Design and methodology of the first open-label trial of MDMA-assisted therapy for veterans with post-traumatic stress disorder and alcohol use disorder: Considerations for a randomized controlled trial

Abstract

Background

Posttraumatic stress disorder (PTSD) and alcohol use disorder (AUD) commonly co-occur and are associated with more severe symptomatology than either disorder alone, increased risk of suicide, and poorer response to existing treatments. A promising therapeutic intervention is the integration of 3,4-methylenedioxymethamphetamine (MDMA) and psychotherapy. The Food and Drug Administration (FDA) designated MDMA- assisted therapy (MDMA-AT) as a Breakthrough Therapy for PTSD based on results from six Phase 2 clinical trials. Case data from the first study evaluating MDMA-AT study for AUD found the treatment was well tolerated and alcohol use was significantly reduced post treatment.

Methods

This manuscript reports the premise, design, and methodology of the first open-label trial of MDMA-AT for military veterans (N = 12) with PTSD and AUD. Neuroimaging and biomarker data are included to evaluate brain changes, and neuroinflammation, pre-post treatment.

Conclusions

The clinical component (comorbidity) and the regulatory processes (Schedule I drug) for setting up this clinical trial are long and complex. The research community will benefit from this work to establish common clinical trial outcomes, standardized protocols, and risk assessments for FDA approval.

Clinicaltrials.gov

NCT05943665.

1. Introduction

1.1. Background and rationale

Across veterans of all eras, the co-occurrence of posttraumatic stress disorder and alcohol use disorder (PTSD-AUD) contributes to decreases in health functioning and difficulties readjusting to civilian life [1]. The Veterans Administration (VA) health care system estimates that 63% of veterans presenting with substance use problems also receive a PTSD diagnosis [2], making comorbidity the rule rather than the exception. Veterans with PTSD-AUD experience more severe symptomatology, increased risk of suicidality, reduced quality of life, and poorer response to existing treatments than veterans with either disorder alone [3,4].

Current evidence-based interventions, including trauma-focused talk psychotherapies such as prolonged exposure [5] and cognitive processing therapy [6], are considered the gold standard treatments for PTSD [7]. However, after completion of these treatments, many patients continue to report clinically significant PTSD symptoms [8,9]. This is further complicated by the fact that dropout is high and the ability to tolerate these treatments is low [10,11]. Regarding pharmacological therapies, there are no FDA-approved medications to treat PTSD-AUD, and therefore approved medications to treat each disorder or off-label pharmacological interventions are used to treat individuals with this comorbidity [12]. A recent review of the literature on pharmacotherapies for PTSD-AUD concluded that there is support for benefits of alcohol-targeted medications (e.g., naltrexone or topiramate) for alcohol symptoms compared with placebo medications alone, but no clear evidence that pharmacologic treatments significantly impacted PTSD severity compared with medication placebo [13]. These findings underscore the need to more effectively and efficiently address comorbidity in veterans who present to treatment.

One promising approach may be the integration of MDMA and psychotherapy. Evidence suggests that acute effects of MDMA last approximately 3–6 h and are characterized by feelings of euphoria, increased well-being, and sociability, along with slight changes in perception and anxiety [[14], [15], [16], [17]]. MDMA produces anxiolytic and prosocial effects [18], which may counteract avoidance and hyperarousal, hallmark PTSD symptoms and primary targets for self-medication with alcohol. MDMA also acutely decreases activity in the amygdala and hippocampus, and increases blood flow to the prefrontal cortex [19]. This action is in contrast to PTSD, which is associated with increased activity in the amygdala, causing heightened encoding of fearful memories, and decreased blood flow to the prefrontal cortex. When MDMA is administered in the context of a therapeutic setting, it appears to increase the tolerability and effectiveness of psychotherapy [14,15,20].

MDMA administration increases levels of several neurotransmitters (e.g., serotonin, norepinephrine, and dopamine) [[21], [22], [23]] and indirectly modulates levels of the other peptides (e.g., oxytocin, arginine vasopressin, and cortisol) [16,24,25]. Serotonin facilitates the experience of positive mood and reduced anxiety and enhances the ability to engage with trauma-related material without feeling overwhelmed [17,26,27]. Norepinephrine, and a minor increase in dopamine, enhances motivation to engage in therapy and improves recall of state-dependent memories to create an optimal arousal zone [28,29]. The release of oxytocin, arginine vasopressin, and cortisol are associated with increases in attachment, feelings of trust, empathy, reduced reactivity to threatening cues, and decreased perception of social rejection [16]. In the context of therapy, these hormonal actions have been shown to improve capacity to reflect on traumatic memories, enhance therapeutic alliance, decrease avoidance, and improve communication of social/emotional relationships [[30], [31], [32], [33], [34], [35], [36], [37]]. Notably, the focus is not on MDMA dosing alone to promote healing, but rather when used in the context of a therapeutic environment, MDMA creates an opportunity for introspection and facilitation of emotional processing.

