MDMA for treatment of PTSD and neurorehabilitation in military populations

Abstract

BACKGROUND:

Neurorehabilitation in military populations is complicated by higher rates of PTSD and unique characteristics of military institutions. These factors can adversely impact the patient-therapist therapeutic alliance and engagement with the rehabilitation process leading to poorer outcomes. MDMA is a non-classical psychedelic with pro-social and fear regulating properties. MDMA-assisted therapy is being explored as a novel treatment for PTSD that potentially offers rapid symptom improvement and enhances therapeutic alliance.

OBJECTIVE:

A review of MDMA-assisted therapy for PTSD is provided in the context of neurorehabilitation in military populations. The molecular mechanism of MDMA is outlined and a novel application of MDMA for neurorehabilitation is proposed.

METHODS:

This is an expert review and synthesis of the literature.

RESULTS:

Results from late-stage clinical trials suggest MDMA-assisted therapy for PTSD would be of particular benefit for military populations with PTSD. The unique pro-social properties of MDMA could be leveraged to enhance the therapeutic alliance and patient engagement during neurorehabilitation.

CONCLUSION:

The unique qualities and benefits of MDMA and MDMA-assisted therapy for PTSD suggest relevant application in military personnel undergoing neurorehabilitation. There are many similarities in patient-therapist dynamics in PTSD treatment and neurorehabilitation. The properties of MDMA which enhance therapeutic alliance, downregulate fear, and increase cognitive flexibility would potentially benefit both military personnel with and without PTSD undergoing neurorehabilitation.

Keywords

MDMA PTSD neurorehabilitation rehabilitation military personnel psychedelics

1 Introduction

Military populations undergoing rehabilitation for neurological injury face unique challenges that range from context of injury, psychiatric co-morbidities, and the cultural implications of disability during service. Neurorehabilitation in this demographic requires unique multidisciplinary considerations to facilitate treatment engagement and achieve optimal recovery outcomes.

Neurological injury in military populations often occurs in the context of physical trauma such as training or combat in a young, healthy population (Armistead-Jehle et al., 2017; Chapman & Diaz-Arrastia, 2014). This is in contrast to cerebral vascular accidents in civilian patients of advanced age, often with multiple medical co-morbidities(Albert & Kesselring, 2012). The context and severity of military injuries lends itself to a higher incident of psychological trauma that can manifest as operational stress injury (OSI) or post-traumatic stress disorder (PTSD). The presence of PTSD can interfere with the rehabilitation process, leading to poorer neurological and functional outcomes. (Armistead-Jehle et al., 2017; Chapman & Diaz-Arrastia, 2014; Jaffee & Meyer, 2009; McMillan et al., 2003; Ressler et al., 2022; Van Praag et al., 2019). Therefore, timely and effective treatment of PTSD is essential for successful neurorehabilitation. While there is robust evidence for existing PTSD therapies, there are limitations with high drop-out rates and large proportions of patients do not respond. This has led to the development of alternative therapeutic methods.

MDMA (3,4-Methylenedioxymethamphetamine) is a non-classical psychedelic with empathogen effects that is being studied for the treatment of PTSD (Sessa et al., 2019). While not yet FDA approved at the time of this publication, the results of two phase III trials for MDMA-assisted therapy (MDMA-AT) for PTSD suggests a favorable efficacy and safety profile (Mitchell et al., 2021; Mitchell, Bogenschutz, et al., 2023). MDMA-AT received breakthrough therapy designation from the FDA, and approval may be forthcoming. As there is a pronounced intersection of neurological trauma, PTSD, and psychological distress in military populations, MDMA may have a unique role in treatment for this demographic.

This review will discuss MDMA-assisted therapy for the treatment of PTSD within a military neurorehabilitation population. We will also describe the mechanism of MDMA and propose a novel application leveraging its empathogenic and neuroplastic properties with application during neurorehabilitation.

2 PTSD and neurorehabilitation

Military personnel requiring neurorehabilitation face a challenging process as there is a significantly higher prevalence of PTSD than in civilian populations (Van Praag et al., 2019). Military service is inherently a high risk profession that exposes personnel to traumatic events, life-threatening scenarios, and secondary traumatic stress. The intertwining of PTSD with physical injuries means that many individuals are not just grappling with physical limitations but are also burdened by psychological symptoms that pose distinct challenges within neurorehabilitation.

PTSD encompasses a multitude of symptoms ranging from re-experiencing traumatic memories to persistent negative mood and thought processes (APA, 2013). Hypervigilance or exaggerated startle responses are common and can interfere with routine physical interventions or exercises. Patients in a hypervigilant state are often scanning their environment for threats and frequently report difficulty with communication, concentration, and memory. These impairments can pose as significant barriers to rehabilitation routines.

Avoidance behaviors are a core feature of PTSD and may prompt patients to avoid exercises or activities that remind them of their trauma (O’Donnell et al., 2007). Often, these behaviors manifest as social isolation and avoidance of public areas which can result in missed medical appointments. Flashbacks are a type of re-experiencing symptom where patients momentarily relive traumatic memories and disengage from their immediate emotional, cognitive, and physical surroundings (McDaniel et al., 2023).

While such examples describe how symptoms can impede the mechanics of neurorehabilitation, PTSD can also interfere with the therapeutic alliance between patient and therapist. This alliance is foundational to effective neurorehabilitation where there must be trust between the patient and therapist. (Rowlands et al., 2020; Sherer et al., 2007; Van Praag et al., 2019). Common PTSD symptoms such as emotional detachment, distrust, or heightened irritability can hinder communication and rapport between the patient and physical therapist. Therefore, treating and managing PTSD is an essential component towards facilitating successful rehabilitation (Jaffee & Meyer, 2009; McMillan et al., 2003; Van Praag et al., 2019).

2.1 Current standards for PTSD treatment- trauma-focused therapies

Trauma-focused therapies (TFTs) represent a cornerstone of treatment options for PTSD. Psychotherapies such as Cognitive Processing Therapy (CPT) and Prolonged Exposure (PE) are designed to target trauma memories and associated cognitive and emotional sequelae (Weber et al., 2021). The basis of these therapies is to facilitate recollection and reprocessing of traumatic memories in a safe and controlled environment. While effective, TFTs require patients to discuss or reimagine their trauma, which can be particularly challenging. This partly explains the high dropout rates in clinical populations that range from 40–50% (Kitchiner et al., 2019; Lewis et al., 2020; Schottenbauer et al., 2008). A complete course of PE or CPT yields a 30–40% remission rate in clinical populations, leaving the majority of patients with ongoing symptoms and impairments (Edwards-Stewart et al., 2021; Lewis et al., 2020).

2.2 Introducing MDMA-AT

Emerging from late-stage clinical development and demonstrating robust efficacy in clinical trials, MDMA-AT for PTSD presents a promising treatment option. The results from two phase III studies demonstrated effect sizes of d = 0.97 and d = 0.7 in reducing PTSD severity as measured by the CAPS-5. Statistically significant improvements were also seen in secondary outcomes of patient functioning and depression severity. The treatment was well tolerated where the most commonly reported adverse effects were muscle tightness, nausea, and decreased appetite (Mitchell et al., 2021; Mitchell, Ot’alora, et al., 2023). Long term follow-up studies have also demonstrated durability with sustained symptom improvements 1 to 4 years post-treatment (Jerome et al., 2020).

