madman
Super Moderator
Abstract
Rates of alcohol use disorder (AUD) are increasing in men and women and there are high rates of concurrent posttraumatic stress disorder (PTSD) and AUD. AUD and PTSD synergistically increase symptomatology and negatively affect treatment outcomes; however, there are very limited pharmacological treatments for PTSD/AUD. Neurosteroids have been implicated in the underlying neurobiological mechanisms of both PTSD and AUD and may be a target for treatment development. This review details the past ten years of research on pregnenolone, progesterone, allopregnanolone, pregnanolone, estradiol, testosterone, and dehydroepiandrosterone/dehydroepiandrosterone-sulfate (DHEA/DHEA-S) in the context of PTSD and AUD, including examination of trauma/alcohol-related variables, such as stress reactivity. Emerging evidence that exogenous pregnenolone, progesterone, and allopregnanolone may be promising, novel interventions are also discussed. Specific emphasis is placed on examining the application of sex as a biological variable in this body of literature, given that women are more susceptible to both PTSD diagnoses and stress-related alcohol consumption.
1. Introduction
Alcohol use, including high-risk drinking and alcohol use disorder (AUD), are increasing at alarming rates1,2 and are identified as the leading risk for disease among individuals 25-49 years old.3 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.4 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.5
There are high rates of psychiatric multimorbidities in the context of AUD,2,6 including PTSD. Individuals with AUD are more likely to be diagnosed with concurrent PTSD than individuals without AUD.2 In fact, those having a lifetime diagnosis of AUD are 3 times more likely to also be diagnosed with PTSD.2 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.5,7
PTSD and AUD synergistically contribute to more severe symptomatology as part of this reciprocal relationship.8-10 PTSD is associated with risky alcohol use11 and alcohol use increases following a traumatic event.12 The majority of individuals with previous problematic alcohol use, including both men and women, use alcohol to cope with emotions following the traumatic event.12 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.13 Specifically,trauma-related symptoms such as intrusive thoughts and emotional numbing predict greater alcohol use,14 while AUD has been associated with increased intrusive and avoidance-based symptoms.9 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.8,11,15,16 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.11,15 These individuals are also more likely to use substances to cope with symptoms compared to individuals without the other concurrent disorder.11 Evidence also suggests that PTSD/AUD is related to impaired physical and mental function and overall lower quality of life.15 While individuals with PTSD/AUD have higher rates of treatment enrollment than those with either disorder alone,11,16 treatments are plagued by high drop-out rates17 and symptoms often persist following treatment.16
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.18 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.18 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 are especially problematic for women. Women are drinking at increasing rates compared to men1,19 and are particularly vulnerable to the development of AUD, as well as the use of and relapse to alcohol in the context of stress.20 Additionally, women are twice as likely to be diagnosed with PTSD following a traumatic event compared to men,7 despite experiencing fewer “potentially traumatic” events.21 Women with PTSD are also more likely to drink to cope with trauma symptoms.22 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.
1.2 Current Review
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.23 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, pregnenolone, allopregnanolone, estradiol, testosterone, and dehydroepiandrosterone (-sulfate; DHEA/DHEAS), 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.
2. Neurosteroids
Neurosteroids are endogenous neuromodulators defined by rapid non-genomic actions24,25synthesized in both the brain and peripheral nervous system, as well as in other tissues.26,27Previous studies have explored the role of neurosteroids in brain function as well as their treatment potential for a variety of neurological and psychiatric disorders (for review see25,27-30). Based on the available literature, this review will focus on pregnenolone, progesterone, pregnenolone, allopregnanolone, estradiol, testosterone, and DHEA/DHEA-S (See Figure 1).
Pregnenolone is synthesized from cholesterol in the brain and in a wide variety of peripheral tissues. Circulating pools of pregnenolone and other neurosteroids come from the gonads and adrenal glands due to significantly higher volumes of steroid production.26,27,31 Metabolism of pregnenolone via multiple pathways results in a cascade of well-characterized neurosteroids, including pregnenolone-sulfate (pregnenolone-s), progesterone, allopregnanolone, and pregnenolone, as well as testosterone, estrogens (i.e., estradiol), and DHEA/DHEA-S.27 These neurosteroids are lipophilic and thus easily cross the blood-brain barrier.31 However, various active transports and enzymatic conversions can affect peripheral and central levels of neurosteroids. Nonetheless, their accumulation in the brain from de novo synthesis or the peripheral circulation has rapid effects on multiple neurotransmitter systems31 related to the development of PTSD and AUD, including γ -Aminobutyric acid (GABA) ergic and glutamatergic systems.31,32 These pregnenolone-derived neurosteroids are also closely related given the synthesis pathways (see Figure 1). Despite this, it is important to acknowledge that factors including biosynthetic enzyme blockades, cofactor saturations, or levels of metabolic enzymes may impact such synthesis.
