Table 5.
Novel interventions for PTSD and proposed mechanisms.
| Intervention | Description and Proposed Mechanism in PTSD |
| PTSD Prophylaxis (“Golden Hours”) | |
| Propranolol | Beta-adrenergic antagonist; blocks NE-driven fear memory reconsolidation. |
| Morphine | Opioid agonist analgesic; inhibits NE through the locus coeruleus; impairs fear memory conditioning. |
| Hydrocortisone | Corticosteroid; negative feedback inhibition of adrenergic stress response; reduces trauma memory formation and facilitates fear extinction. |
| Oxytocin | May increase or decrease the formation and consolidation of trauma-associated memory. |
| Nitrous oxide (NO) | Analgesic and NMDAR antagonist; may impair memory consolidation. |
| Cognitive vaccine | Alters dysfunctional appraisals using cognitive bias modification. |
| Psychopharmacologic Interventions for PTSD | |
| Modulators of the Endocannabinoid System | |
| CB1 receptor agonists (Cannabis, cannabinoids like THC, CBD, nabilone) |
The CB1 receptor is involved in regulation of mood, pain perception, appetite, learning, memory, and inflammation. THC reduces amygdala reactivity and increases mPFC activation and mPFC-amygdala functional coupling during threat. May reduce sleep disturbances and memory reconsolidation. |
| Neuropeptides, Hormones, and Related Compounds | |
| Hydrocortisone, mifepristone | Hydrocortisone causes HPA axis negative feedback inhibition through GRs. Mifepristone is a selective antagonist of the GR. |
| CRF type 1 receptor antagonists | Blocks CRF-mediated stress response and may enhance fear inhibition. |
| Allopregnanolone (Ganaxolone, AC-5216/XBD 173, etifoxine, and YL-IPA08) |
GABAA receptor modulator, with anxiolytic effects. Enhances HPA negative feedback to restore homeostasis. May reduce amygdala and insula activity, NE and glucocorticoid signalling, and increase mPFC activity. |
| Oxytocin | Facilitates trust and social interactions, and improves working memory and executive function. May increase or decrease formation and consolidation of trauma-associated memory. Increased connectivity within dlPFC, and between dlPFC and ACC. |
| Glutamatergic Modulators | |
| NMDA receptor antagonists (ketamine, ifenprodil, lanicemine, xenon) | Blocks NMDA receptor-mediated formation of intrusive memories. Ketamine also has rapid-onset antidepressant and anti-suicidal action, and upregulates BDNF and dendritic spine growth. See below for psychotherapy-enhancing effects. |
| Glutamatergic modulation (riluzole, zonisamide, phenytoin, tianeptine) | Riluzole reduces glutamate excitotoxicity by increasing neuronal and glial uptake, decreasing release, and inhibiting voltage-gated sodium channels. Zonisamide indirectly reduces glutamate neurotransmission. |
| D-serine modulators | Potential for facilitating fear extinction by increasing D-serine mediated NMDA receptor transmission. |
| Anti-inflammatory, Analgesic, and Related Compounds | |
| Opioids (buprenorphine, morphine, nalmefene) and nitrous oxide | Impairs fear memory conditioning. Opioids inhibit noradrenaline through the locus coeruleus; Nitrous oxide is also a NMDA antagonist. |
| Opioid antagonists (nalmefene, naltrexone) |
Block opioid receptors, which may be involved in dissociative symptoms. |
| Neuropeptide Y | A neurotransmitter regulator impacting pain, circadian rhythms, learning, memory, neurogenesis, neuroprotection, and neuropsychiatric conditions such as depression, anxiety, and addiction. Has anxiolytic effects and counteracts the action of CRF. |
| N-acetyl cysteine | Antioxidant, anti-inflammatory, and glutamate modulator. |
| Other anti-inflammatory compounds | Possible role in neuroprotection; minocycline may reduce brain cytokines. Other candidates include ASA, NSAIDs, and doxycycline. |
| Other Pharmacological Interventions | |
| Memantine | NMDA antagonist investigated for cognitive impairment in PTSD. |
| Asenapine, brexpiprazole | Antipsychotics with 5-HT2A and alpha-adrenergic antagonist properties. |
| Orexin receptor antagonists (suvorexant) | May reduce arousal, promote sleep, enhance consolidation of extinction memories, and improve habituation through orexin system antagonism. |
