These findings occur in the context of extreme poverty and account for simultaneous influences of previous recent violent victimization and amphetamine use. Given the consistency of the relationship between dissociation and physical violence over time, identifying individuals who have high levels of dissociation within a broader context of trauma-informed care for homeless and unstably housed women and linking them with specialized mental healthcare and other services may be an additional targeted means to modify risk and reduce physical violence in this particularly vulnerable population. Harmful use of alcohol is the leading risk factor for premature disability and mortality globally among individuals aged 15 to 49 years . Excessive drinking, along with biological and environmental risk factors, can progress to alcohol use disorder , which is characterized by repeated alcohol use despite negative consequences . Notwithstanding the wide range of health and psychological consequences associated with AUD, a large treatment gap remains, with less than 8% of persons with past-year AUD receiving alcohol care and even fewer receiving evidence-based care . Multi-system strategies are needed to advance treatments and increase utilization rates among the diverse set of people with AUD. Development of novel, effective pharmacotherapies is one approach likely to help . To support people in recovery, medications must target factors sustaining drinking. Identifying mechanisms of action,microgreens grow rack such as through randomized controlled trials , human laboratory paradigms, and collection of real-world data represents a vital step in medications development .
Behavioral pharmacology has established subjective response to alcohol as a reliable, multi-faceted phenotype serving as a central bio-behavioral marker of positive and negative reinforcement from alcohol . Individual variability in alcohol’s acute subjective effects, specifically greater stimulation and reward and lower sedation, predict liability for AUD, including escalation of alcohol use and AUD symptomatology . Positive mood, negative mood, and craving are acutely modulated by alcohol use, such that individuals typically experience an increase in positive mood and craving and decrease in negative mood along rising breath alcohol concentrations , serving as reinforcers of alcohol intake . Thus, researchers routinely assess whether pharmacotherapies can effectively modulate subjective response to alcohol through experimental human laboratory paradigms . Importantly, a recent meta-analysis has shown that medication effects on subjective responses to alcohol in the laboratory predict their efficacy in clinical trials for AUD . In an initial safety and efficacy trial, our laboratory used an intravenous alcohol administration paradigm to test whether the novel pharmacotherapy, ibudilast, modulated subjective response in a clinical sample of AUD . While ibudilast did not significantly alter subjective response, subjective effects of mood were dependent on participant’s degree of depression symptomatology. Novel designs testing alcohol’s subjective effects are emerging, such as daily diary methods and ecological momentary assessment in which participants report on their drinking experiences in real-world settings . For instance, using EMA in an RCT that enrolled adolescents with problematic drinking, Miranda Jr. et al. found that naltrexone attenuated alcohol-induced increases in stimulation and enhanced alcohol-induced sedation, as compared to placebo.
These naturalistic reports are consistent with findings on naltrexone’s subjective effects in human laboratory settings . Although less temporally precise than EMA, daily diary methods, which typically include data collection once daily, have lower participant burden and can enhance compliance. While assessment of medication effects on acute subjective response to alcohol via daily diary assessments is limited, past work has utilized these designs to assess daily relationships among urge, mood, and drinking . In a trial of naltrexone for heavy drinking among young adults, morning DDAs revealed that higher daily urge was associated with a greater likelihood of taking the medication, which in return, predicted a lower likelihood of same-day intoxication among the treatment group . The current study consists of a secondary analysis of a two-week experimental medication RCT of ibudilast, which demonstrated treatmentrelated reductions in rates of heavy drinking, as reported through daily diary methods, and reduced neural alcohol cue-reactivity . This study seeks to further test ibudilast’s effects on subjective response to alcohol in the natural environment via DDA. When comparing participant report of drink quantity between these two methods , estimates of alcohol consumption are largely consistent, such that 75% of reports fell within 1 standard drink . Similarly, research from affective science suggests that DDA versus EMA do not meaningfully alter estimates of emotion variability in the real-world nor their associations with health outcomes . In sum, micro-longitudinal, naturalistic daily reporting is a valuable and highly complementary method to clinical trials, as they can increase power and ecological validity, reduce recall error, and result in more cost-effective RCTs . Despite a mounting body of work connecting the immune system with the development and maintenance of AUD and the important implications for the development of these novel therapeutics , few RCTs have tested immunotherapies in the context of AUD to date.
