2026 Volume 51 Issue 2 Pages 131-139
Over-the-counter (OTC) medicines are available without a prescription and are key to the promotion of self-medication. However, they also pose the risks of misuse, overdose, addiction, and abuse. These risks have recently emerged as global public health concerns. An important aspect of OTC drugs in Japan is that they are often combined with drugs with different effects. Although it has been noted that interactions between depressants and stimulants of the central nervous system (CNS) may promote drug dependence, the details remain unclear due to a lack of basic evidence. Therefore, an assessment was conducted to determine the interaction between CNS depressants, including dextromethorphan, diphenhydramine, and bromovalerylurea, and the CNS stimulant caffeine, by employing a conditioned place preference test in mice. Even at low doses, long-term administration of dextromethorphan and diphenhydramine induced place preference. Long-term administration of high-dose bromovalerylurea also induced this effect. The period required for dextromethorphan, diphenhydramine, bromovalerylurea, and morphine to acquire place preference was shortened by co-administration with caffeine, demonstrating that CNS stimulation enhances the preference of these sedatives in mice. Moreover, the preference for these drugs was suppressed by the dopamine D1 receptor antagonist SCH23390, and by the dopamine D2 receptor antagonist sulpiride, suggesting that dopamine is involved in the enhancing effect. These findings underscore the need to reconsider the active ingredients and distribution practices of OTC products, as the prolonged or inappropriate use of OTC medications and polypharmacy increases the risk of dependence.
Self-medication is defined as the use of medicines “to treat self-diagnosed disorders or symptoms, or the intermittent or continued use of a prescribed drug for chronic or recurrent diseases or symptoms” (World Health Organization, 2020). Over-the-counter (OTC) medicines are general-use drugs that can be purchased without a prescription at community pharmacies and drugstores, and they play an important role in self-medication. In European countries and the United States, OTC medicines such as aspirin and chlorpheniramine have been widely available since the 1970s, and self-medication has become widespread there. In addition, the World Health Organization has promoted self-medication in countries around the world since the 1980s. However, owing to the Japanese universal health insurance system, medical costs have been lower than those in Western countries, and so it has taken more time for self-medication to become widespread in Japan. In recent years, self-medication in Japan through OTC medicines has been fostered in a number of ways: through policies aimed at curbing medical expenses, constraints on medical resources due to population aging, shortage of medical personnel, and lifestyle changes such as growing health awareness and the expansion of drugstores.
Self-medication has been identified as potentially leading to the misuse, overdose (OD), addiction, and abuse of OTC medicines, and this abuse has increasingly been recognized as a concern for global public health (Schifano et al., 2021). In Japan, there has been an increase in cases of drug poisoning due to the excessive intake of OTC medicines, particularly among young women (Matsumoto et al., 2024). At the same time, OTC medicine abuse has been documented in the general population, as well as in patients with mental disorders (Kyan et al., 2024; Matsumoto et al., 2024). A survey conducted in 2024 showed that 1.8% of junior high school students (aged 12 to 15 years) had abused OTC medicines within the past year, indicating that OTC medicine abuse is spreading among the younger generation (Shimane, 2024). Among patients with drug dependency visiting psychiatric medical facilities nationwide, the percentage of those dependent on OTC medicines rose from 9.1% in 2018 to 25.6% in 2024, second only to methamphetamine dependency (Matsumoto et al., 2018; Matsumoto et al., 2024). Thus, the abuse of OTC medicines has become a major social issue in Japan.
To prevent the misuse of OTC medicines, medicines containing ephedrine, codeine, dihydrocodeine, bromovalerylurea (BU), pseudoephedrine, and methylephedrine have been designated “medicines with a risk of abuse” and have been subject to sales regulation in Japan. However, in addition to the six regulated components mentioned above, 12 other compounds have been reported to be abused, and approximately 20 products containing these compounds are currently in the market in Japan (Kamijo et al., 2022). These compounds include the central nervous system (CNS) depressants dextromethorphan (DXM), allylisopropylacetylurea (ALU), and diphenhydramine (DPH). One important issue is that, unlike in other countries, OTC medicines in Japan are often combination drugs. Many products that suppress the CNS often contain caffeine (CAF), which has a CNS stimulant effect that prevents side effects such as drowsiness. Interactions between CNS depressants and stimulants may promote drug dependence (Matsumoto and Miyazaki, 2015). However, the details remain unclear, because there is no fundamental evidence supporting an association between drug dependence and the combining of drug-containing substances with opposing effects. Therefore, the aim of this study was to clarify whether the simultaneous administration of drugs with opposing CNS effects changes the ability to form dependencies; and, if so, to investigate the underlying mechanisms. Because DXM, BU, ALU, DPH, and CAF are much more commonly abused in multi-component products than in single-component products (Tanibuchi et al., 2024), we investigated the combined effects of three sedative drugs (DXM, DPH, and BU) and one stimulant (CAF) using a mouse model.
