New Drug Assistance?

Alcohol use disorder (AUD) is a significant global health concern, impacting millions of lives and contributing to a multitude of societal and health problems. In the United States alone, approximately 31% of all traffic crash fatalities involve drunk drivers, equating to a staggering 13,384 lives lost in 2021 – over 36 deaths per day – due to preventable crashes according to the National Highway Traffic Safety Administration. This isn’t an anomaly; indeed, a ten-year review from 2012-2021 showed that nearly 10,850 people died annually from drunk-driving incidents. Beyond traffic accidents, the health implications are equally devastating. In 2015, liver disease caused 78,529 deaths, with nearly half (47%) attributable to alcohol.

Yet, despite this compelling evidence of AUD’s destructive impact, there remains a striking paucity of effective treatment options, underscoring the critical need to explore alternative therapeutic approaches. One promising approach is targeting the enzyme phosphodiesterase 4 (PDE4), suggested to play a central role in neuroimmune modulation and the brain’s reward circuitry and implicated in both the development and maintenance of AUD. A recent study investigated the potential of apremilast – a PDE4 inhibitor approved by the Food and Drug Administration (FDA) for the treatment of psoriasis and psoriatic arthritis – as a novel treatment for AUD, assessing its efficacy and safety through a series of preclinical experiments in mice and a proof-of-concept study in humans.

Why do current treatments fall short?

Currently, only three FDA-approved medications are available for AUD treatment, each with its own set of limitations and challenges. For instance, we have disulfiram, which operates by inhibiting a key enzyme in alcohol metabolism, causing a range of unpleasant symptoms (e.g., facial flushing, headache, nausea, vomiting, and rapid heart rate) which would theoretically discourage the individual from drinking alcohol. In reality, it mostly just discourages the individual from taking the medication, which was recently shown to have adherence rates of only 41.3%. The other two available medications for AUD – acamprosate and naltrexone – are also notorious for aversive side effects and are likewise associated with poor compliance, and relapse rates after just one year of starting either treatment reportedly exceed 60%.

Given these limitations of existing AUD therapies, there is clearly an imperative to find new, effective options with fewer adverse effects. Repurposing a medication that has already been approved for other indications, such as apremilast, is an appealing shortcut, as an existing drug with an established safety profile can translate to clinical use more quickly than a new drug formulation. The question is – does it work?

Efficacy in Mice

Investigators Grigsby et al. first tested apremilast’s efficacy in reducing binge-like alcohol intake and motivation for alcohol consumption in two groups of mice specifically bred for voluntary intoxication, known as “High Drinking in the Dark” mice (HDID-1 and HDID-2 for the two respective groups). The researchers discovered that a single 40-mg/kg systemic injection of apremilast significantly decreased binge-like drinking in both sexes compared to mice injected with a control solution. This reduction was noted in an acute test with a 4-hour post-injection period, as well as a chronic test over a 4-week period in which apremilast (or control solution) was given prior to each period of alcohol availability. 

Furthermore, these animal experiments identified the nucleus accumbens (NAc), a component of the brain’s reward system, as a critical target for apremilast’s effect on alcohol consumption. The study found that binge drinking led to an increase in the expression of PDE4 within the NAc, and by inhibiting PDE4 exclusively in the NAc, apremilast caused a considerable reduction in binge-like alcohol consumption, indicating that PDE4 inhibition in the NAc alone is enough to decrease harmful drinking. 

This evidence strongly suggests that inhibiting PDE4 is effective in controlling the excessive alcohol consumption seen in animals with an inclination towards such behavior, and based on these findings, the authors then sought to investigate apremilast’s potential as a therapeutic approach for human subjects with AUD.

Efficacy in Humans

Following preclinical studies in mice, the researchers conducted a double-blind, placebo-controlled, phase IIa proof-of-concept (POC) study of apremilast’s effects on alcohol consumption in 51 non-treatment-seeking humans diagnosed with AUD. Male and female participants aged 18-65 and presenting with AUD categorized as moderately severe or worse per the fifth edition of the Diagnostic and Statistical Manual for Mental Disorders (DSM-5) criteria were randomized to receive either an oral dose of 90 mg/day apremilast or a placebo over an 11-day period. Apremilast and placebo groups did not differ significantly in baseline characteristics, including AUD severity and duration.

Apremilast was found to significantly reduce both daily alcohol intake and the frequency of heavy drinking days (defined as ≥4 drinks per day for women and ≥5 per day for men) compared to the placebo group. The average daily alcohol consumption decreased from day 1 to day 11 by 2.74 drinks for the apremilast group and 0.48 drinks for the placebo group (P<0.025), while the risk of heavy drinking days declined more in the apremilast group (-0.39) than in the placebo group (-0.05, P<0.03). As expected based on its use in psoriasis, apremilast also exhibited a favorable safety profile, as it was not associated with severe adverse events leading to treatment discontinuation within the study population.

The research on apremilast for the treatment of AUD, though in its early stages, has not yielded further insights into the precise biochemical mechanisms through which this compound reduces daily alcohol intake and frequency of heavy drinking days in humans. However, it should be noted that a significant body of animal research underscores the importance of immune and inflammatory pathways as pivotal regulators of AUD across all stages of the disease – from high motivation to drink, to binge drinking, and ultimately, to alcohol dependence. 

