Substance use disorder (SUD) is currently one of the most prominent mental disorders worldwide (1). According to the “World Drug Report” from 2019 by the United Nations Office on Drugs and Crime, around 36 million people suffer from SUD, which may be an underestimation, given that estimates for Europe reached 15 million cases of alcohol dependence alone in 2011 (2). The large scale of SUD occurrence bears an enormous burden to many individuals and society as a whole (3). For example, the current opioid epidemic leads to a rapidly increasing number of overdose deaths due to opioid misuse (4), and out of all brain disorders, alcohol use disorder is estimated to induce the third highest number of years of life lost (2). These numbers highlight the need for successful treatment of patients with SUD.

Existing treatments of SUD often fail to prevent relapse, and progress has been modest over the last 20 years. Only 17–35% of the individuals treated for alcohol use disorder (including pharmacotherapy, cognitive behavioral therapy, and group sessions) stayed abstinent for at least 1 year as reported in 2001 (5), while in 2016 a conservative estimate of 35% was obtained of SUD patients who can be considered in long-term remission (6). In addition, only a minority of SUD patients receive treatment. Development of effective prevention and cost-efficient novel treatment programs for SUD are, therefore, of significant importance, and alternative approaches should be explored.

New treatment approaches may stem from novel approaches to diagnose psychopathology. Specifically, the traditional categorical approach to psychopathology attempts to identify treatments based on maladaptive behavior and symptoms that characterize a disorder in a narrow sense by intentionally excluding overlap with other disorders. More concretely, a diagnosis for a given disorder is less likely when symptoms can be explained by another disorder. Therefore, the approach largely ignores behavioral and neural deficits shared by different disorders (7), thus potentially overlooking effective treatments. In contrast, contemporary approaches to diagnoses of mental disorders utilize various dimensions of symptoms within and across disorders. For example, deficits in executive functions may be characteristic of multiple mental disorders such as attention-deficit hyperactivity disorder (ADHD) and SUD [but also, among others, schizophrenia, autism, and Alzheimer's disease (1)]. This view is becoming more prevalent as it is acknowledged in the current version of the Diagnostic and Statistical Manual of Mental Disorders [DSM-5; (1)]. Nonetheless, the DSM-5 can still be considered to be in a transitional period, as it does not fully endorse the view. Others take the dimensional approach further. For instance, the Research Domain Criteria project [RDoC; (8)] classifies disorders as quantitative variations on dimensions of a set of constructs (e.g., cognitive control) within domains (e.g., cognitive systems). These constructs are defined by elements that include behavioral performance, self-report, and biological mechanisms (c.f. https://www.nimh.nih.gov/research/research-funded-by-nimh/rdoc/constructs/rdoc-matrix). As these constructs can cut across mental disorders, we consider it reasonable that treatments follow suit by exploring treatments for seemingly different disorders that are similar in, at least some, underlying cognitive constructs and associated biological mechanisms. These shared deficits within the constructs can provide important opportunities for treatment (9, 10). Therefore, the potential of a pharmacological treatment to be used in SUD, but which is currently used for a disorder that shows similarities in the construct of cognitive control, should be explored.

