The need to incorporate polysubstance use in neuropsychopharmacology research: Biological lessons and new opportunities

Abstract

Critical evaluation and refinement of animal models is essential for neuroscientists to understand complex physiological and pathological processes related to psychiatric diseases. In general, preclinical studies modeling drug dependence and problematic substance use have been limited to the administration of a single substance; however, there is a growing appreciation that this approach has failed to capture the complexities of humans and has stifled translational efforts. Polysubstance use represents the overwhelmingly common patterns of alcohol and drug use in humans. For example, epidemiological studies generally determine that between 70–95 % of individuals with alcohol use disorder use tobacco daily, and upwards of 60 % of individuals who use cocaine have a comorbid alcohol use disorder. Based on this, it is imperative for preclinical researchers to consider incorporating nicotine, alcohol, and other drugs into preclinical models of drug use. Here, we discuss the complexities of polysubstance use in the real-world and in rodent models, describing core findings from recent studies that illustrate how the neurobiological mechanisms that drive polysubstance use can differ critically from monosubstance use. Despite these compelling data that justify the support for polysubstance use research, these studies face systemic challenges and barriers to funding that have throttled research in this area. We bring these challenges to light and identify new opportunities for improving the rigor and reproducibility of polysubstance use research in animal models.

Polysubstance use in AUD/SUD

For some substance use disorders (SUD), like opioid use disorder (OUD) and alcohol use disorder (AUD), there are one or more FDA-approved medications available for prescription to patients, but these medications do not work for everyone [1–3]. For other substance use disorders (e.g., cannabis and stimulant use disorders), there are currently no FDA-approved medications. Collectively, this leaves a large percentage of SUD patients without adequate treatment options – a major failure of clinical, preclinical, and translational research efforts. While there are many possible reasons for this gap, we believe that a key factor is that important components of the human condition have not been sufficiently incorporated in animal models. For example, there is 10–20-fold increased prevalence of co-occurring psychiatric disorders in SUD [4–8]; yet, models that combine stress, maternal deprivation, or genetic insults with drug use are not a major component of the preclinical literature. Similarly, there is a bidirectional relationship between chronic pain and use of drugs and alcohol, but few animal studies incorporate both elements [9–15]. Here, we highlight another key aspect of human drug use that is vastly underrepresented in animal models – polysubstance use.

Polysubstance use, defined as the use of one or more substances at the same time or in succession, is extremely common in people with SUD [16–22]. Recent data suggests that among individuals with a heroin or cocaine use disorder, approximately 25 % to 60 % also have AUD, respectively [6]. Nicotine is also commonly used in combination with all other drugs of abuse; for example, epidemiological studies generally determine that between 70–95 % of individuals with SUD or AUD are current or former daily users of tobacco [23–25]. Despite the ubiquity of polysubstance use, human clinical trials that aim to test the efficacy of a therapeutic interventions to reduce drug use for a particular SUD diagnosis almost always exclude individuals that use or misuse other substances. In other cases, human clinical trials aimed at testing the effect of a therapeutic intervention on the use of one drug often fail to gather data on the use of other drugs. The exclusion of polysubstance users from clinical trials does not align with the reality of concurrent or sequential drug use in most individuals with an SUD diagnosis. It is also probable that there are systematic differences in the way that subsets of users combine drugs (which drugs they combine, how they combine them, etc.). Furthermore, it is highly likely that some key biological effects of polysubstance use differ between men and women. It is essential that preclinical research acknowledge and address these clinical complexities while working to investigate mechanisms that drive persistent substance use.

Preclinical assessments of polysubstance use

In contrast to the compelling epidemiology and recent ecological momentary assessment studies in humans, the extant preclinical literature has largely ignored polysubstance use and has examined individual drugs in isolation (see [16,26,27] for other recent reviews on preclinical polysubstance use). Unfortunately, prioritization of monosubstance studies in preclinical models has likely contributed to failures in translation. A similarly hard-learned lesson is exemplified in the schizophrenia literature, where excluding drug administration (i.e., antipsychotics) from preclinical models may have misled preclinical and clinical researchers for years. Despite over a decade of compelling preclinical literature supporting their efficacy in animal models, medications that potentiate the mGlu₂ subtype metabotropic glutamate receptor have not met primary endpoints in clinical trials for schizophrenia [28,29]. Subsequent post-hoc analyses of these trials revealed that prior use of antipsychotics influences the efficacy of mGlu₂ compounds [30]. Later mechanistic studies revealed that the 5-HT_2A serotonin receptor (a key target of second-generation antipsychotics) positively regulates mGlu₂ function via post-translational modifications [31] and epigenetic mechanisms [32]. Based on this, it seems likely that chronic 5-HT_2A inhibition via antipsychotic treatment may lead to reduced mGlu₂ function and expression in many individuals with schizophrenia, thereby throttling potential efficacy of mGlu₂ receptor potentiators. This is a potentially valuable lesson for the drug and alcohol research field in maximizing translational potential of preclinical studies. When mitigating factors are identified in humans, preclinical research is needed to identify underlying mechanisms and maximize the translational potential of novel interventions. For this reason and the neurobiological differences described in the following sections, preclinical research on polysubstance use should be a top priority moving forward.

