Abstract
Chronic stress and traumatic events affect the psychological and physiological state of a person. Post-traumatic stress disorder (PTSD) is a type of psychological stress that occurs in critical situations that pose a direct threat to the life of the person and/or his or her loved ones. The prevalence of PTSD is increasing every year due to growing exposure to traumatic factors such as wars, natural disasters, and other crises. These events lead to severe psychological consequences, affecting a rising number of people worldwide. Currently, PTSD can be challenging to treat due to the complex nature of the disorder, variability in individual responses to treatment, and limitations in available therapeutic options. Considering the emergency need for effective PTSD treatment, a drug repurposing strategy presents a promising avenue to accelerate the availability of therapies. Here, we summarized and described drugs that were repurposed for alleviating PTSD symptoms. Moreover, we discussed the potential of some drugs, including alpha-adrenergic modulators, cannabinoids, glutamatergic modulators, and antipsychotics, for being repurposed for PTSD treatment. Drug repurposing implies the rapid identification of compounds with an established safety profile and known therapeutic effects that may be effective in PTSD. Repurposing existing drugs with already established pharmacokinetics and pharmacodynamics may shorten development timelines, facilitate a direct transition to the second phase of clinical trials, and lower costs. However, potential drawbacks and negative aspects should be discussed comprehensively.
Introduction
Post-traumatic stress disorder (PTSD) is a serious mental condition that may occur in individuals who have experienced traumatic events (TE), such as physical or sexual violence, war, accidents, natural disasters, or other extreme situations. 1 Diagnostic systems were developed to assess PTSD, including the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) and the International Classification of Diseases, 11th Edition (ICD-11). 2 According to DSM-5, there are five specific criteria required for the diagnosis of PTSD, including A – trauma criterion, B – intrusive recollection criterion, C – avoidance criterion, D – negative cognitions and mood criterion, E – alterations in arousal or reactivity criterion. 3 The most significant criterion for PTSD diagnosis is experiencing TE.
In accordance with the World Health Organisation, the lifetime prevalence of PTSD is 3.9% of the world population. 4 Approximately 70% of people worldwide are being subjected to a potential TE at some point in their lives; however, only a small fraction (5.6%) develop PTSD.4,5 Influence of both external and internal risk factors, such as genetic predisposition, neurophysiological changes and social support, determines development and PTSD severity. 6 It is worth noting that the prevalence of PTSD increases up to 15.3% in countries with war conflicts. 7 A recent nationwide cross-sectional study examining stress, anxiety, and PTSD symptoms among Ukrainians revealed that 93% of respondents experienced at least one mental health issue at a moderate or severe level during the first year of the Russian invasion. 8
PTSD is a multifaceted disorder and includes psychological, neurobiological, and physiological aspects. Dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis, hyper-activation of brain structures responsible for stress response, including the amygdala and hippocampus, and chronic inflammation are among the key physiological mechanisms associated with PTSD.6,9–11
Standard therapeutic approaches for the treatment of PTSD focus on psychotherapy (eg, cognitive behavioural therapy) and the use of pharmacological agents, including antidepressants. Psychotherapy is often unavailable due to high costs or a lack of qualified specialists, and the role of pharmacotherapy has been studied more extensively in recent years. However, many pharmaceuticals have undesirable side effects, which reduce their acceptability to patients. 12 Considering these challenges, recent research has focused on finding new therapeutic approaches based on a deeper understanding of the biological mechanisms of PTSD. In this context, there is a growing interest in repurposing drugs for the treatment of PTSD. Drug repurposing is based on the use of already approved drugs for the treatment of other conditions that have the potential to affect PTSD development.
