The dependent variable was drinks per drinking day in the last week of the study.This was the first study to evaluate the effects of ibudilast, a neuroimmune modulator, on mood and drinking outcomes in a clinical sample with AUD. Contrary to our hypothesis, ibudilast did not have a significant effect on negative mood on drinking or non-drinking days. However, in support of our hypotheses, ibudilast significantly reduced the probability of heavy drinking compared to placebo. Ibudilast also significantly attenuated alcohol cue-elicited activation in the bilateral VS. Furthermore, exploratory analyses indicated that ventral striatal activation to alcohol cues was predictive of drinking in the week following the neuroimaging scan. These results suggest a bio-behavioral mechanism through which ibudilast acts, namely, by reducing the rewarding response to alcohol cues in the brain leading to a reduction in heavy drinking per se. Unexpectedly, this study did not find support for an effect of ibudilast on negative mood or a moderating effect of baseline depressive symptomology on medication response. This contrasts with previous findings from our lab in which ibudilast improved mood response to stress and alcohol cues. The current study differs from the previous study in several important methodological variables including using a between-subjects instead of a crossover design and the use of a daily-diary mood reporting approach compared to tightly controlled human laboratory experimental paradigms. Furthermore, the current study did not directly evaluate the effect of drinking on mood, which would be more comparable to the findings reported previously. Additionally, this study recruited individuals with mild-to-severe AUD. Negative mood states and negative reinforcement driven drinking may only occur at more severe presentations of AUD; therefore,cannabis grow tent the present study may have been under powered to identify medication effects on negative mood symptoms.
Regarding the drinking outcomes in this study, IBUD significantly reduced the probability of heavy drinking compared to placebo. Specifically, individuals treated with IBUD were 45.3% less likely to drink heavily compared to individuals treated with placebo. This resulted in a 24% predicted probability of heavy drinking over the course of the study in the ibudilast group, compared with a 37% predicted probability in the placebo group. Of note, there were no significant differences in AE’s between groups, indicating that this reduction was not due to increased side effects, including nausea, in the IBUD group. There was not a significant effect of IBUD on the probability of overall drinking compared to placebo. While non-significant, the effect of IBUD for any drinking days was in the expected direction, such that individuals on IBUD were 16.9% less likely to engage in any drinking relative to placebo, but high variability in the prediction prevented conclusive statistical findings. This non-significant effect may not be surprising, as the study sample was comprised of non-treatment-seekers and therefore not motivated to abstain from drinking altogether. Rather, participants treated with IBUD reduced their heavy drinking, which produces a harm reduction benefit, particularly for those with a mild-tomoderate AUD. This finding is also consistent with preclinical studies, where treatment with ibudilast reduced ethanol intake by 50% under maintenance conditions.Importantly, the drinking results combined with the AE reports indicate that ibudilast is a safe medication for individuals who are still drinking and may want to reduce their drinking. IBUD also reduced craving on non-drinking days, at trend level, as compared to placebo. This effect supports our previous finding of a reduction in tonic craving under ibudilast during a week-long human laboratory study during which participants were instructed not to drink. This study also examined a potential bio-behavioral mechanism underlying IBUD’s action using an fMRI alcohol cue-reactivity paradigm.
IBUD attenuated alcohol cue-elicited reward activation in the VS compared to placebo. PDE4 and PDE10 are highly expressed in the striatum and negatively regulate dopaminergic signaling. Thus, inhibition of these PDEs through IBUD may reduce striatal excitability to alcohol cues. In rats IBUD reduced morphine-induced nucleus accumbens dopamine release. Moreover, IBUD has been shown to enhance the production of neurotrophic factors, including glia-derived neurotrophic factor, which is a critical survival factor for dopamine neurons. Preclinical findings indicate that infusion of GDNF normalizes dopamine levels in the ventral tegmental area and the VS and reduces alcohol seeking and alcohol consumption. In humans with AUD, GDNF levels are reduced in blood serum samples.Furthermore, in individuals with AUD, presentation of alcohol cues reduced interleukin-10, an anti-inflammatory cytokine, and the level of reduction was correlated with increased alcohol craving. Thus, though the underlying molecular mechanism is still unknown, this finding indicates that ibudilast may normalize the dopaminergic response to alcohol cues in individuals with AUD. This study has several strengths and limitations which should be considered when interpreting the results. Study strengths include the use of daily diary reporting, which captures real world drinking and minimizes recall bias, and the combination of neurobiological with behavioral and self-report methodologies. However, this study recruited a non-treatment seeking sample; therefore, these findings may not generalize to a treatment-seeking sample with AUD . An ongoing randomized controlled trial of IBUD in treatment-seeking individuals with AUD will address this open question. Relatedly, this study recruited individuals with mild-to severe AUD, which may not be representative of clinical samples. This limitation may have impacted our ability to detect medication effects that require a pathology associated with more severe AUD, which is particularly relevant for negative mood and withdrawal states. Furthermore, participants were required to have a 0.00 g/dl breath alcohol reading for each in person visit. This requirement was to ensure participant safety; however, it may have artificially reduced drinking on in-person study visit days. Of note, in the daily diary assessment,participants reported on their past day drinking for the full day and were able to begin drinking when they returned home after the study visit. Additionally, the sample size for this experimental study was modest, particularly for the fMRI outcomes.
