2. Main Text

When a person inhales smoke from a cigarette, nicotine gets into the lungs and is absorbed into the pulmonary venous circulation and enters the arterial circulation [Reference Benowitz5]. Nicotine then moves rapidly to the brain and binds to nicotinic cholinergic receptors (nACHRs), particularly the α4β2 receptor [Reference Benowitz5]. Stimulation of nACHRs releases neurotransmitters in the brain such as acetylcholine and dopamine. When dopamine is released in a large amounts, it is associated with intense pleasure and a sense of relief leading to nicotine addiction [Reference Benowitz5]. Varenicline is a selective partial agonist which acts on nACH receptors including α4β2 [Reference Maity, Chand and Murthy6]. It is useful to understand the difference between full and partial nicotine agonists. A full nicotine agonist will cause substantial dopamine release. However, a partial nicotine agonist such as varenicline will release dopamine to a lesser extent than a full agonist [Reference Maity, Chand and Murthy6]. Moreover, the partial antagonist action will block the effects of any nicotine entering the system [Reference Benowitz5]. It activates the receptors at lower concentrations, which is helpful in smoking cessation in two ways. Firstly, the partial agonist action maintains moderate levels of dopamine to counteract the withdrawal symptoms. Secondly, partial antagonist activity reduces smoking satisfaction [Reference Maity, Chand and Murthy6]. Galantamine is an acetylcholinesterase inhibitor and nicotinic receptor agonist [Reference Wilkinson and Gould7]. It is widely recommended and used as a cognitive enhancer as it inhibits acetylcholinesterase which leads to prolonged exposure of acetylcholine in the brain [Reference Wilkinson and Gould7]. This may be useful in reducing the cognitive deficits associated with nicotine withdrawal [Reference Wilkinson and Gould7]. Moreover, since it is also a nicotine receptor agonist, it acts as an allosteric (alteration of the activity) positive modulator of nACH receptors [Reference Wilkinson and Gould7]. The binding sites of full nicotine agonists are between the α and β subunits. However, due to the allosteric function, galantamine binds only to α subunit which includes α4β2 [Reference Wilkinson and Gould7]. It has around 90% bioavailability and has a relatively large volume of distribution and low protein binding [Reference Farlow8]. Metabolism is mainly through the cytochrome P450 system, specifically the CYP2D6 and CYP3A4 isoenzymes [Reference Farlow8]. Polycyclic aromatic hydrocarbons (PAHs) of tobacco smoke interact with cytochrome 450 (CYP) enzymes such as CYP1A1, CYP1A2, possibly CYP2E1, and Uridine diphosphate-glucuronosyl transferase (UGTs) enzymes [Reference Maideen9]. The medications metabolized by CYP1A1, CYP1A2, CYP2E1, and UGT enzymes might be affected by tobacco smoking and require higher doses to be prescribed due to decreased plasma concentrations through increased induction by PAHs of tobacco smoke [Reference Maideen9]. Since galantamine is mainly metabolized through CYP2D6 and CYP3A4 [Reference Farlow8], it may not interact with PAHs.

Based on the description above, varenicline and galantamine appear to have similar mechanism of action in alleviating the symptoms of nicotine withdrawal. However, varenicline is the recommended drug of choice over galantamine for smoking cessation. A study conducted by Ashare et al. in 2016 indicated that galantamine treatment reduces smoking satisfaction and rewards with minimal side effects [Reference Ashare, Kimney, Rupprecht, Bowers, Hayes and Schmidt10]. Maclean et al. [Reference Maclean, Waters, Brede and Sofuoglu11] reported that galantamine reduces smoking behaviour if started prior to a quit attempt [Reference Maclean, Waters, Brede and Sofuoglu11]. If we compare the side effect profile of varenicline and galantamine, both have cardiovascular side effects and are recommended for use with caution. Varenicline is sometimes underutilised due to its cardiovascular and psychiatric side effects [3]. However, there is no caution in place for the use of galantamine in people having mental health problems [12]. A randomized trial by Sangaleti et al. [Reference Sangaleti, Katayama and Angelis13] found that galantamine treatment reduces oxidative stress by increasing antioxidant enzyme activities which includes superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase [Reference Sangaleti, Katayama and Angelis13]. Moreover, galantamine significantly alleviates insulin resistance reducing the risk of metabolic syndrome and cardiovascular diseases [Reference Sangaleti, Katayama and Angelis13].

Several randomized controlled trials have been conducted to determine the effectiveness of varenicline for smoking cessation compared with placebo. However, there are not many studies to illustrate the effectiveness of galantamine for smoking cessation. A randomized, placebo-controlled trial conducted by Diehl et al. [Reference Diehl, Nakovics, Croissant, Smolka, Batra and Mann14] suggested that in 114 randomized smokers who received galantamine (n = 56) or placebo (n = 58) for 12 weeks, there was 20% reduction in cumulative number of cigarettes smoked in the galantamine group compared to placebo [Reference Diehl, Nakovics, Croissant, Smolka, Batra and Mann14]. Moreover, the average number of smoked cigarettes per smoking day as well as the cotinine values reduced by 10% in those on galantamine compared to placebo [Reference Diehl, Nakovics, Croissant, Smolka, Batra and Mann14]. However, the aim should be to abstain from smoking rather than reducing the number of cigarettes and tobacco intake [3]. It would be interesting to do a randomized double-blind controlled trial comparing varenicline with galantamine to determine the effectiveness as both have similar mechanisms of action. The duration of treatment of varenicline is 12 weeks, which begins two weeks before the quit date. It can be prescribed for another 12 weeks to prevent relapse. However, limited evidence suggests that varenicline can contribute to relapse prevention [Reference Cahill, Lindson-Hawley, Thomas, Fanshawe and Lancaster15]. As far as galantamine is concerned, it is generally prescribed lifelong as a cognitive enhancer in dementia. There is a potential for galantamine to be prescribed as a relapse prevention treatment in smoking cessation.