Although progress has been made in elucidating the neurobiological mechanisms underlying PTSD, effective pharmacological options remain limited. Despite several drugs approved for other diseases showing potential for decreasing PTSD symptoms, the supporting evidence is fragmented and often limited. This highlights the need for a comprehensive review to summarize current knowledge that will assist rational selection of candidates for further preclinical and clinical investigation. This review represents the first effort to comprehensively discuss the effectiveness of some pharmaceutical compounds in alleviating PTSD symptoms. In this review, we summarised current approaches to repurpose medicines for the treatment of PTSD, analysed their potential advantages and limitations, and highlighted the prospects for developing this strategy. Current challenges in PTSD treatment and factors that complicate the search for effective therapeutic solutions are discussed.
Methodology
This narrative review includes summaries of 101 papers to describe compounds that are effective in decreasing PTSD symptoms. A comprehensive literature search was performed to identify relevant studies addressing the potential of some drugs for being repurposed for PTSD treatment. The search was performed in PubMed, Scopus, and Web of Science databases for the period from January 2000 to January 2025. The search strategy combined controlled vocabulary (MeSH terms in PubMed) and free-text keywords. The primary search terms included: “post-traumatic stress disorder” OR “PTSD” OR “treatment” OR “drugs” OR “compound”). Boolean operators (“AND,” “OR”) and truncations were used to maximize sensitivity and specificity. Additional articles were identified by manual screening of reference lists from selected papers. Only articles published in English were considered.
Only research, review articles, and chapters published were included in this study. Studies were included if they: (1) investigated compounds that show effectiveness to decrease PTSD symptoms in preclinical models or clinical trials; (2) provided primary data on molecular, physiological, or behavioral outcomes; and (3) were published in peer-reviewed journals. Exclusion criteria included: (1) conference abstracts, theses, or non-peer-reviewed reports; (2) studies not directly related to the topic of review; and (3) duplicate publications.
Common language editing tools were applied to improve grammar and readability in accordance with academic writing standards.
Drug Repurposing in Psychiatry
One of the promising topics in the current research is the repurposing of existing medicines, also known as drug repositioning, which involves identifying new therapeutic applications for already approved drugs.13,14 For example, during the COVID-19 pandemic, several drugs were repurposed, 15 including Remdesivir, an antiviral drug developed to treat Ebola, 16 as well as Dexamethasone, a widely used steroid that reduces mortality among hospitalised patients requiring ventilation. 17
The central nervous system (CNS) is a key focus of the research for drug repurposing due to the limited understanding of the pathophysiology and mechanisms of CNS disorders. Many approved drugs for CNS disorders have unclear modes of action, and disease characterisation relies heavily on clinical symptoms rather than biology. 18 Despite high prevalence and unmet needs, CNS drug development has low success rates and longer regulatory approval times. 19
Repurposing of existing pharmacological drugs is a promising area in the treatment of PTSD, as evidenced by the rapid growth in the number of studies in this area. Drug repurposing involves investigating the potential of existing drugs for new therapeutic uses. This strategy is particularly valuable in fields with a historically high risk of failure, such as psychiatry. 20 Established safety profiles, cost-effectiveness, accelerated timelines, and expanded treatment options are among the main benefits of a drug repurposing strategy. Already known safety and tolerability profiles entail significantly reduced risks associated with the development process compared to novel drug candidates. Based on publicly available data, it was defined that development costs for new therapeutic agents range from $314 million to $2.8 billion. 21 Moreover, drug development from original idea to implementation in clinical practice takes 12–15 years, 21 with an estimated success rate of only 2%. 22 Drug repurposing allows for bypassing early-stage development, which makes it a more cost-effective approach.
Drug repurposing is a complex process that includes several stages, including compound selection, compound acquisition, drug development and safety monitoring. 23 Drug-oriented, disease-oriented and target-oriented are three main approaches to drug repurposing. 23 A drug-oriented approach expands the application of an already approved drug. The disease-oriented approach is especially valuable for rare diseases and involves the identification of the diseases with homologous underlying biological mechanisms to the indication the original drug treats. Investigating the specific molecular targets implicated in a disease's pathology involves a target-oriented approach.
