By binding to a different, non-competitive allosteric site on the GABAB receptor, PAMs allow endogenous GABA, binding at its original orthosteric site, to retain its potency and efficacy, reducing the risk of tolerance development and side effects. A number of PAMs have been studied as potential pharmacotherapies for AUD, and have demonstrated reductions in alcohol-associated behaviors and ethanol self-administration in preclinical models. When directly contrasted against baclofen, a GABAB PAM had a better profile, with dose-dependent reduction of relapse-like alcohol drinking and with no signs of sedation. One such novel GABAB PAM, ASP8062, appears particularly promising as it has been shown to significantly increase the affinity and efficacy of endogenous GABA binding in human and rat GABAB receptors in vitro and with oral administration in an in vivo rodent model of fbromyalgia, demonstrating the ability of oral formulated ASP8062 to cross the blood-brain-barrier. ASP8062 has recently progressed to clinical development. Two Phase I clinical trials with a combined total of 112 participants evaluated single ascending doses and multiple ascending doses of ASP8062, respectively. These studies found that ASP8062 was well tolerated in humans, with no evidence of drug effects on safety, cognition, drug withdrawal, or suicidal ideation. One additional clinical trial, assessing the safety and efficacy of ASP8062 for alcohol use disorder , is currently underway. Overall, ASP8062, and GABAB PAMs in general, appear to be well tolerated in humans and decrease alcohol self-administration in animals. These agents present a potential pathway to better utilize the GABAergic system and reduce the side effects seen with GABAB agonists.Ghrelin,4×8 tray grow a peptide produced by endocrine cells primarily in the stomach, is thought to regulate growth hormone secretion, food intake, and glucose homeostasis. Ghrelin is also thought to play a role in AUD.
Ghrelin signaling is required for stimulation of the reward system by alcohol, and higher ghrelin levels are associated with higher self-reported measures of alcohol craving . In human laboratory studies, intravenous ghrelin administration has been shown to increase the urge to drink, increase alcohol self-administration, and modulate brain activity in regions involved in reward processing and stress regulation. Preclinical studies with ghrelin receptor antagonists have shown reductions in alcohol conditioned place preference, alcohol intake and preference, and alcohol-elicited nucleus accumbens dopamine release in rodents. PF-5190457 is a ghrelin receptor inverse agonist that inhibits GHS-R1a constitutive activity as well as blocking its activation by ghrelin. In a preliminary clinical study in 12 heavy-drinking individuals, PF-5190457, compared to placebo, reduced alcohol craving and cue-reactivity to alcohol. Additionally, when administered in combination with alcohol, PF-5190457 was safe and well-tolerated with no drug-alcohol interactions. This was the first clinical study of a GHS-R1a inverse agonist in a sample of heavy alcohol drinkers. PF-5190457 may increase somnolence, heart rate, and lower blood glucose concentrations, although clinical results indicate that these side effects were not exacerbated by alcohol co-administration and in general PF-5190457 is well tolerated. In summary, preclinical and early clinical evidence support additional research toward investigating PF-5190457 as a pharmacological approach to treat AUD.Cannabidiol , one of the main compounds found in Cannabis sativa, has shown promise as a novel therapeutic to treat AUD. CBD is nonintoxicating and has diverse pharmacological effects throughout the central nervous system, including functioning as a negative allosteric modulator of CB1 and CB2 receptors, and blocking anandamide update and inhibiting enzymatic hydrolysis. CBD may also interact with non-endocannabinoid signaling systems, including the serotonergic system and the opioidergic system, among others. Preclinical studies have shown that CBD reduces alcohol administration, decreases motivation for alcohol, reduces relapse-like behavior, and improves withdrawal symptoms in animals exposed to chronic alcohol.
Evidence in healthy individuals demonstrates that CBD is well tolerated, does not interact with the subjective effects of alcohol, and has no abuse liability. Two recent studies investigated signals for potential efficacy of CBD as a treatment for heroin use disorder and cannabis use disorder. Regarding heroin use disorder, acute CBD reduced cueinduced craving for heroin and reduced anxiety in a sample of 42 abstinent individuals, which was maintained one-week following the last CBD exposure. The cannabis use disorder study found that CBD was more efficacious at reducing cannabis use than placebo in a sample of 48 subjects. In both clinical samples, CBD was well tolerated and not associated with serious adverse events. CBD is currently being evaluated as a potential treatment for AUD, AUD with comorbid PTSD, and alcohol withdrawal in AUD in three clinical trials . In brief, preclinical evidence and clinical evidence in other substance use disorders indicate the promise of CBD as a novel therapeutic for AUD.This qualitative literature review discusses the efficacy, mechanism of action, and tolerability of approved, repurposed, and novel pharmacotherapies for the treatment of AUD. This information is summarized in Table 1. As of 2018, the APA recommends acamprosate and naltrexone for the treatment of AUD and suggests gabapentin and topiramate for patients with the goal of reducing alcohol consumption or achieving abstinence, while disulfram is suggested for achieving and maintaining abstinence only. Similarly, while not included in the APA’s recommendations, aripiprazole and mifepristone are associated with drinking reduction, while baclofen shows association with abstinence and mixed results with drinking reduction. Additional repurposed medications show clinical effectiveness for the treatment of AUD. Some of these appear to have particular promise in specific cases, such as varenicline’s use for nicotine and alcohol co-users, baclofen for individuals with liver disease, and aripiprazole for more impulsive individuals. Novel agents such as GET73 and ASP8062 have also reduced alcohol intake in preclinical studies.
