Addiction Craving and Cue Reactivity Initiative Network (ACRIN)

In recent years, there has been an increasing recognition of the role of drug cue-reactivity in addiction, wherein exposure to drug-related cues can trigger intense craving and subsequent drug-seeking behavior. Pictorial drug cue databases have emerged as valuable tools for investigating the neural and cognitive processes underlying cue-reactivity. This project aims to compare these databases and define standards for drug cue-reactivity databases, enhancing the quality and rigor of research in this field. By developing guidelines and consensus statements on how to develop validated cue databases, we hope to encourage development of new databases, increase transparency, improve quality of data acquisition, facilitate collaboration among researchers, improve data sharing, and promote advancements in our understanding of drug cue reactivity and its implications in addiction research.

Drug craving is a dynamic emotional-appetitive state for drug use subjectively experienced as urge/craving and can be triggered in response to drug related cues. Craving is now one of the criteria for diagnosis of substance use disorders in DSM-5 and contributes to relapse to drug use in people who are in abstinence/recovery. Craving is frequently measured by single-item questionnaires, e.g., “How much craving do you experience now?”; however, several multi-item scales have also been developed to improve measurement validity. The heterogeneity of the available drug craving assessment tools have led to challenges in data aggregation and replicability assessments. There is still no consensus on a decision tree on how to select a measurement tool to assess craving as an outcome measure in a trial. We are conducting two parallel systematic reviews of craving self-reports aimed to catalog and summarize craving assessment tools registered in ClinicalTrials and PubMed, focusing on the diversity and frequency of self-report questionnaires along with their time frame and structure. We are also conducting a content analysis project on all published craving self-reports to map the constructs targeted across the available tools.

i.  Craving as an Outcome Measure in Drug Addiction Trials: A Systematic Review of the ClinicalTrials.gov 

This projects protocol has been submitted on https://osf.io/vmcf7/ 

ii. Craving as an outcome measure in trials with substance use disorder: A systematic review within PubMed (below).

This projects protocol has been submitted on https://osf.io/jcpt9/ 

FDCR studies have gained significant popularity as a means of assessing brain function in individuals with SUDs. Numerous tasks have been developed to present cues to participants in addiction research studies. However, the full range of task variations has not been thoroughly described. While acknowledging the importance of task design variations in FDCR studies, we are currently investigating the possibility of collectively proposing a narrower parameter space for FDCR tasks. This aims to enhance replicability and establish FDCR tasks as a validated outcome measure in clinical trials, particularly those focused on developing potential treatments for SUDs.

Cue-reactivity is one of the most frequently used paradigms in functional magnetic resonance imaging (fMRI) studies of substance use disorders (SUDs). Although there have been promising results in recent years among FDCR studies, there still are not any consortiums to test the replicability of results across labs and variations in tasks. Within the Enhancing NeuroImaging Genetics through Meta‐Analysis (ENIGMA) consortium, ENIGMA Addiction Cue-Reactivity Initiative (ENIGMA-ACRI) has started to fill this gap by starting a consortium to gathering FDCR databases to be able to do mega analyses.

Cue-reactivity can be used across multiple species, but there is still a lack of consensus on how to optimize cross species studies. This work group is interested in bringing together PIs who believe cue reactivity studies in rodents and non-human primates can inform human studies and vice versa. This can open doors for cross-species biomarkers and treatment development for SUDs.

A “biomarker” as a defined characteristic measured as an indicator of normal or pathogenic biological processes, or biological responses to an exposure or intervention, including therapeutic interventions. The development of clinically relevant biomarkers is a major goal of translational addiction sciences and translational psychiatry more broadly. The literature on fMRI drug cue-reactivity (FDCR) has matured significantly in recent years, suggesting that brain activations in cue-reactivity across addictive disorders and in specific SUDs are complex phenomena. Meta-analyses of the literature have demonstrated the involvement of disparate brain regions, circuits, and networks in cue-reactivity and suggest that FDCR tasks effectively engage neural circuitry underpinning different aspects of addiction-relevant cue processing. Response biomarkers may indicate the presence of a treatment effect on neuroimaging biomarkers of recognized importance in SUDs and provide some estimate of the intensities and locations of such effects. This can also be used to screen candidate therapeutics and prioritize those with plausible effectiveness. After more than three decades and more than 400 FDCR studies, there has not been an FDA-approved biomarker that can show the effect of an intervention using FDCR. This working group is aiming at collecting enough evidence and conducting future studies to be able to fill this gap.