Many psychiatric disorders, such as depression, bipolar disorder, schizophrenia, and certain anxiety disorders, have limited effective pharmacological treatments. This raises an urgent need for innovative strategies to expand therapeutic options. Existing compounds were suggested to be effective in alleviating various CNS conditions. Ketamine, originally developed as an anaesthetic, has been successfully repurposed for treatment-resistant depression.24,25 Ketamine exerts rapid antidepressant effects through N-methyl-D-aspartate (NMDA) receptor antagonism and does not cause adverse effects. 26 Similarly, lithium has been used for gout and other medical conditions and was proven to be effective in the treatment of bipolar disorder. 27 The mood-stabilising properties of lithium are associated with its neurotrophic properties, which affect several molecular targets, including neurotrophins, glycogen synthase kinase 3 (GSK-3), and key proteins of the mitochondrial/endoplasmic reticulum. 28 Another example of drug repurposing in psychiatry is modafinil, which has been initially approved for narcolepsy, and recently investigated as an adjunctive treatment for major depressive disorder (MDD) 29 and schizophrenia.30,31 Antiepileptic drugs, lamotrigine and valproate, were effectively used for mood stabilisation in bipolar disorder.32,33 Atypical antipsychotics such as aripiprazole and quetiapine, initially used to treat schizophrenia, are now extensively used for depression and anxiety disorders.34,35
The drug repurposing approach presents several challenges, including the need to reevaluate dosage, long-term effects, and regulatory considerations for new indications. Nevertheless, the cost-effectiveness and faster development timelines make drug repurposing an attractive option, particularly in the context of increasing mental health issues globally. Psychological disorders often have complex and multifactorial mechanisms involving genetic, neurochemical, and environmental factors. To repurpose drugs for the treatment of psychological disorders, the detailed pathophysiology of these conditions should be studied.
Repurposing Existing Drugs for PTSD Therapy
Understanding the neurobiology of PTSD accelerates the development of effective pharmacotherapy. Post-traumatic stress disorder is a multidimensional disorder that combines a wide range of neurobiological changes, including disturbances of the hypothalamic-pituitary-adrenal gland axis, hyperactivation of the amygdala, and disruption of some hippocampal and cortical functions.36,37 Stress leads to an elevated release of stress hormones such as adrenaline and epinephrine into the bloodstream, initiating changes in the brain and triggering the stress response. 38 One of the key players in this stress response is corticotropin-releasing hormone (CRH), which is secreted by neurons in the paraventricular nucleus of the hypothalamus. CRH stimulates the release of adrenocorticotropic hormone (ACTH) from the anterior pituitary gland.39,40 ACTH moves through the bloodstream to the adrenal glands, prompting the release of cortisol. Cortisol plays a crucial role in regulating metabolic and immune functions, contributing to the overall stress response. Targeting cortisol levels and function could help alleviate the physiological and emotional symptoms of PTSD.
The renin-angiotensin-aldosterone (RAA) system is involved in the stress response and works in tandem with the HPA axis to regulate physiological and metabolic processes during stress. Stress-induced increase in the levels of angiotensin results in activation of the HPA axis and an increase in circulating cortisol. 41 Conversely, ACTH induces aldosterone secretion. 42 Overactivation of RAA system contributes to neuroinflammation and oxidative stress, which are associated with PTSD pathophysiology. 43 High aldosterone levels may cause depressive and anxiety-related behavior through direct impacts on brain regions, including the amygdala and prefrontal cortex. 44 Stress activates the sympathetic nervous system (SNS) and triggers the release of renin into the bloodstream. Renin converts angiotensinogen into angiotensin I, which is then converted into angiotensin II by angiotensin-converting enzyme (ACE). 45 Angiotensin II enhances the activity of the HPA axis, 46 playing a central role in the stress response in PTSD.