Modeling polysubstance exposure in animals to identify neurobiological mechanisms

To say that preclinical models of polysubstance use are complicated is an understatement. Key experimental considerations include model system, dosage, timing, and route of exposure. Behavioral effects of polysubstance combinations in preclinical models have been previously reviewed [16]. Timing and route of administration are critical in regulating the physiological effects of drug combinations. For example, psychostimulant effects can override sedation from other drugs, while alcohol and opioids can attenuate anxiogenic effects of other substances. Such combinatorial effects can lead to higher levels of drug use when multiple drugs are used concurrently (e.g., alcohol and nicotine [33,34]; Δ9-tetrahydrocannabinol (THC) and nicotine [35]). Drug-drug interactions can also occur at the level of metabolism, whereby one drug alters the pharmacokinetics of another drug through enzymatic competition or induction [36,37]. It is also possible (but probably not a generalizable mechanism) for a drug combination to result in the formation of a new, psychoactive metabolite (e.g., cocaethylene formed by alcohol and cocaine in the liver [38,39]). The complexities and ubiquity of polysubstance use in humans make the urgent case for prioritizing preclinical research aimed at examining the behavioral and physiological effects of drug combinations. To highlight the importance of using models that more closely mimic human consumption, we will now provide several examples where the neurobiology of polysubstance use diverges from that of monosubstance use.

Polysubstance use induces divergent neurobiological effects in animals

Nicotine and THC

Co-use of cannabis and nicotine is prevalent [40], with cannabis use being widespread in the general population and as many as 80 % of cannabis users reporting concurrent nicotine use [41]. While cannabis and nicotine are often used separately but concurrently (rapid sequential consumption) with nicotine often being used immediately following cannabis as a “chaser”, it is also common for cannabis and nicotine products to be combined and consumed together in the same delivery system [41–43]. Recent epidemiological data suggest that simultaneous use of nicotine and THC-containing products is on the rise, and importantly, that individuals who co-administer these drugs (either at the same time or sequentially) tend to exhibit worse psychosocial and functional outcomes compared to those who use both substances on separate occasions [42]. These data imply that simultaneous or near simultaneous exposure to nicotine and cannabis produces physiological and neurobiological outcomes that differ from exposure to each substance alone.

Preclinical research investigating interactions between nicotine and cannabinoid exposure is sparse. This limited are research is partly owed to inherent difficulty of developing robust nicotine or cannabinoid self-administration in animal models, which can be done but is technically challenging [44–47]. As such, the few studies that do exist usually involve experimenter administration of agents that manipulate the nicotinic acetylcholine or endocannabinoid system followed by self-administration or conditioned place preference tests for the other compound. For example, prior exposure to intraperitoneal (i.p., 2, 4 and 8 mg/kg 2x/day) THC increases subsequent intravenous (i.v.) nicotine self-administration relative to controls [48], though another study found that continued post-session exposure to high doses of THC (3 or 30 mg/kg, i.p.) limits ongoing i.v. nicotine self-administration [49]. In addition, THC self-administration in rats and squirrel monkeys is reduced by negative modulation of the α7 nicotinic acetylcholine (nACh) receptor [50,51]. However, none of these studies addressed how self-administration of nicotine or THC influences self-administration of the other drug. This gap in knowledge was recently addressed through a dual i.v. catheter model allowing concurrent choice self-administration of nicotine and either THC or the synthetic cannabinoid receptor agonist WIN55,212–2. Concurrent access to nicotine enhances self-administration of both cannabinoids, while nicotine self-administration is either unchanged or slightly reduced when THC was also available [35]. Comparable effects were also observed following a non-contingent nicotine injection. These findings suggest that nicotine exerts cannabinoid reinforcement-enhancing effects, consistent with earlier studies showing that nicotine increases responding for other weakly reinforcing stimuli [52–54]. Furthermore, antagonism of nACh receptors differentially influences nicotine or THC self-administration when the two are concurrently available. Interestingly, the α7 nACh receptor antagonist, MLA, reduces nicotine self-administration only in rats with concurrent access to THC [55]. Thus, the pharmacology underlying drug reinforcement may depend on the milieu of substances available or being used at a given time, which has important implications for identifying effective treatments for SUDs. As with most polysubstance research, these studies are still in their infancy and much more research is needed to understand the interactions between nicotine and cannabis use.

