A new study may have found a way for smokers to quit for good, with FDA-approved medications used to improve cognition in those with Alzheimer’s disease.
In a study at the University of Pennsylvania that included a rat trial and a human trial, researchers Drs. Rebecca Ashare and Heath Schmidt studied the effects of two acetylcholinesterase inhibitors (AChEIs), called galantamine and donepezil, on overall nicotine intake.
The rat component showed that pretreating the rodents with an AChEI decreased their nicotine consumption.
Consistent with these effects, clinical trial participants taking the AChEI smoked 2.3 fewer cigarettes daily, a 12 percent decrease, and noted feeling less satisfied with the cigarettes they did smoke, according to the researchers.
The research took a translational approach, what Ashare, a professor in Pennsylvania Medicine’s psychiatry department, calls bi-directional. In other words, the preclinical data informed the clinical study and vice versa, she explained.
At Pennsylvania’s Center for Interdisciplinary Research on Nicotine Addiction, work on smoking cessation has been going on since 2001. Research from Caryn Lerman, CIRNA’s director, found that people who quit smoking often report a decrease in what’s commonly called their executive functions.
“They feel fuzzy. They’re forgetful,” Ashare said. “Those deficits are related to their ability to quit smoking. It was this clinical aspect of smoking cessation we thought would be useful to take further.”
That’s when the researchers turned to the acetylcholinesterase inhibitors.
In the brain, the neurotransmitter acetylcholine is important to cognitive functions like learning and short-term memory. When nicotine enters the body, it binds to the same receptors in the brain that acetylcholine binds to, resulting in smoking’s rewarding and reinforcement effects. Acetylcholinesterase inhibitors increase acetylcholine levels in the brain and, in effect, substitute nicotine’s effects.
Schmidt, a professor in Pennsylvania’s School of Nursing and Perelman School of Medicine, had successfully employed such a model with other addictive substances like cocaine.
He divided a group of rats into galantamine and donepezil cohorts. To mirror voluntary drug taking in humans, the rats self-administered nicotine using a lever pushed at will. Once nicotine-taking stabilized, the rats were pretreated with one of the two AChEIs.
For both drugs, “we were able to show a reduction in total nicotine self-administered,” Schmidt said, noting that there was a caveat.
“We know from the literature that upward of 30 percent of patients will report nausea and vomiting [when taking these drugs], and this will limit their compliance,” he said. “We had seen that these drugs reduced nicotine self-administration, but we wanted to make sure it wasn’t because the rats were sick.”
Unlike humans who can report when they don’t feel well and whose bodies react to nausea, rats lack the reflex to vomit.
In previous research, Dr. Matthew Hayes, who has appointments in Penn Medicine and Penn Nursing, had shown that, in rats, kaolin clay consumption coats the stomach like an antacid and quells any ill effects. Collaborating with Hayes, Schmidt offered the animals kaolin clay, then compared how much they ate normally and with the addition of the AChEIs.
“At the doses shown to reduce nicotine self-administration, the AChEIs did not make our animals sick,” Schmidt said.
The findings sparked the clinical trial, which has to date studied 33 smokers between the ages of 18 and 60.
People who were interested in quitting smoking signed on for 23 days. Before the trial began, researchers assessed the smokers’ cognitive function to get a baseline.
For the first two weeks of the trial, they continued to smoke, but also took either galantamine or a placebo. They were then asked to not smoke for one full day.
Two more assessments took place: After the two weeks on the cigarette-drug combination and again after that initial smoke-free day.
Finally, the researchers asked the study subjects to do their best to not smoke for seven straight days, a time during which the participants still took either galantamine or a placebo.
“That week-long period is a proxy for longer-term cessation,” Ashare said. “The ability to quit smoking the first week after you make a quit attempt is highly predictive of long-term success.”
She’s still actively recruiting for the trial, with an aim of 80 people total. Once the trial reaches that number, she’ll dig into overall quit data.
She said that what she’s learned so far — that smokers who used the FDA-approved galantamine smoked fewer cigarettes per day and enjoyed them less — is promising, particularly given that those who don’t smoke during that first crucial week are 32 times more likely to quit smoking permanently.
“Our goal in investigating these different repurposed medications is not to replace the medications that are already available,” she said. “We know that they’re effective. Our goal is to target different populations of smokers who may be more likely to experience these cognitive deficits.”
The study was published in the Nature journal Translational Psychiatry.