MDMA has empathogenic properties which are proposed to promote feelings of trust and foster interpersonal connections (Hysek et al., 2014; Wardle & de Wit, 2014). These effects are believed to strengthen patient-therapist engagement and enrich the psychotherapeutic experience. Furthermore, there is evidence that MDMA can modulate amygdala activity, downregulating emotions of fear, anger, and shame (Singleton et al., 2022). This innovative approach is postulated to offer advantages over traditional TFTs, particularly in enhancing interpersonal trust and treatment engagement (Singleton et al., 2022).

MDMA-AT leverages the empathogenic effects of MDMA with a psychotherapy method that emphasizes an inner-directed approach. The treatment protocol begins with several preparatory sessions before drug administration. Subjects are asked to consider life events or relationships of relevance to their psychological situation. The purpose of these pre-dosing sessions is to establish the patient mindset and recall relevant memories in preparation for the MDMA experience. During MDMA dosing, patients are administered between 120–180 mg of MDMA and monitored by therapists over the course of 6–8 hrs. Patients are instructed to look inward and notice what memories, thoughts, and emotions arise during the drug experience. During the drug session, the content and direction of therapy is principally dictated by the patient, while the therapist serves in an observational and supportive role. After MDMA dosing, subjects meet with the therapists over the ensuing four weeks to discuss and process the content and meaning of material elicited during the MDMA experience. This cycle is repeated for a total of three MDMA dosing sessions (Mitchell et al., 2021; Mitchell, Ot’alora, et al., 2023).

There is initial evidence that MDMA-AT yields symptom improvement early in the treatment course. While the complete protocol extends over three months, improvements can be seen after the first MDMA dosing session (Mitchell et al., 2021; Mitchell, Ot’alora, et al., 2023). As better neurological outcomes are associated with timely initiation of rehabilitation, achieving accelerated PTSD symptom response would have significant value for patients where PTSD may delay initiation or interfere with the rehabilitation process (Königs et al., 2018).

While there are no direct comparisons of MDMA-AT to standard TFTs, preliminary evidence suggests MDMA-AT may be superior in regard to treatment tolerability and drop-out rates. The patient driven approach of the inner-directed therapy in conjunction with the fear mitigating properties of MDMA may cause less anxiety and distress than that seen during early stages of TFTs. This anxiety and distress partly explain the early treatment discontinuation and high drop-out rates seen with current TFTs (Edwards-Stewart et al., 2021; Kitchiner et al., 2019). Worsening of symptoms is also common in the initial stages of TFTs. Exacerbations of social avoidance, nightmares, or sleep disturbances could interfere with concurrent neurorehabilitation. While MDMA-AT may avoid these aspects of standard TFTs resulting in lower drop-out rates and improved treatment tolerability, this remains to be empirically proven in real-world clinical populations.

3 Military populations in neurorehabilitation- special considerations

Beyond the higher prevalence of PTSD, military populations may face unique challenges during neurorehabilitation. First, they are a demographic of young, healthy individuals with robust functional capacity. Following injury, service members are confronted with the psychological effects associated with an acute and substantial decline in functioning. This can be further aggravated by the military establishment’s culture and structure that emphasizes a guiding ethos centered around group cohesion and operational readiness(Caforio & Nuciari, 2006; Winslow, 2000). Injury and disability can be incompatible with these foundational tenets leading injured service members to experience a sense of exclusion from their former roles and identity.

3.1 Fear and shame of disability

Military culture and institutions staunchly prioritize the collective good over individual needs. Every service member is gauged and recognized based on their sacrifice for the collective mission objective (Redmond et al., 2015; Winslow, 2000). Unsurprisingly, injured service members can struggle with intense feelings of shame and anxiety, viewing themselves as “defective” or “liabilities” when they cannot meet their duty obligations (Frank et al., 2018; Griffin & Stein, 2015; Lunasco et al., 2010). Military organizational culture may inadvertently potentiate feelings of alienation, exacerbating shame and psychological distress (Frank et al., 2018; Redmond et al., 2015). This self-perception is further intensified when they are estranged from their colleagues particularly in rehabilitation centers where they are separated from their routine unit activities (Frank et al., 2018).

This fear of disability may be magnified given the acute change in their functional status (Vermetten & Ambaum, 2019). Unlike civilian populations where neurological injury generally occurs in patients of advanced age and who have multiple medical co-morbidities, military personnel are in peak physical condition prior to neurological impairment. This abrupt development of impairment may result in increased self-awareness of their functional limitations. In some studies of traumatic brain injury patients, greater self-awareness is associated with non-productive coping strategies such as avoidance and self-blame, which can complicate rehabilitation efforts (Anson & Ponsford, 2006). In situations of severe injury, the prospect of medical discharge ending their military career further complicates the psychological landscape. These factors may heighten feelings of fear, anger, and shame, and thus create barriers to rehabilitative efforts (Mukherjee et al., 2014; O’Keeffe et al., 2020). The complexities of military populations requiring neurorehabilitation underscores the need for specialized approaches.

4 A novel approach to neurorehabilitation: MDMA-assisted neurorehabilitation

The potential value of MDMA-AT in the setting of neurorehabilitation is underscored by the potential for rapid improvement of PTSD symptoms and greater treatment tolerability. However, in the absence of PTSD, there remains emotional and cognitive challenges that complicate treatment and recovery. A novel proposal employing MDMA during the neurorehabilitation process may improve outcomes through several mechanisms. This includes enhanced therapeutic alliance, improved self-esteem, and increased neural and behavioral plasticity.

4.1 Therapeutic alliance

Therapeutic alliance represents a cornerstone in neurorehabilitation and describes the collaborative connection between patients and therapists which may predict treatment efficacy (Flückiger et al., 2018). Mutual trust, collaboration, and a shared understanding of goals and expectations strengthens the therapeutic alliance, and can predict treatment adherence, patient motivation, and overall outcomes (Hall et al., 2010; Rowlands et al., 2020; Sherer et al., 2007). Patients navigating the challenges of neurological injuries can experience fluctuations in morale, making consistent support and understanding from a trusted clinician invaluable. A robust therapeutic alliance ensures that individual needs and concerns are addressed, interventions are tailored with empathy, and patients feel actively involved in their recovery process. Furthermore, it fosters an environment where patients feel safe communicating their fears, frustrations, and aspirations, leading to more personalized and effective rehabilitation strategies (Van den Broek, 2005). In essence, while physical techniques and interventions are pivotal, the quality of the therapeutic relationship often determines the trajectory of recovery in neurorehabilitation (Hall et al., 2010; Rowlands et al., 2020; Sherer et al., 2007).

Therapeutic alliance is generally described to be comprised of three components: agreement on therapeutic goals, agreement on therapeutic tasks, and the patient-practitioner bond (Bordin, 1979). While no studies have directly investigated the effects of MDMA on therapeutic alliance in neurorehabilitation, there is accumulating evidence that it can act to facilitate social connection and amplify the salience of social reward. These effects on social dynamics have implications for improving the patient-practitioner bond.