Male C57BL/6j mice aged 8 weeks were obtained from Sankyo Lab Service (Tokyo, Japan). The mice were housed in plastic cages in a temperature-controlled room (22 ± 1°C) and maintained on a 12-hr light-dark cycle with free access to food and water. All animal care procedures were conducted in accordance with both the National Institutes of Health Guide for the Care and Use of Laboratory Animals and the Care and Use Committee of Showa Medical University (approval #324008, 325017). Every effort was made to minimize the number of animals used and their suffering.
Morphine (MOR) was obtained from Takeda Chemical Industries (Osaka, Japan) and handled under the control of a narcotics researcher (S. Numazawa) licensed under the narcotics and psychoactive control law. CAF, DXM, and (+)-SCH23390 (SCH) were purchased from FUJIFILM Wako Pure Chemical Co., Ltd. (Osaka, Japan). DPH hydrochloride and (±)-sulpiride (SUL) were purchased from Wako Pure Chemical Industries (Osaka, Japan). BU was purchased from CombiBlocks (San Diego, CA, USA). All other reagents used were commercially available and of the highest grade.
Drug treatmentIn this study, all drugs were administered intraperitoneally to mice to avoid factors related to intestinal absorption. The dosage of each drug was determined based on previously reported effects in rodents. MOR was set at 3 mg/kg, which has been confirmed to cause dependence with long-term administration (Meng et al., 2014). DXM (Kim et al., 2003) and DPH (Halpert et al., 2003) were set at a high-dose level of 40 mg/kg, which has also been reported to cause dependence. For doses of CAF, DXM, and DPH considered unlikely to cause dependency, the following were used: 1.5 mg/kg CAF, 10 mg/kg DXM, and 20 mg/kg DPH. There have been no reports of dependency formation in mice using these doses.
BU was administered at a low-dose level of 200 mg/kg, which induces a hypnotic effect (Takeda et al., 2023), and at a high-dose level of 400 mg/kg. The doses of the dopamine D1 receptor antagonist SCH and the dopamine D2 receptor antagonist SUL were set at 50 µg/kg and 50 mg/kg, respectively (Kaizaki et al., 2014). BU and SUL were suspended in saline containing 0.5% carboxymethylcellulose (Imaizumi et al., 2000). MOR, DXM, DPH, and SCH were dissolved in saline solution.
Conditioned place preference paradigmThe conditioned place preference (CPP) apparatus consisted of a two-compartment box (400 mm [W] × 400 mm [D] × 250 mm [H]). One compartment was black, the other was white, and they were separated by a plastic shutter. The black box contained a smooth floor, while the white box had a rough floor. This experiment consisted of preconditioning, conditioning, and postconditioning tests. The conditioning and postconditioning tests were repeated as necessary. All tests were conducted at the same time each day.
Pre-conditioning testOn day 1, the mice were allowed to freely explore the two compartments for 15 min, and the time they spent in each box was measured. The box in which the mice spent more time was designated the vehicle treatment box, whereas the other box was designated the drug treatment box. After the preconditioning test, the mice were randomly assigned to experimental groups.
Conditioning testTwenty-four hours after the pre-conditioning test, the mice were subjected to the conditioning test. After treatment with a CNS depressant, either alone or in combination with CAF, the mice were confined to the drug treatment box for 30 min. Six hours after the administration of MOR alone or in combination with CAF, or 24 hr after the administration of other drugs (DXM, DPH, or BU alone, or in combination with CAF), the mice were administered the vehicle (10 mL/kg i.p.) and confined in a separate box for 30 min. This was considered a single session. In experiments using dopamine receptor antagonists, a conditioning test was performed 30 min after SCH or SUL administration.
Post-conditioning testTwenty-four hours after three or six sessions, the mice were allowed to freely explore the two compartments for 15 min, as in the pre-conditioning test. The time spent in each box was measured. The place preference was evaluated based on the time spent in the drug treatment box. The post-conditioning test after three sessions was defined as “Post 1,” and the post-conditioning test after six sessions was defined as “Post 2.”
