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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