed nearly half a million peo- National Laboratory in Upton, New through the pain without the help of drugs. ple in the United States (see ‘Tackling the opioid York. Ice had covered the trees and That night, a discomfort she had never felt epidemic’). In response, her agency has started the roads, making them sparkle. But before overran her body. She felt restless, projects to monitor drug use and has ploughed as the couple drove down a slope, agitated, desperate. Volkow took a painkiller money into medications that can reduce the Othe tyres lost their grip. The vehicle spun out and, like an apparition, the feeling faded away. cravings and pleasurable effects of drugs. of control. Volkow curled up to shield herself as “It was then that I realized how fast depend- Critics have long argued that Volkow’s an oncoming car crashed into her door. ence develops,” she says. “It also made me emphasis on the brain minimizes the roles Metal bit into her flesh. The pain was realize that I’m very afraid of opiates.” that social and economic forces have in mak- unrelenting. Finally, the fire service arrived Twenty-five years later, Volkow’s name has ing people prone to addiction. In the past year, to break her free and an ambulance rushed her become widely known in the addiction field and Volkow has begun to acknowledge that factors to the nearest emergency department, where beyond. As a neuroscientist who has directed such as homelessness, unemployment and a doctor gave her Demerol, a powerful and the US National Institute on Drug Abuse (NIDA) isolation can make people more vulnerable highly addictive opioid painkiller also known in Rockville, Maryland, since 2003, she has to drugs and less likely to recover. But some as pethidine, which is similar to morphine. championed the idea of addiction as a disease researchers contend that the agency’s funding Volkow had spent countless hours talking to of the brain rather than a moral failing. Under decisions have been slow to reflect this shift people with addiction and had read hundreds her direction, NIDA has prioritized research on in mindset. They say that NIDA’s focus on the of papers on the mechanisms of drug abuse. the biological basis of addiction, and fought brain is disproportionate, and they worry Neither prepared her for what happened next. against the mistreatment of drug abusers in about its outsized power over policies tack- “It was extraordinary, those impressive both the medical and criminal-justice systems. ling drug use and addiction. “NIDA’s influence sensations,” she says. A moment of ecstasy, Her quest has taken on a new urgency as is significant; people follow that lead,” says one she describes as comparable only to the United States finds itself contending with Ingrid Walker, a cultural-studies researcher long-lasting sexual pleasure, eclipsed all shifts in the legal status of cannabis, a grow- at the University of Washington in Tacoma. other feelings. She stayed on the medication ing market for electronic cigarettes, a sudden Nonetheless, Volkow’s obsession with

says Brodie. “Her enthusiasm was boundless.” Volkow soon became involved in every project, from looking for brain-tumour biomarkers1 to detecting differences in brain activity between people with and without schizophrenia2. Her reputation as a rebellious yet brilliant scientist began to take shape. “Nora was certain that she was always right, and sometimes she was,” says Brodie. “Perhaps, even, most of the time.”

Scanning for insights By the mid-1980s, Volkow had completed a psychiatry residency at NYU and moved to the University of Texas Health Science Center in Houston to work in its imaging facility. She intended to study schizophrenia, but the cocaine craze was bringing with it a surge of addicted people. In PET scan after PET scan, Volkow spotted anomalies in these individuals’ brains. “You’d see holes, gaps where blood flow should be,” she says. She suggested that cocaine chokes blood vessels to the extent that they don’t allow proper circulation3 — similar to small strokes. Her findings contradicted the belief, common at the time, that cocaine was a relatively safe substance — although the 1986 deaths of two celebrated US sportsmen (basketball player Len Bias and American football player Don Rogers) changed that perception. In 1987, Volkow moved to Brookhaven National Laboratory, where for the next 16 years she continued to probe the effects of drugs on the brain. She used radioisotopes to label cocaine, tracking how rapidly it triggers the neurotransmitter dopamine in the brain Nora Volkow at her childhood home in Mexico City. and how quickly it dissipates, and arguing that the speed of its effect could explain why the understanding the biological effects of do with science, the answer was ‘yes’,” she says. drug is so powerfully addictive. excessive drug use — fuelled in part by her own She once asked him if she could bring home a While at Brookhaven, Volkow kept question- family’s past — has not only shattered dogmas corpse and dissect it. He approved; Volkow’s ing long-held assumptions in neuroscience. in neuroscience; it has also helped to mitigate mother and sisters threatened to leave the The general agreement was that addictive the stigma faced by those living with addiction. house. But she did end up with some bones to substances impaired the brain’s reward “Her mission in life was to harvest the power examine. “When something interests me,” she centres, tempting people to keep trying the