Neurotransmitter systems play a critical role in PTSD severity and represent key targets for drug therapy. Dysregulation of serotonin in PTSD is associated with heightened anxiety, aggression and depression. 47 Serotonin reuptake inhibitors (SSRIs) work by inhibiting the reuptake of serotonin and increasing serotonin levels in the brain, leading to a reduction of PTSD severity. Dopamine dysfunction is increasingly recognised as a contributing factor to the symptoms of anhedonia and emotional numbing commonly seen in PTSD. 48 Glutamate and glutamatergic systems are implicated in synaptic plasticity and fear learning. Increased blood glutamate levels are closely associated with mood disorders.49–51 Drugs targeting the glutamatergic systems could be effective in alleviating PTSD symptoms.
SSRIs paroxetine and sertraline had been initially used to treat depression and anxiety disorders. 52 Currently, paroxetine and sertraline are the only drugs approved by the Food and Drug Administration as first-line treatments for PTSD. 53 The therapeutic actions of SSRIs are associated with the enhancement of serotonin levels that are decreased under stress or depression (Table 1). 54 SSRIs work by blocking the serotonin transporter (SERT) located at the presynaptic axon terminal. This inhibition prevents serotonin (5-hydroxytryptamine, or 5-HT) reabsorption by presynaptic neurons. As a result, serotonin accumulates in the synaptic cleft, allowing it to activate postsynaptic receptors for a more extended period. 55 Enhancement of the serotonergic neurotransmission causes improvement of mood, anxiety, and sleep. 56
Existed Drugs That Show Effectiveness in Alleviation PTSD Symptoms.
The study of existing cannabinoid drugs [NCT04448808] led by Charité University was focused on the effectiveness of dronabinol in overcoming nightmares caused by PTSD. 57 Dronabinol modulates the endocannabinoid system, which influences emotional regulation, fear extinction, and sleep. Preliminary evidence from open-label and small-scale trials suggested significant improvements in nightmare frequency, sleep quality, and hyperarousal symptoms. 57
A study [NCT04877093] conducted by the Minneapolis Veterans Affairs Healthcare System investigated the effectiveness of low-dose clonidine for the treatment of PTSD in veterans who often have PTSD.58,59 Clonidine, an alpha-2 adrenergic agonist, showed promise in improving PTSD symptoms, particularly sleep disturbances and nightmares. It was reported that significant improvements in symptoms occurred for doses above 0.1 mg/day, with 49–85% of patients experiencing partial or marked relief. 58 Mild side effects, including grogginess and dizziness, were reported in 23% of patients. 58 Clonidine acts centrally to inhibit norepinephrine release with subsequent inhibition of sympathetic overactivation associated with PTSD. 60 Moreover, clonidine can stabilise adrenergic activity and lead to improved mood and a reduction of aggressive behaviours. 61
Doxazosin was approved for the treatment of hypertension as well as urinary tract obstruction, and was shown to be effective in reducing PTSD symptoms 62 and may also be used for comorbid PTSD and alcohol use disorders. 63 Improved sleep quality and decreased frequency and intensity of trauma-related nightmares were documented in combat veterans with PTSD after 8 weeks of treatment with 4 mg/day of doxazosin. 64 The study by Rodgman and colleagues 65 showed alleviation of PTSD symptoms after four days of treatment with 16 mg/day of doxazosin. The efficiency of doxazosin for PTSD was also proven in several studies.66,67
Propranolol, used initially for the treatment of hypertension, anxiety, and migraine prevention, was repurposed for reducing the emotional intensity of traumatic memories associated with PTSD. 68 Propranolol acts as a non-selective beta-adrenergic blocker to reduce overactivation of the sympathetic nervous system caused by stress. 69 However, some controversial studies showed that posttrauma propranolol treatment had no efficacy for preventing subsequent PTSD 70 or did not reduce PTSD incidence. 71
A repurposed anti-hypertensive drug, prazosin, was shown to be beneficial for treating PTSD symptoms.72–74 By blocking alpha-1 adrenergic receptors, prazosin improves sleep quality and reduces nightmares and PTSD symptoms. 75