Due to its role as a precursor to the neurosteroids mentioned above, pregnenolone increases circulating levels of neurosteroids, including allopregnanolone.27,29 Unlike other neurosteroids, it has poor affinity for GABA-A receptors, as well as low bioavailability and rapid metabolism, suggesting its therapeutic potential may be mediated by downstream metabolites.27Nonetheless, pregnenolone has been identified as a ligand for sigma1 receptors and type-1cannabinoid receptors.27 Pregnenolone has also been implicated as a biomarker in pre-clinical studies for anxiety/depression, cognitive functioning, stress-related disorders, schizophrenia, and drug use,27,29,33 as well as clinical studies of schizophrenia and schizoaffective disorder.34
;;; Progesterone is a 21-carbon hormone that is metabolized from pregnenolone by the 3βhydroxysteroid dehydrogenase enzyme.35 Progesterone is subsequently converted into allopregnanolone via a two-step process. Progesterone becomes 5α-dihydroprogesterone (5αDHP) via 5α-reductase and 5α-DHP is converted into allopregnanolone via 3α-hydroxysteroiddehydrogenase (3α-HSD).36 Pregnanolone is derived from progesterone by a similar two-step process. 5β-reductase converts progesterone to 5β-dihydroprogesterone (5β-DHP). 5β-DHP is then converted into pregnanolone via 3α-HSD.37 Notably, the conversion of dihydro progesterone via 3α-HSD into either allopregnanolone or pregnanolone is a bidirectional reaction. 5α-DHP or 5β-DHP can be reduced to allopregnanolone or pregnanolone, respectively. Conversely, allopregnanolone and pregnanolone can be reconverted into 5α-DHPor 5β-DHP.38 Progesterone and its metabolites, allopregnanolone and pregnanolone, act through genomic and nongenomic mechanisms.39 Specifically, progesterone, 5α-DHP, and 5βDHP have genomic action, whereas allopregnanolone and pregnanolone have non-genomic effects.38,40 Genomic, or classic steroid action, is a relatively slow process, in which progesterone binds to intracellular progesterone receptors, which in turn regulate genetic transcription. The nongenomic function, or “neurosteroid actions” occur via a more immediate interaction with various neurotransmitter systems, including GABAA, glycine, sigma1, and serotonin receptors.39,41
For example, fluctuations in neurosteroid levels have been shown to impact excitatory and inhibitory signaling via GABAergic mechanisms of action. Generally low concentrations of neurosteroid levels increase excitatory signaling via the potentiation of the extrasynaptic GABAA receptors, whereas large increases in neurosteroid levels result in reduced excitability and enhance GABAergic inhibition.42 Such shifts in the balance between excitatory and inhibitory GABAergic signaling are also related to the duration of exposure to neurosteroid levels. Acute, small increases (e.g., following a stressor), result in increased tonic inhibition via preferential action at receptors containing the δ subunit, whereas chronic exposure to high levels of neurosteroids (e.g., pregnancy) results in tonic and phasic inhibition (via receptors containing theγ2 subunit).43
In particular, progesterone, allopregnanolone, and pregnanolone have positive modulatory effects on GABAA receptors, which result in increased GABAergic signaling.29,39 This increase in GABA transmission may be advantageous in the treatment of stress-related disorders, as well as alcohol use and GABAergic agents are emerging as a promising treatment target for concurrent PTSD and AUD.32 For example, allopregnanolone is one of the more potent allosteric modulators of GABAA receptors.44 Pretreatment with allopregnanolone decreases stress responses and chronic stress reduces allopregnanolone levels. Allopregnanolone levels also quickly rise during acute stress and provide negative feedback on the acute stress response.39
Allopregnanolone downregulates expression of the corticotropin-releasing hormone (CRH) gene, thereby decreasing the activity of the hypothalamic–pituitary–adrenal (HPA) axis, likely resulting in its anxiolytic effects.45 Additionally, preclinical evidence suggests that after a stress-based exposure, progesterone’s metabolites, including allopregnanolone, enhance GABA-Areceptor mediate inhibition of the stress response.46
