Internet gaming disorder (IGD), now classified as an addictive disorder in the International Classification of Diseases 11th revision [1], is becoming increasingly common, with a recent large-scale meta-analysis indicating global prevalence as high as 3.1% [2]. IGD is characterized by impaired control over gaming, increasing priority given to gaming to the extent that gaming takes precedence over other life interests, and continuation or escalation of gaming despite the occurrence of negative consequences. While IGD falls under a larger umbrella of problematic internet use (PIU), research has identified IGD as unique and distinct from other forms of PIU, such as internet addiction [3,4]; whereas PIU spans a range of online behaviors, including online chatting and social media use, IGD refers specifically to excessive engagement and associated problems with online gaming.

Psychological and pharmacological treatments are the most common treatment options for IGD [5]. Psychological treatments for IGD have predominantly drawn on cognitive-behavioral therapy and have demonstrated good effectiveness in reducing symptoms [6]. Conversely, the types of pharmacological treatments used to treat IGD have varied considerably. Indeed, treatments have included psychostimulants [7], selective serotonin reuptake inhibitors (SSRIs) [8], serotonin and norepinephrine reuptake inhibitors [9], and non-selective inhibitors of dopamine and norepinephrine transporters [10]. To date, empirical research has yet to consolidate the effectiveness of these different drugs, precluding insight as to whether pharmacological treatment is generally effective in reducing symptoms of IGD, and if so, the types that may be most effective.

There is strong evidence to suggest that pharmacological treatments for IGD may be effective, stemming from research demonstrating the functional and structural neurobiological underpinnings of IGD [11]. For example, a recent systematic review found that individuals with IGD display increased activity in brain regions associated with reward, reduced activity in brain regions associated with impulse control, and reduced functional connectivity in brain networks implicated in motivation, reward, and executive function, and cognitive control [12]. This review also identified structural differences among individuals with IGD, with regard to reduced grey-matter volume and white-matter density [12]. Importantly, these neurobiological abnormalities are consistent with those observed in other addictive disorders, such as gambling disorder and substance use disorders—addictive disorders for which pharmacological treatments have demonstrated effectiveness [13-15].

Given increasing understanding of IGD as an addictive disorder and relatively high prevalence rates, an improved understanding of its potential pharmacological treatments is warranted. A previous systematic review [5] examining interventions for IGD identified eight studies that reported on clinical trials of pharmacological interventions for IGD, observing reductions in IGD symptoms following the administration of pharmacological treatments across studies. This review, however, did not focus specifically on pharmacological treatments, thus omitting search terms needed to identify pharmacological treatments and precluding a fulsome identification of relevant studies. As such, we conducted a systematic review of studies examining the effectiveness of pharmacological treatments in reducing symptoms of IGD.

Our search generated 912 articles, of which 828 remained after the removal of duplicates (Figure 1). Of these 828 articles, 19 were retrieved for full-text review. A total of 12 articles met all eligibility criteria and were included in the present review.

The aim of the present review was to synthesize the existing literature on pharmacological treatments for IGD. Overall, there is preliminary support that a wide range of pharmacological treatments may be effective in reducing symptoms of IGD and its associated comorbidities, including ADHD and depression. Although promising, the present review identified several gaps in the literature that warrant future address.

First, only 1.4% of the total sample were females. This differs markedly from the global demographic composition of video game players, in which women represent roughly 50% of gamers worldwide [29-31]. Furthermore, the rates of IGD in women are increasing, with current prevalence rates of 4%-5% [2], suggesting a need to examine gender differences in the efficacy of pharmacological treatment for IGD. Secondly, all studies included in the present review were conducted in South Korea. This may reduce the generalizability of the findings to people with IGD in other countries due to cross-cultural differences in IGD. For example, there may exist physiological differences among people of East Asian descent that may impact the efficacy of pharmacological treatments for IGD. Indeed, studies have reported on neurogenetic variance by ethnicity, particularly in dopamine polymorphism, which is implicated in addictive behaviors and depression symptoms [32,33].

Interestingly, most participants presented with psychiatric comorbidities, with only 24.0% of the total sample presenting exclusively with IGD. This finding is consistent with previous studies that have shown that IGD often presents with other mental health comorbidities [34]. The presence of comorbidities may render difficulties disentangling the intervention effects of pharmacological treatments on multiple co-occurring disorders. For example, in studies in which the samples were comprised of patients with IGD and ADHD who were treated with psychostimulants, it is difficult to determine whether the reductions in IGD symptoms were a direct result of the intervention, or were caused indirectly through reductions in ADHD symptoms [7,20]. The same challenge was presented in studies examining the treatment of IGD in the presence of comorbid depressive symptoms [10,19,24,26] and anxiety symptoms [24]. That said, the inclusion of people with IGD and mental health comorbidities better reflects clinical reality and likely provides more generalizable results. Future studies that investigate whether different pharmacological treatments have differential outcomes based on comorbid psychopathology would be highly informative.

