"Despite several safe drug therapies available to help smokers quit threequarters report relapsing within six months of a quit attempt. University of Pennsylvania researchers Rebecca Ashare and Heath Schmidt saw potential for a permanent cessation solution in a class of FDAapproved medications used to improve cognitive impairments from Alzheimers disease. In a study consisting of a rat trial and a human trial Ashare and Schmidt studied the effects of two acetylcholinesterase inhibitors or 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 not the placebo smoked . fewer cigarettes daily a  percent decrease and noted feeling less satisfied with the cigarettes they did smoke. Were very interested in screening potential efficacy of antiaddiction medications in our models said Schmidt a professor in Penns School of Nursing and Perelman School of Medicine. For this study we looked at potential smokingcessation medications. The research itself took a translational approach what Ashare a professor in Penn Medicines psychiatry department calls bidirectional. In other words the preclinical data informed the clinical study and vice versa. At Penns Center for Interdisciplinary Research on Nicotine Addiction work on smoking cessation has been ongoing since . Specifically research from Caryn Lerman CIRNAs director and the Mary W. Calkins Professor in Psychiatry concluded that people who quit smoking often report a decrease in whats commonly called their executive functions. They feel fuzzy. Theyre 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. Thats when they turned to the acetylcholinesterase inhibitors. In the brain the neurotransmitter called acetylcholine is important to cognitive functions like learning and shortterm memory. When nicotine enters the body it binds to the same receptors in the brain that acetylcholine binds to resulting in smokings rewarding and reinforcement effects. Acetylcholinesterase inhibitors increase acetylcholine levels in the brain and in effect substitute nicotines effects. Schmidt 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 selfadministered nicotine using a lever pushed at will. Once nicotinetaking stabilized the rats were pretreated with one of the two AChEIs. For both drugs we were able to show a reduction in total nicotine selfadministered Schmidt said however there was a caveat. We know from the literature that upward of  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 selfadministration but we wanted to make sure it wasnt because the rats were sick. Unlike humans who can verbally report when they dont feel well and whose bodies react to nausea rats lack the reflex to vomit. In previous research 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 selfadministration the AChEIs did not make our animals sick Schmidt said. The findings sparked the CIRNA clinical trial which has to date studied  smokers ages  to . People who were interested in quitting smoking signed on for  days. For the first two weeks they continued to smoke but also took either galantamine or a placebo. Before the trial began researchers assessed the smokers cognitive function to get a baseline. Participants followed the regimen for two weeks and then were asked to not smoke for one full day. Two more assessments took place after the two weeks on the cigarettedrug combination and again after that initial smokefree 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 weeklong period is a proxy for longerterm cessation. The ability to quit smoking the first week after you make a quit attempt is highly predictive of longterm success Ashare said. Shes still actively recruiting for the trial with an aim of  people total. Once the trial reaches that number shell dig into overall quit data. What shes learned so far  that smokers who used the FDAapproved galantamine smoked fewer cigarettes per day and enjoyed them less  is promising particularly given that those who dont smoke during that first crucial week are  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 theyre effective. Our goal is to target different populations of smokers who may be more likely to experience these cognitive deficits. Theres no data to suggest that a clinician treating a smoker should prescribe one of these AChEIs now. But Ashare and Schmidt are forging a path and if it leads where they think it might it could provide smokers yet another option to help them quit. Ashare and Schmidt published their work in the Nature journal Translational Psychiatry."