PDE4, found predominantly in immune cells, epithelial cells, and neurons, functions as an intracellular enzyme, modulating inflammation and maintaining epithelial integrity. This enzyme, the expression of which is upregulated by chronic alcohol intake, has been linked to alcohol dependence in a genome-wide association study, and its inhibition has been found to reduce alcohol intake in various animal models through the suppression of several neuroimmune signaling pathways involving PDE4. However, while we know that alcohol intake induces PDE4 expression, which in turn mediates neuroinflammation, the exact role of neuroimmune alterations in fostering alcohol dependence remains largely unclear.

Limitations

While this study offers encouraging insights into apremilast’s potential for curbing alcohol consumption in those with AUD, certain details in methodology and results leave plenty of open questions with regard to interpretation.

The study’s dependence on participants’ self-reported alcohol intake raises concerns about data reliability, as it’s often difficult to assess the quantity of alcohol consumed per drink, introducing a potentially significant source of error in participants’ self-reported alcohol intake. Further, self-reporting can introduce social desirability bias or recall bias, leading to skewed or under-reported intake estimates. The net effect of such biases is unclear – it’s possible that they have no impact on results because both groups are equally biased, or these biases may partially mask the benefits of apremilast if, for instance, those who drink more heavily (presumably, the placebo group) are more likely to under-report consumption. To ensure the credibility and robustness of the findings, adopting a more objective approach, such as utilizing blood or breath alcohol levels, would have been a superior method for assessing alcohol consumption.

We should also be careful to note potential limitations related to the specificity of apremilast’s apparent effects. Although the study did not report any severe adverse effects necessitating treatment discontinuation, the apremilast group had twice the likelihood of experiencing unpleasant symptoms such as diarrhea, nausea, abdominal pain, and somnolence (drowsiness) compared to the placebo group. These side effects raise the question of whether the observed reduction in alcohol consumption may be attributed to a general sense of malaise rather than the drug’s specific mechanism of action on PDE4. Indeed, the study revealed that apremilast also led to a decline in binge-like water and saccharin consumption in HDID-2 mice, which points to the possibility of a more general effect on liquid intake or consummatory behavior, rather than a targeted influence on alcohol consumption.

This question of specificity has implications for compliance among those on the drug, as well as for its potential use among those who may not fit the criteria for AUD but who nevertheless wish to reduce their alcohol intake. Similar to observations with existing pharmacological treatments for alcohol dependence, patients are unlikely to continue taking apremilast if it is associated with substantial malaise. And if the mechanism of action does indeed impact overall liquid intake or consummatory behavior, the risk of dehydration or malnutrition might be too great to justify the use of this medication for those simply looking to reduce alcohol intake by one or two drinks per week.

A Need for Long-Term Data

Even in the case that the observed effects of apremilast in reducing alcohol consumption were genuine and not due to side effects or off-target influences, long-term data on the drug’s efficacy and the risk of post-treatment relapse will be essential to evaluate its promise as an AUD therapy.

Grigsby et al. note that in a two-week post-treatment follow-up period, the treatment and placebo groups did not demonstrate significant differences in rebound drinking, though the authors fail to define or provide specific data regarding “rebound drinking,” leaving us unable to determine whether participants in the apremilast group reached or surpassed their initial intake levels after the study’s conclusion. Still, the occurrence of any noteworthy degree of rebound drinking implies that apremilast does not lead to sustained reductions in alcohol intake after cessation of treatment, which in turn would suggest that the drug would need to be taken for long periods of time or indefinitely to have a meaningful benefit for health.

This implication calls for further investigation into apremilast’s long-term health effects. As an approved psoriasis drug, apremilast has already been shown to be safe over more extended periods in a general population, but these findings do not guarantee safety specifically in those with a history of AUD – who, as a group, are more likely than the average individual to have compromised liver function. Since the liver is a key organ for clearing drugs from the body, assessing chronic effects of apremilast on liver function and in those with pre-existing liver damage is an important task for future research, especially considering that apremilast as an AUD treatment would likely require higher doses than are typically used for apremilast as a psoriasis treatment. (The estimated human dose equivalence for AUD based on animal studies is 50% higher than doses indicated for psoriasis.)

We must also take into account the potential for addiction transfer among recovering alcoholics. This phenomenon describes the tendency for individuals recovering from one addiction (such as to alcohol) to substitute with another form of addiction (such as to other drugs, food, or maladaptive behaviors). The study did not examine whether apremilast might improve, worsen, or have no influence on addiction transfer, a critical factor in evaluating its overall impact on patients’ quality of life. Investigation of this question will be vital in future research with longer follow-up. 

The POC study showcases apremilast’s potential to decrease alcohol consumption over an 11-day period, but AUD is a chronic condition, so it is crucial to evaluate the drug’s long-term effectiveness, safety, and relapse risk following discontinuation. The two-week post-treatment follow-up is not adequate to evaluate the full impact, since even the short bursts of motivation could account for the observed decrease in alcohol consumption.

Cautious Optimism

The pursuit of innovative therapies for AUD, such as apremilast, is undeniably a critical endeavor. This quest not only provides hope for countless individuals worldwide grappling with this condition, but it also hints at potential benefits for a broader demographic. As our understanding of addiction and alcohol consumption deepens, there is an increasing recognition that there may be value in providing treatment options for those who do not meet the clinical criteria for AUD but are nonetheless concerned about their alcohol intake and want to drink less. 

While apremilast shows promise as a new treatment option, as evidenced by its ability to decrease excessive alcohol use in both preclinical and clinical studies, many questions regarding its efficacy and safety still persist. The preliminary successes of apremilast warrant further study, but for now, optimism should remain cautious.