Nicotine and alcohol

Nicotine and alcohol co-use is increasing in prevalence, and combined use has been shown to increase the perceived rewarding or pleasurable effects of either drug alone [56]. Nicotine increases alcohol drinking in dependent and nondependent rodents [57,58] as well as in human drinkers [59,60]. The subjective effects of ethanol, including feelings of intoxication and euphoria, increase with nicotine treatment prior to drinking and these enhanced feelings occurred in parallel with increases in heart rate and increased time to peak blood ethanol concentration [59]. Synergistic effects with nicotine can increase the risk for problematic alcohol use, as regular daily smokers have higher levels of chronic alcohol use and more binge alcohol drinking [61], both of which can contribute to the development of AUD. More than 80 % of individuals with an AUD report smoking cigarettes [62], smokers have a 95 % greater risk of developing an AUD, and daily smokers have a 17 % increased risk of relapse to alcohol use [63]. Historically, the most prevalent nicotine delivery method was smoking tobacco products like cigarettes. While the prevalence of smoking is decreasing in the general population, the use of electronic nicotine delivery systems (ENDs) is increasing, and the problematic effects of combined alcohol and nicotine use persist with ENDs. ENDs users have an increased risk of alcohol misuse, including binge drinking or chronic alcohol use, as compared to non-ENDs users [64,65]. ENDs users also report higher scores on the alcohol use disorders identification test, suggesting increased risk for AUD compared to non-ENDs users [66].

Previous studies using i.v. administration found that nicotine increases alcohol self-administration in rats [67–69], however effects were dose-dependent as lower doses have no effect or even decrease ethanol intake [67,70]. Other studies have also shown that nicotine pretreatment or pre-exposure can differentially alter the aversive and physiological effects of alcohol, thus timing and dose may be important factors in understanding nicotine and alcohol co-use [71,72]. Studies in mice using alcohol and nicotine administered in the drinking water in separate bottles, report higher alcohol preference over nicotine, however nicotine drinking and preference increase with quinine adulteration of the alcohol, in a sex-specific manner [73]. Another study in mice examined long access ethanol drinking following nicotine vapor inhalation and found that nicotine acutely increases alcohol drinking in males and produces modest increases in chronic drinking in females [74]. A subsequent study found that nicotine vapor exposure acutely reduces short access ethanol drinking but not binge drinking in male and female mice [75]. These findings indicate that schedule, duration of access, and route of administration are all important variables in modeling alcohol and nicotine co-use in animals.

There is considerable evidence suggestive of a role for neuroimmune signaling in alcohol/nicotine co-use [76]. Activation of the innate immune response via toll-like receptors (TLRs) can increase alcohol self-administration [77–81] and alcohol intake itself increases expression of TLRs in both humans and animals [77,82,83]. Indeed, post-mortem analysis of human brain tissue revealed several TLRs and their endogenous ligand, high mobility group box-1 (HMGB-1) protein, are correlated with lifetime alcohol intake [84]. In contrast to the alcohol literature, there is some debate regarding nicotine and cholinergic modulation of neuroimmune signaling [85]. In macrophage cell culture (RAW264.7 cells), nicotine decreases both TLR3 and TLR4 agonist-induced increases in numerous genes demonstrating that nicotine modulates signaling in multiple TLR pathways [83]. Nicotine has been shown to increase expression of the antiviral interferon-β and decrease mRNA expression of several immune-related genes following activation by the TLR3 agonist polyinosinic:polycytidylic acid (poly(I:C)) [86]. Nicotine can also regulate innate immune function through macrophages and microglia, interfering with TLR-induced NF-κB and the induction of pro-inflammatory cytokines [87]. Potentially through these mechanisms, daily nicotine exposure is capable of decreasing or even blocking alcohol-related inflammatory responses in the brain [83]. Moreover, rats self-administering both alcohol and nicotine over long periods of time (>6 months) show increased expression of the anti-inflammatory nicotinic α7 receptor in brain regions known to drive drug-seeking behavior [88]. Taken together, these studies show that the ability of nicotine and nicotine-alcohol combinations to modulate neuroimmune function is not well characterized and merits further research.

