New research from the Scripps Institute may pave the way to more efficient — and more enjoyable — ways of weaning off of nicotine.
Nicotine addiction is an immensely powerful force, one that makes smokers keep smoking despite the habit’s well-documented impact on health. It’s what gets people hooked, and what makes most of those who gave up smoking relapse. Current estimations point to 60% of those who try cigarettes ending up as daily smokers, about 75% of daily smokers relapsing after quitting. However, one new, lab-tailored enzyme could help us fight against nicotine addiction by breaking most of it down before reaching the brain.
The compound was, thus far, shown to be efficient in rat models.
“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,” says principal investigator Olivier George, Ph.D., associate professor at Scripps Research.
The enzyme the team tested is known as NicA2-J1, and it’s a variation of a natural compound produced by Pseudomonas putida — which, interestingly, is the first patented organism in the world. This compound has previously been shown to reduce nicotine levels in the blood of mice.
And there lies the crux of the researchers’ interest in the enzyme. It breaks down nicotine before it even reaches the brain, making it very attractive as a means of fighting nicotine dependence. However, the original enzyme didn’t scrub nicotine fast enough for such a treatment strategy to work. So George’s team started by tweaking the enzyme to make it more efficient, increase its staying time in the bloodstream, and add a few other pharmacological properties.
The next step was to treat nicotine-dependent rats with the tweaked enzyme. For the first stage of the experiments, rats spent 21 hours per day, for 12 days, in a chamber where they could press a lever to receive a shot of nicotine. The rats soon understood the system, and self-administered nicotine until they became addicted to the substance. After these 12 days, the rats were only allowed access to nicotine once every 48 hours.
The rats experienced obvious withdrawal symptoms between these windows of time. They started escalating their intake while nicotine was available — a hallmark of deepening addiction — in a psychological bid to reduce discomfort caused by withdrawal.
However, not all rats fared the same. Those treated with the highest doses of NicA2-J1 (10 mg/kg) continued to pull the lever for a shot of nicotine if given the chance, but had significantly lower blood-nicotine levels compared to the rest of the animals. They also exhibited less pronounced signs of nicotine withdrawal, such as such as susceptibility to pain and aggressiveness, compared to the control group. One of the most encouraging finds is that NicA2-J1 treatment didn’t instantly trigger withdrawal symptoms, which usually happens when nicotine is blocked in a highly-dependent animal — think of quitting ‘cold-turkey’, but much more abruptly.
“It’s as if they were smoking 20 cigarettes but receiving the nicotine dose of only one or two, so that made their withdrawal process much less severe,” says study first author Marsida Kallupi.
“[W]hat’s unique about this enzyme is that it removes enough nicotine to reduce the level of dependence, but leaves enough to keep the animals from going into severe withdrawal,” George adds.
One of the most insidious effects of nicotine dependence is the continuation of use despite its adverse consequences — short-term impairment of lung function and physical fitness, alongside the longer-term risks of cancers, heart disease, or stroke. In other words, the compound is so addictive that users are compelled to seek it out no matter the cost. NicA2-J1 could also help in this regard, the team writes. When each lever-press had a 30% chance of directing an electric shock to the rats’ feet, those treated with NicA2-J1 quickly reduced their lever presses; those in the control group did not.
To model how effective the enzyme would be at fighting relapses, the team took the rats off of nicotine for 10 days straight — any smoker here will shiver at the mere thought (yes, nicotine addiction is that bad). The team gave each rat an injection of nicotine after the 10 days to restart their desire for the drug, and then restored their access to the lever. Untreated rats responded in a rather predictable way: they pressed the lever as much as they could, as fast as they could. Rats treated with NicA2-J1, in contrast, used the lever more sparingly. The same effect was seen when the team triggered relapse in all the rats using a stress-inducing compound (which was meant to mimic the way stress can cause relapse in humans).
Nicotine is an extremely hard habit to kick as it fosters both physical and psychological dependence, and users develop tolerance over time. It’s an extremely addictive compound, similar to heroin and cocaine. Discontinuation of use (after dependence sets in) is particularly nasty, involving both affective (mood-related) and somatic (body-related) withdrawal symptoms, ranging from anxiety and poor mood to tremors. Withdrawal effects peak in the first few days of discontinuation but can last for upwards of several weeks. Most people don’t make it past the first few days.
“The majority of smokers would like to stop smoking, and each year about half try to quit permanently. Yet, only about 6 percent of smokers are able to quit in a given year,” reports the National Institute on Drug Abuse (NIDA).
Since nicotine is extremely addictive, it’s hard to give up; even worse, those that do manage this feat are very prone to relapse. That, in itself, isn’t necessarily a bad thing; as the team notes in the paper’s opening line, however, “[t]obacco use disorder is the leading cause of disease and preventable death worldwide” (which is very bad). The CDC also supports this statement. NicA2-J1 shows a lot of promise as a treatment to help smokers wean off of nicotine since it prevents the substance from reaching the brain in the first place, takes the edge off of withdrawal, and makes relapses less likely to happen. The team hopes to start clinical trials with human subjects soon — but first, they’ll work on making the enzyme even more effective.
The paper “An enzymatic approach reverses nicotine dependence, decreases compulsive-like intake, and prevents relapse” has been published in the journal Science Advances.
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