Data analysisAll results are presented as mean ± S.E.M. (standard error of the mean). Data analysis was performed using the JMP Student Edition 18 software. Statistical analyses were performed using paired t-tests for comparisons between pre-conditioning and post-conditioning, and one-way ANOVA followed by Tukey’s multiple comparison test in experiments involving dopamine receptor antagonists. The statistical significance level was set at 5%.
All of the mice used in this study spent extended periods in a black box during the preconditioning test (data not shown). Therefore, for all experiments, a black box was used for vehicle treatment and a white box was used for drug treatment. There was no significant difference between Post 1 and Post 2 in regards to the time spent in the drug treatment box (D-box time) compared to the preconditioning test (Pre) for either the vehicle or CAF groups (Figs. 1–3).
Effects of caffeine on morphine-induced changes in CPP in mice. The CPP test was performed on saline (Veh), caffeine (CAF, 1.5 mg/kg), morphine (MOR, 3 mg/kg), and a combination of morphine and caffeine (Comb) groups. Data are presented as the mean ± S.E.M. (n = 6). *p<0.05, **p<0.01 vs. Pre.
Effects of caffeine on sedative-induced changes in CPP in mice. (a) The CPP test was performed on saline (Veh), dextromethorphan (DMX10, 10 mg/kg; DMX40, 40 mg/kg), and a combination of DXM10 and caffeine (Comb) groups (n=6). (b) The CPP test was performed on Veh, diphenhydramine (DPH20, 20 mg/kg; DPH40, 40 mg/kg), and a combination of DPH20 and CAF (Comb) groups (Veh, DPH20, and Comb groups, n=6; DPH40 group, n=5). (c) The CPP test was performed on 0.5% CMC (Veh), bromovalerylurea (BU200, 200 mg/kg; BU400, 400 mg/kg), and a combination of BU (200 mg/kg) and CAF (Comb) groups (Veh, BU200, and Comb groups, n=6; BU400 group, n=5). Data are expressed as mean ± S.E.M. *p<0.05, **p<0.01 vs Pre.
Effects of dopamine receptor antagonists on the CAF-induced changes in CPP in mice. Mice were pretreated either with 0.5% CMC (Veh), SCH 23390 (SCH, 50 µg/kg), or sulpiride (SUL, 50 mg/kg). (a) The CPP test was performed on a saline (Veh) group and on a combination of dextromethorphan (DXM, 10 mg/kg) and caffeine (Comb) group. (b) The CPP test was performed on a saline (Veh) group and on a diphenhydramine (DPH, 20 mg/kg) and caffeine (Comb) group. (c) The CPP test was performed on a 0.5% CMC (Veh) group and a bromovalerylurea (BU, 200 mg/kg) and caffeine (Comb) group. Data are expressed as mean ± S.E.M. (n = 6) **p<0.01 vs Pre, #p<0.05, ##p<0.01 vs Post1 Comb.
The MOR group showed no significant difference in D-box time at Post 1 compared with Pre; however, a significant increase in D-box time was observed at Post 2 (Fig. 1). The MOR and CAF combination group showed significantly longer D-box times at Post 1 and Post 2 than at Pre (Fig. 1). In addition, CAF tended to further enhance the effect of MOR on increasing the D-box time, particularly at Post 2 (Fig. 1).
Although the D-box time at Post 1 in the low-dose DXM (10 mg/kg) group was comparable with that at Pre, significant prolongation was observed at Post 2 (Fig. 2a). Meanwhile, the low-dose DXM and CAF combination group showed significantly longer D-box times at both Post 1 and Post 2 than at Pre (Fig. 2a). The high-dose DXM (40 mg/kg) group showed significantly longer D-box times at both Post 1 and Post 2 than at Pre (Fig. 2a).
The low-dose DPH (20 mg/kg) group showed no significant difference in the D-box time at Post 1 compared to Pre. However, a significant increase in the D-box time was observed at Post 2 (Fig. 2b). The low-dose DPH and CAF combination group showed significantly longer D-box times at both Post 1 and Post 2 than at Pre (Fig. 2b). The high-dose DPH (40 mg/kg) group showed significantly longer D-box times at Post 1 and Post 2 than at Pre (Fig. 2b).
For the low-dose BU (200 mg/kg) group, there was no significant difference in D-box time at Post 1 and Post 2 compared with that at Pre (Fig. 2c). Meanwhile, the low-dose BU and CAF combination group showed significantly longer D-box times at both Post 1 and Post 2 than at Pre (Fig. 2c). In the high-dose BU (400 mg/kg) group, the D-box time at Post 1 was similar to that at Pre, but increased significantly at Post 2 (Fig. 2c).