Alcohol and stimulants

The limited number of preclinical studies on the topic have found that voluntary alcohol-stimulant polysubstance use has profound effects on behavior and neurobiology. In rats, cocaine-alcohol polysubstance use has been modeled via daily sessions of intravenous cocaine self-administration followed by oral alcohol consumption [89]. In this model, cocaine intake does not alter alcohol drinking, nor does alcohol consumption alter cocaine self-administration. Nonetheless, major differences in persistent neurobiological changes during withdrawal were observed in the cocaine-alcohol polysubstance use group that were distinct from those observed in the cocaine only group. Cocaine-alcohol self-administration results in increased glutamate transporter 1 (GLT-1) surface expression, whereas cocaine self-administration alone reliably decreases GLT-1 expression [89]. During the reinstatement of cocaine seeking, in the cocaine-alcohol condition, there is an absence of glutamate efflux in the nucleus accumbens, and inhibition of the prelimbic cortex to nucleus accumbens projection no longer attenuates reinstatement as it does in the cocaine-only condition [89–91]. Notably, the antibiotic ceftriaxone, which reliably prevents the reinstatement of cocaine-seeking in dozens of studies [92] is ineffective in cocaine-alcohol polysubstance use [89]. These findings suggest that the molecular adaptations following long-term drug use, as well as responses to approved or investigational treatments, can vary tremendously based on whether preclinical models incorporate polysubstance use.

Similar studies in monkeys are beginning to define important individual differences in polysubstance use and identify potential mechanisms. In cynomolgus monkeys, self-administration of alcohol prior to cocaine reduces the initial reinforcing properties of cocaine [93]. This effect is driven by socially subordinate individuals [94], suggesting that social stress may have unique effects on alcohol-cocaine co-use. In related model in rhesus monkeys, long-term sequential self-administration of cocaine and alcohol does not alter the ability of dopamine antagonists to reduce cocaine intravenous self-administration, but prevents the cocaine-induced downregulation of D2 dopamine receptor in the striatum and increases D3 receptor sensitivity [95,96]. Like the aforementioned studies in rats, these findings indicate that neurobiological mechanisms underlying existing and developing treatments may exhibit important differences in polysubstance use models.

Alcohol and opioids

Relative to monosubstance models, interactions between alcohol and opioids can induce unique molecular adaptations and responses to potential treatments. Studies using sequential access to opioids and then alcohol have found enhanced motivation to seek opioids in rats who also drink. In a model using intravenous oxycodone then voluntary drinking, female rats in the polysubstance use condition show enhanced motivation to seek intravenous oxycodone and increased cue-primed reinstatement of oxycodone-seeking relative to oxycodone-only rats [97]. From a mechanistic standpoint, the enhanced reinstatement may be related to increased recruitment of central nucleus of the amygdala neurons and D1-expressing neurons of the nucleus accumbens [97]. The unique changes in neural circuit activation following polysubstance use are likely to have important ramifications for the efficacy of potential treatments. For example, differences in the actions of oxytocin have been observed in a rat model of sequential opioid-alcohol use [98]. Oxytocin produces long-lasting reductions in alcohol intake in the alcohol-only condition but not in the oxycodone-alcohol polysubstance use condition. In related studies, the psychedelic compounds tabernanthalog and DOI reduce the motivation to seek intravenous heroin in a concurrent heroin-alcohol polysubstance use model [99,100], as reported in alcohol-only and opioid-only models [101–104]. These differential effect patterns of serotonergic compounds (retained efficacy in polysubstance use) and oxytocin (reduced efficacy in polysubstance use) may stem from several factors, including the therapeutic mechanism of action, the manner of oxycodone-alcohol use (concurrent vs. sequential), the level of daily alcohol intake in these studies (<1 g/kg/day vs. 2–6 g/kg/day), or a combination of these factors. Clearly, more work is needed to understand how polysubstance use alters neurobiology and pharmacotherapeutic efficacy.