ALEJANDRA RAJAL FOR NATURE FOR RAJAL ALEJANDRA of science to change lives of millions of peo- says, “I won’t quit until I understand it.” substances to feel good. But that didn’t explain ple,” says Bertha Madras, a psychobiologist That same curiosity and stubbornness why so many patients had told her that they felt at Harvard Medical School who is based at would guide most of her career. After graduat- compelled to take the drugs, even when they McLean Hospital in Belmont, Massachusetts. ing top of her class, she was accepted to study had long lost that pleasure. It was as if they had “And she has done that.” psychology at the Massachusetts Institute of lost the power to decide. This more-complex Technology in Cambridge. But a 1980 article in reaction seemed to implicate more than just Revolutionary heritage Scientific American disrupted her plans. the brain areas that process reward. Volkow grew up in Mexico City, one of four The piece described how a new technol- A series of key discoveries came in the 1990s. daughters of Soviet and Spanish immigrants. ogy, positron emission tomography (PET), Volkow noticed that the prefrontal cortex, the Their mother, an haute-couture dressmaker was allowing neuroimagers to look into brain region that regulates decision-making from Madrid, sought refuge in Mexico to escape living brains and watch their activity patterns. and self-control, was underactive in men who Francisco Franco’s dictatorship. Their father, Volkow was instantly hooked. were addicted to cocaine — an anomaly that a chemist, was also a refugee. He had come to Soon after reading the article, she secured a might sometimes precede addiction, making Mexico City as a 13-year-old in 1939 to live with research job in the lab of psychiatrist Jonathan a person more vulnerable to it. Dysfunction his only surviving relative — his grandfather, the Brodie at what was then New York University in decision-making regions, she suggested, exiled Soviet revolutionary leader Leon Trotsky. (NYU) Medical Center in New York City, which was why drug-addicted people felt they had As a teenager, Volkow was captivated by had a vibrant programme using the technol- lost control. Furthermore, she and her team the human brain and studied medicine at the ogy for neuroimaging. Brodie was starting to found, repeated cocaine use desensitized the National Autonomous University of Mexico in do PET scans with the aim of studying various brain by killing off dopamine receptors, which Mexico City. Her father encouraged her with- brain disorders in people. diminished the reward people felt from the out limits. “Whatever I asked my dad that had to “Clearly, she was a star from the beginning,” drug even as it increased their dependence on