| Nepicastat | Inhibits dopamine-β-hydroxylase, blocking conversion of dopamine to noradrenaline, thereby reducing catecholamine levels. May disrupt formation and consolidation of traumatic memories. |
| Optimization of Current Evidence-Based Psychotherapies | |
| Improving efficiency, access and drop-out rates |
Shortening treatment by eliminating unnecessary components or improving effectiveness of components. Group therapy formats, or lay therapists, to improve cost-effectiveness. Incorporating self-help or digital components. Remote (telehealth, videoconferencing) delivery, and in-home treatment, to reduce barriers to treatment. |
| Altering length of exposure element |
Conventional wisdom is that lengthy trauma memory exposures are necessary (e.g., PE). However, newer interventions with micro exposures (e.g., Flash Technique), brief exposures (e.g., modified exposure), pendulating exposure (e.g., Somatic Experiencing), or fluctuating exposure (e.g., 3MDR) have been developed. |
| Combining TFP components | Combining cognitive strategies to PE, for example, or EMDR with PE. |
| EMDR 2.0 | Includes three core elements: a) motivating the patient to focus on the distressing memory, b) optimizing activation of the memory network and the body, and c) use of multiple and often multi-modality working memory-taxing tasks. May incorporate techniques such as modifying posture, adding music, movement and imaginal interweaves (similar to rescripting), and techniques to titrate exposure. |
| Adding non-trauma-focused elements | Addition of coping (PE-Stress Inoculation Training), emotion regulation skills (e.g., DBT-PE, STAIR-PE), or SUD treatment (Creating Change, COPE). |
| Intensive scheduling | “Intensive” or “massed” treatment involving multiple sessions per week, in order to accelerate recovery and reduce dropout. |
| Emerging Psychotherapies and Behavioral Treatments | |
| Emerging Trauma-Focused Psychotherapies | |
| Accelerated Resolution Therapy (ART) | Manualized therapy combines features of EMDR with imaginal rescripting of traumatic events, visual imagery, use of metaphors, and Gestalt techniques. |
| Imaginal Rehearsal Therapy (IRT) | CBT and exposure-based intervention for trauma-related nightmares. The person is asked to recall and then rescript nightmares, including more adaptive interpretations, active responses, and positive or acceptable endings. This is rehearsed to displace unwanted content. |
| Reconsolidation of Traumatic Memories (RTM) |
Traumatic memories are reviewed in an imaginary movie theater as a rapid black-and-white movie. The patient modifies key aspects of the target memory (e.g., color, clarity, speed, distance, perspective) to make it less impactful. |
| Dialogical Exposure Therapy (DET) | Combines exposure with gestalt theory, with a focus on “self-processes” distorted by trauma. Major goals include self-acceptance, restoring a sense of self-continuity, and regaining the ability to shape interactions in the environment. Four phases: safety, stabilization, confrontation, and integration. |
| Somatic, body-oriented psychotherapies |
Includes Somatic Experiencing and Sensorimotor Psychotherapy; focuses on interoceptive awareness and titrated experiencing of bodily states, including sensation, posture, urges, and defensive motor patterns. Uses mindful attention to regulate bodily arousal. |
| Emotional Freedom Technique | Combines somatic and cognitive therapy, combining cognitions with bodily tapping of various acupressure points. |
| Non-Trauma-Focused Psychotherapies (Non-exposure based) | |
| Adapting psychotherapies developed for other disorders | Adapting therapies for other disorders to PTSD. For example, ACT, Metacognitive Therapy, Interpersonal Psychotherapy, DBT, and Behavioral Activation (see below). |
| Acceptance and Commitment Therapy (ACT) | Cognitive therapy emphasizing psychological flexibility through mindfulness and acceptance strategies, and committed, value-based action to change behavior. |
| Metacognitive Therapy | Cognitive-based therapy that emphasizes modifying metacognitive beliefs that perpetuate rumination, worry, hypervigilance, and subsequent maladaptive behaviors. Focuses on the person’s reaction to PTSD symptoms, rather than details of the trauma. |