The combination groups of the low-dose drugs (DXM, DPH, or BU) and CAF showed significantly longer D-box times at Post 1 than at Pre (Fig. 3, reproducing the results shown in Fig. 2. In contrast, no significant difference was observed between the D-box time at Post 1 and Pre in the SCH and SUL pre-treatment groups. In other words, SCH and SUL almost completely eliminated the effect of these sedatives combined with CAF in prolonging the D-box time (Fig. 3).
In this study, we conducted a CPP test in mice to ascertain if the development of dependence could be altered by combining drugs with opposing CNS effects. First, to verify whether preference assessment could be conducted using the two-compartment box employed in this study, we evaluated the dependence-forming potential of the representative CNS depressant, MOR (3 mg/kg). The MOR treatment demonstrated an acquired preference (Fig. 1), consistent with previous reports (Meng et al., 2014), and indicating that this methodology could be used to evaluate dependence-forming potential. The influence of the CNS stimulant CAF on dependence formation induced by CNS depressants was then examined. A dose of 1.5 mg/kg CAF was selected because it produced neither preference nor aversion, even after extended conditioning, when administered alone (Fig. 1). A preliminary investigation using MOR revealed that concurrent administration of CAF at this dose resulted in a more rapid onset of preference compared to MOR alone (Fig. 1). These findings suggested that low-dose CAF potentiates the dependence-forming potential of MOR.
The manifestation of reward effects, which are critical for dependence formation, involves dopaminergic projections from the ventral tegmental area (VTA) to the ventral striatum, particularly to the nucleus accumbens and olfactory tubercle (Kobayashi, 2022). Dopamine D1 receptors are abundantly expressed in the striatum, even more so in the nucleus accumbens shell, and have been implicated in reward-related learning and memory. In contrast, D2 receptors are thought to regulate excessive dopaminergic activity and control motivated behavior. The balanced stimulation of both receptors is necessary for the expression of reward effects (Kobayashi, 2022). MOR exerts its effects on µ-opioid receptors present on GABAergic neurons within the VTA, where the cell bodies of the mesolimbic dopaminergic system are located, leading to the inhibition of these GABAergic neurons. This phenomenon induces the disinhibition of glutamatergic inputs from the medial prefrontal cortex (mPFC) to VTA dopaminergic neurons, selectively promoting glutamate release. Consequently, MOR facilitates dopamine release in the mesolimbic system and increases dopamine outflow from the nucleus accumbens, one of its major projection sites, thereby inducing place preference (Yang et al., 2020).
CAF is a xanthine derivative that stimulates the CNS and exerts non-selective antagonistic effects on adenosine A1 and A2A receptors. Chronic administration of 10 mg/kg CAF has been reported to induce place preference in mice (Hsu et al., 2009). In addition, chronic administration of CAF or the selective adenosine A2A receptor antagonist SCH58261 elevates striatal dopamine levels and promotes Ser31 phosphorylation of tyrosine hydroxylase, the rate-limiting enzyme in dopamine synthesis (Hsu et al., 2010). These findings suggest that CAF induces preference by increasing dopamine levels through its antagonistic action on adenosine A2A receptors. However, in the present study, chronic administration of low-dose CAF alone did not induce place preference under the experimental conditions (Fig. 1), suggesting that the acquisition of preference by CAF in mice necessitates chronic administration above a certain threshold dose. Although MOR and CAF exert opposing primary effects on the CNS (depressant and stimulant actions, respectively), both drugs promote dopamine release via different mechanisms. Consequently, the combination of these two drugs likely results in an additive or synergistic enhancement of dopamine release, which may explain the earlier acquisition of preference observed with co-administration compared with MOR alone.
