obituary Remembering Mary Jeanne Kreek and her many contributions to addiction science hen Dr. Mary Jeanne Kreek World Health Organization’s (WHO) list of passed away on March 27, at the most efficacious, safe, and cost-effective Wage 84, the field of addiction medicines for priority conditions3, and it science lost a true giant. Her research not has helped countless patients with opioid only paved the way for the first medication addiction toward leading healthy and treatment for opioid addiction, but also productive lives. made landmark contributions to our In the 1970s, when methadone was understanding of addiction as a brain first making inroads treating patients with disorder, the genetic factors underlying opioid addiction, the mechanisms of opioid addictive disorders, and the close links compounds’ actions in the brain were still between injection drug use and HIV. poorly understood. Opioid receptors were Kreek had been the Patrick E. and Beatrice first identified in 1973, and opioid peptides M. Haggerty Professor and Head of the were discovered in 1975. Kreek’s research Laboratory of the Biology of Addictive in her lab at The Rockefeller University Diseases at The Rockefeller University in over the following years clarified how the New York City and Senior Physician of The endogenous opioid signaling system plays a Rockefeller University Hospital. role not only in opioid addiction but also in Bitten by the science bug at an early age, addiction to alcohol and cocaine. Kreek already knew when she was a little Among her many important girl that she would go into medicine. As contributions to the field of addiction she tells it in an oral history interview for research over subsequent decades, Kreek The Rockefeller University1, she entered was the first to identify injection drug use Credit: JOSIE ANDERSON her first science fair in the sixth grade, and as the second major risk behavior (after at age 15 participated in a TV series called unprotected sex) for HIV transmission. Youth Wants to Know. Following a bout of Kreek also played a role in the development polio in her early teens, she studied and failing. Working with formerly incarcerated of the opioid partial agonist buprenorphine practiced ballet to help recover, and then people in active opioid use whom they as an opioid addiction treatment, which was danced semi-professionally in the National brought to Rockefeller University Hospital, finally approved for that indication in 2002 Ballet Company in Washington DC, where the research team found that individuals (and is also on the WHO list of essential she lived. She then taught dance to support with severe heroin addiction were no longer medicines). Later she went on to elucidate herself during her undergraduate education able to obtain a high (euphoria) from the the genetic underpinnings of addictive at Wellesley College. After graduating in drug but took it just to feel normal—a crucial disorders, including polymorphisms 1958, she went on to receive her medical distinction that remains central to how controlling the expression of mu and kappa degree from Columbia University College of we understand addictive behavior today. opioid receptors, as well as polymorphisms Physicians & Surgeons in 1962. This was the theme of a landmark paper2 associated with atypical stress responses Kreek’s initial contributions to addiction Kreek co-wrote with Dole and Nyswander contributing to vulnerability for drug and medicine started in 1964, while she was in about their research, “Narcotic blockade” in alcohol addiction. her second year of residency in Internal Archives of Internal Medicine in 1966. Kreek received many honors for her Medicine at Cornell University–New York Kreek went on to develop techniques to pathbreaking contributions, including the Hospital Medical Center. She was invited measure methadone concentration in blood Betty Ford Award from the Association for to join the lab of Vincent Dole at The and other tissues, which facilitated studies Multidisciplinary Education and Research Rockefeller Institute for Medical Research. on its efficacy and safety and eventually led in Substance use and Addiction in 1996, Vincent Dole, along with psychiatrist to the US Food and Drug Administration the R. Brinkley Smithers Distinguished Marie Nyswander, was researching the (FDA) approval of methadone as a treatment Scientist Award of the American Society biology of addiction. Together with for heroin addiction in 1973. For the of Addiction Medicine in 1999, and the Kreek, the researchers determined that next 20 years, until the FDA approved National Institute on Drug Abuse’s Lifetime heroin addiction involved neurochemical levo-alpha-acetyl-methadol (LAAM) for Science Award in 2014. The College on alterations and that the longer-acting orally this indication in 1993, methadone was the Problems of Drug Dependence awarded administered opioid analgesic methadone only medication available to people with her the Nathan B. Eddy Memorial Award could potentially be used to help treat it. heroin addiction. While LAAM is no longer for Lifetime Excellence in Drug Abuse The recognition by Kreek and her on the market, methadone is the preferred Research in 1999 and the Marian Fischman colleagues that heroin addiction was a treatment in many countries for patients Lectureship Award in 2005. In 2000, the disorder of the brain that had behavioral with severe addiction, who inject heroin Doctor Honoris Causa was conferred on her consequences was a major shift in a world and other opioids and are at highest risk for by the University of Uppsala, Sweden. where addiction was still considered by most relapsing, overdosing, and dropping out of Kreek’s emphasis on addiction as a brain people to be a criminal behavior or a moral treatment. Methadone is included on the disorder and her discoveries of how brain NATURE NEUROSCIENCE | VOL 24 | JULY 2021 | 899–900 | www.nature.com/natureneuroscience 899 obituary stress responses contribute to addiction climbing a mountain to enjoy lunch ‘with Institutes of Health, Bethesda, MD, USA. were far ahead of their time. But besides her a view’ during an International College of 2National Institute on Alcohol Abuse and brilliant scientific mind, she also possessed Neuropsychopharmacology meeting in Alcoholism, National Institutes of Health, Bethesda, an extraordinary ability to interface with Colorado—and her drive was infectious. MD, USA. the ‘real world’ to help translate her research Her brilliance, alongside her insatiable ✉e-mail: [email protected] findings to inform policy. energy, her sharp sense of mission, and Mary Jeanne’s loss is particularly her kindness inspired and transformed Published online: 14 May 2021 painful to those of us who knew and many of us in the field. https://doi.org/10.1038/s41593-021-00863-z worked with her because, apart from her And importantly, in 2021 as we continue scientific contributions, she was also an to confront the worst opiod crisis our References extraordinary role model and mentor, country has ever experienced, Mary Jeanne’s 1. Interview with Mary Jeanne Kreek. Te Rockefeller University especially for women scientists. There were work left us with some of the most powerful https://www.rockefeller.edu/about/history/oral-history-project/ interview-mary-jeanne-kreek/ (2021). no obstacles that would stop her—whether tools we have to prevent mortality and 2. Dole, V. P., Nyswander, M. E. & Kreek, M. J. Narcotic blockade. it was undertaking the laborious research achieve recovery. ❐ Arch. Intern. Med. 118, 304–309 (1966). necessary to prove a hypothesis, speaking up 3. 21st WHO Essential Medicines List (EML). WHO Model List 1 ✉ 2 of Essential Medicines https://www.who.int/groups/expert- to support minority scientists, confronting Nora D. Volkow and George F. Koob committee-on-selection-and-use-of-essential-medicines/ atavistic ways of treating addiction, or even 1National Institute on Drug Abuse, National essential-medicines-lists (World Health Organization, 2019). 900 NATURE NEUROSCIENCE | VOL 24 | JULY 2021 | 899–900 | www.nature.com/natureneuroscience.