Acute effects of inhaled menthol on cognitive effects of intravenous nicotine among young adult cigarette smokers
Introduction
Although cigarette use has decreased in the U.S., preference for menthol flavoring in cigarettes among smokers has continued to increase, particularly among minority and vulnerable populations (Cwalina et al., 2020, Villanti et al., 2016). With menthol potentially contributing to the initiation and maintenance of tobacco use (Mills et al., 2020), the impact of menthol flavoring in tobacco products continues to remain a public health concern. Menthol has long been added to cigarettes for its cooling effect to ease the harshness of smoking; however, menthol also has additional neurobiological impacts beyond being a notable flavor (Wickham, 2020). Therefore, it is important to explore potential factors that may increase menthol’s appeal and contribution to addiction. Especially with the multifaceted effects of menthol and nicotine, understanding both direct and interactive effects on various neurobiological and behavioral processes may help to shed light on smoking behaviors and treatments.
As nicotine can directly sustaining behavior leading to use or magnify the rewarding value of other stimuli accompanying smoking (Caggiula et al., 2009, Perkins and Karelitz, 2013, Perkins and Karelitz, 2014), it is important to consider menthol’s independent role in the reinforcement of smoking behavior. Non-nicotine-based studies in humans have found that peppermint odor exposure improves various areas of cognitive performance, including attention, concentration, discrimination, and memory (Ho and Spence, 2005, Kennedy et al., 2018, Moss et al., 2008, Warm et al., 1991). Menthol is commonly added to cigarettes due to its ability as a transient receptor potential melastatin 8 (TRPM8) ion channel agonist to induce a cooling sensation and counteract the harshness of cigarette smoke (Paschke et al., 2017, Peier et al., 2002, Willis et al., 2011). However, rodent studies have found menthol to enhance the reinforcing effects of nicotine independent of inhalation sensory effects, even at a low dose of menthol incapable of direct reinforcement. In rats, intraperitoneal injection of menthol was shown to significantly increase IV nicotine self-administration in a dose-dependent manner with a threshold menthol dose of 2.5 mg/kg (Biswas et al., 2016). Menthol had also only significantly increased lever-press responses for nicotine self-administration at ≤ 0.015 mg/kg per nicotine infusion, whereas an opposite effect of menthol was observed at ≥ 0.03 mg/ kg per nicotine infusion (Biswas et al., 2016). The effect of intraperitoneal menthol on IV nicotine-seeking behavior also did not change in the presence of a TRPM8 antagonist (Harrison et al., 2017).
While development of nicotine addiction is largely attributed to the positive reinforcing effect of nicotine, evidence suggests that the cognitive-enhancing effects of nicotine may also contribute to the initiation and maintenance of nicotine addiction (Valentine & Sofuoglu, 2018). The activation of nicotinic acetylcholine receptors (nAChRs) that are located on the dopamine neurons in the ventral tegmental area and the resultant dopamine release in the nucleus accumbens and the prefrontal cortex contribute to the rewarding and cognitive-enhancing effects of nicotine, respectively (Wallace & Bertrand, 2013). The cognitive effects of menthol flavoring in smoking products may be an additional important factor to consider in sustaining nicotine addiction (Valentine & Sofuoglu, 2018). Menthol has been shown to interact with nicotine by altering the expression, stoichiometry, and function of nAChRs to alter the release of dopamine in the brain reward system (Wickham, 2020). In rats, combined intraperitoneal menthol and subcutaneous nicotine injections significantly increased dopamine levels compared to nicotine or menthol alone (Zhang et al., 2018). Among basic science studies, there is evidence that menthol may potentially increase the neurobiological effect of nicotine to enhance various domains of cognition in the presence of acute cigarette smoking (Jao et al., 2020). Menthol has been shown to increase neural activation and excitability, including increasing the upregulation of nAChRs in the brain (Brody et al., 2013). In addition, menthol has been shown to be an allosteric inhibitor of alpha 7 type nAChR (Ashoor et al., 2013), which are densely located in the hippocampus and the prefrontal cortex and modulate a broad range of cognitive functions (Tregellas & Wylie, 2019).
