Alcohol use, including high-risk drinking and alcohol use disorder (AUD) are increasing at alarming rates (Grant et al., 2017, Grant et al., 2015) and are identified as the leading risk for disease among individuals 25-49 years old. (Mark, xxxx) In 2021, 16.2 million adults in the United States reported heavy drinking in the past month, while 28.6 million adults met diagnostic criteria for AUD in the past year. (Niaaa, 2023) Posttraumatic Stress Disorder (PTSD) is also highly prevalent among adults. Approximately 70% of adults report exposure to a potentially traumatic event and over six percent of adults in the United States have met diagnostic criteria for PTSD. (Goldstein et al., 2016)

There are high rates of psychiatric multimorbidities in the context of AUD, (Grant et al., 2015, Castillo-Carniglia et al., Dec 2019) including PTSD. Individuals with AUD are more likely to be diagnosed with concurrent PTSD than individuals without AUD. (Grant et al., 2015) In fact, those having a lifetime diagnosis of AUD are 3 times more likely to also be diagnosed with PTSD. (Grant et al., 2015) Similarly, individuals diagnosed with PTSD are 1.2-1.7 times more likely to have an AUD compared to individuals without PTSD, indicating that more than 40% of individuals with PTSD also meet diagnostic criteria for an AUD. (Goldstein et al., 2016, Pietrzak et al., 2011)

PTSD and AUD synergistically contribute to more severe symptomatology as part of this reciprocal relationship. (Simpson et al., Jun 2019, Kaysen et al., Jun 2006, Back et al., Sep 2006) PTSD is associated with risky alcohol use (Blanco et al., 2013) and alcohol use increases following a traumatic event. (North et al., Feb 2011) The majority of individuals with previous problematic alcohol use, including both men and women, use alcohol to cope with emotions following the traumatic event. (North et al., Feb 2011) Additionally, greater trauma symptom severity has been linked to increased subsequent alcohol use, while greater alcohol use is related to increased severity in future trauma symptoms among individuals completing treatment for PTSD/AUD. (Tripp et al., Jun 2020) Specifically, trauma-related symptoms such as intrusive thoughts and emotional numbing predict greater alcohol use, (Langdon et al., 2016) while AUD has been associated with increased intrusive and avoidance-based symptoms. (Kaysen et al., Jun 2006) These data highlight a bidirectional relationship between the two disorders.

The reciprocal relationship between AUD and PTSD is especially problematic as these concurrent disorders are related to increased functional impairment and lower treatment success. (Simpson et al., Jun 2019, Blanco et al., 2013, Norman et al., 2018, Simpson et al., Nov 2020) Compared to those with either AUD or PTSD alone, individuals with both disorders have higher rates of other psychiatric diagnoses, increased prevalence of suicide attempts, endorse more trauma-related and alcohol-related symptoms, and have an earlier onset of PTSD diagnosis. (Blanco et al., 2013, Norman et al., 2018) These individuals are also more likely to use substances to cope with symptoms compared to individuals without the other concurrent disorder. (Blanco et al., 2013) Evidence also suggests that PTSD/AUD is related to impaired physical and mental function and overall lower quality of life. (Norman et al., 2018) While individuals with PTSD/AUD have higher rates of treatment enrollment than those with either disorder alone, (Blanco et al., 2013, Simpson et al., Nov 2020) treatments are plagued by high drop-out rates (Roberts et al., 2015) and symptoms often persist following treatment. (Simpson et al., Nov 2020)

Limited pharmacological treatments are available to target concurrent trauma symptoms and alcohol consumption. Thus, novel treatments are urgently needed for PTSD/AUD. A recent review illustrated that only nine studies to date have explored pharmacotherapies for concurrent PTSD and AUD. (Petrakis and Simpson, 2017/02/01 2017) Unsurprisingly, medications for the treatment of PTSD (i.e., sertraline, desipramine) can reduce trauma-related symptoms, and medications for AUD (i.e., naltrexone) can affect alcohol outcomes, but no treatment has demonstrated clear efficacy in reducing both trauma symptoms and alcohol use in individuals with concurrent PTSD and AUD. (Petrakis and Simpson, 2017/02/01 2017) This evidence suggests that the reciprocal relationship between PTSD and AUD is likely not targeted with currently available pharmacotherapies and there is a need to identify novel treatment targets to address the underlying mechanisms of both PTSD and AUD.

The limited, effective treatment options for concurrent PTSD and AUD is especially problematic for women. Women are drinking at increasing rates compared to men (Grant et al., 2017, White, 2020) and are particularly vulnerable to the development of AUD, as well as the use of and relapse to alcohol in the context of stress. (Peltier et al., 2019/02/08/) Additionally, women are twice as likely to be diagnosed with PTSD following a traumatic event compared to men, (Pietrzak et al., 2011) despite experiencing fewer “potentially traumatic” events. (Tolin and Foa, Nov 2006) Women with PTSD are also more likely to drink to cope with trauma symptoms. (Lehavot et al., 2014) Given the increasing rates of alcohol use, drinking to cope with distress, and high rates of PTSD among women, it is especially critical to explore treatment targets for women with PTSD/AUD.

Emerging evidence suggests that pregnenolone-based neurosteroids may be a potential treatment target for PTSD/AUD. Our group has previously outlined the therapeutic potential of neurosteroids (including progesterone, allopregnanolone, pregnanolone, estradiol, testosterone and DHEA) for stress-related psychiatric disorders (i.e., disorders characterized by stress and/or negative affect) and alcohol use. (Peltier et al., 2021/04/01/) At the time of that review, research had demonstrated that there are altered levels of neurosteroids in stress-related psychiatric disorders and in alcohol use, with differing results among the neurosteroids studied. These data illustrated that neurosteroids likely affect the underlying neurobiological mechanisms of stress-related psychiatric disorders, as well as AUD. However, these associations are not often linear. It is therefore critical to better understand how neurosteroids might address the overlapping vulnerabilities attributed to stress, negative affect, and alcohol use. Nonetheless, existing findings are promising and may offer therapeutic potential for PTSD and AUD.

The current review builds upon this previous work, by exploring the emerging literature over the past ten years detailing the role of pregnenolone-based neurosteroids specific to PTSD and alcohol in human populations. Subsequent sections will provide background information on prominent neurosteroids, including pregnenolone, progesterone, pregnanolone, allopregnanolone, estradiol, testosterone, and dehydroepiandrosterone (-sulfate; DHEA/DHEA-S), and then explore the role of these neurosteroids in the symptomatology of PTSD and alcohol use. These sections will conclude with an overview of current treatment studies using exogenous neurosteroids for the treatment of PTSD and alcohol use, as well as future directions for clinical research. While discussing this literature we will highlight sex differences, including sexually dimorphic findings, to provide a full scope of the application of sex as a biological variable (SABV) and understand the current literature from a rigor and reproducibility standpoint. This information will inform future treatment development, especially for women who are vulnerable to PTSD and stress-related alcohol use.