MDMA increases how social and connected participants feel as measured by self-report across a range of doses from 75 mg to 125 mg. This includes ratings of feeling “sociable,” “friendly,” “talkative,” “close to others,” and “loving”(Baggott et al., 2016; Kirkpatrick et al., 2012; Tancer & Johanson, 2003; van Wel et al., 2012). Studies in healthy volunteers have shown that MDMA may act to positively bias interpretation of social cues, boosting perception of positive emotions and reducing reactivity to negative emotions (Bedi et al., 2009; Bershad et al., 2019; Dolder et al., 2018; Frye et al., 2014; Kirkpatrick et al., 2014; Schmid et al., 2014; Wardle & de Wit, 2014). During neurorehabilitation, physical therapists often employ positive feedback and encouragement as a rewarding social stimulus to motivate patients. MDMA has been shown to enhance the experience of social reward across multiple dimensions including time spent socializing with a confederate, and responses to social images, attention to positive facial expressions, and social touch (Bedi et al., 2009; Bershad et al., 2019; Wardle & de Wit, 2014). Using MDMA to enhance these reward responses may improve patient engagement and enhance the patient-practitioner bond during rehabilitation.

Beyond the direct effects of MDMA on the patient, there is the potential for MDMA to indirectly enhance the physical therapist’s propensity to engage more effectively with the patient. MDMA promotes cooperative behavior, generosity, and empathy (Gabay et al., 2019; Hysek et al., 2014; Kirkpatrick et al., 2015; Kuypers et al., 2017). These effects on the patient may in turn create conditions that amplify the therapist’s likelihood to build stronger rapport with the patient. A patient exhibiting greater social and cooperative inclinations may enhance the therapist’s own pro-engagement behaviors and attitudes. In a pre-clinical model involving a mouse administered MDMA and an untreated mouse, the untreated mouse appeared to exhibit more social behaviors when in proximity to the MDMA-treated mouse (Heifets et al., 2019). Thus, MDMA may work in several ways to strengthen the patient-therapist bond and enhance the therapeutic alliance.

4.2 Self-esteem

One of the major personal factors predictive of success in neurorehabilitation is self-esteem (Koehler, 1989; Perin, 2017). Self-esteem has been described as a judgement of one’s self-worth or acceptance. It has two dimensions incorporating both the positive and negative evaluation of oneself (Rosenberg, 1979). Lower self-esteem is associated with maladaptive coping strategies and emotional dysfunction, which lead to poorer functional outcomes in rehabilitation (Anson & Ponsford, 2006; Vickery et al., 2008). Given the acute nature of functional decline and the cultural implications of disability during military service, self-esteem is likely to be negatively impacted in military populations. MDMA may act to positively bias both the positive and negative dimensions of self-esteem. MDMA may reduce shame in individuals who have experienced trauma (Mitchell et al., 2021). It appears to buffer the drop in self-esteem induced by simulated social rejection in healthy volunteers (Frye et al., 2014). With respect to positive self-image, early trials of MDMA suggested that patients reported feeling more authentic and more in touch with their true selves (Adamson & Metzner, 1988; Greer & Tolbert, 1990). To our knowledge, these effects have not yet been tested in controlled studies of clinical populations. Nonetheless, this evidence suggests MDMA may also act to improve self-esteem and could thereby improve outcomes in rehabilitation.

4.3 Neural and behavioral plasticity

Neuroplasticity is proposed to underlie the effectiveness of rehabilitation for patients suffering from neurological injury (Caeyenberghs et al., 2018; Khan et al., 2017). The restoration of function is a relearning process, necessitating neuroplastic change on a molecular, structural, and behavioral level (Warraich & Kleim, 2010). MDMA has shown promise in enhancing neuroplasticity in preclinical studies, and clinical studies suggest it may facilitate behavioral markers of plasticity. One study in mice showed that repeated doses of MDMA produce neuroplastic effects, inducing long term sensitization of noradrenergic and serotonergic neurons via stimulation of alpha1B-adrenergic and 5HT2A receptors (Lanteri et al., 2014). In rats, repeated doses reduced anxiety behavior, improved working memory, and increased hippocampal BDNF expression suggestive of neuroplastic change (Abad et al., 2014). A recent study in mice demonstrated that a single dose of MDMA reopened a critical period for social reward learning which was mediated by oxytocinergic transmission (Nardou et al., 2019). This opening of critical periods may represent metaplastic changes that produce conditions optimal for rehabilitation after neurological injury (Dromerick et al., 2021; Nardou et al., 2023). A follow up study by Nardou et al. described that this critical period opening may last for several weeks in mice (Nardou et al., 2023). This suggests that in humans MDMA induced metaplastic changes may occur with sufficient durability such that a course of neurorehabilitation can leverage the benefits of a MDMA with minimal repeated dosing.

There have been limited investigations into the effects of MDMA on neuroplasticity in humans, but a handful of studies have shown that the drug may affect a related dimension of openness to change. Increased openness may be helpful during neurorehabilitation in adaptive goal setting, an essential element of therapeutic success (Van De Weyer et al., 2010). Clinical trials of MDMA in the treatment of PTSD have shown the drug may increase the personality dimension of “openness,” an effect that lasts beyond the drug sessions themselves (Wagner et al., 2017). Thus, MDMA may facilitate both neural and behavioral plasticity that is essential in the rehabilitation process.

5 Mechanism

MDMA was originally created by Merk Pharmaceuticals in 1912 as a precursor in the synthesis of a hemostatic agent. Its specific central nervous system effects were only realized several decades later and the first evidence of its use as a recreational drug was detected in the 1970 s (Freudenmann et al., 2006). The subjective effects have been described as pleasant and enhancing both the effects of and the desire for social contact.

The molecular targets for MDMA may include neurotransmitter receptors, biosynthetic enzymes and neurotransmitter transporters (Docherty & Alsufyani, 2021; Green et al., 2003; Rothman & Baumann, 2003). However, the most current research on MDMA has focused on neurotransmitter transporters for biogenic amines such as dopamine, serotonin, and noradrenaline. Mammals express three distinct transporters for dopamine, serotonin and noradrenaline that reside on the plasma membranes of dopaminergic, serotonergic and noradrenergic neurons respectively (Docherty & Alsufyani, 2021; Green et al., 2003; Rothman & Baumann, 2003).

Drugs that act through membrane bound serotonin transporters (SERTs), dopamine transporters (DATs), and norepinephrine transporters (NETs) are generally thought to use one of three mechanisms. The most attributed mechanism is blockade of neurotransmitter uptake. Blockade is generally caused by drugs that are not transporter substrates and are not taken up into the cell. Blockers include methylphenidate and many antidepressants including the SSRIs, SNRIs, and TCAs which block transport of serotonin, epinephrine, or dopamine from the synapse back into neurons (Keighron et al., 2023). This increases the concentration of serotonin, norepinephrine, or dopamine in the synapse that is available to bind to post-synaptic receptors and activate downstream pathways (Coleman et al., 2019; Rothman & Baumann, 2003). A second mechanism is competitive inhibition whereby the drug competes against the endogenous neurotransmitter for transport by the re-uptake transporter. In the case of MDMA and SERT, if SERT is transporting MDMA into the cell, endogenous serotonin builds up in the synaptic space as SERT is limited by how much substrate, either serotonin or MDMA, it can transport back into the cell (Docherty & Alsufyani, 2021; Hysek et al., 2011).