DXM is a non-narcotic cough suppressant that has been used as a prescription drug for many years. Owing to its efficacy and safety, it became available as an OTC medicine in 2002. However, OD of DXM can cause euphoria, hallucinations, and ataxia, and discontinuation after long-term use can cause withdrawal symptoms such as flashbacks (Antoniou and Juurlink, 2014). Therefore, many states in the United States have banned the sale of DXM to individuals under 18 years of age, whereas Indonesia has prohibited the sale of DXM as a single ingredient. In the high-dose DXM group (40 mg/kg), early acquisition of place preference was observed (Fig. 2a), which is consistent with previous reports (Kim et al., 2003). Moreover, even at a low dose (10 mg/kg), prolonged administration was found to elicit place preference (Fig. 2a), a result which has not previously been reported. DXM is a selective σ1 receptor ligand that also exhibits non-selective antagonistic actions at α4β3 receptors (Hernandez et al., 2000) and NMDA receptors (Shin et al., 2005). Non-competitive NMDA receptor antagonists such as phencyclidine (PCP) and MK-801 have been reported to inhibit GABA release, thereby facilitating dopamine release in the mPFC (Yonezawa et al., 1998) and increasing dopamine concentrations in the nucleus accumbens shell (Marcus et al., 2001; Mathé et al., 1999). In humans, DXM is metabolized by CYP2D6 via O-demethylation to dextrorphan (DX). While DX has a relatively low affinity for σ1 receptors, it exhibits approximately tenfold higher affinity for the PCP site of NMDA receptors compared with DXM (Huang et al., 2003). Thus, both DXM and its active metabolite, DX, are likely to contribute to the acquisition of the preferences observed following DXM administration in mice. Furthermore, dopamine release induced by PCP and MK-801 is suppressed by σ1 and σ2 receptor antagonists (Ault and Werling,1999), suggesting that σ receptor-mediated pathways may also be involved in the dependence-forming potential of DXM. In this study, the time required for DXM to acquire preference was shortened by co-administration with CAF (Fig. 2a), demonstrating that CAF enhanced DXM-induced place preference in mice. Furthermore, the combination of DXM and CAF elicited a preference that was suppressed by pretreatment with either SCH (dopamine D1 receptor antagonist) or SUL (dopamine D2 receptor antagonist) (Fig. 3a), indicating that dopamine is involved in the preference-enhancing effect of CAF. When DXM and CAF were administered concomitantly, we hypothesized that dopamine release from both agents was induced additively or synergistically.
DPH is a first-generation H1 receptor antagonist that is used in the treatment of allergies, as a sleep aid, and to mitigate the effects of motion sickness. This substance has been observed to traverse the blood-brain barrier and has been documented to induce anticholinergic symptoms, including hallucinations (Ali et al., 2020). In the high-dose DPH group (40 mg/kg), early acquisition of place preference was observed (Fig. 2b), which is consistent with previous reports (Halpert et al., 2003). Moreover, even at a low dose of DPH, which has been reported not to induce preference in mice (Halpert et al., 2003), prolonged administration was found to elicit place preference (Fig. 2b), highlighting the potential risks associated with long-term use. The time required for DPH to acquire preference was shortened by co-administration with CAF (Fig. 2b), demonstrating that CAF enhanced DPH preference in mice. Furthermore, the combination of DPH and CAF elicited a preference that was suppressed by pretreatment with SCH or SUL (Fig. 3b), indicating that dopamine receptor signaling is involved in the cross-potentiating effect of CAF and DPH on place preference. Antihistamines have been reported to promote dopamine release in the nucleus accumbens (Dringenberg et al., 1998) and inhibit dopamine reuptake in the striatum (Lapa et al., 2005), thereby increasing locomotor activity (Tanda et al., 2008) and inducing place preference (Suzuki et al., 1999). However, as H1 receptor affinity does not correlate with dopamine receptor affinity or the potency of dopamine reuptake inhibition (Oleson et al., 2012; Tanda et al., 2008), the precise mechanism by which histamine receptor antagonists facilitate dopamine release remains unclear. Nevertheless, the fact that the preference induced by DPH and CAF was suppressed by pretreatment with SCH or SUL signaled the involvement of dopamine in this process. Thus, the potentiation of preference observed with the combination of DPH and CAF is likely attributable, as with MOR and DXM, to the additive or synergistic dopaminergic effects of the two drugs.
Both DXM and DPH have been utilized as prescription medications for an extended period. Their established efficacy and safety have led to their subsequent approval as OTC medicines for specific indications. However, the present study suggests that the prolonged use of these drugs can lead to dependence, highlighting the risks of indiscriminate or prolonged use of such OTC medicines. A substantial body of literature has documented abuse and dependence associated with OTC medicines containing these ingredients (Kamijo et al., 2002). Furthermore, because the concomitant use of CAF enhances the dependence-forming potential of DXM and DPH, even the short-term use of OTC preparations containing these drugs for symptomatic relief of cough due to the common cold or seasonal allergic symptoms should be approached with caution.