| Behavioral Activation | A CBT strategy to improve mood through activity scheduling and reinforcement strategies, understanding impacts of behaviors on thoughts and emotions, and developing positive coping responses. |
| Creative art therapies | An eclectic mix of therapies, which may include artistic expression, dance, music, theatre, and expressive writing, to facilitate psychological and emotional exploration and experiencing. |
| Skills based treatments | Seeking Safety, TARGET, and the Unified Protocol all incorporate emotion regulation skills training, often with elements of mindfulness and interpersonal components. |
| Animal-assisted therapy (canine or equine therapy) | Use of dogs or horses to increase social and community engagement, sense of safety, and attentional control. |
| Moral Injury (MI) Interventions | Interventions used for MI include PE, CPT, Adaptive Disclosure Therapy, ACT, the Impact of Killing in War, and Trauma-Informed Guilt Reduction Therapy. These often include elements of disclosure, empathy, choice, taking responsibility, forgiveness, making amends, and reconnecting with self and others. Emerging treatments for MI include psychedelic-assisted therapy, virtual reality supported psychotherapy (i.e., 3MDR), and animal-assisted therapies. |
| Spiritually oriented interventions | Interventions that integrate spiritual/religious components, such as Spiritual-Integrated CPT, Soul Repair, and Building Spiritual Strength. Chaplains also draw on the following: pastoral counselling, meaning-making activities, forgiveness and relational repair, spiritual/religious coping, and other practices (e.g., prayer; meditation; spiritual guidance/direction; narratives, storytelling, spiritual writing, etc.). |
| Mind-Body Based Interventions | |
| HRV Biofeedback | Self-regulation training through modulation of vagus nerve activity, using real-time feedback from measured HRV. |
| Mindfulness-based treatments, meditation |
Non-judgemental, compassionate attention to the present moment, which facilitates emotion regulation and disentanglement from beliefs. |
| Yoga | May include movement-based and breathing-based interventions to improve interoceptive awareness, emotion regulation, autonomic function, and connection with the body. May improve tolerance of bodily and other experiences. |
| Acupuncture | Insertion of thin needles at specific bodily locations to modulate autonomic function through the vagus nerve, and, possibly, modulation of periaqueductal gray, amygdala, and DMN. |
| Technology Supported Interventions | |
| Internet-delivered treatments | Telehealth, videoconferencing, and asynchronous delivery (internet or computer-delivered interventions, hybrid treatments, apps, and bibliotherapy). |
| Virtual Reality Exposure Therapy (VRET) | Virtual reality and augmented reality interventions counter avoidance by using visual, auditory, and other sensory elements to activate traumatic memory networks and enhance exposure and engagement. |
| Computerized cognitive interventions | Attention bias modification, attention control training, etc., which aims to normalize attention biases towards and away from threat. |
| 3MDR | An exposure-based intervention incorporating treadmill walking within a personalized, multi-modal, immersive virtual reality environment, and dual attention tasks from EMDR. |
| Medication Augmented Psychotherapy | |
| D-cycloserine (DCS) | NMDA receptor agonist; enhancement of fear extinction during exposure tasks. |
| Yohimbine | Alpha-2-adrenergic receptor antagonist thought to facilitate fear extinction by increasing noradrenergic activity and arousal in the presence of conditioned stimuli. |
| Propranolol, hydrocortisone, oxytocin | As per the descriptions above under “PTSD Prophylaxis” section. |
| Psychedelic Assisted Psychotherapy | |