Feature it4. Volkow and her colleagues later replicated until it changed its policy in 2018, the FDA — absorbing the history of Volkow’s family. these results in people who had misused had approved such treatments only if they Volkow has come back to Mexico City to visit alcohol, heroin or methamphetamine. could show that they fostered abstinence7. relatives, as she does almost every year. She The blobby PET images were diagnostic And Volkow alleges (although some critics stares at the little metal door in the headstone enough for Volkow to identify which belonged disagree) that reframing addiction as a patho- that contains her great-grandfather’s urn and to addicted people and which didn’t. “It put a logical condition contributed, at least in part, stays quiet for a moment. totally different picture on it,” says radiochemist to legislation such as the US Mental Health “It was kind of shocking, having death so Joanna Fowler, one of Volkow’s closest collabo- Parity and Addiction Equity Act of 2008, close, almost tangible,” she finally murmurs. rators and friends at Brookhaven who retired in which requires insurance companies to put “No one grows up having someone buried in 2014. “Going from that perception of addiction substance-use disorders on an equal footing their garden.” as a moral weakness or a lack of willpower to with other diseases. Trotsky, one of the leaders of the October that of a brain disease.” “I think that the United States and the world Revolution of 1917 that ultimately led to the Volkow added more discoveries: she found is very fortunate that Nora accepted the job as creation of the Soviet Union, dreamt of estab- that some brain changes wrought by alcohol NIDA director,” says Madras. lishing a mass upheaval worldwide that would addiction can be reversed after months of give power to the most vulnerable and foster abstinence5, for example, and that dopamine In the family equality. influences people’s motivation6, a process that A headstone engraved with a hammer Similar ideals live on in Volkow. During her is dysregulated in drug addiction. and sickle guards the ashes of Volkow’s career, she has often felt that the US medical Her ideas went against convention, says great-grandfather in the garden of her child- and criminal systems discriminate against psychologist Alan Leshner, former chief hood home, in a cobblestoned neighbourhood addicted people by ignoring their drug mis- executive of the American Association for the in Mexico City. In 1940, long before Volkow use, denying them medical attention and Advancement of Science in Washington DC was born, Trotsky was killed in the house by a locking them up. That “opened my eyes to and Volkow’s predecessor at NIDA. Implicating Stalinist agent bearing an ice axe. The house the opportunity to use evidence to change decision-making brain regions went against is a monument to Trotsky’s attempts to evade these practices” and provide a scientific way decades of work. “I know that people thought harm: bricked-up windows, armoured doors to explain and treat addiction, she says. she was weird.” and three watchtowers. But she also has a more personal motivation If Volkow knew, she didn’t care. “She was an It is the day after Christmas, and tourists — addiction ran deep on her mother’s side of extremely courageous scientist” who broke drift around the house — now a museum the family. As a child, Volkow remembers huge open an entirely new approach to looking at the secrecy surrounding her uncle Rafael, a hand- brain, says Leshner. In 2003, Volkow took over some and kind man who struggled with alco- as director of NIDA, now a US$1.3-billion-budget hol misuse. And it wasn’t until her mother was agency that funds more scientific research on dying, decades later, that she told Volkow that addiction than any other in the world. her grandfather had not died of heart com- Volkow is the longest-standing director plications, as everyone was told; not able to in NIDA’s history. During her tenure, she has THE WORLD IS VERY control his alcoholism, he had killed himself. continued her own investigations, amassing The confession was heart-breaking. Volkow evidence on the basic biology of drug abuse, FORTUNATE THAT NORA had devoted her entire academic life to show- and her agency has supported many others. ing how addiction was a disease like any other, NIDA has funded studies showing how ACCEPTED THE JOB AS not a shameful condition. marijuana can be addictive, especially for “That is what stigma does,” she says. “My young or regular consumers, for example, and NIDA DIRECTOR.” poor mom had to wait until the last moment has supported research into the role of genetic to tell me something she didn’t dare to.” and epigenetic factors related to addiction. The stigma of addiction is still powerful. It The agency has also lent its support to the could explain why only 17% of the 21.2 million treatment and prevention of drug misuse. It people in the United States diagnosed with helped to develop the first US-approved med- substance-use disorders in 2018 received ication (lofexidine) that alleviates physical treatment. Yet Volkow’s message has not been symptoms of opioid withdrawal, and funded entirely lost. She has helped to reframe addic- early trials of long-acting implants under the tion in society, giving public talks, educating skin that are now used in patients to ease opioid local and federal judges, providing training withdrawal over months. tools for physicians and pushing to make over- Furthermore, NIDA funds research to develop dose-reversing and anti-craving medications technologies aimed at helping people who are more available in rehabilitation facilities and addicted — including an app that connects them prisons. with coaches and with others in recovery, and a tool that uses data science to find prescription Brain bias painkillers being sold online illegally. But a substantial number of researchers disap- Some of that work fits in with other efforts prove of how NIDA conceptualizes addiction as that have led to positive trends in the opi- a disease of the brain, an approach that Volkow oid crisis. For the first time since 1990, for has strengthened during her tenure. They claim instance, drug-overdose deaths in the United that the science behind the agency’s vision is States dropped by around 5% in 2018. valuable, but incomplete; that its focus on

Volkow has questioned the standards neuroscience skews research on drug misuse VOLKOV ESTEBAN for approving addiction medication set by A young Nora Volkow in the late 1970s. by neglecting economic and social-scientific the Food and Drug Administration (FDA): approaches to curtailing addiction; that it

hasn’t delivered many new medications; and TACKLING THE OPIOID EPIDEMIC 50 that it implicitly, and perhaps unconsciously, Funding for the US National Institute on Drug perpetuates the war on drugs. Abuse (NIDA) tracks the increase in deaths from opioid overdoses in the past decade. 40 In 2009, Wayne Hall, an addiction epide- miologist at the University of Queensland in All opioids Brisbane, Australia, began to scrutinize the Oxycodone, morphine and other natural and semi-synthetic opioids 30 neuroimaging evidence of addiction. By the Heroin end of the project, “I came to the view that the Fentanyl, tramadol and science wasn’t as clear as it’s often presented”, other synthetic opioids 20 he says. Other psychostimulants, He and his colleagues found that most of the including methamphetamine

studies, including Volkow’s, used small sam- Cocaine Number of deaths (thousands) 10 ples of people who were severely addicted, and Methadone did not tease out which brain differences they Mortality data are based on provisional counts where records 0 might have had beforehand8. The data did not are incomplete or a cause of death has not yet been allocated. Death counts are likely to be an underestimate. 2015 2016 2017 2018 seem strong enough to justify the emphasis on the brain as an explanation for addiction. “If Funding 1,600 you focus on what goes on between the ears,” NIDA’s budget jumped in Presidential proposal Hall says, “you often tend to neglect broader 2018, and the agency has social policies that we know can have a big since targeted funding 1,200 specifically to the opioid impact on the prevalence of drug problems.” crisis. It has boosted the amount of support for Others echo that criticism. NIDA’s 800 research into the social overemphasis on neurobiology has extracted and economic conditions drug misuse from its societal and economic that foster drug misuse, context, such as poverty and racism, and dis- and continues to fund 400 more neuroscience

regarded other models that see addiction as projects than any other (US$, millions) levels Funding 9 something people can unlearn , says Derek type of addiction research. 0 Heim, an addiction psychologist at Edge Hill 2012 2013 2014 2015 2016 2017 2018 2019 2020 2021 University in Ormskirk, UK. “It’s more than just Total final budget 2019 brains having gone wrong.” US$1,408.2 million

