Acetylcholinesterase Inhibitor and Nicotine

I have read several social media articles about smokers explaining why they could not quit smoking even when they were aware of its health consequences. Since nicotine is a psychoactive drug, I wanted to find a study that used an antagonist drug to reduce nicotine intake in humans or rats. I found a 2016 study, which confirmed that the administration of an acetylcholinesterase inhibitor (galantamine or donepezil) reduces nicotine reinforcement in rats and smoking behavior in humans with minor side effects.  

For methodology, three different tests were done on rats: nicotine self-administration following repeated AChEI administration, sucrose self-administration (as a control), and pica or affect food intake. For sucrose and nicotine self-administration tests, rats were pre-trained on a fixed-ratio-5 schedule of reinforcement and divided into different treatment groups. In all experiments, rats were pretreated with galantamine or donepezil 20 minutes before the beginning of the operant test sessions for 10 consecutive test days. The total kaolin intake was used to measure for pica behavior. The total chow intake was used to measure ad libitum feeding behavior changes per day. Rats were weighed before the test and the changes in body weight were recorded over the 24 hour testing session. On the other hand, human participants were healthy smokers, ages 18-60 years old, who had smoked at least 10 cigarettes per day over the past 6 months. The human testing took place over a 2-week period. For the first week, participants took either placebo or 8 mg galantamine daily and for the second week, either placebo or 16 mg galantamine daily. After each week, participants attended a brief 20 minute observation to assess side effects. Craving and withdrawal were considered exploratory outcomes because subjects were still smoking during the two weeks. The placebo and galantamine were packaged in similar capsules to ensure double-blind testing conditions. 

The results of the experiment showed that the repeated galantamine administration led to a decrease in nicotine intake for rats, but no changes were observed in the ones who took the sucrose. The decrease in nicotine intake in rats was measured by the decrease in the total lever responses. Total lever responses decreased from 100 to 50 per day and nicotine infusion was decreased from 20 to 7 infusions per day in comparison with the group who had 0 mg/kg of galantamine (Figure 1). Similarly, donepezil reduced nicotine intake for rats from 100 to 40 lever responses (Figure 3). Galantamine and donepezil did not alter pica or feeding behavior in rats (Figure 2 and 4). Total change in body weight was also unaffected by the repeated intake of the two drugs in comparison with the control. For the human study, repeated galantamine treatment in smokers reduced their smoking rate during the two weeks from 15 to 13 cigarettes per day (Figure 5). Also, on a six point scale, galantamine reduced smoking satisfaction and reward by the end of the second week from 5 to 3 for smoking satisfaction and from 4 to 2 in comparison with the baseline (Figure 6). However, repeated galantamine was associated with increased side effects, such as nausea when compared with the placebo (Figure 7). Repeated donepezil had no effect on the smoking behavior which could be due to the dosage. Therefore, no data on donepezil for human participants was provided. To sum up, the findings of this study are consistent with previous studies of the effects of acute AChE inhibitor on nicotine intake in rats. This study proves that increased cholinergic transmission is sufficient to reduce nicotine reinforcement. Also, the results showed how galantamine treatment reduces smoking behavior compared with placebo in healthy human smokers without causing major side effects. Future studies should identify the specific cholinergic mechanisms and nAChR subtypes that mediate the effects of AChEIs on nicotine self-administration.


Ashare, R L, et al. “Repeated Administration of an Acetylcholinesterase Inhibitor Attenuates Nicotine Taking in Rats and Smoking Behavior in Human Smokers.” Nature News, Nature Publishing Group, 19 Jan. 2016 


Nascimento, F., et al. “Balanced cholinergic modulation of spinal locomotor circuits via M2 and M3 muscarinic receptors.” Nature News, Nature Publishing Group, 01 October 2019.