To assess the effect of medication on alcohol-induced changes in mood and craving, three-level models were run for each positive mood, negative mood, craving, and urge scores, as predicted by medication condition, time and a medication × time interaction. Two sets of exploratory analyses were conducted. First, to explore how medication effects might impact drinking outcomes, we tested whether ibudilast moderated the effect of stimulation/ sedation on same-day drinking during the trial, given support for these variables as strong predictors of alcohol use . As such, a within-subject cross-level interaction of medication × stimulation or sedation was added with random slopes, and same-day number of drinks served as the outcome. In a similar fashion, we also tested whether ibudilast moderated the effect on stimulation/ sedation on next-day drinking using cross-lagged logistic models; this analysis served to test whether subjective response predicted future drinking behaviors. Second, given the trial’s a priori interest in a withdrawal-related dysphoria characteristic, we tested whether dysphoria would moderate ibudilast’s effects on alcohol-induced changes in mood and craving. A three-way interaction was added to models estimating the outcomes- positive mood, negative mood, urge, and craving . Stimulation and sedation variables were limited to a single time point and were thus excluded from analyses testing before to during drinking changes.The final sample of randomized participants who completed at least one DDA, consisted of 50 non-treatment seeking individuals with current AUD . Overall, 66% of the sample reported their sex as male, 68% reported an annual household income < $60,000, and the average age was 32.7 years . Regarding race, participants most frequently identified as White ,cannabis grow racks followed by 14% Black or African American, and 12% mixed race. In addition, 24% of the sample identified as Hispanic/ Latinx. Participants had an average of 5.6 DPDD in the month prior to their baseline visit. Medication adherence was high, as both medication groups exceeded 97% adherence rates.

In this secondary analysis, we tested bio-behavioral mechanisms of ibudilast, a neuroimmune modulator, through naturalistic daily reporting of subjective response to alcohol collected during a two-week RCT enrolling 50 non-treatment seeking participants with AUD. Electronic DDAs were administered each morning to participants to capture their previous day drinking behaviors and subjective alcohol response measures. First, we were interested in understanding whether ibudilast altered average levels of stimulation and sedation during drinking episodes. Results showed that ibudilast treatment did not significantly change average levels of stimulation nor sedation during the trial compared with placebo. These findings are consistent with an initial safety trial in which ibudilast did not significantly affect any subjective response variables during an experimentally controlled alcohol infusion in the laboratory . Relatedly, a trial combining laboratory and EMA methods showed that topiramate reduced drinking-related craving but not the stimulant or sedative effects of alcohol . However, animal literature shows that apremilast, another PDE inhibitor, did alter a wide range of ethanol-induced effects in mice, such as reducing acute functional tolerance and increasing the sedative, intoxicating effects, and aversive properties of ethanol . Perhaps unlike certain pharmacotherapies for AUD such as naltrexone, neuroimmune modulators, like ibudilast may not reduce drinking by robustly suppressing alcohol’s stimulant properties or amplifying its sedative effects. Rather, ibudilast may more directly alter other central mechanisms like alcohol craving or may exert a wider range of effects on multiple mechanisms that cumulatively impact drinking outcomes. Second, we tested a related exploratory aim examining the moderating effect of ibudilast on alcohol-related stimulation and sedation and same-day number of drinks consumed. Participants on ibudilast reported a significant, positive relationship between their stimulation and sedation ratings and same-day drinking levels, neither of which was observed in the placebo condition. This suggests that participants randomized to ibudilast consumed more alcohol on days when they retrospectively reported feeling more stimulated during a drinking episode than on days when they felt less stimulated . Yet for those on placebo, we did not detect a significant relationship between one’s feelings of stimulation or sedation and alcohol use. These findings are consistent with EMA data showing that naltrexone potentiated participant’s subjective “high” across rising levels of estimated BrAC . Similarly, topiramate was shown to strengthen the association between mean positive affect and frequency of cannabis use .

These results are also in line with a secondary analysis of our lab’s initial efficacy trial, whereby ibudilast potentiated the association between mood states and one’s craving for alcohol following a stress exposure paradigm compared with placebo . Mechanistically, PDE4 inhibitors attenuate alcohol-induced neuroimmune activation and dysregulation of GABAergic signaling . These important processes are connected to behavioral responses to ethanol . Thus, micro-longitudinal reports collected during the current trial helped to elucidate dynamic, day-to-day associations between within-person subjective effects and drinking, such that ibudilast seemed to moderate these relationships for a given individual, rather than by altering average subjective response levels across participants. For our second primary aim, we assessed whether ibudilast, compared with placebo, attenuated daily alcohol-induced changes in positive mood, negative mood, urge, and craving . Among the full sample, we found that ibudilast significantly dampened within-person alcohol-induced increases in craving seen under the placebo condition, but not other subjective response indicators. This suggests that one of the mechanisms by which ibudilast exerts its effects on drinking outcomes, such as reductions in heavy drinking ), may be by diminishing one’s desire to continue drinking during an episode. Considering its immunomodulatory actions, ibudilast may reduce the acute and chronic proinflammatory effects of alcohol, either indirectly through suppression of peripheral inflammation or directly by altering cAMP signaling pathways and suppressing cytokine expression and in the brain . In return, acute alcohol-induced increases in craving are blunted. Supporting these findings is research on methamphetamine use disorder . An RCT for inpatients with MUD showed that ibudilast significantly blunted the rewarding effects of methamphetamine during an infusion in the laboratory and similarly diminished drug-induced increases in proinflammatory levels during infusion . Continuing, previous results from our group implicate ibudilast in the reduction of tonic craving and neural alcohol-cue reactivity, as evidenced by attenuation of cue-elicited activation in the ventral striatum compared with placebo .