Stimulants and opioids

While estimates of heroin use among cocaine users ranged from 15 % to 25 % in the 1980s and 90 s [105], opioid-cocaine co-use has declined in recent years, with only 7 % of opioid users reporting cocaine use in a more recent study [106]. However, opioid-methamphetamine co-use has surged in recent years, ranging from 47 % to 75 % of opioids users also reporting methamphetamine use [107,108]. Combined heroin and cocaine in the same injection has been reported to have enhanced euphoric effects relative to cocaine and heroin separately [109–112]. Studies examining stimulant-opioid co-use in animal models have primarily focused on the mesolimbic dopamine system. The synergistic increase in dopamine likely underlies effects on reward and reinforcement [113–120]. Administration of dopamine and mu opioid receptor antagonists systemically and directly into the nucleus accumbens attenuates cocaine, opioid, and cocaine-opioid seeking in self-administration models [121–123]. In rats with a history of heroin, cocaine, or combination self-administration, non-additive effects on nucleus accumbens dopamine transmission are found during self-administration and non-contingent drug administration. In rats with a history of cocaine-opioid self-administration, in vivo microdialysis finds that nucleus accumbens dopamine is elevated by approximately 1000 % during cocaine-opioid self-administration, whereas cocaine self-administration increased dopamine to 400 % of baseline, and heroin was without effect, indicating synergistic effects of polysubstance use on dopamine efflux [113,124]. In vivo fast-scan cyclic voltammetry conducted under anesthesia, as opposed to during self-administration, found that infusions of cocaine and a cocaine-opioid combination increase dopamine in a similar manner but the rate of dopamine reuptake is greater in the combination condition [125]. Long-term opioid--stimulant co-administration has also been shown to have unique long-term effects on the dopamine system [126]. Fentanyl-methamphetamine co-administration precipitates greater changes in dopamine release and re-uptake relative to self-administration of either drug alone [126]. In further support of distinct neurobiological mechanisms mediating stimulant-opioid seeking, sustained-release D-amphetamine only reduces the motivation to seek cocaine, and not cocaine-opioid combination or hydro-morphone alone, in humans with a current history of both cocaine and opioid use disorders maintained on buprenorphrine [127]. Taken together, the preclinical research on stimulant-opioid combinations illustrates that synergistic actions of the drug combination may underlie altered responses to potential treatments.

Refining variables in animal models and incorporating open-source devices

It is well-established that pharmacological factors such as route of administration can have a large impact on the behavioral and neurobiological effects of drugs. In addition, single-drug self-administration studies have reported that patterns of drug self-administration (e.g. short versus long-access; continuous versus intermittent access) are major determinants in the development and expression of addiction-like behavior [128–132]. Therefore, to maximize the translational relevance of preclinical polysubstance use research, it is critical that we incorporate key features of human patterns of substance use into our models. Specifically, factors such as frequency of use of each substance (e.g., number of uses per day and per week), and time of use for each substance (i.e., daytime versus nighttime) must be considered. In addition, the pattern of use (i.e., simultaneous versus sequential use, including spacing intervals) is especially important since interactions between substances can alter the pharmacokinetics and pharmacodynamics of each substance. Given that most people that use substances typically start with a single substance, history of use, including the duration of single-drug use prior to initiation of additional substance(s), should also be integrated into the models. Finally, designing studies that compare the effects of distinct patterns of polysubstance use to experimenter-delivered drug exposure will allow us to separate the neural circuit changes that are pharmacologically driven from those that may uniquely contribute to motivation associated with specific addiction-like behaviors.

Animal models also provide essential opportunities to set the termination of drug administration to examine changes related to abstinence. One key application for this approach is to study how abstinence (or continued use) of one drug may lead to changes in motivation, craving, or use of another substance. This question is particularly important involving legal, pervasive drugs (e.g., nicotine and alcohol) and emergent drug combinations (e.g., xylazine-fentanyl [133–136]). There is increasing evidence that smoking cessation improves treatment outcomes for other substances [137,138]. Meta-analysis of 7 studies found a 25 % greater likelihood of long-term opioid abstinence following interventions that incorporated smoking cessation. In another meta-analysis of 24 studies, a plurality (46 %) reported solely positive impacts of smoking cessation, and no evidence was found in any study for increased substance use during smoking cessation. By contrast, continued smoking is associated with twice greater odds of relapse, and initiating or renewing smoking is associated with nearly five-fold greater odds of relapse [25]. Despite these findings, smoking cessation treatments are not commonly provided during treatment for substance use, largely out of fears that quitting tobacco may add stress or additional challenges to drug treatment programs [137,138]. While it is important to note that correlation does not imply causation, the challenges and limitations in observational human studies provide a blueprint for studies with animals where drug exposure can be carefully monitored and manipulated.