Testosterone is the main androgen circulating in humans.47 It modulates neuronal excitability via genomic and non-genomic mechanisms.47 Testosterone upregulates the expression of neuropeptide Y (NPY), a neuropeptide with anti-stress effects.48,49 Additionally, metabolites of testosterone (e.g., 3α-androstanediol) may positively affect GABAA function.30
Estradiol, the primary endogenous form of estrogen, is most potent during pre-menopause 50 and is converted from testosterone via aromatase enzymes. Estradiol is produced primarily in the gonads, as well as other organs, including the heart, brain, and skin.50 Estradiol signal throughout the body via classic nuclear (slow) receptors (ERα and ERβ), as well as more rapidacting receptors (e.g., GPR30 and ER-X).50 Estradiol has been shown to have anxiolytic-like effects and to potentiate fear extinction via binding to both ERα and ERβ.30,51 Furthermore, estradiol modulates the serotonergic system, as well as the activity of the HPA axis.41 Estradiol inhibits the expression of the serotonin transporter (SERT), thereby increasing the time serotonin is available to signal in the synapse.52 Estradiol also modulates levels of adrenocorticotropic hormone (ACTH) and cortisol via actions on glucocorticoid and CRH signaling.28 Preclinical evidence also shows that estradiol modulates the release of dopamine in the striatum and nucleus accumbens via binding to membrane estradiol receptors, most notably in female rodents.53,54 Chronic administration of estradiol in female rodents, increases D2 binding in these brain areas via Erβ. However, rapid administration of estradiol heightens amphetamine-stimulated striatal-dopamine response in female rodents. It has also been hypothesized that this relationship between estradiol and dopamine may be regulated via GABAergic striatal neurons in females.54
DHEA is also derived from pregnenolone via 17α‐hydroxypregnenolone.24,55 DHEA has been suggested to interact with sigma 1 receptors56 and it is a positive modulator of NDMA receptors.30,57,58 DHEA also modulates the GABAergic system,32 with evidence that DHEA and DHEA-S block GABAA receptors.30,56 DHEA has been implicated in the modulation of HPA axis activity. Ongoing DHEA administration resulted in lower cortisol levels, possibly because DHEA promotes the conversion of cortisol to an inactive metabolite.30 Additionally, administration of DHEA has been associated with increased levels of estradiol, testosterone, and allopregnanolone.30
Given the evidence that neurosteroids modulate neurotransmitter systems, such as the GABAergic system, a better understanding of the relationship between neurosteroids, and PTSD, and AUD has the potential to elucidate novel treatments for these disorders.
3. PTSD
3.1 Pregnenolone
3.2 Progesterone
3.3 Allopregnanolone
3.4 Pregnanolone
3.5 Testosterone
3.6 Estradiol
3.7 DHEA/DHEA-S
3.8 PTSD Summary
Taken together, recent literature illustrates the complex relationship between neurosteroids and PTSD. This relationship is plagued by discordant findings and likely reflects differences between men and women with PTSD, as well as various populations (e.g., Veterans/civilians) and methodologies to study PTSD and trauma-related variables. Additionally, many of the studies use subphases of the menstrual cycle, which can be challenging to interpret across studies.97 Most importantly, most studies did not employ SABV in study design or analyses (See Table 1). Future research among women also needs to account for hormonal fluctuations across reproductive stages, including pre-, peri-, and postmenopause. Despite these difficulties, there is emerging evidence that pregnenolone-derived neurosteroids, specifically progesterone and allopregnanolone, mitigate PTSD symptoms, diagnoses, and treatment responses (See Table 2). Thus, these neurosteroids warrant additional research regarding their utility in treating PTSD. Conversely, results are mixed among estradiol, testosterone, and DHEA/DHEA-S. Overall, further research is needed to explore the relationship between these neurosteroids and PTSD.