A third proposed mechanism is reverse-transport or efflux of intracellular neurotransmitter through the membrane bound transporter and out into the synapse. While MDMA may also modulate serotonin signaling through blockade or competitive inhibition, efflux is currently thought to be the prevailing mechanism of action for MDMA and related drugs. Similar to SSRIs, the increase in synaptic concentrations of serotonin increases activation of post-synaptic receptors and associated signaling pathways. However, MDMA’s distinct acute subjective effects could potentially result from a more rapid increase in extracellular serotonin, via the efflux mechanism, compared to SSRIs (Baumann et al., 2018; Rudnick & Wall, 1992).

The proposed mechanism for efflux is fundamentally different from blockade or inhibition because it circumvents the normal vesicular release by directly releasing neurotransmitter through the transporter. This difference raises the possibility that efflux may have distinct physiological effects from transporter blockade, including the acute subjective psychotropic properties of MDMA. Other drugs that cause efflux include methamphetamines, fenfluramine and several designer drugs such as “bath salts”. These drugs have high translational relevance since they are used both therapeutically and are also drugs of abuse (Baumann et al., 2018; Magee et al., 2020).

Several molecular mechanisms have been proposed for how efflux agents induce transport of amines out of the cell through DAT, NET or SERT. The simplest mechanism is direct exchange of the extracellularly applied efflux agent for intracellular neurotransmitter. An alternative, and currently the dominant hypothesis of efflux agents, is that they induce a novel change in transporter structure and function (Kahlig et al., 2005). This mechanism first requires that they be a substrate for the transporter and are transported into the cell. Once inside the cell, MDMA and other efflux agents have been suggested to mediate a complex cascade of biochemical events that change the confirmation of the transporter, and thereby allow the movement of neurotransmitter out of the cell. The precise mechanism by which this conformation change occurs remains an active area of investigation. The N-terminus of the serotonin transporter has been proposed as essential for efflux and may act as a “lever” to change the conformation of SERT. Importantly, this conformational change leads to a pore or channel-like state where the neurotransmitter may exit the cell in a non-stoichiometric manner(Sucic et al., 2010). The implication of this phenomenon is that neurotransmitter efflux may theoretically occur at a higher rate compared to canonical re-uptake transport.

This mechanism of efflux requires initial transport of MDMA into the cell by the membrane-bound SERT to act on this N-terminus domain which is located within the cell. Thus, SSRI/SNRIs that inhibit SERT activity would prevent not only serotonin transport into the cell, but MDMA as well. This would preclude MDMA from reaching the intracellular domain of SERT where MDMA is proposed to initiate the conformational change of SERT. This is one reason why human subjects in MDMA clinical trials to date who are taking SSRIs/SNRIs are titrated off these medications for at least 5 -half-lives before MDMA dosing (Mitchell et al., 2021; Mitchell, Bogenschutz, et al., 2023).

As noted above, efflux agents such as MDMA also competitively inhibit transport of 5-HT through SERT. That is, as a molecule of MDMA is being transported into the cell, a molecule of serotonin, that would otherwise be moved into the cell under normal conditions, remains in the synaptic space. Therefore, efflux is unlikely to be the sole mechanism of action for MDMA. Nevertheless, differences between the behavioral effects of agents that can only inhibit uptake versus those that can also promote efflux raises the possibility that efflux is responsible for the unique behavioral effects. In particular, antidepressants such as fluoxetine and citalopram may not increase social connectivity, or at least to the extent, that appear to be mediated by MDMA. It is therefore possible that efflux at one or more circuits within the brain is responsible for the prosocial effects of MDMA.

6 Challenges and international perspectives for MDMA-assisted therapy

The stigma surrounding MDMA and similar drugs is especially notable within the United States given the history and policies regarding enforcement and regulation of recreational drugs (Sacco, 2014). Currently, MDMA is a DEA schedule one drug in the United States with no officially recognized medicinal value or application. If approved by the FDA, it would likely undergo DEA rescheduling and made available for clinical purposes. However, given its history as a recreational drug, wide adoption of MDMA based treatments may face challenges in settings such as the military. While there is anecdotal evidence of significant enthusiasm amongst the veteran community for this treatment, adoption for active-duty service members remains an open question.

Outside the United States, acceptance of MDMA-based treatments may be less controversial in countries with different societal and governmental perspectives towards drugs with a history of recreational use (De Kort & Korf, 1992). The Netherlands has a history of psychotrauma therapeutic regimes involving the use of psychedelics established by Jan Bastiaans after World War II (Vermetten et al., 2020; Vermetten & Olff, 2013). Bastiaans made significant contributions to post-war psychotraumatology with his treatment of survivors from concentration camps and other traumatic experiences. Starting in 1947, Bastiaans began narcoanalytic treatments in cases where insight-oriented psychotherapy yielded limited results, and where he felt patients were emotionally blocked. This was a psychotherapeutic approach initially employing pentothal but later included psychedelics such as LSD, psilocybin, and ketamine (Snelders, 2000).

In 2023, Australia became the first country to allow MDMA to be prescribed by physicians for the treatment of a psychiatric disorder (Haridy, 2023). Intuitively, many questions remain regarding optimal treatment and safety parameters. Australia’s Therapeutic Goods Administration (TGA) is proceeding cautiously with stringent regulations governing the use of MDMA. Prescribing is restricted to treatment of PTSD in combination with psychotherapy, and patients must have failed other treatments before consideration of MDMA. Other requirements include a clinical treatment protocol approved by a registered Human Research Ethics Committee (HREC), and evidence that the prescribing psychiatrists and therapists are adequately trained in psychedelic-assisted therapy (Australian Government, 2023).

7 Summary considerations

MDMA currently has no approved clinical applications in most countries. Significant advocacy and research efforts aim to change its regulation for therapeutic contexts. Within the United States, formal approval as a medical treatment by federal regulatory agencies could occur in the next several years.

Given the conservative nature of military organizations, there may be varying degrees of acceptance for a treatment involving MDMA. Implementing MDMA-assisted therapy or using MDMA to bolster therapeutic alliance would require scientific validation and cultural recognition within the military community.

Administering MDMA-assisted therapy requires specially trained therapists to guide patients through the experience and ensure safety. Establishing a framework for professionals within military healthcare systems such as the DoD and VAs would be critical for access.

Military servicemembers with neurological injury requiring neurorehabilitation face unique challenges beyond PTSD. A novel approach employing MDMA during neurorehabilitation could enhance the therapeutic alliance and neural plasticity to overcome these challenges.

8 Conclusion

Rehabilitation of neurological injury can be a difficult and arduous process. Within military populations, the increased prevalence of PTSD and distinctive features of military institutions can further complicate this effort. MDMA-AT for PTSD may offer advantages over current TFTs including accelerated symptom resolution and improved treatment adherence. In the absence of PTSD, there are challenges unique to military populations where the pro-social and plasticity effects of MDMA may offer particular benefit.