It is thus plausible that reductions in alcohol craving and reward, across these contexts, represent a primary mechanism of action of ibudilast for AUD. Craving likely represents a more proximal determinant of alcohol use than stimulation and sedation, which are shown to indirectly influence alcohol self-administration through craving . An additional exploratory aim was to test whether a characteristic of AUD severity, withdrawal-related dysphoria, moderated ibudilast’s effects on daily alcohol-induced changes in mood and craving. Notably, we found that individuals without a reported history of withdrawal-related dysphoria who were treated with ibudilast showed attenuation of alcohol-induced changes in craving, urge, and positive mood when compared to placebo. This tempering of alcohol’s effects may reflect ibudilast’s enhancement of anti-inflammatory and neurotrophic factors suspected to impact dopaminergic signaling in rewards regions,cannabis grow system such as the nucleus accumbens, where PDE4 and PDE10 are highly expressed . However, individuals who endorsed this withdrawal-dysphoric profile did not appear to benefit from treatment via this mechanism, such that ibudilast did not significantly blunt acute rewarding and reinforcing effects of alcohol. Although intriguing, these moderation findings should be interpreted with caution given the limited sample size, particularly the subgroup of individuals reporting experiences with withdrawal-related dysphoria . Despite these findings, preliminary analyses from this two-week RCT show that withdrawal dysphoria did not moderate clinical response to ibudilast regarding rates of heavy drinking or drinks per drinking day. Notably, these subjective response results are somewhat in contrast to what might be expected for individuals with a history of withdrawal and experiencing the “dark side of addiction”, such that these individuals may potentially show greater dysfunction of the immune system and thus may be predicted to have better response to an anti-inflammatory treatment, such as ibudilast. However, it is suspected that other mechanisms may be central to the maintenance of AUD among individuals with withdrawal dysphoria, beyond the enhancing effects of alcohol. Namely, these individuals may primarily drink to feel ‘normal’ and alleviate physiological or psychological distress, particularly during early abstinence , which was not the focus on the current study. The present findings also differ somewhat from our laboratory’s initial efficacy trial of ibudilast, in which individuals with higher levels of depression showed attenuation of alcohol-induced increases in positive mood and ‘wanting’ during intravenous alcohol administration . A relevant difference between these studies is that participants enrolled in the efficacy trial were likely in a state of early abstinence, as they were asked to refrain from drinking for safety reasons; yet those enrolled in the present trial were not asked to change their drinking behaviors and consumed alcohol on roughly 60% of trial days and around 6 DPDD on average. In preclinical models, withdrawal increases the expression of innate immune markers in brain regions regulating autonomic and emotional states and while speculative, may thus represent a unique condition with the potential to impact ibudilast’s therapeutic effects. For instance, ibudilast reduced opioid withdrawal symptoms among individuals with heroin dependence and another PDE4 inhibitor, rolipram, diminished withdrawal-induced behaviors indicative of negative affect in rodents . Future research evaluating the impact of withdrawal states on immune signaling in larger clinical samples is needed to advance understanding of these complex processes and immune intervention. These findings should be considered in the context of the study’s strengths and limitations. One limitation is that DDAs were reported retrospectively once daily, which is less temporally accurate than EMA designs. As such, items on subjective response and drinking were reported by participants concurrently the morning following a drinking episode and did not capture one’s subjective response level at a specific BrAC or blood alcohol curve limb. As such, this weakens our ability to draw a causal link between the effect of subjective response on alcohol intake and may introduce recall bias. Next, participants with more non-drinking days and incomplete DDAs during the trial are suspected to have greater error variance in their data given the lower number of observations with subjective response data. The lack of daily pre-drinking data on stimulation and sedation prevented us from examining daily changes in these variables, such that we could not account for pre-drinking levels. The sample was comprised of non-treatment seeking individuals with moderate AUD on average and the majority did not fall in the withdrawal-related dysphoria category. Future work with ibudilast in more diverse and treatment-seeking samples with more significant experiences of withdrawal-related dysphoria is needed. This study’s strengths include a clinical AUD sample enrolled in a rigorous double-blind RCT testing a promising novel pharmacotherapy. This trial displayed strong medication adherence rates and tolerability. Further, DDAs had high completion rates and the data comprise a substantial number of drinking episodes . Morning reports are also less likely to be affected by the intoxicating effects of alcohol that may lend to reporting errors, as could be seen with EMA or nightly reports. Finally, to our knowledge, this is the first study on the effect of immune modulation on subjective alcohol response in the natural environment. In closing, this daily diary study complements findings from our previous reports of ibudilast treatment for AUD by examining medication effects on subjective response during real-world drinking episodes. The nuanced nature of the findings, including the distinction among those with and without withdrawal-related dysphoria and within vs. between person subjective response effects, speak to the heterogeneity of AUD and dynamic mechanisms maintaining alcohol use. Ibudilast’s effects on subjective alcohol responses, such as positive mood and craving, appear to be nuanced and perhaps most salient for individuals drinking for positive reinforcement as opposed to normalizing. Treatment with ibudilast potentiated the within-person relations between stimulation/ sedation and alcohol intake in this trial, such that an individual’s quantity of consumption on a given day appears to be more tightly connected to subjective response. The ecologically valid nature of these DDA, through retrospective reports of past day drinking and subjective responses to alcohol, provide a clinically useful window into how individuals experience and recall alcohol’s effects while taking ibudilast, compared to placebo.