4. Alcohol
4.1 Pregnenolone
4.2 Progesterone
4.3 Allopregnanolone
4.4 Pregnanolone
4.5 Estradiol
4.6 Testosterone
3.7 DHEA/DHEA-S
4.8 Alcohol Summary
In parallel to the recent literature on PTSD, allopregnanolone appears to reduce alcohol consumption, and this is likely to be mediated through the mitigation of negative affect and stress. Results remain mixed for progesterone, whereas scant research demonstrates that pregnenolone is related to increased alcohol use and cravings (see Table 2). Additionally, levels of estradiol, testosterone, and DHEA appear to be related to increased alcohol consumption. Nonetheless, it is important to note that these findings potentially differ between men and women. This body of research is similarly marred by the inconsistent evaluation of SABV, which makes it difficult to generalize results across sexes and reproductive stages (see Table 3). Additional research is needed to elucidate the complex relationship between neurosteroids and alcohol use, considering menstrual cycle phases, reproductive stages (pre-, peri- and postmenopause), smoking status, as well as other racial and age variables.
5. Neurosteroids as novel treatments: Pregnenolone, progesterone, and allopregnanolone
5.1 Pregnenolone
5.2 Progesterone
5.3 Allopregnanolone
6. Summary and future directions
7. Conclusion
This review highlights the clinical literature over the past ten years and explores the relationships between neurosteroids, PTSD, and AUD. Recent data supports the idea that neurosteroids can improve trauma-related symptomatology and PTSD, as well as alcohol consumption and alcohol-related variables, such as cravings. Additionally, preliminary evidence supports the possibility that exogenous neurosteroids may be novel treatments, by targeting the underlying mechanism of PTSD/AUD. In particular, pregnenolone, progesterone, and allopregnanolone have shown the most promise in addressing the reciprocal relationship between PTSD and AUD, and thus warrant additional research. It is especially critical to explore such potential interventions among individuals with concurrent PTSD/AUD, as only one study to the authors’ knowledge has examined neurosteroids in populations with co-occurring PTSD and AUD.
While these findings are intriguing and offer promise for the development of novel interventions for PTSD and AUD, this review also highlights the inconsistent application of SABV and the lack of rigor in the assessment of menstrual cycle status and reproductive states in most studies. In particular, consistency in categorizing menstrual cycle status, the inclusion of pre-and perimenopausal women, and analysis of exogenous hormonal therapies should be addressed in future studies. Future research should also power studies adequately to address SABV, including stratifying analyses and reporting findings by sex. Such strategies will create homogeneity across studies and provide more rigorous data on the role of neurosteroids in the etiology, maintenance, relapse, and treatment of PTSD and AUD.
Rates of alcohol use disorder (AUD) are increasing in men and women and there are high rates of concurrent posttraumatic stress disorder (PTSD) and AUD. AUD and PTSD synergistically increase symptomatology and negatively affect treatment outcomes; however, there are very limited pharmacological treatments for PTSD/AUD. Neurosteroids have been implicated in the underlying neurobiological mechanisms of both PTSD and AUD and may be a target for treatment development. This review details the past ten years of research on pregnenolone, progesterone, allopregnanolone, pregnanolone, estradiol, testosterone, and dehydroepiandrosterone/dehydroepiandrosterone-sulfate (DHEA/DHEA-S) in the context of PTSD and AUD, including examination of trauma/alcohol-related variables, such as stress reactivity. Emerging evidence that exogenous pregnenolone, progesterone, and allopregnanolone may be promising, novel interventions are also discussed. Specific emphasis is placed on examining the application of sex as a biological variable in this body of literature, given that women are more susceptible to both PTSD diagnoses and stress-related alcohol consumption.
1. Introduction
Alcohol use, including high-risk drinking and alcohol use disorder (AUD), are increasing at alarming rates1,2 and are identified as the leading risk for disease among individuals 25-49 years old.3 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.4 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.5
There are high rates of psychiatric multimorbidities in the context of AUD,2,6 including PTSD. Individuals with AUD are more likely to be diagnosed with concurrent PTSD than individuals without AUD.2 In fact, those having a lifetime diagnosis of AUD are 3 times more likely to also be diagnosed with PTSD.2 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.5,7
PTSD and AUD synergistically contribute to more severe symptomatology as part of this reciprocal relationship.8-10 PTSD is associated with risky alcohol use11 and alcohol use increases following a traumatic event.12 The majority of individuals with previous problematic alcohol use, including both men and women, use alcohol to cope with emotions following the traumatic event.12 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.13 Specifically,trauma-related symptoms such as intrusive thoughts and emotional numbing predict greater alcohol use,14 while AUD has been associated with increased intrusive and avoidance-based symptoms.9 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.8,11,15,16 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.11,15 These individuals are also more likely to use substances to cope with symptoms compared to individuals without the other concurrent disorder.11 Evidence also suggests that PTSD/AUD is related to impaired physical and mental function and overall lower quality of life.15 While individuals with PTSD/AUD have higher rates of treatment enrollment than those with either disorder alone,11,16 treatments are plagued by high drop-out rates17 and symptoms often persist following treatment.16
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.18 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.18 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 are especially problematic for women. Women are drinking at increasing rates compared to men1,19 and are particularly vulnerable to the development of AUD, as well as the use of and relapse to alcohol in the context of stress.20 Additionally, women are twice as likely to be diagnosed with PTSD following a traumatic event compared to men,7 despite experiencing fewer “potentially traumatic” events.21 Women with PTSD are also more likely to drink to cope with trauma symptoms.22 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.
