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Posttraumatic Stress Disorder (PTSD) and Alcohol Use Disorder (AUD) commonly co-occur among ‎veterans.1,2 PTSD is related to increased alcohol use3,4 and hazardous alcohol use increases following combat ‎exposure.5,6 This reciprocal relationship contributes to heightened impairment and lower treatment success.3,7-9 ‎Individuals with comorbid PTSD/AUD enroll in treatment at higher rates;3,9 however, they experience poor ‎treatment outcomes. There are no current pharmacological interventions to target comorbid PTSD/AUD.10 ‎Thus, novel pharmacological treatments are urgently needed to improve treatment outcomes. ‎

One strategy to improve treatment of PTSD/AUD is to develop medications that target shared, underlying ‎mechanisms of both disorders. Stress dysregulation has historically been linked to the development and ‎maintenance of PTSD and AUD,10 and hormones may play a role in modulating stress reactivity. Emerging ‎evidence suggests that hormones may be a potential treatment target for PTSD/AUD.11 Evidence suggests that ‎augmenting hormone levels may help regulate the stress response and associated negative affective states in ‎individuals with co-occurring PTSD/AUD. Accordingly, this may translate into decreased PTSD symptom ‎severity and reduced stress-related alcohol consumption in veterans. Below we will succinctly review the ‎available emerging data for hormone-based pharmacological treatments for PTSD/AUD. ‎

Pregnenolone is an endogenous hormone that may show promise as an emerging treatment for comorbid ‎PTSD/AUD, as it interacts with multiple neurotransmitter symptoms related to both disorders, including the ‎GABAergic/glutamatergic systems.12 While studies of male veterans have demonstrated mixed findings ‎related to levels of pregnenolone and PTSD,13,14 pregnenolone levels increase in response to alcohol in other ‎studies.15 Administration of pregnanolone reduces symptoms of depression in individuals with bipolar ‎disorder16 and, interestingly, pregnanolone decreases stress- and alcohol-cue-induced craving.17 However, the ‎effects of pregnanolone on drinking behavior in humans is generally understudied and no studies have included ‎veterans to date. ‎

Progesterone is a metabolite of pregnenolone and may also be an advantageous treatment for PTSD/AUD. ‎Generally, evidence suggests that high levels of progesterone lessen trauma-related symptoms, including low ‎mood and hyperarousal, as well as mitigate alcohol consumption.11,18,19 Administering progesterone ‎exogenously has attenuated stress reactivity, including ratings of negative emotions and cortisol levels,20 ‎which may be important in targeting stress-induced alcohol use among veterans with PTSD; however, there is ‎not clear data showing that progesterone reduces alcohol consumption. Furthermore, like pregnenolone, the ‎studies to date have not included veterans. ‎

Allopregnanolone, a metabolite of progesterone, dampens the endocrine response to stress, and this ‎dysregulation may underlie the development and/or maintenance of PTSD and AUD. Findings demonstrate ‎that allopregnanolone levels are low in individuals with PTSD and levels of allopregnanolone increase in ‎response to acute alcohol use, but decrease with habitual use.11,21 Thus, administration of allopregnanolone for ‎these conditions may also show promise. In fact, brexanolone (Zulresso®), a formulation identical to ‎endogenous allopregnanolone administered via intravenous infusion, has been FDA-approved for the treatment ‎of postpartum depression and shows significant improvement in emotional outcomes.21 Similarly, Zuranolone, ‎an oral formulation of brexanolone, has shown initial promise reducing depressive symptoms in severe ‎postpartum depression.22 It should be noted that administration of a synthetic derivative of allopregnanolone, ‎ganaxolone, did not show improvement in PTSD symptoms among a group of veterans and civilians; however, ‎it is possible that higher dosing would yield symptom improvement. 23,24  This is noteworthy, as preclinical ‎work demonstrates that high-dose ganaxolone reduces anxiety-like behavior25 and decreases alcohol drinking ‎in rodents.26 While preliminary evidence suggests administering allopregnanolone may yield improved ‎treatment outcomes for veterans with PTSD/AUD, it remains understudied in this population. ‎