Treatments for ADHD may be useful in SUD as both disorders are characterized by poor performance within the construct of cognitive control. The more specific aim of this study was to evaluate the potential of pharmacological ADHD treatment for successful use in SUD. At the core of the idea to utilize pharmacological treatment for ADHD in SUD lies the cognitive control deficit represented by inhibitory control failures as the most prominent (11, 12), which is shared between the two conditions (13) and the underlying dopaminergic dysfunction. In general, inhibitory control is the ability to suppress a prepotent or habitual response when necessary (14). When inhibitory control is lacking, actions are immediately and impulsively executed, often at the expense of long-term consequences, and with the disregard for long-term goals. These actions are inappropriate to the situation and are difficult to terminate once started. On a surface level, poor inhibitory control in SUD is demonstrated by displaying addiction behavior (e.g., consuming drugs), while rationally being aware that it is better not to do so given the long-term consequences (1). Similarly, in ADHD, poor impulse control is expressed by the inability to remain physically immobile and by frequent engagement in distractions (1). On the task-performance level, individuals with ADHD or SUD both perform poorly on laboratory measures of inhibitory control, such as the stop-signal task (SST) (11, 15). Lower response regulatory abilities have also been coined a risk factor for substance abuse (16). On a neurotransmitter level, dopamine (DA) receptor families play a prominent role in cognitive and inhibitory control (17), particularly deficient D2-like receptors are observed in individuals with high impulsivity (18). In addition, both ADHD and SUD patients show abnormal dopaminergic neurotransmission (18–20). Therefore, this transdiagnostic impairment in both ADHD and SUD suggests inhibitory control to be a suitable construct to investigate further as a target for pharmacological treatment (13). The potentially shared underlying neurobiological correlates should be explored to validate the pharmacological treatment. However, it should be noted that other disorders may share the neurobiological atypicalities as well as ADHD and SUD. Those disorders may not be suitable (e.g., schizophrenia) to be treated with typical ADHD medication. Therefore, the rationale presented below should be considered within the boundaries defined by the suitability of disorders to be treated with stimulant medication.

Existing pharmacotherapy for SUD does not appear to effectively target cognitive control (21). Nonetheless, neuropharmacological therapy is the most prominent treatment to target cognitive control deficits and deficient DA transmission in ADHD and is considered effective. DA-based ADHD interventions have a success rate of around 70% (1). While various stimulant drugs exist to treat ADHD, methylphenidate (MPH) is the most widely used and therefore, given the suggested overlap, can be considered a prime candidate for treating SUD. MPH blocks dopamine (DAT) and noradrenaline (NAT) transporters (22) and thereby increases extracellular DA and noradrenaline (NA) levels. MPH improves response inhibition task performance and reduces impulsive behavior in children with ADHD (23). MPH also has been shown to improve inhibitory control abilities in cocaine-dependent patients (24, 25), although this may be due to normalizing catecholamine levels by MPH in these particular patients. In addition, MPH has been considered safe with low addiction liability due to the slower onset and elimination of its effects (26). These findings suggest that MPH may successfully increase inhibitory control in SUD as it does in ADHD.

The purpose of this perspectives paper was to evaluate the potential for methylphenidate to be a suitable treatment option in SUD. By comparing ADHD and SUD on a (a) theoretical level, (b) behavioral/clinical level, and (c) neurobiological level, seemingly similar deficits are explored to assess the stimulant treatment's potential. Second, some direct evidence for the efficacy and effects of MPH in SUD treatment and criticism are reviewed, and finally, a guide is proposed for future research into knowledge gaps, ultimately to establish new treatments for SUD.

The primary objective of this paper was to explore shared behavioral and neurobiological atypicalities between ADHD and SUD to evaluate the potential usefulness of MPH treatment for SUD. Overlap between disorders can be considered based on their independent explanatory hypotheses stating impaired or biased cognitive control. Empirically, both show inhibitory behavior deficits as subjectively and objectively measured using the BIS-11, and SST, antisaccade, perseveration, conflicting motor response, and go/no-go paradigms. Functionally, they both show hyperactivation of the mesolimbic pathways, albeit for ADHD only in animal models. Atypical neurotransmission is shared by both disorders characterized by low tonic DA signaling and higher phasic response given appropriate stimuli. Finally, behavioral control networks, including frontal gyri, ACC, OFC, and DLPFC (53, 155), and frontal gray matter is prominently compromised in both disorders, which is in line with the behavioral deficits. These observations support the application of DA-based stimulants as a treatment for SUD, and current evidence identifies MPH as the main candidate among other stimulants.