1.2 Current Review
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.23 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, pregnenolone, allopregnanolone, estradiol, testosterone, and dehydroepiandrosterone (-sulfate; DHEA/DHEAS), 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.
2. Neurosteroids
Neurosteroids are endogenous neuromodulators defined by rapid non-genomic actions24,25synthesized in both the brain and peripheral nervous system, as well as in other tissues.26,27Previous studies have explored the role of neurosteroids in brain function as well as their treatment potential for a variety of neurological and psychiatric disorders (for review see25,27-30). Based on the available literature, this review will focus on pregnenolone, progesterone, pregnenolone, allopregnanolone, estradiol, testosterone, and DHEA/DHEA-S (See Figure 1).
Pregnenolone is synthesized from cholesterol in the brain and in a wide variety of peripheral tissues. Circulating pools of pregnenolone and other neurosteroids come from the gonads and adrenal glands due to significantly higher volumes of steroid production.26,27,31 Metabolism of pregnenolone via multiple pathways results in a cascade of well-characterized neurosteroids, including pregnenolone-sulfate (pregnenolone-s), progesterone, allopregnanolone, and pregnenolone, as well as testosterone, estrogens (i.e., estradiol), and DHEA/DHEA-S.27 These neurosteroids are lipophilic and thus easily cross the blood-brain barrier.31 However, various active transports and enzymatic conversions can affect peripheral and central levels of neurosteroids. Nonetheless, their accumulation in the brain from de novo synthesis or the peripheral circulation has rapid effects on multiple neurotransmitter systems31 related to the development of PTSD and AUD, including γ -Aminobutyric acid (GABA) ergic and glutamatergic systems.31,32 These pregnenolone-derived neurosteroids are also closely related given the synthesis pathways (see Figure 1). Despite this, it is important to acknowledge that factors including biosynthetic enzyme blockades, cofactor saturations, or levels of metabolic enzymes may impact such synthesis.
Due to its role as a precursor to the neurosteroids mentioned above, pregnenolone increases circulating levels of neurosteroids, including allopregnanolone.27,29 Unlike other neurosteroids, it has poor affinity for GABA-A receptors, as well as low bioavailability and rapid metabolism, suggesting its therapeutic potential may be mediated by downstream metabolites.27Nonetheless, pregnenolone has been identified as a ligand for sigma1 receptors and type-1cannabinoid receptors.27 Pregnenolone has also been implicated as a biomarker in pre-clinical studies for anxiety/depression, cognitive functioning, stress-related disorders, schizophrenia, and drug use,27,29,33 as well as clinical studies of schizophrenia and schizoaffective disorder.34
;;; Progesterone is a 21-carbon hormone that is metabolized from pregnenolone by the 3βhydroxysteroid dehydrogenase enzyme.35 Progesterone is subsequently converted into allopregnanolone via a two-step process. Progesterone becomes 5α-dihydroprogesterone (5αDHP) via 5α-reductase and 5α-DHP is converted into allopregnanolone via 3α-hydroxysteroiddehydrogenase (3α-HSD).36 Pregnanolone is derived from progesterone by a similar two-step process. 5β-reductase converts progesterone to 5β-dihydroprogesterone (5β-DHP). 5β-DHP is then converted into pregnanolone via 3α-HSD.37 Notably, the conversion of dihydro progesterone via 3α-HSD into either allopregnanolone or pregnanolone is a bidirectional reaction. 5α-DHP or 5β-DHP can be reduced to allopregnanolone or pregnanolone, respectively. Conversely, allopregnanolone and pregnanolone can be reconverted into 5α-DHPor 5β-DHP.38 Progesterone and its metabolites, allopregnanolone and pregnanolone, act through genomic and nongenomic mechanisms.39 Specifically, progesterone, 5α-DHP, and 5βDHP have genomic action, whereas allopregnanolone and pregnanolone have non-genomic effects.38,40 Genomic, or classic steroid action, is a relatively slow process, in which progesterone binds to intracellular progesterone receptors, which in turn regulate genetic transcription. The nongenomic function, or “neurosteroid actions” occur via a more immediate interaction with various neurotransmitter systems, including GABAA, glycine, sigma1, and serotonin receptors.39,41