The investigation of polysubstance use, especially concurrent voluntary self-administration procedures, will require novel hardware and software solutions and/or modification and customization of existing equipment resources. Recent open-source options for home cage pellet or liquid self-administration have been developed that can be deployed in polysubstance use models [139–142]. Multiple groups have utilized commercially available chambers to investigate concurrent self-administration using multiple levers connected to liquid receptacles and/or intravenous infusion pumps, where each lever is connected to delivery of a discrete drug solution [35,143–145]. Likewise, study of polysubstance use that includes vapor delivery has been investigated using custom chambers for inhalation [88]. Open-source options to study polysubstance use in rodents are also increasingly available, including the Socially Integrated Polysubstance System [146], where up to eight liquid solutions are available to group-housed animals identified using radio-frequency identification technology. Furthermore, open source solutions to study self-administration in group-housed animals such as FARESHARE [147], HOMECAGE [148], LIQ PARTI [149], and Peer Pub [150] may be adapted to polysubstance research.

Challenges and potential solutions for obtaining support for research on polysubstance use

Based on the above challenges and limitations to research, it is not at all surprising that currently available SUD therapeutics are scarce and only have efficacy in specific subsets of individuals. Indeed, some treatments that reduce drug use in monosubstance-using rodents do not even “translate” to polysubstance rodent models. There are at least two and probably more reasons for this: 1) polysubstance use alters the background biology upon which therapeutics are developed and applied, and 2) the use of one drug is often fundamentally modified by co-use of a second drug (e.g., quantity and pattern of use).

In general, preclinical science has done a very poor job addressing this major gap in knowledge. The studies described in this piece only scratch the surface of the deep complexities inherent to polysubstance use. There are likely several reasons for the paucity of polysubstance use studies. First, the work is difficult to design and perform and is often larger in scope than monosubstance work. Second, as an extension of the first point, at the level of scientific review, it is far easier for reviewers to find imperfections in grant applications proposing polysubstance work. Third, there are few funding opportunities or research portfolios that truly prioritize polysubstance use.

Collectively, these issues have led to relatively low levels of support for extramural research on polysubstance use from the National Institutes of Health. We queried the National Institutes of Health online database (reporter.nih.gov) to determine the support provided to extramural preclinical research on polysubstance use (Fig. 1). While funding allocated to polysubstance use research has trended upward over the last five years, there remain disproportionately low resources allocated to this critical issue. In 2024, funds for polysubstance use represented only 1.9 % and 0.4 % of extramural preclinical research supported by NIDA and NIAAA, respectively. These numbers are in stark contrast to the >70 % of individuals with SUD and AUD who use multiple substances.

Fig. 1.

Extramural support for preclinical research on polysubstance use (PSU). A, The number of R01-equivalent projects (black, left) and related funding (green, right) provided per fiscal year by the National Institute on Drug Abuse (NIDA) and National Institute on Alcohol Abuse and Alcoholism (NIAAA) to support preclinical PSU research. Reporter.nih.gov was queried on 9/30/25 with search terms (preclinical OR animal OR mice OR rat). Additional criteria were R-level grant mechanisms (e.g., R00, R01, R03, R21, DP) and (NIDA OR NIAAA). B, Number of PSU preclinical projects and associated funding support by NIDA and NIAAA. Search terms included [polysubstance AND (preclinical …]. C, Cumulative fraction of funding devoted to PSU between 2021 and 2025.

We posit that there are two ways to improve this situation. First, in a top-down approach, funding agencies must truly prioritize this work, communicate specific priorities to the scientific community, instruct grant reviewers how to handle these research applications, and make programmatic decisions that reflect this priority area. Second, in a bottom-up approach, the addiction neuroscience and biomedical research fields must buy into the idea that this gap represents a critical disconnect between preclinical research and the human condition, embrace complicated models and forgive at least some compromises in experimental design that must be made to rigorously perform this type of research while also keeping projects achievable in scope. The true solution for addressing this major gap in the field is for both these efforts to occur in unison. We are optimistic that this shift is achievable, and that addressing this gap will have an appreciable positive impact on human health.

Data availability

Data will be made available on request.