In summary, while currently approved medications are somewhat effective, there remains a crucial need to develop new and improved pharmacotherapies for AUD. Novel and repurposed agents show significant promise as treatments that may improve upon currently approved pharmacotherapies.While considerable progress has been made in this field, there are a number of areas which require our attention to realize the benefit of AUD pharmacotherapy. First, despite the prevalence of AUD, the rate of seeking treatment for AUD remains very low. In order for anyone to benefit from the advances in medication development reviewed herein, the treatment gap must be closed. This will require engagement at multiple levels, from prevention to public education about AUD and the available treatments. Researchers and clinicians can help in these efforts by reducing stigma surrounding AUD and other substance use disorders by choosing appropriate language to describe these disorders and the people who are affected by them. A related issue is the need to improve access to FDA approved pharmacotherapies for AUD. A recent analysis of the 2019 National Survey on Drug Use and Health found that only 1.6% of people with a past-year AUD received an evidence-based medication to treat their AUD. Medication use was associated with living in a large metropolitan area,horticulture solutions use of the emergency department, and receiving mental health care, indicating that these services and residing in an urban environment appear to increase access to evidence based medications. There is also a great need to improve the education of physicians and clinicians on the availability of evidence-based treatments for AUD. Ongoing efforts in this area are underway by the American Society of Addiction Medicine and the American Academy of Addiction Psychiatry, as well as by the National Institute on Alcohol Abuse and Alcoholism. To further improve access to treatments and increase treatment-seeking, there is a need to increase the menu of approved pharmacological treatments towards AUD, especially those that have shown promise internationally. Currently, the FDA only accepts two primary outcomes for Phase 3 trials: abstinence and no heavy-drinking days. These outcomes do not always mirror the goals of patients with AUD for their recovery, which may be better reflected by a harm reduction endpoint.
Recent work has found that harm reduction endpoints, including reductions in WHO based drinking levels, are associated with improvements in physical health and quality of life and can be used as efficacy outcomes in clinical trials. The acceptance of these outcomes as clinical trial endpoints could have a substantial impact on the medication development field and ultimately result in a larger pharmacotherapy toolbox for clinicians.Another area of development is the move towards personalized treatment, also referred to as precision medication. AUD is a highly heterogenous disorder, and it unlikely that any medication will work for all individuals with an AUD. As such, there have been efforts to use precision medicine approaches to tailor pharmacotherapies to individuals with different presentations of AUD. Studies have taken several approaches towards personalized treatments, such as pharmacogenetics, sex differences, family history, severity of alcohol withdrawal, drinking phenotypes, and biobehavioral markers. However, even these efforts may be overly simplistic given the complex nature of AUD. It is likely that personalized treatment approaches will need to account for multiple factors to truly tailor treatments to individual patients. Conversely, the public health significance of the improved efficacy of AUD pharmacotherapy with clinically accessible phenotypes argue for wider dissemination and implementation of precision treatment recommendations identified to date. A final issue to consider is the need to develop treatments for individuals with AUD and comorbid psychiatric disorders and for individuals with AUD and AALD. AUD often co-occurs with other psychiatric disorders, including other substance use disorders, personality disorders, major depressive disorder, anxiety disorders, and PTSD. The development of integrated treatments, including combined behavioral and pharmacological interventions, which simultaneously address AUD and other cooccurring disorders, is difficult due to the complexity of treating multiple disorders and the limited understanding of the underlying mechanisms. However, this is a necessary area of research given the high rates of comorbidity in the AUD population. Treatment options for individuals with AALD are limited; of the FDA-approved medications, only acamprosate can be used without concerns of hepatotoxicity. Of the non-FDA medications that may prove useful in this population, only baclofen has been evaluated in an RCT. There is a clear need to develop additional treatments for this population.Unisexual flowers are the exception in angiosperms; the vast majority of flowering plants bear hermaphroditic flowers that have both pollen producing stamens and ovule-containing ovaries . Nevertheless, a substantial number of angiosperms produce nonhermaphroditic flowers. In a recent data analysis, 5-6% of plant species were found to be dioecious, but 43% of plant families were shown to contain dioecious members. The rarity of dioecy at the species level, coupled with its widespread occurrence across the angiosperm lineage, shows that dioecy must have evolved multiple times. In this chapter, we will first discuss the possible benefits and costs to producing imperfect flowers, before considering the likely routes evolution has taken to produce these floral types, and the molecular mechanisms that underlie the development of imperfect flowers. Through a sequence of case studies, this chapter will detail a likely route that an ancestor bearing perfect flowers could take to arrive in the derived states of dioecy and monoecy, through the intermediary steps of protogyny and protandry; andro- and gynomonoecy; and andro- and gynodioecy .A historical theory for why imperfect flowers might be beneficial was that it could promote outcrossing. Clearly a dioecious species is an obligate outcrosser, since the male and female flowers exist on separate plants. However, it is not so clear that this would be true for monoecious plants. It was hypothesised that if monoecy were to promote outcrossing inherently, monoecious plants would not have to rely on other costly mechanisms to promote outcrossing such as molecular self-incompatibility . Studies have not shown this to be the case, indeed monoecy is just as common in self-compatible species as it is it in SI species5 , though of course this does not rule out the possibility that avoiding self-fertilisation could still be a factor in the evolution of imperfect flowers, especially for dioecious plants. Instead of making a theory and trying to find data to support it, it is more fruitful to look at the natural world and make a theory to explain it. For this, we might ask: “what kinds of plants are likely to bear imperfect flowers?”. Analysis of large datasets has shown that species with imperfect flowers are likely to be viniferous or woody, wind-pollinated plants with small green flowers, and for dioecious plants, the bearing of fleshy fruits . One theory proposed by Bertin to explain enrichment in wind-pollinated plants is the relatively low cost of their flowers allows for monoecy to develop.