For example, fluctuations in neurosteroid levels have been shown to impact excitatory and inhibitory signaling via GABAergic mechanisms of action. Generally low concentrations of neurosteroid levels increase excitatory signaling via the potentiation of the extrasynaptic GABAA receptors, whereas large increases in neurosteroid levels result in reduced excitability and enhance GABAergic inhibition.42 Such shifts in the balance between excitatory and inhibitory GABAergic signaling are also related to the duration of exposure to neurosteroid levels. Acute, small increases (e.g., following a stressor), result in increased tonic inhibition via preferential action at receptors containing the δ subunit, whereas chronic exposure to high levels of neurosteroids (e.g., pregnancy) results in tonic and phasic inhibition (via receptors containing theγ2 subunit).43
In particular, progesterone, allopregnanolone, and pregnanolone have positive modulatory effects on GABAA receptors, which result in increased GABAergic signaling.29,39 This increase in GABA transmission may be advantageous in the treatment of stress-related disorders, as well as alcohol use and GABAergic agents are emerging as a promising treatment target for concurrent PTSD and AUD.32 For example, allopregnanolone is one of the more potent allosteric modulators of GABAA receptors.44 Pretreatment with allopregnanolone decreases stress responses and chronic stress reduces allopregnanolone levels. Allopregnanolone levels also quickly rise during acute stress and provide negative feedback on the acute stress response.39
Allopregnanolone downregulates expression of the corticotropin-releasing hormone (CRH) gene, thereby decreasing the activity of the hypothalamic–pituitary–adrenal (HPA) axis, likely resulting in its anxiolytic effects.45 Additionally, preclinical evidence suggests that after a stress-based exposure, progesterone’s metabolites, including allopregnanolone, enhance GABA-Areceptor mediate inhibition of the stress response.46
Testosterone is the main androgen circulating in humans.47 It modulates neuronal excitability via genomic and non-genomic mechanisms.47 Testosterone upregulates the expression of neuropeptide Y (NPY), a neuropeptide with anti-stress effects.48,49 Additionally, metabolites of testosterone (e.g., 3α-androstanediol) may positively affect GABAA function.30
Estradiol, the primary endogenous form of estrogen, is most potent during pre-menopause 50 and is converted from testosterone via aromatase enzymes. Estradiol is produced primarily in the gonads, as well as other organs, including the heart, brain, and skin.50 Estradiol signal throughout the body via classic nuclear (slow) receptors (ERα and ERβ), as well as more rapidacting receptors (e.g., GPR30 and ER-X).50 Estradiol has been shown to have anxiolytic-like effects and to potentiate fear extinction via binding to both ERα and ERβ.30,51 Furthermore, estradiol modulates the serotonergic system, as well as the activity of the HPA axis.41 Estradiol inhibits the expression of the serotonin transporter (SERT), thereby increasing the time serotonin is available to signal in the synapse.52 Estradiol also modulates levels of adrenocorticotropic hormone (ACTH) and cortisol via actions on glucocorticoid and CRH signaling.28 Preclinical evidence also shows that estradiol modulates the release of dopamine in the striatum and nucleus accumbens via binding to membrane estradiol receptors, most notably in female rodents.53,54 Chronic administration of estradiol in female rodents, increases D2 binding in these brain areas via Erβ. However, rapid administration of estradiol heightens amphetamine-stimulated striatal-dopamine response in female rodents. It has also been hypothesized that this relationship between estradiol and dopamine may be regulated via GABAergic striatal neurons in females.54
DHEA is also derived from pregnenolone via 17α‐hydroxypregnenolone.24,55 DHEA has been suggested to interact with sigma 1 receptors56 and it is a positive modulator of NDMA receptors.30,57,58 DHEA also modulates the GABAergic system,32 with evidence that DHEA and DHEA-S block GABAA receptors.30,56 DHEA has been implicated in the modulation of HPA axis activity. Ongoing DHEA administration resulted in lower cortisol levels, possibly because DHEA promotes the conversion of cortisol to an inactive metabolite.30 Additionally, administration of DHEA has been associated with increased levels of estradiol, testosterone, and allopregnanolone.30
Given the evidence that neurosteroids modulate neurotransmitter systems, such as the GABAergic system, a better understanding of the relationship between neurosteroids, and PTSD, and AUD has the potential to elucidate novel treatments for these disorders.
