In his view, “Alcoholism is a set of multiple, complex diseases that change over time [and are influenced by] environment and medication. It is a set of diseases that can be staged and that would require treatment protocols, much like cancer—there would be different protocols for different kinds,” he told a Lipsett Amphitheater audience that gathered on May 21 for the NIAAA-sponsored event.
“Abstinence might not be the gold standard,” he continued. “Reducing harm is just as important, I would argue.”
Johnson’s lecture confirmed a number of personality traits described by NIAAA acting director Dr. Kenneth Warren, who introduced the guest speaker. “A love of adventure defines Dr. Johnson as both a scientist and a person,” said Warren, noting that “Kole” is a helicopter pilot, car racer and the recipient, from the Queen of England, of a coat of arms. Johnson’s talk combined happy-hour conviviality with a review of six successive experiments that illustrated yet another of his proverbs: “When a needle falls in a deep well, many will look, but few will go deep after it.”
NIAAA acting director Dr. Kenneth Warren (l), who introduced the guest speaker, said, “A love of adventure defines Dr. Johnson as both a scientist and a person.”
Photos: Ernie Branson
Emphasizing science’s reliance on a curious and receptive community, he observed, “Science depends on providence, some luck, a lot of guessing and really a lot of fear…we could have failed tremendously. Every building block of scientific discovery depends on small things, not on big ones.”
The “small thing” for which he is best known is discovery that ondansetron—an off-label medication (also, he said, “the only word I know that begins and ends with ‘on’”) he thought might be effective in treating alcoholism—effectively suppresses the craving for alcohol in a subset of patients.
“Alcoholism is a medical disease with moderate to high heritability,” he explained, “but even today, many people don’t believe it. It is not a disease of personality.” Studies have shown that it is about 60 percent heritable, which leads to an obvious question: How to remove the pathways of heritability?
Johnson, who chairs the psychiatry department at the University of Virginia, and his colleagues have found that cortico-mesolimbic dopamine neurons are the principal neurocircuitry through which alcohol’s reinforcing effects are expressed. “There are around 104 or 105 neuronal networks that explain why people drink too much. It’s a very complicated process,” he said.
Alcoholism, he argues, is a heterogeneous disorder, not a uniform one, and has distinct biological subtypes. For example the biology underlying early-onset versus late-onset alcoholism is different; ondansetron works in the former category, but not in the latter.
“It is a very tall order,” he said, “getting the right medicine for the right patient at the right time and for the right length of time.”
His team has focused on two major brain neurotransmitters, dopamine and serotonin, guessing that “something big must control this process.” In their studies of what controls gating of serotonin function, they found that healthy control subjects had a gene type that promotes increased scavenging of serotonin in the brain. “In alcoholics, something really strange happens—the system reverses itself,” he said, with lower amounts of serotonin uptake a distinguishing factor. Alcoholics actually had a hypofunctional serotonin state.
Johnson’s team found that carriers of the “L” form of a particular gene were at risk of developing alcoholism, vulnerable to a “fast-forward” process. Carriers of the “SS” form of the gene, conversely, seemed protected. Skeptical, owing to the proverb “A single tree cannot make a forest,” that craving for alcohol might be genotype-dependent, the scientists did further work, in test tubes, showing that mRNA expression levels indeed confirmed the gene’s usefulness as a biomarker.
Johnson said treatment of alcoholism is proceeding toward personalized medicine, where therapy is tailored to underlying biology.
Johnson applauded the rationality of proceeding from a patient’s DNA sample, to determining genotype, to finding a useful drug as vastly superior to the treatment that prevailed when he was a young intern in London, when patients would endure a bit of hectoring on the part of a physician, then pop a pill and vomit.
Johnson said treatment of alcoholism is proceeding toward personalized medicine, where therapy is tailored to underlying biology. In addition to ondansetron, a number of drugs have been effective, he said, including olanzapine, naltrexone, baclofen and topiramate. “Genotype can predict treatment response,” he said.
Johnson wonders whether excessive drinking is a symptom or a disease, and if abstinence is still relevant. What new drug targets can science uncover? “We presume all alcoholism is the same,” he lamented. The placebo response, too, is a mystery: Is it a molecular characteristic? Is it the same for everyone? Johnson says he can imagine a day when placebo becomes an option for treatment, not an exclusion from treatment.
He predicts a future in which physicians employ a panel of medications that “can work downwards or sideways…This is one of the most exciting areas of science,” he concluded, “and one of the most exciting areas of discovery. We need to get the message out. It’s better than just guessing.”