Ketamine had been approved initially as a general anaesthetic and was repurposed for several other disorders, including depressive disorders, suicidal ideation, substance-use disorders, anxiety disorders, and bronchial asthma complications. 76 The beneficial effects of ketamine on mental health are realised via inhibition of NMDA receptors 77 and regulation of glutamate pathways. 78 A randomised controlled trial involving 30 individuals with chronic PTSD showed that the ketamine-treated group showed significant improvement in PTSD symptoms and depression. 79
Primarily used to treat schizophrenia and bipolar disorder, risperidone and quetiapine have shown potential in addressing PTSD symptoms.80,81 The effects of low-dose risperidone on aggression and PTSD symptoms in male combat veterans with PTSD were previously evaluated. 81 In this study, risperidone significantly reduced irritability and intrusive thoughts, suggesting its potential efficacy in managing these PTSD-related symptoms. 81 The beneficial effects of risperidone in PTSD are associated with the regulation of the dopaminergic system and HPA axis. 82 Quetiapine is recommended for persons with PTSD to decrease symptoms of hyperarousal and re-experience disorder.83,84 Moreover, the combination therapy with quetiapine, SSRI and gabapentin significantly reduced flashbacks. 85
Anticonvulsants, including lamotrigine and valproate, were found to be effective for the treatment of PTSD. Treatment with lamotrigine leads to improvement in reexperiencing and avoidance/numbing symptoms in both combat and civilian PTSD. 86 Lamotrigine inhibits voltage-gated sodium channels, reduces glutamate release in the brain, and inhibits overactivation of the amygdala. 87 Valproate shows potential for the treatment of PTSD by mitigating symptoms such as hyperarousal, irritability, and mood disturbances.88,89 It acts by increasing GABAergic activity and reducing glutamatergic excitotoxicity, addressing neural hyperactivity and stress-related neuroplastic changes observed in PTSD.88,89
Targeting biological pathways involved in PTSD with pharmaceutical components may be promising for investigating new approaches for its treatment. Inflammation was shown to play a key role in the pathogenesis and pathophysiology of PTSD.9,10 Anti-inflammatory drugs, including non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids, and cytokine inhibitors, could show promise in PTSD treatment based on their mechanisms of action. Statins may potentially help reduce neuroinflammation and cognitive decline associated with PTSD. To prevent or treat PTSD, common antibiotics with neuroprotective and anti-inflammatory effects may be effective. An example is minocycline, which passed phase IV of clinical trials, and its treatment is associated with reduced inflammation and reduced mood symptoms of PTSD. 93 Corticosteroid hydrocortisone, which is used for replacement therapy in primary, secondary, or acute adrenocortical insufficiency, showed promising effects in alleviating PTSD symptoms.94,95 Decreased intensity of chronic stress and PTSD symptoms at 6 months after traumatic event (cardiac surgery) was shown in patients exposed to hydrocortisone treatment. 96 A randomised double-blind trial showed that low-dose hydrocortisone treatment results in fewer PTSD and depression symptoms. 95 Moreover, the antibiotic rapamycin may be used as a treatment for anxiety disorders. 96
Metformin, initially approved for the treatment of Type 2 diabetes, was later shown to be effective in antiviral treatments.97,98 It was also able to decrease PTSD symptoms in both PTSD animal 99 and veterans. 100 Metformin activates the 5′-adenosine monophosphate-activated protein kinase (AMPK) pathway, attenuates oxidative stress and preserves mitochondrial function in the hippocampus of rat models of PTSD. 99
Challenges and Limitations of Drug Repurposing for PTSD
The process of drug repurposing is often considered to be a highly advantageous strategy; however, potential drawbacks and negative aspects should be discussed comprehensively (Figure 1). Within the area of PTSD, drug repurposing presents several challenges and limitations. The complexity of PTSD pathophysiology, with neurobiological and psychological aspects, significantly complicates the identification of repurposed drugs. PTSD pathophysiology is associated with alterations in multiple systems, including the HPA axis, the serotonergic and dopaminergic pathways, and inflammation-related processes.9,10 Considering the multifaceted nature of PTSD, identifying a drug that can comprehensively address these diverse mechanisms is challenging.