MDMA produces prosocial and neuroplastic effects both combined with and in the absence of psychotherapy. It is not known to what extent MDMA acts directly versus as a catalyst to the therapeutic relationship to induce therapeutic change. Nor is it known which elements of psychotherapy may be best suited to leverage the unique effects of the compound. As we advance our understanding of its underlying mechanisms, we anticipate MDMA will find applications for other psychiatric disorders and in healthcare settings beyond mental health.

Conflict of interest

None to report.

References

Abad,

, Fole,

, del Olmo,

, Pubill,

, Pallas,

, Junyent,

, Camarasa,

, Camins,

, Escubedo,

(2014). MDMA enhances hippocampal-dependent learning and memory under restrictive conditions, and modifies hippocampal spine density. Psychopharmacology (Berl), 231(5), 863–874. https://doi.org/10.1007/s00213-013-3304-5

Adamson,

, Metzner,

(1988). The nature of the MDMA experience and its role in healing, psychotherapy and spiritual practice. ReVision, 10(4), 59–72.

Albert,

S. J.

, Kesselring,

(2012). Neurorehabilitation of stroke. Journal of neurology, 259(5), 817–832.

Anson,

, Ponsford,

(2006). Coping and emotional adjustment following traumatic brain injury. J Head Trauma Rehabil, 21(3), 248–259. https://doi.org/10.1097/00001199-200605000-00005

APA,

A. P. A.

(2013). Diagnostic and statistical manual of mental disorders. The American Psychiatric Association.

Armistead-Jehle,

, Soble,

J. R.

, Cooper,

D. B.

, Belanger,

H. G.

(2017). Unique Aspects of Traumatic Brain Injury in Military and Veteran Populations. Phys Med Rehabil Clin N Am, 28(2), 323–337. https://doi.org/10.1016/j.pmr.2016.12.008

Australian Government,

T. G. A.

(2023). Access to MDMA (3,4-methylenedioxymethamphetamine) and psilocybin for therapeutic purposes, Information for psychiatrist prescribers. (3.0). https://www.tga.gov.au/resources/resource/guidance/access-mdma-34-methylenedioxy-methamphetamine-and-psilocybin-therapeutic-purposes-information-psychiatrist-prescribers: Austrailian Government

Baggott,

M. J.

, Coyle,

J. R.

, Siegrist,

J. D.

, Garrison,

K. J.

, Galloway,

G. P.

, Mendelson,

J. E.

(2016). Effects of 3,4-methylenedioxymethamphetamine on socioemotional feelings, authenticity, and autobiographical disclosure in healthy volunteers in a controlled setting. J Psychopharmacol, 30(4), 378–387. https://doi.org/10.1177/0269881115626348

Baumann,

M. H.

, Walters,

H. M.

, Niello,

, Sitte,

H. H.

(2018). Neuropharmacology of Synthetic Cathinones. Handb Exp Pharmacol, 252, 113–142. https://doi.org/10.1007/164_2018_178

10.

Bedi,

, Phan,

K. L.

, Angstadt,

, de Wit,

(2009). Effects of MDMA on sociability and neural response to social threat and social reward. Psychopharmacology (Berl), 207(1), 73–83. https://doi.org/10.1007/s00213-009-1635-z

11.

Bershad,

A. K.

, Mayo,

L. M.

, Van Hedger,

, McGlone,

, Walker,

S. C.

, de Wit,

(2019). Effects of MDMA on attention to positive social cues and pleasantness of affective touch. Neuropsychopharmacology, 44(10), 1698–1705. https://doi.org/10.1038/s41386-019-0402-z

12.

Bordin,

E. S.

(1979). The generalizability of the psychoanalytic concept of the working alliance. Psychotherapy: Theory, research & practice, 16(3), 252.

13.

Caeyenberghs,

, Clemente,

, Imms,

, Egan,

, Hocking,

D. R.

, Leemans,

, Metzler-Baddeley,

, Jones,

D. K.

, Wilson,

P. H.

(2018). Evidence for Training-Dependent Structural Neuroplasticity in Brain-Injured Patients: A Critical Review. Neurorehabil Neural Repair, 32(2), 99–114. https://doi.org/10.1177/1545968317753076

14.

Caforio,

, Nuciari,

(2006). Handbook of the Sociology of the Military. Springer.

15.

Chapman,

J. C.

, Diaz-Arrastia,

(2014). Military traumatic brain injury: a review. Alzheimers Dement, 10(3 Suppl), S97–104. https://doi.org/10.1016/j.jalz.2014.04.012

16.

Coleman,

J. A.

, Yang,

, Zhao,

, Wen,

P. C.

, Yoshioka,

, Tajkhorshid,

, Gouaux,

(2019). Serotonin transporter-ibogaine complexes illuminate mechanisms of inhibition and transport. Nature, 569(7754), 141–145. https://doi.org/10.1038/s41586-019-1135-1

17.

De Kort,

, Korf,

D. J.

(1992). The development of drug trade and drug control in the Netherlands: a historical perspective. Crime, Law and Social Change, 17, 123–144.

18.

Docherty,

J. R.

, Alsufyani,

H. A.

(2021). Pharmacology of Drugs Used as Stimulants. J Clin Pharmacol, 61Suppl 2, S53–S69. https://doi.org/10.1002/jcph.1918

19.

Dolder,

P. C.

, Muller,

, Schmid,

, Borgwardt,

S. J.

, Liechti,

M. E.

(2018). Direct comparison of the acute subjective, emotional, autonomic, and endocrine effects of MDMA, methylphenidate, and modafinil in healthy subjects. Psychopharmacology (Berl), 235(2), 467–479. https://doi.org/10.1007/s00213-017-4650-5

20.

Dromerick,

A. W.

, Geed,

, Barth,

, Brady,

, Giannetti,

M. L.

, Mitchell,

, Edwardson,

M. A.

, Tan,

M. T.

, Zhou,

, Newport,

E. L.

, Edwards,

D. F.

(2021). Critical Period After Stroke Study (CPASS): A phase II clinical trial testing an optimal time for motor recovery after stroke in humans. Proc Natl Acad Sci U S A, 118(39). https://doi.org/10.1073/pnas.2026676118

21.

Edwards-Stewart,

, Smolenski,

D. J.

, Bush,

N. E.

, Cyr,

B. A.

, Beech,

E. H.

, Skopp,

N. A.

, Belsher,

B. E.

(2021). Posttraumatic Stress Disorder Treatment Dropout Among Military and Veteran Populations: A Systematic Review and Meta-Analysis. J Trauma Stress, 34(4), 808–818. https://doi.org/10.1002/jts.22653

22.

Flückiger,

, Del Re,

A. C.

, Wampold,

B. E.

, Horvath,

A. O.

(2018). The alliance in adult psychotherapy: A meta-analytic synthesis. Psychotherapy (Chic), 55(4), 316–340. https://doi.org/10.1037/pst0000172

23.

Frank,

, Zamorski,

M. A.

, Colman,

(2018). Stigma doesn’t discriminate: physical and mental health and stigma in Canadian military personnel and Canadian civilians. BMC Psychol, 6(1), 61. https://doi.org/10.1186/s40359-018-0273-9

24.

Freudenmann,

R. W.

, Oxler,

, Bernschneider-Reif,

(2006). The origin of MDMA (ecstasy) revisited: the true story reconstructed from the original documents. Addiction, 101(9), 1241–1245. https://doi.org/10.1111/j.1360-0443.2006.01511.x

25.