While menthol alone has been shown to suppress dopamine neuron excitability and nicotine reward-related behavior (Henderson et al., 2016), menthol + nicotine enhances dopamine neuron excitability and nicotine reward-related behavior likely by increasing the number of high-sensitivity nAChRs (Henderson et al., 2017). In mice, menthol + nicotine vs. nicotine alone has been shown to promote significant increases in nAChR activation in the hippocampus, prefrontal cortex, and striatal areas (Alsharari et al., 2015). In rats, administration of menthol + nicotine vs. nicotine alone also increased locomotor sensitization and functional connectivity (Thompson et al., 2018). In positron emission tomography scanning, menthol cigarette smokers have also shown greater densities and upregulation of nAChRs compared to non-menthol cigarette smokers (Brody et al., 2013).
The current study examined the interactive effects of acute intravenous (IV) nicotine and inhaled menthol administered during a human laboratory study utilizing computerized cognitive performance tasks (Valentine et al., 2018). Based on the basic science literature, we hypothesized that menthol flavoring may also show a dose-dependent, curvilinear effect on nicotine’s enhancement of human cognitive performance, with low levels of menthol demonstrating improved performance compared to high levels of menthol or placebo. In an outpatient, double-blind, placebo-controlled study, participants were exposed intravenously to three doses of nicotine (0.0 mg/saline control, 0.25 mg/low, 0.5 mg/high) and inhaled three levels of menthol flavoring (0.0%/tobacco control, 0.5%/low, 3.2%/high) through an electronic cigarette (e-cigarette) following a smoking procedure. The usage of precisely dosed nicotine infusion and controlled vaping procedure allowed for examination of dose-dependent and interactive effects on cognitive performance without the confounding influence of individual smoking behavior on nicotine or menthol intake.
Section snippets
Participants
The current study is a secondary data analysis of an outpatient, double-blind, placebo-controlled study examining the reinforcing effect of IV nicotine and inhaled menthol among young adult, non-treatment seeking, cigarette smokers (Valentine et al., 2018). The study was conducted through VA Connecticut Healthcare System, which provided Institutional Review Board oversight and approval. A total of 38 participants (20 menthol (MS) and 18 non-menthol (NMS) cigarette smokers) completed all three
Sample characteristics
Participants characteristics by cigarette type preference (20 MS vs. 18 NMS) are presented in Table 1. MS were significantly more likely than NMS to identify as female (p < .05) and ethnic/racial minority (p < .05), but there were no statistically significant differences between MS and NMS for any other demographic or smoking-related variables.
Cognitive performance tasks
Results are presented below focusing on significant effects including cigarette type preference, menthol dose, nicotine dose, and related interactions.
Discussion
To our knowledge, this is the first study to explore the dose-dependent effects of inhaled menthol and IV nicotine on cognitive performance among a group of MS and NMS. Participants completed three randomized sessions with three levels of menthol flavoring (0.0%/tobacco control, 0.5%/low, 3.2%/high) inhaled through an e-cigarette. Within each session, participants were administered a randomized order of IV nicotine dosage (0.0 mg/saline control, 0.25 mg/low, 0.5 mg/high) and then completed
Funding
The research reported in this publication was supported by grant number P50DA036151 from the National Institute on Drug Abuse (NIDA) and Food and Drug Administration (FDA) Center for Tobacco Products (CTP). NCJ was supported by T32HL076134 and RG was supported by U54DA036151 and UL1TR001863. The content is solely the responsibility of the authors and does not necessarily represent the official views of NIH or FDA. NIH and FDA had no role in the study design, collection, analysis or
CRediT authorship contribution statement
Nancy C. Jao: Conceptualization, Methodology, Formal analysis, Data curation, Writing - original draft, Visualization. Ralitza Gueorguieva: Methodology, Validation, Writing - review & editing. Brian Hitsman: Resources, Writing - review & editing, Supervision. Mehmet Sofuoglu: Conceptualization, Methodology, Investigation, Resources, Data curation, Writing - review & editing, Supervision, Project administration, Funding acquisition.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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