Despite the shared characteristics, there are differences between ADHD and SUD patients. For example, a prominent ADHD symptom is inattentiveness, which is not commonly observed in SUD individuals (1). In addition, SUD individuals' impulsive behavior appears to be restricted to responding to drug-related cues, whereas ADHD patients behave disinhibited regardless of the context (60). For example, ADHD individuals show increased reward-circuit response during a monetary incentive task (112), while SUD patients often show a reduced response [e.g., Luijten et al. (225)]. ADHD patients commonly use compensatory strategies involving parietal attention areas to mask their cognitive deficits, while SUD patients do not show these additional activity patterns (53). Until now, only individuals with ADHD show unusual activity patterns in the DMN and the OFC is dysfunctional primarily in SUD patients (101, 151). Structural differences between these populations are also present with putamen having been shown to be enlarged (170) in SUD, but decreased in ADHD (28). Important for the present purpose of evaluating MPH suitability as a treatment for SUD, DA-related characteristics in ADHD appear to be mostly represented by high levels of DAT (85, 86), while results for SUD are inconsistent. As MPH blocks the DAT, similar characteristics may be desired. However, both conditions share low tonic DA and high phasic DA (79, 226) that may be reversed using MPH regardless of the DAT differences.

Future studies should be aimed at clarifying apparent discrepancies, behavioral relevance of neurobiological and neurofunctional atypicalities, and the effects of MPH on these measures of performance. For example, on a behavioral level studies may directly compare ADHD and SUD individuals on BIS-11 scores and SST performance. It may be established whether both populations differ to an equal extent from neurotypical, healthy controls. Performance on the SST may also be subject to boundary conditions. For example, it should be established whether SUD individuals only show higher SSRT when presented with addiction-relevant cues or whether they are impaired across a variety of task conditions. Such knowledge can aid in designing situation-specific treatments.

In addition to behavior, further direct comparisons between the populations should also be made concerning brain activation [e.g., Gerhardt et al. (78)]. The key questions that need to be answered are (1) whether ADHD and SUD individuals show similar altered responses of brain networks governing behavioral control, and if so, (2) are hypofunctional frontal brain areas equally relevant in both disorders for behavioral control specifically? (3) What is the contribution of other executive function deficits to the maintenance of the disorders? Multiple executive functions are impaired in both groups, e.g., reward processing, and further studies should establish similarities between the disorders and the effects of stimulant treatment of these functions (49). These functions can be assessed using various well-established performance tasks addressing different aspects of behavioral control like SST assessing motor control (42), gambling tasks assessing reward learning (227), and devaluation tasks assessing goal-directed behavior (228). Concerning the latter, and in parallel to the theory that addiction is characterized by a transition from goal-directed toward habitual behavior, a direct comparison would be very valuable to determine whether ADHD individuals show a similar shift in activation of brain areas governing goal-directed/habitual behavior as is often observed in SUD individuals [e.g., Sjoerds et al. (229)]. In addition, future studies may investigate whether factors that are known to elicit habitual behavior [e.g., stress, Schwabe and Wolf (230)] are equally effective in these populations in affecting brain activation and associated goal-directed behavior.

Further key questions concern explaining the inconsistent observations of DAT levels in SUD. For example, it may be argued that if DAT levels are a consequence of drug use, different drugs may affect DAT levels to a different extent. Drugs exerting their effects through strong activation of catecholaminergic neurotransmission (e.g., amphetamine, cocaine) may induce downregulation of DAT, while drugs like cannabis and heroin may do this to a lesser extent. Within that context, most evidence for the efficacy of MPH in SUD comes from studies in stimulant use disorder patients. It appears reasonable that SUD involving catecholaminergic drugs (e.g., cocaine, amphetamine) may benefit most from MPH treatment. It remains an empirical question whether all addictive disorders are equally suitable to be treated with MPH. It is assumed that all addictions share underlying neurobiological alterations, and based on that notion, it can be hypothesized that MPH is potentially effective in all forms of addiction. However, such extrapolation should be made carefully and awaits empirical confirmation, as most studies showing efficacy in SUD only concern stimulant use disorder patients.

If subpopulations within SUD can be identified, treatments may be tailored to these groups such that MPH treatment may be suitable for one but not the other group or that different dosages may be needed. As well as SUD subgroups, ADHD subgroups (inattentive, impulsive, combined) should be considered. It may be predicted that the impulsive type shares most behavioral and neurobiological characteristics compared with the inattentive type. However, the efficacy of MPH in potential subgroups remains an empirical question that future studies should answer.