Frye,

C. G.

, Wardle,

M. C.

, Norman,

G. J.

, de Wit,

(2014). MDMA decreases the effects of simulated social rejection. Pharmacol Biochem Behav, 117, 1–6. https://doi.org/10.1016/j.pbb.2013.11.030

26.

Gabay,

A. S.

, Kempton,

M. J.

, Gilleen,

, Mehta,

M. A.

(2019). MDMA Increases Cooperation and Recruitment of Social Brain Areas When Playing Trustworthy Players in an Iterated Prisoner’s Dilemma. J Neurosci, 39(2), 307–320. https://doi.org/10.1523/JNEUROSCI.1276-18.2018

27.

Green,

A. R.

, Mechan,

A. O.

, Elliott,

J. M.

, O’Shea,

, Colado,

M. I.

(2003). The pharmacology and clinical pharmacology of 3,4-methylenedioxymethamphetamine (MDMA, “ecstasy”). Pharmacol Rev, 55(3), 463–508. https://doi.org/10.1124/pr.55.3.3

28.

Greer,

G. R.

, Tolbert,

(1990). The Therapeutic Use of MDMA. In Peroutka

S. J.

(Ed.), Ecstasy: The Clinical, Pharmacological and Neurotoxicological Effects of the Drug MDMA (pp. 21–35). SpringerUS. https://doi.org/10.1007/978-1-4613-1485-1_2

29.

Griffin,

C. L.

, Stein,

M. A.

(2015). Self-perception of disability and prospects for employment among U.S. veterans. Work, 50(1), 49–58. https://doi.org/10.3233/WOR-141929

30.

Hall,

A. M.

, Ferreira,

P. H.

, Maher,

C. G.

, Latimer,

, Ferreira,

M. L.

(2010). The influence of the therapist-patient relationship on treatment outcome in physical rehabilitation: a systematic review. Phys Ther, 90(8), 1099–1110. https://doi.org/10.2522/ptj.20090245

31.

Haridy,

(2023). Australia to prescribe MDMA and psilocybin for PTSD and depression in world first. Nature, 619(7969), 227–228. https://doi.org/10.1038/d41586-023-02093-8

32.

Heifets,

B. D.

, Salgado,

J. S.

, Taylor,

M. D.

, Hoerbelt,

, Cardozo Pinto,

D. F.

, Steinberg,

E. E.

, Walsh,

J. J.

, Sze,

J. Y.

, Malenka,

R. C.

(2019). Distinct neural mechanisms for the prosocial and rewarding properties of MDMA. Sci Transl Med, 11(522). https://doi.org/10.1126/scitranslmed.aaw6435

33.

Hysek,

C. M.

, Schmid,

, Simmler,

L. D.

, Domes,

, Heinrichs,

, Eisenegger,

, Preller,

K. H.

, Quednow,

B. B.

, Liechti,

M. E.

(2014). MDMA enhances emotional empathy and prosocial behavior. Soc Cogn Affect Neurosci, 9(11), 1645–1652. https://doi.org/10.1093/scan/nst161

34.

Hysek,

C. M.

, Simmler,

L. D.

, Ineichen,

, Grouzmann,

, Hoener,

M. C.

, Brenneisen,

, Huwyler,

, Liechti,

M. E.

(2011). The norepinephrine transporter inhibitor reboxetine reduces stimulant effects of MDMA (“ecstasy”) in humans. Clin Pharmacol Ther, 90(2), 246–255. https://doi.org/10.1038/clpt.2011.78

35.

Jaffee,

C. M. S.

, Meyer,

K. S.

(2009). A brief overview of traumatic brain injury (TBI) and post-traumatic stress disorder (PTSD) within the Department of Defense. The Clinical Neuropsychologist, 23(8), 1291–1298.

36.

Jerome,

, Feduccia,

A. A.

, Wang,

J. B.

, Hamilton,

, Yazar-Klosinski,

, Emerson,

, Mithoefer,

M. C.

, Doblin,

(2020). Long-term follow-up outcomes of MDMA-assisted psychotherapy for treatment of PTSD: a longitudinal pooled analysis of six phase 2 trials. Psychopharmacology (Berl), 237(8), 2485–2497. https://doi.org/10.1007/s00213-020-05548-2

37.

Kahlig,

K. M.

, Binda,

, Khoshbouei,

, Blakely,

R. D.

, McMahon,

D. G.

, Javitch,

J. A.

, Galli,

(2005). Amphetamine induces dopamine efflux through a dopamine transporter channel. Proc Natl Acad Sci U S A, 102(9), 3495–3500. https://doi.org/10.1073/pnas.0407737102

38.

Keighron,

J. D.

, Bonaventura,

, Li,

, Yang,

J. W.

, DeMarco,

E. M.

, Hersey,

, Cao,

, Sandtner,

, Michaelides,

, Sitte,

H. H.

, Newman,

A. H.

, Tanda,

(2023). Interactions of calmodulin kinase II with the dopamine transporter facilitate cocaine-induced enhancement of evoked dopamine release. Transl Psychiatry, 13(1), 202. https://doi.org/10.1038/s41398-023-02493-4

39.

Khan,

, Amatya,

, Galea,

M. P.

, Gonzenbach,

, Kesselring,

(2017). Neurorehabilitation: applied neuroplasticity. J Neurol, 264(3), 603–615. https://doi.org/10.1007/s00415-016-8307-9

40.

Kirkpatrick,

, Delton,

A. W.

, Robertson,

T. E.

, de Wit,

(2015). Prosocial effects of MDMA: A measure of generosity. J Psychopharmacol, 29(6), 661–668. https://doi.org/10.1177/0269881115573806

41.

Kirkpatrick,

M. G.

, Gunderson,

E. W.

, Perez,

A. Y.

, Haney,

, Foltin,

R. W.

, Hart,

C. L.

(2012). A direct comparison of the behavioral and physiological effects of methamphetamine and 3,4-methylenedioxymethamphetamine (MDMA) in humans. Psychopharmacology (Berl), 219(1), 109–122. https://doi.org/10.1007/s00213-011-2383-4

42.

Kirkpatrick,

M. G.

, Lee,

, Wardle,

M. C.

, Jacob,

, de Wit,

(2014). Effects of MDMA and Intranasal oxytocin on social and emotional processing. Neuropsychopharmacology, 39(7), 1654–1663. https://doi.org/10.1038/npp.2014.12

43.

Kitchiner,

N. J.

, Lewis,

, Roberts,

N. P.

, Bisson,

J. I.

(2019). Active duty and ex-serving military personnel with post-traumatic stress disorder treated with psychological therapies: systematic review and meta-analysis. Eur J Psychotraumatol, 10(1), 1684226. https://doi.org/10.1080/20008198.2019.1684226

44.

Koehler,

M. L.

(1989). Relationship between self-concept and successful rehabilitation. Rehabil Nurs, 14(1), 9–12. https://doi.org/10.1002/j.2048-7940.1989.tb00665.x

45.

Königs,

, Beurskens,

E. A.

, Snoep,

, Scherder,

E. J.

, Oosterlaan,

(2018). Effects of Timing and Intensity of Neurorehabilitation on Functional Outcome After Traumatic Brain Injury: A Systematic Review and Meta-Analysis. Arch Phys Med Rehabil, 99(6), 1149–1159.e1141. https://doi.org/10.1016/j.apmr.2018.01.013

46.