| MDMA | Increased release of serotonin, catecholamines, oxytocin, cortisol, prolactin and vasopressin; increased cognitive flexibility and ability to access and process painful emotions, improved fear extinction learning, reduced amygdala activation, and increased vmPFC activity. Oxytocin facilitates self-compassion (reduced shame), connection, trust, and empathy. MDMA-induced positive state interrupts the expectation of intolerable negative emotions upon recall of traumatic memory. |
| Ketamine | NMDA antagonist; in addition to chemical effects highlighted above (rapid antidepressant effects, blockade of intrusive memory formation, upregulation of BDNF), ketamine may disrupt the DMN, altering self-referential processing. Dissociation from usual defenses, bodily senses, and rigid thought patterns allows access and reprocessing of traumatic or unconscious material, and perspective taking. Higher doses can induce mystical or archetypal experiences, like classic psychedelics. |
| Classical psychedelics (LSD, psilocybin, DMT) |
Cognitive, mood and perceptual effects, due to 5-HT2 agonism, impacts on serotonergic, dopamine, and TAAR, and downstream effects on glutamate and BDNF. LSD also increases oxytocin release, associated with increased empathy and connectedness. Network alterations disrupt cortical control, increase functional connectivity between usually unconnected brain areas, and release inhibition over sensory, interoceptive, and other information, leading to alterations in perception of the self and reality, including mystical or life-changing transcendent experiences. |
| Neuromodulation and Nerve Blockade | |
| DBS | An electrical pulse generator is placed directly into the brain, targeting specific areas. |
| ECT, LAP-ST | Electrical induction of a seizure, under anaesthesia, which stimulates specific brain areas and is thought to induce neuroplasticity through increased BDNF. |
| rTMS | A magnetic field is passed through the scalp and skull, at specific locations, which alters underlying cortical and subcortical activity in specific brain networks. |
| tDCS | Direct current, via scalp electrodes, is passed through the skull to specific cortical areas, to inhibit (e.g., amygdala) or activate (e.g., dlPFC) the brain. |
| tcVNS, TNS, and acoustic stimulation | Targets autonomic dysregulation through electrical stimulation of the vagus, trigeminal or acoustic nerve. |
| Neurofeedback | EEG facilitated biofeedback. Individuals learn to self-regulate by changing brain rhythms to impact a video game display on the screen. |
| Stellate ganglion blockade (SGB) | Ultrasound-guided injection of local anesthetic into the neck to temporarily block the cervical sympathetic trunk, which controls the body's fight-or-flight response. |
Abbreviations: NE, norepinephrine; NMDAR, NMDA Receptor; CB1, Cannabinoid Receptor type 1; THC, ∆9-tetrahydrocannabinol; CBD, cannabidiol; mPFC, medial prefrontal cortex; HPA, Hypothalamic-pituitary-adrenal; GR, Glucocorticoid Receptor; CRF, corticotropin-releasing factor; GABAA, gamma-aminobutyric acid type A; dlPFC, dorsolateral Prefrontal Cortex; ACC, anterior cingulate cortex; NMDA, N-methyl-D-aspartate; BDNF, Brain Derived Neurotrophic Factor; ASA, Acetylsalicylic acid; NSAID, Non-steroidal anti-inflammatory drug; 5-HT, Serotonin; PE, Prolonged Exposure; 3MDR, Multi-Modal Motion-Assisted Memory Desensitization and Reconsolidation; EMDR, Eye Movement Desensitization and Reprocessing; DBT, Dialectical Behavior Therapy; STAIR-PE, Skills Training for Affective and Interpersonal Regulation combined with PE; SUD, Substance Use Disorder; COPE, Concurrent Treatment of PTSD and Substance Use Disorders Using Prolonged Exposure; CBT, Cognitive Behavioral Therapy; ACT, Acceptance and Commitment Therapy; TARGET; Trauma Affect Regulation: Guide for Education and Therapy; MI, Moral Injury; CPT, Cognitive Processing Therapy; HRV, Heart Rate Variability; MDMA, Methylenedioxy-methylamphetamine; LSD, Lysergic acid diethylamide, DMT, N,N-dimethyltryptamine; TAAR, trace amine-associated receptors; DBS, Deep Brain Stimulation; ECT, Electroconvulsive Therapy; LAP-ST, Low Amplitude Seizure Therapy; rTMS, Repetitive transcranial magnetic stimulation; tDCS, Transcranial Direct Current Stimulation; PFC, Prefrontal Cortex; tcVNS, transcutaneous cervical Vagus Nerve Stimulation; TNS, Trigeminal Nerve Stimulation; EEG, Electroencephalogram.