BU is a monouridine with both sedative and hypnotic effects. Although BU has a relatively brief half-life of 2.5 hours, its metabolite bromun has a considerably longer half-life of 12 days. Repeated use has been reported to lead to the accumulation of the substance in the body, resulting in mental symptoms such as hallucinations and delusions (Hashida et al., 2001). Currently, its commercialization is strictly prohibited in many countries. In Japan, it has been classified as a "medication with potential for abuse," and was removed from the market of prescription drugs in March 2025. However, OTC drugs containing BU and CAF remain widely available. The present study demonstrated that while low-dose BU alone did not readily induce preference in mice, high-dose BU was capable of inducing preference even as a single agent (Fig. 2c). Importantly, this study revealed that BU produced a preference when combined with CAF, even at doses insufficient to induce preference when administered alone (Fig. 2c). These findings highlight the potential risks associated with products containing both components. To date, no basic research has evaluated the dependence-forming potential of BU, and the mechanisms underlying BU-induced dependence remain unclear. However, in the present study, the preference induced by BU and CAF was suppressed by dopamine receptor antagonists (Fig. 3c). This suggests that dopaminergic signaling is involved in the dependence-forming potential of both drugs. Although the precise mechanism underlying the hypnotic effects of BU is not well established, it has been suggested that, similar to barbiturates, BU may act through GABAA receptors (Takeda et al., 2023). Pentobarbital, a barbiturate, has been reported to induce place preference (Bossert and Franklin, 2001), an effect that is reduced by the co-administration of antagonists of the GABAA receptor or dopamine D2/D3 receptors (Bossert and Franklin, 2001). Dopaminergic neurons in the VTA project to the nucleus accumbens, contributing to reward effects. The VTA contains many GABAergic interneurons that normally inhibit local dopaminergic neurons directly (Creed et al., 2014). Barbiturates suppress the GABAA receptor-mediated activity of GABAergic interneurons in the VTA, thereby disinhibiting dopaminergic neurons, enhancing dopamine release into the nucleus accumbens, and contributing to reward effects (Vashchinkina et al., 2014). Although direct evidence for the effects of BU is lacking, it is conceivable that, similar to barbiturates, BU acts on GABAA receptors and facilitates dopamine release, thereby inducing reward effects. Accordingly, the potentiation of preference observed with the combination of BU and CAF was likely attributable to the additive or synergistic enhancement of dopamine release by both drugs.
This study has several important limitations that should be acknowledged. First, we have not confirmed whether the dependence-suppressing effect of dopamine receptor antagonists persists over the long term. Therefore, it remains unclear whether the increase in the addictive potential of each drug induced by caffeine under the Post 2 experimental conditions can be explained solely by dopamine. Second, the present study employed only a behavioral approach to evaluate the role of dopamine in caffeine-mediated augmentation of each drug's propensity to induce dependence, without delving into the details of the underlying mechanisms. Subsequent research endeavors should involve the examination of brain dopamine levels and the gene expression changes that are implicated in the development of dependence.
In conclusion, this study revealed that long-term use of low doses of DXM and DPH, which have not previously been reported to cause dependence in rodents, can lead to dependence, and that BU possesses dependence-forming potential. Furthermore, CAF, a CNS stimulant included in various OTC medications to counteract side effects such as drowsiness caused by CNS depressants, has been found to enhance the dependence-forming potential of multiple drugs that exhibit sedative effects through different mechanisms. These findings underscore the need to reconsider the active ingredients and distribution practices of OTC products, as the prolonged or inappropriate use of OTC medications and polypharmacy increases the risk of dependence.
FundingThis work was supported by JSPS KAKENHI Grant Number JP23K0842.
Conflict of interestThe authors declare that there is no conflict of interest.
Data availabilityThe data in this study are included in the article/supplementary materials. Contact the corresponding author directly to request the underlying data.
Author contributionsConceptualization: Asuka Kaizaki-Mitsumoto, Satoshi Numazawa
Funding acquisition: Asuka Kaizaki-Mitsumoto, Satoshi Numazawa
Investigation: Ayaka Yonemura-Hirata
Supervision: Asuka Kaizaki-Mitsumoto
Visualization: Ayaka Yonemura-Hirata.
Writing – original draft: Ayaka Yonemura-Hirata, Asuka Kaizaki-Mitsumoto
Writing – review & editing: Asuka Kaizaki-Mitsumoto, Satoshi Numazawa
Ethical approval and consent to participateNot applicable.
Patient consent for publicationNot applicable.