Kuypers,

K. P. C.

, Dolder,

P. C.

, Ramaekers,

J. G.

, Liechti,

M. E.

(2017). Multifaceted empathy of healthy volunteers after single doses of MDMA: A pooled sample of placebo-controlled studies. J Psychopharmacol, 31(5), 589–598. https://doi.org/10.1177/0269881117699617

47.

Lanteri,

, Doucet,

E. L.

, Hernandez Vallejo,

S. J.

, Godeheu,

, Bobadilla,

A. C.

, Salomon,

, Lanfumey,

, Tassin,

J. P.

(2014). Repeated exposure to MDMA triggers long-term plasticity of noradrenergic and serotonergic neurons. Mol Psychiatry, 19(7), 823–833. https://doi.org/10.1038/mp.2013.97

48.

Lewis,

, Roberts,

N. P.

, Gibson,

, Bisson,

J. I.

(2020). Dropout from psychological therapies for post-traumatic stress disorder (PTSD) in adults: systematic review and meta-analysis. Eur J Psychotraumatol, 11(1), 1709709. https://doi.org/10.1080/20008198.2019.1709709

49.

Lunasco,

T. K.

, Goodwin,

E. A.

, Ozanian,

A. J.

, Loflin,

E. M.

(2010). One Shot-One Kill: a culturally sensitive program for the warrior culture. Mil Med, 175(7), 509–513. https://doi.org/10.7205/milmed-d-09-00182

50.

Magee,

C. P.

, German,

C. L.

, Siripathane,

Y. H.

, Curtis,

P. S.

, Anderson,

D. J.

, Wilkins,

D. G.

, Hanson,

G. R.

, Fleckenstein,

A. E.

(2020). 3,4-Methylenedioxypyrovalerone: Neuropharmacological Impact of a Designer Stimulant of Abuse on Monoamine Transporters. J Pharmacol Exp Ther, 374(2), 273–282. https://doi.org/10.1124/jpet.119.264895

51.

McDaniel,

J. T.

, Seamone,

E. R.

, Xenakis,

S. N.

(2023). Preventing and treating the invisible wounds of war: combat trauma, moral injury, and psychological health. Oxford University Press.

52.

McMillan,

T. M.

, Williams,

W. H.

, Bryant,

(2003). Post-traumatic stress disorder and traumatic brain injury: A review of causal mechanisms, assessment,and treatment. Neuropsychol Rehabil, 13(1-2), 149–164. https://doi.org/10.1080/09602010244000453

53.

Mitchell,

J. M.

, Bogenschutz,

, Lilienstein,

, Harrison,

, Kleiman,

, Parker-Guilbert,

, Ot’alora,

G. M.

, Garas,

, Paleos,

, Gorman,

, Nicholas,

, Mithoefer,

, Carlin,

, Poulter,

, Mithoefer,

, Quevedo,

, Wells,

, Klaire,

S. S.

, van der Kolk,

,... Doblin,

(2021). MDMA-assisted therapy for severe PTSD: a randomized, double-blind, placebo-controlled phase 3 study. Nat Med, 27(6), 1025–1033. https://doi.org/10.1038/s41591-021-01336-3

54.

Mitchell,

J. M.

, Bogenschutz,

, Lilienstein,

, Harrison,

, Kleiman,

, Parker-Guilbert,

, Ot’alora,

G. M.

, Garas,

, Paleos,

, Gorman,

, Nicholas,

, Mithoefer,

, Carlin,

, Poulter,

, Mithoefer,

, Quevedo,

, Wells,

, Klaire,

S. S.

, van der Kolk,

,... Doblin,

(2023). MDMA-Assisted Therapy for Severe PTSD: A Randomized, Double-Blind, Placebo-Controlled Phase 3 Study. Focus (Am Psychiatr Publ), 21(3), 315–328. https://doi.org/10.1176/appi.focus.23021011

55.

Mitchell,

J. M.

, Ot’alora,

G. M.

, van der Kolk,

, Shannon,

, Bogenschutz,

, Gelfand,

, Paleos,

, Nicholas,

C. R.

, Quevedo,

, Balliett,

, Hamilton,

, Mithoefer,

, Kleiman,

, Parker-Guilbert,

, Tzarfaty,

, Harrison,

, de

Boer, A.

, Doblin,

, Yazar-Klosinski,

, Group,

M. S. C.

(2023). MDMA-assisted therapy for moderate to severe PTSD: a randomized, placebo-controlled phase 3 trial. Nat Med, 29(10), 2473–2480. https://doi.org/10.1038/s41591-023-02565-4

56.

Mukherjee,

, Reis,

J. P.

, Heller,

(2014). Women living with traumatic brain injury: Social isolation, emotional functioning and implications for psychotherapy. In Women with visible and invisible disabilities (pp. 3–26). Routledge.

57.

Nardou,

, Lewis,

E. M.

, Rothhaas,

, Xu,

, Yang,

, Boyden,

, Dolen,

(2019). Oxytocin-dependent reopening of a social reward learning critical period with MDMA. Nature, 569(7754), 116–120. https://doi.org/10.1038/s41586-019-1075-9

58.

Nardou,

, Sawyer,

, Song,

Y. J.

, Wilkinson,

, Padovan-Hernandez,

, de Deus,

J. L.

, Wright,

, Lama,

, Faltin,

, Goff,

L. A.

, Stein-O’Brien,

G. L.

, Dolen,

(2023). Psychedelics reopen the social reward learning critical period. Nature, 618(7966), 790–798. https://doi.org/10.1038/s41586-023-06204-3

59.

O’Keeffe,

, Dunne,

, Nolan,

, Cogley,

, Davenport,

(2020). “The things that people can’t see” The impact of TBI on relationships: an interpretative phenomenological analysis. Brain Inj, 34(4), 496–507. https://doi.org/10.1080/02699052.2020.1725641

60.

O’Donnell,

M. L.

, Elliott,

, Lau,

, Creamer,

(2007). PTSD symptom trajectories: From early to chronic response. Behaviour research and therapy, 45(3), 601–606.

61.

Perin,

(2017). The Influence of Personal Factors in Neurorehabilitation. Current Advances in Neurology and Neurological Disorders, 1, 1–4.

62.

Redmond,

S. A.

, Wilcox,

S. L.

, Campbell,

, Kim,

, Finney,

, Barr,

, Hassan,

A. M.

(2015). A brief introduction to the military workplace culture. Work, 50(1), 9–20. https://doi.org/10.3233/WOR-141987

63.

Ressler,

K. J.

, Berretta,

, Bolshakov,

V. Y.

, Rosso,

I. M.

, Meloni,

E. G.

, Rauch,

S. L.

, Carlezon,

W. A.

Jr. , (2022). Post-traumatic stress disorder: clinical and translational neuroscience from cells to circuits. Nat Rev Neurol, 18(5), 273–288. https://doi.org/10.1038/s41582-022-00635-8

64.

Rosenberg,

(1979). Conceiving the self. Basic Books.

65.

