Engineered Enzyme Stops Nicotine Addiction Without Withdrawal Symptoms

A man lighting a cigarette

About 60% of people who try a cigarette will end up a daily smoker. After quitting, about 75% of them relapse within the first year. Why? Because nicotine dependence keeps them smoking despite all the harm it does to their health. Thanks to a newly engineered enzyme by scientists at Scripps Research, nicotine in the bloodstream is broken down before it can reach the brain reducing the desire for more nicotine.

 

chart showing the nicotine addiction cycle in rats

The bacterium Pseudomonas putida produces one version of the natural enzyme NicA2-J1. For this study it was modified to optimize its staying time in the blood, its potency, and other pharmacological properties. The objective of this research is to be able to use this enzyme as an aid for battling nicotine dependence so addicts will refrain from relapsing when given access to nicotine again.

A hallmark of tobacco use disorder is the continual administration of nicotine in the face of adverse consequences. Smoking is responsible for over 400,000 deaths in the United States of America alone and yet people continue to do it. The fact that backs up this behavior is that abstinence from chronic nicotine intake leads to withdrawal symptoms of irritability, aggression, and hyperalgesia causing an increase in a person’s cravings for nicotine, hence, a powerful urge to smoke tobacco in order to relieve the negative effects.

What is special about this enzyme approach is that it removes enough nicotine to reduce the level of dependence but leaves enough to keep from going into severe withdrawals. In other words, it’s as if a person was smoking 20 cigarettes yet receiving the nicotine dose of only one or two making their withdrawal process much less grim.

A study was conducted on rats where one group was treated with NicA2-J1 while the other was not. Both were supplied with a lever to self-administer nicotine. The lever was rigged with a 30% chance to shock the animal on contact. The group that had been treated with the enzyme exhibited a significant reduction of nicotine intake while the group that was not continued to respond for nicotine despite the adverse consequences of possible foot shocks.

Principal investigator Olivier George, PhD, Associate Professor at Scripps Research says, “This is a very exciting approach because it can reduce nicotine dependence without inducing cravings and other severe withdrawal symptoms, and it works in the bloodstream, not the brain, so its side effects should be minimal.”

The scientists also looked into the susceptibility to relapse after abstinence. The rats were taken off nicotine for 10 days and were then given a nicotine injection to re-awaken their desire for nicotine. The rats untreated with the enzyme returned to their lever presses by a large amount, and those treated, much less.

The same effects were seen when instead of injecting the rats with nicotine, they used a stress-inducing drug, mimicking the way that stress causes relapse in humans.

The Scripps Research team now hopes to take NicA2-J1 into clinical trials in humans. However, first scientists plan to do further work to optimize its properties as a drug. They also plan to test the enzyme against varenicline (Chantix), a compound that blocks nicotine activity in the brain and which is currently viewed as the most effective smoking-cessation drug.

An enzymatic approach reverses nicotine dependence, decreases compulsive-like intake, and prevents relapse was published online in Science Advances on October 17, 2018.