Thus, our understanding of how these medications influence complex AUD profiles, including subjective response, is limited . Alcohol is believed to alter immune signaling and contribute to neuroinflammation indirectly through systemic inflammation and directly via events in the brain that stimulate release of inflammatory molecules, induce neural damage, and alter neural signaling . In preclinical models, an inflammatory state alters ethanol intake, preference, and behavioral responses to ethanol . In human AUD samples, peripheral proinflammatory markers are consistently elevated and correlate with alcohol use . As such, considerable interest exists for novel treatments that can restore healthy levels of inflammation and immune signaling to promote recovery from AUD . Phosphodiesterase inhibitors are a class of immune therapies tested extensively in preclinical models of AUD . PDEs are enzymes that play a central role in the regulation of intracellular levels of cyclic adenosine monophosphate , along with its downstream signal transductions . Acute alcohol exposure activates cAMP signal transduction, while chronic exposure to alcohol attenuates cAMP signaling pathways in specific brain regions . PDE4 isoforms are expressed in neuronal and glial cells in brain regions implicated in the rewarding and reinforcing effects of alcohol, such as the nucleus accumbens and amygdala . Ibudilast is a selective PDE inhibitor and macrophage migration inhibitory factor inhibitor that crosses the blood-brain barrier , attenuates astrocyte and microglial activation, and increases anti-inflammatory cytokine expression . Notably, preclinical work demonstrated that ibudilast reduced voluntary ethanol intake in three different rodent models of AUD . Thus, ibudilast represents a promising pharmacotherapy for AUD, but its mechanisms of action remain largely unknown in clinical samples. To date, our laboratory has tested ibudilast in two clinical samples with AUD. In an initial safety and efficacy trial,ebb and flow flood table ibudilast improved mood resilience following stress exposure and reduced tonic levels of craving . Mood resilience was defined as a faster recovery of positive mood to baseline levels in the treatment condition following exposure to a stressful personal narrative. However, as noted above, ibudilast did not robustly alter subjective response during an alcohol administration paradigm. Yet, this study had a relatively small sample size , and findings could not be extended to subjective effects of alcohol in real-world settings, as participants were required to maintain abstinence during the trial for safety reasons. Extending medications development to naturalistic settings, particularly for novel pharmacotherapies like ibudilast, is needed, as it enables researchers to assess medication effects with far greater ecological validity and to examine dynamic within-person processes through repeated assessments. Electronic real-world data capture is a cost-effective way to collect numerous occasions of alcohol self administration and related subjective effects in participants’ natural environment . As such, work testing ibudilast’s ability to modulate subjective response in naturalistic drinking settings has the potential to further our understanding of its biobehavioral mechanisms, particularly in the context of powerful natural reinforcers and cues. For this reason, the present study will extend findings published from a two-week clinical trial of ibudilast in our laboratory, which utilized daily diary methods . DDAs of subjective alcohol response were collected during this trial to identify bio-behavioral mechanisms of ibudilast, but had yet to be analyzed.
The present study sought to test the effect of neuroimmune modulation by ibudilast on subjective response to alcohol in the naturalistic environment. This secondary analysis leveraged DDAs from a two-week experimental medication RCT of ibudilast, stratified on sex and withdrawal-related dysphoria, that enrolled non-treatment seeking participants with AUD. The DDAs included reports of alcohol use and subjective response measures of stimulation, sedation, mood, and craving. Each morning, participants retrospectively reported on their mood and craving levels both before and during the previous day’s drinking episodes, as well as stimulation and sedation levels during the previous day’s drinking episodes. We hypothesized that ibudilast would significantly reduce average levels of alcohol-related stimulation and increase average levels of alcohol-related sedation compared with placebo during participant naturalistic drinking episodes. Second, we hypothesized that ibudilast would significantly attenuate daily alcohol-induced changes in craving and mood compared with placebo. Two sets of exploratory analyses were also undertaken in which we tested if ibudilast moderated the effect of alcohol-related stimulation and sedation on same-day number of drinks consumed and if the presence of withdrawal-related dysphoria moderated ibudilast’s effects on daily alcohol-induced changes in mood and craving.The current study is a secondary analysis of data collected during a two-week clinical trial of ibudilast for heavy drinking reduction and negative mood improvement in a sample of non-treatment seeking individuals with AUD . Fifty-two eligible participants were randomized to either ibudilast or matched placebo. Randomized participants were asked to attend in-person study visits on Day 1 , Day 8 , and Day 15 , and complete electronic DDAs to report on previous day craving, mood, and alcohol and cigarette use. When participants endorsed previous day alcohol consumption, they also reported on levels of stimulation and sedation. Participants completed a neuroimaging scan at study midpoint. The clinical trial was approved by the University of California, Los Angeles Institutional Review Board [UCLA IRB#17–001741]. Prior to completing study procedures, all participants provided written informed consent after receiving a full study explanation. A community-based sample of individuals with current DSM-5 AUD was recruited for the trial through social media and mass transit advertisements in the greater Los Angeles area. Study inclusion criteria were: between 21 and 50 years of age; meet current DSM-5 diagnostic criteria for mild-to-severe AUD ; and report heavy drinking levels 30 days prior to their screening visit, as defined by the National Institute on Alcohol Abuse and Alcoholism as >14 drinks per week for men and >7 drinks per week for women. Exclusion criteria were: currently receiving or seeking treatment for AUD; current DSM-5 diagnosis of another substance use disorder ; lifetime DSM-5 diagnosis of bipolar disorder or any psychotic disorder; current use of psychoactive drugs, other than cannabis, as verified by a urine toxicology screen; if female: pregnancy, nursing, or decision to not use a reliable method of birth control; presence of nonremovable ferromagnetic objects, claustrophobia, serious head injury, or prolonged period of unconsciousness ; medical condition that could interfere with safe study participation; and recent use of medications contraindicated with ibudilast treatment . Participants were also required to have reliable internet access to complete electronic DDAs. A total of 190 individuals consented to participate in the initial in-person screening visit. Of those, 81 individuals were deemed clinically eligible and were invited to complete a physical screening to determine medical eligibility. A total of 52 participants were randomized to study medication or placebo . Included in the present analyses are 50 participants who completed at least one daily diary report after randomization. Participants were compensated up to $250 for their participation in the study and received an additional $100 bonus if all study visits and ≥80% of DDAs were completed. The clinical trial was conducted at an outpatient research clinic in an academic medical center. Interested individuals completed an initial telephone-screening interview and eligible callers were then invited to the laboratory for an in-person behavioral screening visit. At the start of all in-person visits, participants were required to have a BrAC of 0.00g/dl and a urine toxicology test negative for all drugs excluding cannabis. Eligible participants were asked to complete an in-person physical screening visit consisting of laboratory tests and physical exam by a study physician. Participants meeting all study eligibility criteria who attended the in-person randomization visit were randomly assigned to receive either 50 mg BID of ibudilast or matched placebo.