Rothman,

R. B.

, Baumann,

M. H.

(2003). Monoamine transporters and psychostimulant drugs. Eur J Pharmacol, 479(1-3), 23–40. https://doi.org/10.1016/j.ejphar.2003.08.054

66.

Rowlands,

, Coetzer,

, Turnbull,

O. H.

(2020). Building the bond: Predictors of the alliance in neurorehabilitation. NeuroRehabilitation, 46(3), 271–285. https://doi.org/10.3233/NRE-193005

67.

Rudnick,

, Wall,

S. C.

(1992). The molecular mechanism of “ecstasy” [3,4-methylenedioxy-methamphetamine (MDMA)]: serotonin transporters are targets for MDMA-induced serotonin release. Proc Natl Acad Sci U S A, 89(5), 1817–1821. https://doi.org/10.1073/pnas.89.5.1817

68.

Sacco,

L. N.

(2014). Drug enforcement in the United States: History, policy, and trends (Vol. 7). Congressional Research Service Washington, DC.

69.

Schmid,

, Hysek,

C. M.

, Simmler,

L. D.

, Crockett,

M. J.

, Quednow,

B. B.

, Liechti,

M. E.

(2014). Differential effects of MDMA and methylphenidate on social cognition. J Psychopharmacol, 28(9), 847–856. https://doi.org/10.1177/0269881114542454

70.

Schottenbauer,

M. A.

, Glass,

C. R.

, Arnkoff,

D. B.

, Tendick,

, Gray,

S. H.

(2008). Nonresponse and dropout rates in outcome studies on PTSD: review and methodological considerations. Psychiatry, 71(2), 134–168. https://doi.org/10.1521/psyc.2008.71.2.134

71.

Sessa,

, Higbed,

, Nutt,

(2019). A Review of 3,4-methylenedioxymethamphetamine (MDMA)-Assisted Psychotherapy. Front Psychiatry, 10, 138. https://doi.org/10.3389/fpsyt.2019.00138

72.

Sherer,

, Evans,

C. C.

, Leverenz,

, Stouter,

, Irby,

J. W.

Jr. , Lee,

J. E.

, Yablon,

S. A.

(2007). Therapeutic alliance in post-acute brain injury rehabilitation: predictors of strength of alliance and impact of alliance on outcome. Brain Inj, 21(7), 663–672. https://doi.org/10.1080/02699050701481589

73.

Singleton,

S. P.

, Wang,

J. B.

, Mithoefer,

, Hanlon,

, George,

M. S.

, Mithoefer,

, Coker,

A. R.

, Yazar-Klosinski,

, Emerson,

, Doblin,

, Kuceyeski,

(2022). Altered brain activity and functional connectivity after MDMA-assisted therapy for post-traumatic stress disorder. Front Psychiatry, 13, 947622. https://doi.org/10.3389/fpsyt.2022.947622

74.

Sucic,

, Dallinger,

, Zdrazil,

, Weissensteiner,

, Jørgensen,

T. N.

, Holy,

, Kudlacek,

, Seidel,

, Cha,

J. H.

, Gether,

, Newman,

A. H.

, Ecker,

G. F.

, Freissmuth,

, Sitte,

H. H.

(2010). The N terminus of monoamine transporters is a lever required for the action of amphetamines. J Biol Chem, 285(14), 10924–10938. https://doi.org/10.1074/jbc.M109.083154

75.

Tancer,

, Johanson,

C. E.

(2003). Reinforcing, subjective, and physiological effects of MDMA in humans: a comparison with d-amphetamine and mCPP. Drug Alcohol Depend, 72(1), 33–44. https://doi.org/10.1016/s0376-8716(03)00172-8

76.

Van De Weyer,

R. C.

, Ballinger,

, Playford,

E. D.

(2010). Goal setting in neurological rehabilitation: staff perspectives. Disabil Rehabil, 32(17), 1419–1427. https://doi.org/10.3109/09638280903574345

77.

Van den Broek,

(2005). Why does neurorehabilitation fail?The Journal of Head Trauma Rehabilitation, 20(5), 464–473.

78.

Van Praag,

D. L. G.

, Cnossen,

M. C.

, Polinder,

, Wilson,

, Maas,

A. I. R.

(2019). Post-Traumatic Stress Disorder after Civilian Traumatic Brain Injury: A Systematic Review and Meta-Analysis of Prevalence Rates. J Neurotrauma, 36(23), 3220–3232. https://doi.org/10.1089/neu.2018.5759

79.

van Wel,

J. H.

, Kuypers,

K. P.

, Theunissen,

E. L.

, Bosker,

W. M.

, Bakker,

, Ramaekers,

J. G.

(2012). Effects of acute MDMA intoxication on mood and impulsivity: role of the 5-HT2 and 5-HT1 receptors. PLoS One, 7(7), e40187. https://doi.org/10.1371/journal.pone.0040187

80.

Vermetten,

, Ambaum,

(2019). Exposure to combat and deployment; reviewing the military context in The Netherlands. Int Rev Psychiatry, 31(1), 49–59. https://doi.org/10.1080/09540261.2019.1602517

81.

Vermetten,

, Krediet,

, Bostoen,

, Breeksema,

J. J.

, Schoevers,

R. A.

, van den Brink,

(2020). [Psychedelics in the treatment of PTSD]. Tijdschr Psychiatr, 62(8), 640–649. https://www.ncbi.nlm.nih.gov/pubmed/32816292 (Psychedelica bij de behandeling van PTSS.)

82.

Vermetten,

, Olff,

(2013). Psychotraumatology in the Netherlands. Eur J Psychotraumatol, 4. https://doi.org/10.3402/ejpt.v4i0.20832

83.

Vickery,

C. D.

, Sepehri,

, Evans,

C. C.

(2008). Self-esteem in an acute stroke rehabilitation sample: a control group comparison. Clin Rehabil, 22(2), 179–187. https://doi.org/10.1177/0269215507080142

84.

Wagner,

M. T.

, Mithoefer,

M. C.

, Mithoefer,

A. T.

, MacAulay,

R. K.

, Jerome,

, Yazar-Klosinski,

, Doblin,

(2017). Therapeutic effect of increased openness: Investigating mechanism of action in MDMA-assisted psychotherapy. J Psychopharmacol, 31(8), 967–974. https://doi.org/10.1177/0269881117711712

85.

Wardle,

M. C.

, de Wit,

(2014). MDMA alters emotional processing and facilitates positive social interaction. Psychopharmacology (Berl), 231(21), 4219–4229. https://doi.org/10.1007/s00213-014-3570-x

86.

Warraich,

, Kleim,

J. A.

(2010). Neural plasticity: the biological substrate for neurorehabilitation. PM R, 2(12 Suppl 2), S208–219. https://doi.org/10.1016/j.pmrj.2010.10.016

87.

Weber,

, Schumacher,

, Hannig,

, Barth,

, Lotzin,

, Schafer,

, Ehring,

, Kleim,

(2021). Long-term outcomes of psychological treatment for posttraumatic stress disorder: a systematic review and meta-analysis. Psychol Med, 51(9), 1420–1430. https://doi.org/10.1017/S003329172100163X

88.

Winslow,

(2000). Army culture. Research and Advanced Concepts Office, US Army Research Institute for the Behavioral and Social Sciences.