Some also argue that the political attention Center for Clinical Trials Network 3% the agency gets could translate into harmful policies. Spreading the message that drugs Neuroscience and behaviour Opioid crisis Intramural 33% 19% research 7% cause a brain disease often results in draconian measures aimed at controlling drug supply at all costs, says David Courtwright, a drug historian Epidemiology, services Therapeutics Research and prevention research and medical management at the University of North Florida in Jacksonville. 23% consequences and support

./US NATL CENTER FOR HEALTH STATISTICS. BUDGET AND ACTIVITY: NIDA. ACTIVITY: AND BUDGET STATISTICS. HEALTH FOR CENTER AHMAD ET AL ./US NATL B. F. COUNTS: DEATH SOURCES: “I think that sometimes makes Nora and others 10% 5% at NIDA feel uncomfortable because they really don’t want to see addicts sent to jail — they want that can reduce opioid-prescription rates, to eat, they won’t have a fighting chance of them to be treated,” he says. that increase the number of people receiv- breaking out of their addiction — no matter But even among her detractors, Volkow has ing medication-assisted treatment and that how many medications NIDA funds or how unexpected support. “I really admire her,” says expand the distribution of naloxone — an anti- many brains she scans. Courtwright. “I think she’s been a very effec- dote that is sprayed into the nose or injected to During her December visit to the Trotsky tive leader for NIDA.” And they recognize try to save those who have overdosed. museum, her old house, Volkow goes to the important improvements. On a hot day in October 2019, Volkow visited quiet library, away from the crowd. Memories Last year, for example, Volkow launched a Kensington, a neighbourhood in Philadelphia, of her uncle and grandfather begin to reso- project that will follow almost 11,900 healthy Pennsylvania, where the US drug crisis has left nate, and the scenes she saw in Philadelphia children into early adulthood, using neuro- a deadly trail. Syringes littered the streets. fill her thoughts. imaging to capture how a child’s biology and People injected themselves in broad daylight She knows now that there is a lot more to social environment — including any substance and others lay on the ground, showing clear their struggles with addiction than a damaged use — affect their brain development. This symptoms of withdrawal. An emaciated man brain. could help to clarify which brain anomalies shared a piece of glazed doughnut with a precede addiction and which might cause it. shivering friend. Emiliano Rodríguez Mega is a science The results will be complemented by another The scene shocked her. She had decades journalist in Mexico City. study, currently being planned, that will eval- of experience studying drug addiction in the uate the long-term impact of prenatal and lab and funding the research of others, and it 1. Volkow, N. et al. Science 221, 673–675 (1983). 2. Volkow, N. D. et al. J. Cerebr. Blood Flow Metab. 6, postnatal drug exposure on the brain. was not enough. “This is real,” she thought. She 441–446 (1986). NIDA is also spearheading a project that realized that if she didn’t address the social 3. Volkow, N. D. et al. Br. J. Psychiatry 152, 641–648 (1988). aims to reduce opioid-related deaths in realities of drug addiction, she wouldn’t solve 4. Volkow, N. D. et al. Synapse 14, 169–177 (1993). 5. Volkow, N. D. et al. Am. J. Psychiatry 151, 178–183 (1994). badly affected regions. The $354-million the epidemic or prevent future ones. 6. Volkow, N. D., Fowler, J. S., Wang, G.-J. & Swanson, J. M. effort, launched last year, aims to cut deaths Months have passed since Volkow’s trip to Mol. Psychiatry 9, 557–569 (2004). by 40% by 2023 in 67 communities in the Kensington, but a thought has swung back and 7. Volkow, N. D. et al. Sci. Transl. Med. 10, eaan2595 (2018). 8. Hall, W., Carter, A. & Forlini, C. Lancet Psychiatry 2, states of Ohio, New York, Massachusetts and forth in her head like a pendulum ever since. 105–110 (2015). Kentucky. Researchers will test strategies If people don’t have a place to sleep or food 9. Lewis, M. N. Engl. J. Med. 379, 1551–1560 (2018).