Mechanistic studies and clinical trials have provided increasing evidence for the effectiveness of non-invasive neuromodulation with transcranial electrical (tES) or magnetic stimulation (TMS) in the treatment of people with SUDs, including SUDs related to alcohol, tobacco, cocaine, cannabis, methamphetamine, and opioids. The enthusiasm for non-invasive neuromodulation approaches to SUD treatment is buoyed by a growing body of work demonstrating an important relationship between non-invasive stimulation of the frontal-striatal circuits and drug-related behaviors. At the end of 2018, only 84 published tES/TMS trials had been conducted in the field of SUDs. By the end of 2022, 205 tES/TMS trials had been published in the treatment of SUDs. Following a decade of rapid growth and expansion of the non-invasive neuromodulation tools into the SUD research field, the United States Food and Drug Association (FDA) approved TMS for smoking cessation (FDA: K200957) in 2020. The supporting multicenter, double-blind, randomized controlled trial included 135 participants with tobacco use disorders and showed that the active rTMS group had significantly higher smoking abstinence rates at weeks 2, 4, and 12 compared to the sham group.  Since then, there has been an accelerating pace of new clinical trials using novel tools and protocols of non-invasive neuromodulation for SUDs, and the list of devices and indications that have received CE marking in Europe is growing. Cue reactivity and craving have become an important part of both assessment and intervention in tES/TMS trials in SUDs. The FDA clearance for TMS for smoking cessation includes the “cue exposure” as a part of the treatment protocol. In this workgroup, we hope to optimize using FDCR as a target biomarker. 

Exposure to drug-related cues could elicit conditioned responses (e.g., drug craving) which can lead to relapse even in people who had formerly used substances and are in long-term abstinence. Drug cues may activate cognitive and neural correspondence to addiction and promote responsiveness to interventions. Furthermore, to increase ecological validity, real-world drug cues could be integrated within various models of addiction interventions. Applying different models of cue-based interventions (e.g., cue-exposure therapy, cognitive-bias modification) could potentially reduce cue sensitivity and cue reactivity and subsequently lead to lower relapse rates. This set of interventions engage various cognitive processes ranging from basic (e.g., attention, working memory) to more complex (e.g., flexibility, future thinking) ones. The Cue-Based Interventions subnetwork of ACRIN aims to collect and review the existing evidence, build consensus and guidelines on clinical and mechanical framework for cue-based interventions, and synergize activities across members’ labs.

Cue-reactivity is one of the most frequently used paradigms in functional magnetic resonance imaging (fMRI) studies of substance use disorders (SUDs). Although there have been promising results elucidating the neurocognitive mechanisms of SUDs and SUD treatments, the interpretability and reproducibility of these studies are limited by incomplete reporting of many important aspects. Therefore, a consensus paper and Delphi study was conducted among 45 prominent scientists in the field of fMRI Drug Cue Reactivity (FDCR) from around the world led by several members of the ACRIN team. This checklist presented structured recommendations for more comprehensive methods reporting and reviewed the FDCR literature to assess the reporting of items that are deemed important. Published on nature protocols (https://www.nature.com/articles/s41596-021-00649-4) this checklist can help improve experimental design, reporting and the widespread understanding of the FDCR protocols. This checklist can also provide a sample for developing consensus statements for protocols in other areas of task-based fMRI.

In the last 25 years, hundreds of fMRI drug cue-reactivity (FDCR) studies in people with substance use disorders (SUDs) have formed an extensive body of evidence characterizing the neural substrates of drug-related processing bias in addictions. However, no FDCR-derived biomarker has obtained FDA drug development approval or clinical adoption. Traversing this translational gap requires a systematic assessment of the available evidence, mapping of the methodological heterogeneity of FDCR, and an evaluation of possible clinical uses of FDCR-derived biomarkers to focus research and reliability/validation efforts. This systematic review of 415 FDCR studies published from 1998 up to 2022 summarizes the state of the field, provides a systematic assessment of their potential for biomarker development for the first time, and outlines the biomarker validation process to guide future validation efforts. Based on this systematic review and a biomarker development framework, we outlined a pathway for the development and regulatory qualification of FDCR-based biomarkers of addiction and recovery. Further validation and cost-benefit analyses could support the use of FDCR-derived biomarkers clinically, potentially accelerating treatment development and improving diagnostic and prognostic judgments.