Another characterization that may define a suitable sub-population of patients may be neuroimaging measures of the dopamine system. For example, cocaine-dependent patients that show high D2/3 receptor binding and dopamine release following MPH choose a monetary incentive over cocaine more often compared with patients showing less D2/3 binding and dopamine release (231). Such methods may even be hypothesized to assess sensitivity to treatment effects on an individual level. It has been argued that individual tonic dopamine levels are associated with the clinical effectiveness of treatments (21). Such variability in tonic dopamine levels can further be utilized to define individual treatment needs. For example, monetary rewards can be an effective reward for cocaine (231, 232) and smoking (233) abstinence. It is an outstanding hypothesis that the level of dopamine responding to MPH or D2/3 receptor binding can define the height of the monetary incentive, such that lower dopamine system level responding requires larger rewards. In conclusion, more detailed information concerning subgroups, individual differences, and other boundary conditions is needed to determine the suitability of MPH in treating SUD.

The current paper is limited in its scope in evaluating the potential use of MPH as treatment for SUD. Nonetheless, alternative approaches to treating SUD should be considered. Thus far, part of the rationale presented in the current paper to treat SUD patients with MPH is based on a current theoretical explanation of addiction (31, 32). Addiction-related cues elicit a DA response in the ventral striatum, which is associated with an intense craving (“wanting”) of the drug. MPH is theorized to be able to reduce the phasic DA response and therefore the craving. An alternative approach to the function of DA and the mesolimbic system is one in which the system provides a learning signal whenever a reward is larger than predicted [reward-prediction error; (234)]. This signal aims to strengthen the association between the stimulus, response, and outcome (235). In rodents (236) and humans (237, 238), high doses of nicotine have been observed to enhance this signal, which may consequently continue the learning of and strengthen the associations between smoking cigarettes and obtaining reward. An effective treatment may be the dampening of the DA signal whenever a cigarette is smoked to reduce the positive reward-prediction error. MPH has been shown to reduce ventral striatal activation in response to receiving a reward (198). In addition, psilocybin (a hallucinogenic substance found in “magic mushrooms”) may also reduce phasic DA neurotransmission in the mesolimbic pathway. Psilocybin is a 5-HT2A agonist, which predominantly is expressed in the mesolimbic pathways. There is consensus that 5-HT2A activation inhibits DA release (239). Therefore, it can be hypothesized that psilocybin administration leads to a reduced positive reward-prediction error and the association between substance taking and reward. Future, studies should test these hypotheses derived from this rationale.

Concerning alternative approaches, non-invasive brain stimulation or neurofeedback increases prefrontal activity, reduces impulsivity, and enhances cognitive functions (14, 88, 140) and may therefore be considered a potential treatment. In addition, for drug-dependent individuals it is important to train psychosocial skills alongside pharmacological treatment to ensure abstinence. Learning new coping skills, developing a new support system, and challenging expectations about drugs are important factors that enhance self-regulation abilities (156).

Taken together, this perspectives paper provides evidence toward a dimensional approach of psychopathology and serves as an illustration for the promise of developing transdiagnostic treatment programs. More specifically, it contributes to the development of novel pharmacological treatment approaches that may be based on treatments for disorders that are similar in underlying etiology (9). The transdiagnostic symptoms of disinhibition and impulsivity that are characteristic of both SUD and ADHD may have overlapping underlying etiology, namely, abnormal tonic/high phasic DA transmission that leads to a strong drive to perform a given action. This behavior may be associated with prefrontal hypoactivity and brain structural deficits. The DA transmission deficit can be treated with MPH, which has been proven successful in ADHD and may be suitable for use in SUD. The key question is whether the maladaptive behaviors in ADHD that can be treated with MPH are indeed resulting from the DA atypicalities that are shared by both conditions. Also, it is clear that ADHD and SUD are not the same, and it should be studied whether the neurobiological differences underlie other aspects of the respective phenotypes.

PR and LF contributed to establish the first draft of the manuscript and contributed to developing the rationale. LF summarized the existing studies. PR wrote the first draft of the manuscript. NM, JR, and PS contributed to the manuscript in its current version. All authors contributed to the article and approved the submitted version.