Despite decades of public health messaging, smoking tobacco persists as the leading cause of preventable death in the U.S., where the Centers for Disease Control and Prevention estimate close to 40 million adults smoke. And despite the availability of nicotine replacement therapies—gums, the patch—and medications designed to ease cravings such as varenicline, many people still fail to quit despite their best intentions to do so.
“It is difficult to quit because nicotine withdrawal is severe,” acknowledges Marisa Kallupi, Ph.D., a researcher in the Olivier George lab at the Scripps Research Institute. In a recently published paper in Science Advances, Dr. Kallupi and her colleagues noted that between 75–80% of people who attempt to quit smoking relapse within 12 months. That sent them looking for a different approach to helping people quit smoking, one that keeps nicotine from flooding receptors in the brain to begin with.
In their paper, Dr. Kallupi and colleagues describe the use of a novel enzyme, NicA2-J1, which degrades nicotine in the blood stream of nicotine-dependent rats. Derived from Pseudomonas putida, a bacterium that was successfully living on the tobacco plant, the hope was that the enzyme would degrade enough of the nicotine the rats consumed before it reached their brains so that the reinforcing effects of nicotine would dissipate, but it would allow enough nicotine to persist so that the animals would not experience withdrawal symptoms.
“The dose effect of nicotine is like an inverted U-curve,” Dr. Kallupi says. Give too small a dose, and there isn’t enough of a reward, so the animal doesn’t pick up the habit. Give a little more, and they will seek nicotine, exhibiting addictive behavior; give too much, and they cut back. By keeping the amount of nicotine actually reaching the brain at the low end of that curve, Dr. Kallupi says, the hope was that the smoking habit would be extinguished as the rats lost the rewarding effects of nicotine over time. She and her colleagues noted in the paper that a similar strategy had been tried with vaccines, but that they allowed too much nicotine to reach the brain to extinguish the habit.
NicA2-J1 had been previously shown to prevent rats from becoming dependent on nicotine, but to be a useful treatment for nicotine addiction in people, notes Dr. Kallupi, the enzyme would need to prove useful in rodents already dependent on nicotine, and in a context of active, compulsive self-administration, which characterizes human tobacco use. “We have to make sure we’re mimicking what happens in humans,” she says.
Hallmark of Nicotine Dependency
The team placed already nicotine-dependent rats in self-administration boxes where they could choose between food, water, and nicotine infusions for 21 hours a day. They then paired 30% of nicotine administrations with an electric shock to see if rats would continue to choose nicotine in the face of negative consequences, “a hallmark of tobacco use disorder.”
The rats who received NicA2-J1 significantly reduced their nicotine intake after the shocks began, while the control rats persisted in seeking the drug did not. The NicA2-J1 treated rats were also more resistant to relapsing in the face of stress—more shocks, chemical stressors—or from being given nicotine after a 10-day period of abstinence. Crucially, according to Dr. Kallupi, the NicA2-J1 treated rats appeared to experience fewer of the negative symptoms associated with quitting tobacco.
“The study is certainly well done, elegant, and will have an impact on the field,” says M. Imad Damaj, Ph.D., professor of pharmacology and toxicology and co-director of the Translational Research Initiative for Pain and Neuropathy Virginia Commonwealth University Medical Center. His research focuses on the role of nicotinic receptors in addiction and pain.
“The current vaccine approach did not work well for now so this one is exciting,” Dr. Damaj says. “It sounds like a ‘nicotine reduction strategy’ with a potentially better outcome.”
There are some limitations to the study that Dr. Damaj says he would like to see addressed in future work. For one, the study used male rats, which could have implications for translatability to humans. “Women experience both a greater number and a wider variety of withdrawal symptoms than men following either a quit attempt in clinical studies or a period of smoking abstinence in laboratory studies,” he says. “Women may have more difficulty quitting than men and studies found poorer outcomes in women versus men in using nicotine patches.”
One other potential drawback is if the enzyme should make it to clinical trials, Dr. Kallupi admits, human smokers might actually smoke more initially, as they would need to smoke more cigarettes to receive the same reward. But absent withdrawal symptoms, and with a present intent to quit, she believes “they will stop smoking little by little because it is not worth it smoking one pack to have the effect of two cigarettes.”
Human clinical trials are still a bit away. Next up, Dr. Kallupi says, is obtaining funding for another study looking at optimal dose ranges of NicA2-J1, potential toxicity, and if the enzyme could be combined with other smoking cessation medications for synergistic effect.
“For example, varenicline. What happens if low doses of this enzyme are combined with low doses of varenicline?” she says. “Does it reduce the negative effects of varenicline? Does it make the withdrawal better than the enzyme by itself?”
And whether or not NicA2-J1, alone or in combination with other medications, proves ready for human clinical trials, Dr/ Kallupi sees this study as a proof-of-concept for this strategy, one that could potentially be pursued with similar enzymes for other drugs of abuse.
“I think the pharmacological treatment now will be substituted with this engineered enzyme or vaccines,” she says. “I think this is the future now.”