Worth mentioning, oxytocin, a hormone involved in HPA axis regulation, may be suitable as an emerging ‎target for comorbid PTSD/AUD. Intranasal oxytocin reduces PTSD symptom severity and normalizes ‎functional connectivity in the amygdala, a key brain region involved in stress pathophysiology.27 Clinical trials ‎among individuals with AUD suggest that intranasal oxytocin may reduce alcohol craving, alcohol withdrawal ‎symptoms and anxiety in AUD.28 Emerging data among veterans with concurrent PTSD/AUD show that ‎intranasal oxytocin reduces cortisol response following a laboratory stress task, but did not impact alcohol ‎craving;29 thus illustrating the exciting potential for oxytocin as an emerging treatment for veterans with ‎PTSD/AUD that should be further studied in this population. ‎

Taken together, there is evidence that hormone-based pharmacological treatments may target stress ‎dysregulation, an underlying mechanism of PTSD/AUD, and offer promise as treatments for veterans with ‎PTSD/AUD. However, despite these results, administration of hormones to treat both PTSD and AUD remains ‎understudied, especially among veteran populations. Future work should address this critical literature gap to ‎advance and optimize pharmacological treatment options in those with comorbid PTSD/AUD.‎

About the authors

MacKenzie Peltier, PhD, is an Assistant Professor in Psychiatry at Yale School of Medicine where she studies ‎sex differences in substance use disorders, with specific focus on the role of stress-reactivity, hormones, and ‎medication response in alcohol use disorder. Her research includes investigating medications for the treatment ‎of concurrent PTSD and alcohol use using human laboratory models. Dr. Peltier is also a Staff Psychologist at ‎the Veterans Affairs Connecticut Healthcare System, specializing in treating Veterans with co-occurring ‎posttraumatic stress disorder (PTSD) and substance use disorders. ‎

Terril Verplaetse, PhD, is an Assistant Professor of Psychiatry at Yale School of Medicine. Her research ‎focuses on human laboratory modeling of addictive behaviors, including examining mechanisms underlying ‎stress-related drinking and medication screening for sex-appropriate treatments for alcohol use disorder. Her ‎research interests also include using PET to image a putative marker of stress in alcohol use disorder, as well ‎as using epidemiologic data to examine interactive effects of sex and stress in the development of substance ‎use disorders.‎

Sherry McKee, PhD, is a Professor of Psychiatry at Yale School of Medicine, where she is the Founder and ‎Director of the Yale Behavioral Pharmacology Laboratory, and the Clinical Director of the Forensic Drug ‎Diversion Clinic. Dr. McKee’s research over the past 25 years has been directed at developing effective ‎treatments for addiction, with a particular focus on women and more recently, criminal justice populations. ‎Her translational work spans human laboratory paradigms, clinical trials, and epidemiological research to ‎uncover the mechanisms underlying poor outcomes and to translate these findings into improved interventions ‎for women and men. She is currently the Principal Investigator on the NIH-funded Yale-Specialized Center of ‎Research Excellence on Sex Differences in Alcohol Use Disorder, which is focused on expediting the ‎development of gender-sensitive therapeutics and providing a national resource on women and alcohol. ‎

Ismene Petrakis, MD, is a Professor of Psychiatry at Yale School of Medicine, Director of the Mental Health ‎Service line at Veterans Affairs Connecticut Healthcare System, and Medical Director of the National Center ‎for PTSD (Clinical Neurosciences Division). Since 1995, Dr. Petrakis consistently received VA, Department of ‎Defense, and NIH-based funding to investigate the underlying neurobiological mechanisms of dually ‎diagnosed individuals with PTSD and substance use disorder, including alcohol and opioid use disorders. Her ‎work includes laboratory studies to examine the neurobiology of these disorders and the behaviors that ‎accompany them including a stress reactivity paradigm, which can evaluate the relationship between stress, ‎trauma and substance-related craving. These paradigms have also been used with pharmacologic agents as ‎neurobiological “probes” to help develop new medications.‎


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