This limited our ability to conduct additional,grow lights for cannabis whole-brain analyses which are necessary to fully elucidate the neural mechanism of ibudilast. Finally, this study did not include a fixed-dose alcohol challenge to evaluate the safety and efficacy of ibudilast in combination with alcohol and to replicate our previous work. However, given that our sample did report drinking while taking ibudilast, we believe that ibudilast can be safely taken with alcohol with limited side effects. In conclusion, this is the first combined clinical and neuroimaging study of ibudilast , a neuroimmune modulator, to treat AUD. Ibudilast did not improve negative mood on drinking or non-drinking days, indicating that its mechanism of action may be non-mood dependent in non-treatment-seeking individuals. Ibudilast reduced the probability of HDDs over 2 weeks for non-treatment-seeking individuals relative to placebo. Ibudilast also attenuated alcohol cue-elicited activation in the VS, potentially through a dopaminergic-related mechanism. This is a critical proof-of-mechanism whereby modulation of neuroimmune signaling via ibudilast reduced the incentive salience of alcohol cues in the brain. Exploratory analyses indicated that ventral striatal activation to alcohol cues was predictive of subsequent drinking in the ibudilast group, such that individuals who had attenuated ventral striatal activation and were treated with ibudilast had the fewest number of drinks per drinking day in the week following the scan. Overall, these findings extend preclinical and human laboratory demonstrations of the efficacy of ibudilast for the treatment of AUD and suggest a potential bio-behavioral mechanism through which ibudilast acts. This study also demonstrates that ibudilast has a favorable side effect profile, even when combined with alcohol. These findings also provide novel insights into the role of neuroimmune modulation in AUD, including its effects on neural and behavioral outcomes of high clinical significance.Recently, neuropsychiatric disorders have been conservatively estimated to be 14% of the global burden of disease, more than the burden of cardiovascular disease or cancer, and their conditions account for a quarter of disability adjusted life-years . The World Health Organization also estimates that 25% of the world’s population will suffer from mental, behavioural, and neurological disorders such as schizophrenia, mental retardation, alcohol and drug abuse, dementias, stress related disorders, and epilepsy during their lifetime. Mostly affecting the poor and people from developing countries, depression impinges on more than 450 million people and might become the second most important cause of disability by 2020. Despite these new insights, as the 20th century revealed Herculean advancements in somatic healthcare worldwide, the mental aspect of healthcare has remained stagnant and in some cases, gravely depreciated. Mentally ill people are some of the most vulnerable people in society. They are often subject to discrimination, social isolation and exclusion, human rights violations, and an ancient, demeaning stigma which leads to bereavement of social support, self-reproach, or the decaying or straining of important relationships. Consequences of poor mental health also include being predisposed to a variety of physical illnesses, having quality of life be reduced, having fewer opportunities for income, and having lower individual productivity, which affects total national output. Poor mental health can also account for violence, drug trafficking, child abuse, paedophilia, suicide, crime, and other social vices. Even though mental health is becoming a serious international health concern, many countries, specifically the more impoverished countries, struggle to address the inadequate amount of resources being funnelled into the nonphysical sector of health.
Low-income countries often have insufficient implementations of policies and limited mental health services confined to short staffed institutions. Furthermore, in both developed and undeveloped countries, the poor are more vulnerable to common mental disorders due to experiences of rapid social change, risks of violence, poor physical health, insecurity, and hopelessness. Women, slum dwellers, and people living in conflict, war prone, and disaster areas of civil unrest constitute a large portion of the population in developing countries, and are specifically susceptible to the burden of mental illness. For instance, 90% of the 12 million worldwide schizophrenia sufferers who do not receive adequate psychiatric services are located in developing countries. Only 50% of countries in Africa have a mental health policy, and if they do have a law, it is usually archaic and obsolete. Ninety percent of African countries have less than one psychiatrist per 100,000 people, and 70% of the countries allocate the mental health sector with less than 1% of the total health budget. Less than 60% of African countries have community mental health care while the rest are focused on psychiatric hospitals. The World Psychiatric Association suggested that the development of mental health programmes are impeded in Africa because of the scarcity of economic and staff resources, lack of awareness on the global burden of mental illness, and the stigma associated with seeking psychiatric care. Mental health has been shunned in Africa, and several reports disclose a higher prevalence of stigma in developing countries than in first world countries. Similar to many other developing countries, treatment of mental health in Ghana, West Africa is low and continues to rely on institutional care, a vestige from colonialism. In Ghana, it is roughly estimated that at least 2,816,000 people are suffering from moderate to severe mental disorders, and only 1.17% of these people receive treatment from public hospitals because only 3.4% of the total health budget is dedicated to psychiatric hospitals. Because there is one psychiatrist per 1.5 million people in the whole country, and the three major psychiatric hospitals are under-financed, congested, and under-staffed, many resort to more ever-present and more affordable, traditional or faith healing. Ghana has a deep-seated tradition of religious observance. Thus, 70– 80% of Ghanaians utilize unorthodox medicine from the 45,000 traditional healers, located in both urban and rural areas, for their vanguard healthcare despite recent advances in orthodox psychiatric services. Although research shows that mental-health patients who used spiritual healing usually reported an improvement in their condition, the quality of treatment is not easy to ensure. Sometimes in order to exorcise supposed demons, individuals are chained, flogged, or incarcerated into spiritual, prayer camps. In spite of these atrocious facts, policy-makers seem to have little concern for mental health, and focus more on physical health and population mortality. The Lunatic Asylum Ordinance of 1888, enacted by the Governor of the Gold Coast, Sir Griffith Edwards, marked the first official patronage to Ghana’s mental health services. This ordinance encouraged officials to arrest vagrant “insane people and place them in a special prison in the capital city of Accra.