Bupropion was the most frequently used drug in the treatment of IGD. Given that IGD is conceptualized as a behavioral addiction and most frequently co-occurs with depression, anxiety, and ADHD, this was not surprising, as bupropion is the only pharmacological treatment that has demonstrated efficacy in the treatment of smoking [35]; depressive disorders [36]; anxiety symptoms [37]; and ADHD [38]. These findings may illuminate the neurobiological mechanisms of action of bupropion in IGD, given the shared pathophysiology of dysregulated dopaminergic signaling across these conditions [39-41] and the role of bupropion in regulating dopamine release [42,43]. Furthermore, previous studies have also found increased default mode network (DMN) connectivity to correspond with dysregulated dopamingergic and norepinephrinergic signaling [44] as well as greater addictive behaviors [45,46], including impulsivity and risk-taking [47]. Importantly, two studies included in this review that investigated bupropion treatment of IGD observed decreases in functional connectivity within DMN [9,26] while one found decreased connectivity between the DMN and cognitive control network in people with IGD, which correlated with changes in IGD and MDD symptoms [26], potentially indicating a mechanism of action for bupropion in the treatment of IGD via regulation of dopamine and norepinephrine [43]. Comparatively, two studies investigated the efficacy of an SSRI in individuals with IGD [22,26]; one found decreased connectivity of the DMN, but not between the DMN and cognitive control network, and efficacy was lower relative to bupropion [26]. The other found normalization of absolute delta and theta power that correlated with reductions in IGD symptoms [22]. Normalization of resting state delta and theta waves may have implications for decreased DMN activity [48] and reflect improvements in inhibitory control [22]. However, this treatment did not correlate with reductions in co-occurring psychiatric symptoms. Thus, the co-occurring psychiatric symptoms presenting in IGD may have relevant implications for the preferred treatment method.

Worth noting, no studies in the current review examined pharmacological treatments targeting craving. Naltrexone is an anti-craving pharmacological intervention that is effective in the treatment of alcohol use disorder [49] and opioid use disorder [50], due to its antagonist actions in the mu-opioid system, thereby reducing rewarding effects of exogenous agonists such as alcohol and opioids. Some studies have investigated the use of naltrexone in behavioral addictions, with one small meta-analysis finding statistically significant improvements of naltrexone relative to placebo in treatment of gambling, kleptomania, trichotillomania, and impulsive-compulsive disorders [51]. In addition, one case-study reported reductions in IGD symptoms after naltrexone was administered to a 15-year old male [52]. However, research in the application of naltrexone to behavioral addictions is in its infancy, with existing studies having substantial heterogeneity, no randomized controlled trials of naltrexone on IGD, lack of long-term follow-ups, and limited empirical evidence on mechanisms of action. Nonetheless, the potential utility of naltrexone in treating IGD is a promising avenue of further study; long-term randomized clinical trials are needed to assess its effects.

This review is limited by several studies that did not provide a clear description of instruments used to measure primary and secondary outcomes. Most studies used the YIAS as an outcome measure, which may be problematic as the YIAS was originally developed for diagnosing PIU. As such, future pharmacological studies of IGD would benefit from including scales that have been developed specifically for the measurement of IGD, such as the Ten-Item Internet Gaming Disorder Test [53]. Further, the majority of the included studies were rated as having at least some concern of bias, with two rated as having serious concern. Potential bias in study findings limits adequate comparison of pharmacological treatments for IGD and may reduce confidence in the validity of the findings. Other methodological limitations include small sample sizes, inability to rule out regression to the mean in open label trials and lack of long follow up periods. Thus, future studies should ensure rigorous methodology.

An additional limitation is that studies rarely described the type(s) of games played by participants (e.g., role-playing, first-person shooter). Gaming preference is a relevant consideration as some game types, such as massively multiplayer online role playing games (MMORPG), are more strongly related to IGD than others, irrespective of player characteristics [54]. In addition, psychological profiles associated with game types may differ. For example MMORPGs are associated with high social anxiety, escapism, impulsivity, and sensation-seeking [55], which may not be the case for other game-types (e.g., offline computer games, arcade games). Given the heterogeneity in IGD presentation with respect to both game-level and player-level differences, future studies should examine the type of games to inform the selection of optimal pharmacological treatments for IGD.

Relatedly, examining the reasons why people play video games (i.e., gaming motivations) may also help to inform the selection of optimal treatments. For example, if a primary motivation for an individual with IGD is to regulate their affect due to symptoms of depression and anxiety, then antidepressant and anti-anxiety medications may be warranted. On the other hand, if individuals are motivated by need for achievement/advance (i.e., increase rank/pass levels), and purchase microtransactions such as loot boxes which operate on an intermittent reward schedule, then naltrexone may be of benefit. Furthermore, for individuals whose primary motivation is for social-relationships or high social anxiety then cognitive behavioral interventions may be the optimal treatment. However, we caution that further research is needed to examine whether gaming motives may have utility in selecting the most optimal treatments in IGD.

In summary, the literature examining pharmacological interventions is in its infancy. Although limited, results are promising and suggest that a wide array of pharmacological interventions may be leveraged in the treatment of IGD. Additional research is needed to further our understanding of pharmacological treatments for IGD. In particular, future studies using the gold standard methodology (i.e., double-blind randomized controlled trials), recruiting adequate sample sizes, controlling for psychiatric comorbidities, and consisting of more representative samples would better inform our understanding of the potential pharmacological treatments for this increasingly prevalent disorder. Moreover, an important direction for future research will be to explore heterogeneity in IGD presentation and treatment response to inform the selection of optimal treatments.