The significance of the results of our study could be summarized as follows: menthol infusion elicited neither the effect on the amplitude, vigor, and integrity of the primary peristalsis nor the barrier function of the LES. No impact on the esophageal peristalsis parameters was observed despite significant differences in the baseline peristaltic activity between the healthy volunteers and the GERD patients. We observed only marginal significance in the increase of the distal latency both in healthy volunteers, and in GERD patients. To the best of our knowledge, this is the first high resolution manometry study evaluating the effect of the menthol infusion in patients with GERD.

The issue of the influence of menthol on the esophageal motility has several aspects. From the clinical point of view, alteration of esophageal motility and LES function that could theoretically lead to more reflux is particularly relevant in the context of dietary recommendations suggesting avoiding menthol and/or peppermint oil in patients with GERD. These were most probably based on the clinicians’ and patients’ observation that menthol induces heartburn, and further supported by older studies delineating the altered barrier function of the LES and triggering reflux. The scientific viewpoint is related to the (potential) ability of intraesophageal menthol to alter esophageal motility as was already demonstrated in other substances, e.g., acid or capsaicin [13, 14]. Proximity of afferent receptors to the esophageal luminal surface can impact sensory perception and consequently, peristaltic vigor [15, 16].

The physiologic effect of peppermint oil/menthol on the gastrointestinal tract involves the impact on both the motor function and the esophageal sensitivity. The motor function was investigated, and the antispasmodic and cramps-alleviating impact of peppermint oil was utilized in the symptomatic treatment of irritable bowel syndrome (IBS), although without significant difference from placebo [17,18,19]. Available evidence suggests that the capability of menthol to block calcium channels is most probably involved [20]. According to in vitro studies, peppermint oil also antagonizes serotonine-induced contraction and reverses acetylcholine-induced contraction [1]. It was the aim of the studies performed previously to ascertain whether similar effect was possible in the esophagus. Studies with peppermint oil demonstrated the decrease of the LES pressure and the increase of the likelihood of reflux by equating the pressures across esophageal body, LES, and stomach [8]. These results defy ours, however, their study employed conventional manometry (not HRM). Peppermint oil was also demonstrated to decrease esophageal spasms [21]. It is questionable whether the significant increase of distal latency that we observed in 10 and 15 ml swallows reflect the same mechanism that led to the reduction of spasms. Nevertheless, we are cautious about overinterpretation as the significance was neither reproduced for 5 ml swallows, nor for the multiple rapid swallows. As our study included only patients with normal or ineffective motility, the results are not directly comparable.

We observed that following the esophageal menthol infusion there was no significant effect on the esophageal motility parameters, related either to the esophageal body contractility or the LES barrier function. When evaluating the effect of menthol on the barrier function of the LES we consider the inspiratory augmentation of the LES a relevant parameter as it is correlated with the positive pH metry findings [12, 22]. In the group of GERD patients, the inspiratory augmentation of the LES is of nonsignificant decrease (8.8 ± 1.18 vs. 8.22 ± 0.91 mmHg, p = 0.43) and so is in healthy volunteers (8.67 ± 1.09 vs. 7.69 ± 0.96 mmHg, p = 0.15) (Table 1).

The only difference between the pre- and post-menthol was the decrease of the IRP in the multiple rapid swallows and the increase in the distal latency. We suggest caution in the interpretation of the IRP finding because the pathophysiological relevance of this parameter in terms of GERD has not been demonstrated. Also, the DL result must not be overemphasized, as is difficult to assess outside a distal esophageal spasm patient cohort.

During the menthol infusion, we observed similar symptom pattern in terms of the quality (cold sensation, heartburn) and intensity as was already reported by our group [6]. Menthol infusion induced mostly cold sensation with mild intensity in HV group, however, heartburn was reported in all GERD patients, with significantly higher intensity (Fig. 3). This observation suggests that rather direct stimulation of esophageal sensory afferents (and possibly TRPM8 receptors) than alteration of esophageal motility is responsible for the symptoms.

Investigation of the effect of menthol on the esophageal motor function was also the intention of the recent HRM study, similar to ours in terms of the design and the concentration and duration of menthol infusion used [11]. This study also performed esophageal infusion of the placebo (saline), however, included only healthy volunteers and no patients with GERD of heartburn. This study demonstrated the effect of menthol infusion on the reduction of the basal UES (upper esophageal sphincter) pressure and the frequency of secondary peristalsis induced by rapid air injections. Otherwise, no effect of menthol infusion on the parameters of esophageal peristalsis was shown, which is in accordance with our results. The authors assume that this mild effect of menthol infusion on the esophageal motor function is modulated by the activation of TRPM8 receptors.

Taken together, the effect of menthol on primary esophageal peristalsis and the LES function seems to be mild. Despite that, this does not particularly rule out the possibility of menthol of triggering reflux or extend contact of the refluxate and the esophageal mucosa as impaired esophageal peristalsis is only one of the pathophysiological mechanisms of GERD.

The possibility of menthol to trigger transient lower esophageal sphincter relaxations (TLESRs) has not been investigated yet. This could be a mechanism of relevance as, e.g., postprandial acid infusions can increase the number of TLESRs [23]. Another option, yet still not investigated is the ability of esophageal luminal content (e.g., intraesophageal menthol) to affect the contraction amplitude due to the proximity of afferent (e.g., TRPM8) receptors to the esophageal luminal surface. Although proven for capsaicin [13], our results do not support this concept. What is more, the putative mechanism that would explain the direct role of TRPM8 receptors on the esophageal motor function has not been established.

Our study has limitations. Firstly, the protocol of our study did not include the infusion that would serve as a control. Therefore, despite not substantial, the changes of the esophageal motility (distal latency) carry the eventuality of the placebo effect. This was partially overcome by the fact that neither the healthy volunteers, nor patients with GERD symptoms were aware of the composition of the menthol infusion. Still, the not-interchangable scent of menthol lead the patients to correctly sense that the infusion is indeed the menthol solution. Secondly, we assessed only primary peristalsis and the function of the LES. Thus, one cannot exclude the effect of menthol on secondary peristalsis and the esophageal clearance as its impairment could prolong the contact time between the refluxate and esophageal mucosa. Finally, the number of GERD patients confirmed by pH/impedance is somewhat low and the rest was included based on symptoms One cannot exclude the possibility of, e.g., reflux hypersensitivity in this subset of patients.