3. PTSD
3.1 Pregnenolone
3.2 Progesterone
3.3 Allopregnanolone
3.4 Pregnanolone
3.5 Testosterone
3.6 Estradiol
3.7 DHEA/DHEA-S
3.8 PTSD Summary
Taken together, recent literature illustrates the complex relationship between neurosteroids and PTSD. This relationship is plagued by discordant findings and likely reflects differences between men and women with PTSD, as well as various populations (e.g., Veterans/civilians) and methodologies to study PTSD and trauma-related variables. Additionally, many of the studies use subphases of the menstrual cycle, which can be challenging to interpret across studies.97 Most importantly, most studies did not employ SABV in study design or analyses (See Table 1). Future research among women also needs to account for hormonal fluctuations across reproductive stages, including pre-, peri-, and postmenopause. Despite these difficulties, there is emerging evidence that pregnenolone-derived neurosteroids, specifically progesterone and allopregnanolone, mitigate PTSD symptoms, diagnoses, and treatment responses (See Table 2). Thus, these neurosteroids warrant additional research regarding their utility in treating PTSD. Conversely, results are mixed among estradiol, testosterone, and DHEA/DHEA-S. Overall, further research is needed to explore the relationship between these neurosteroids and PTSD.
4. Alcohol
4.1 Pregnenolone
4.2 Progesterone
4.3 Allopregnanolone
4.4 Pregnanolone
4.5 Estradiol
4.6 Testosterone
3.7 DHEA/DHEA-S
4.8 Alcohol Summary
In parallel to the recent literature on PTSD, allopregnanolone appears to reduce alcohol consumption, and this is likely to be mediated through the mitigation of negative affect and stress. Results remain mixed for progesterone, whereas scant research demonstrates that pregnenolone is related to increased alcohol use and cravings (see Table 2). Additionally, levels of estradiol, testosterone, and DHEA appear to be related to increased alcohol consumption. Nonetheless, it is important to note that these findings potentially differ between men and women. This body of research is similarly marred by the inconsistent evaluation of SABV, which makes it difficult to generalize results across sexes and reproductive stages (see Table 3). Additional research is needed to elucidate the complex relationship between neurosteroids and alcohol use, considering menstrual cycle phases, reproductive stages (pre-, peri- and postmenopause), smoking status, as well as other racial and age variables.
5. Neurosteroids as novel treatments: Pregnenolone, progesterone, and allopregnanolone
5.1 Pregnenolone
5.2 Progesterone
5.3 Allopregnanolone
6. Summary and future directions
7. Conclusion
This review highlights the clinical literature over the past ten years and explores the relationships between neurosteroids, PTSD, and AUD. Recent data supports the idea that neurosteroids can improve trauma-related symptomatology and PTSD, as well as alcohol consumption and alcohol-related variables, such as cravings. Additionally, preliminary evidence supports the possibility that exogenous neurosteroids may be novel treatments, by targeting the underlying mechanism of PTSD/AUD. In particular, pregnenolone, progesterone, and allopregnanolone have shown the most promise in addressing the reciprocal relationship between PTSD and AUD, and thus warrant additional research. It is especially critical to explore such potential interventions among individuals with concurrent PTSD/AUD, as only one study to the authors’ knowledge has examined neurosteroids in populations with co-occurring PTSD and AUD.
While these findings are intriguing and offer promise for the development of novel interventions for PTSD and AUD, this review also highlights the inconsistent application of SABV and the lack of rigor in the assessment of menstrual cycle status and reproductive states in most studies. In particular, consistency in categorizing menstrual cycle status, the inclusion of pre-and perimenopausal women, and analysis of exogenous hormonal therapies should be addressed in future studies. Future research should also power studies adequately to address SABV, including stratifying analyses and reporting findings by sex. Such strategies will create homogeneity across studies and provide more rigorous data on the role of neurosteroids in the etiology, maintenance, relapse, and treatment of PTSD and AUD.