Representations of Benefits and Challenges of Drug Repurposing for PTSD Treatment.
High comorbidity of PTSD with other psychiatric and physical health conditions, such as depression, anxiety disorders, substance use disorders, and cardiovascular diseases, 101 makes drug repurposing challenging. Indeed, treatments for PTSD may interact with medications prescribed for co-occurring conditions.
Additional limitations for drug repurposing may be caused by the heterogeneity of PTSD symptoms across individuals. A repurposed drug may be effective for one subset of symptoms and may not work for others. Moreover, drugs used to treat a particular disorder may exhibit one set of side effects, but those used to treat another disease may show completely different side effects. Consequently, the potential safety risks and side effects when using drugs outside their approved indications, particularly in vulnerable PTSD populations, should be tested. Addressing all these limitations requires a multidisciplinary approach that integrates insights from neuroscience, pharmacology, and clinical practice.
Conclusion and Future Directions
Drug repurposing is a promising and cost-effective strategy for the development of new therapeutic approaches for PTSD. Applying a drug repurposing strategy allows for saving costs and expediting the drug development process. Using existing data on approved or investigational drugs within a drug repurposing strategy significantly reduces the time and costs associated with early-stage research and preclinical trials. Moreover, drug repurposing facilitates the development of combination therapies that address multiple aspects of PTSD pathophysiology, potentially providing more comprehensive and effective treatment options.
Despite these advantages, several challenges must be carefully addressed to maximise the success of this strategy. Potential obstacles include a limited understanding of PTSD heterogeneity, the need for robust clinical validation, possible off-target effects, and regulatory hurdles in repurposing drugs for new indications. Overcoming these challenges requires interdisciplinary collaboration and integration of advanced technologies and high-throughput screening methods.
Future research phase III clinical trials should prioritize alpha-adrenergic modulators, cannabinoids, glutamatergic modulators, and antipsychotics, given their demonstrated potential to alleviate core symptoms of PTSD. Furthermore, a key direction for future research is the application of precision medicine in PTSD treatment. Tailoring drug repurposing efforts based on individual patient profiles, including genetic factors and severity of symptoms, might be addressed by precision medicine in the context of PTSD. Genetic variations play a crucial role in shaping individual susceptibility to PTSD and treatment response. Additionally, considering the heterogeneity of PTSD symptoms, precision medicine approaches may help identify the most suitable repurposed drugs for different symptom clusters, ultimately leading to more personalised and targeted interventions. Consequently, further research is essential to optimise its implementation, address existing limitations, and ensure its successful integration into clinical practice.
As a narrative review, this work does not follow the complete set of guidelines of a systematic review, which may introduce limitations such as selection bias. Furthermore, the absence of meta-analytic synthesis restricts quantitative comparison across studies. Nonetheless, by critically integrating existing preclinical and clinical findings, the review provides an integrated overview and highlights key directions for future research.
Footnotes
List of abbreviations
Ethics Approval and Consent to Participate
This article is a literature review and does not involve human participants or primary data collection. Therefore, ethical approval and consent to participate declarations are not applicable.
Consent for Publication
Not applicable.
Author Contributions
OL led the development and writing of the manuscript. OS contributed to the literature search, data extraction for the table, and writing the manuscript. OL and OS reviewed and provided feedback. All authors approved the final manuscript.
Funding
The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by a grant from the Ministry of Education and Science of Ukraine [grant number 0125U000396].
Declaration of Conflicting Interests
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.