Recent research demonstrates increased brain connectivity and brain network integration following treatment with psychedelics, effects that continued after the treatment ended [38]. This research also suggests that inflammatory processes may play a role in maintaining mental health problems and that the beneficial effects of psychedelics may be a result of decreased inflammation. Further investigation incorporating anatomical imaging and measurement of relevant cytokines [39] is critical to better understand these processes.

Several theories have been suggested to better understand the co-occurrence of PTSD-AUD, with the self-medication hypothesis receiving the most empirical support [40]. This theory suggests that individuals with PTSD are at heightened risk for the development of a substance use disorder (SUD) due to the desire to mitigate distressing trauma-related symptoms. MDMA-AT may be particularly relevant for veterans who rely on substances to avoid or alter psychiatric symptoms by facilitating a therapeutic environment in which veterans can safely turn towards painful emotions with reduced reactivity to threatening cues and enhanced feelings of trust and compassion. As such, the integration psychotherapy sessions included in the MDMA-AT protocol are vital to the success of the treatment as they help process material that comes up during the experimental session and address difficult emotions that arise as the experience from the experimental session continues to unfold. In sum, the combined neurobiological effects of MDMA increase compassion for self and others [18,30,41,42], reduce defenses and fear of emotional injury, and enhance communication and introspection [43]. Therefore, the synergy of MDMA and psychotherapy may be especially useful for treating PTSD-AUD.

1.1.1. Previous trials for PTSD

In 2017, the FDA designated MDMA-AT as a Breakthrough Therapy for PTSD based on promising safety and efficacy results from six completed Phase 2 clinical trials [14]. These randomized, double-blind, placebo-controlled trials, conducted from 2004 to 2017, demonstrated significant reductions in PTSD symptom severity [[44], [45], [46], [47]]. Notably, participants maintained gains in PTSD symptom relief an average of 45 months after the completion of the first MDMA-AT trial [44,45].

Comparisons between data used for the approval of paroxetine and sertraline and pooled data from Phase 2 clinical trials by the Multidisciplinary Association for Psychedelic Studies (MAPS) and Lykos Therapeutics, Inc. (Lykos), formally MAPS Public Benefit Corporation (MAPS-PBC), demonstrated substantial support for MDMA-AT over available pharmacotherapies in terms of safety and efficacy. Studies of MDMA-AT had lower dropout rates compared to drug trials. Regarding safety, given that MDMA is only administered under direct observation, there is little chance of diversion, accidental or intentional overdose, or withdrawal symptoms upon discontinuation [14].

Two published Phase 3 studies by Lykos found significant treatment effects of active MDMA compared to placebo. In the first Phase 3 study [48], 88% of those in the active MDMA-AT group experienced a clinically significant reduction in PTSD scores; 67% no longer met criteria for PTSD at the 2-month follow-up (compared to 60% and 32% of placebo participants, respectively). The most recent Phase 3 study [49] showed similar results – those in the active MDMA-AT group had significantly greater reductions in PTSD symptoms; 71% no longer met PTSD diagnosis versus 48% in the placebo group.

1.1.2. Previous trials for AUD

Most research on MDMA-AT has focused on the treatment of PTSD; however, the observed changes in social cognition, interpersonal closeness, and communication elicited by MDMA administration may positively influence AUD outcomes [50]. MDMA-AT may be an effective AUD treatment through its capacity to enhance the psychotherapeutic process and treat underlying trauma [51]. Sessa and colleagues [52] published the first open-label pilot trial of MDMA plus psychotherapy for AUD (N = 14). At the 9-month follow-up, 11 participants (78.6 %) were drinking fewer than 14 units of alcohol per week (M = 130.6 units per week at baseline). The treatment was well-tolerated with no serious adverse events (SAEs) reported. In addition, secondary data analyses from a Lykos Phase 3 study found significantly greater reductions in Alcohol Use Disorders Identification Test (AUDIT [53]) scores in the active vs. placebo group [54]. These studies provide the foundation for a randomized controlled trial (RCT) testing the efficacy of MDMA-AT as a treatment for AUD.

To our knowledge, this is the first study to evaluate MDMA-AT in veterans with co-occurring PTSD-AUD, a population for whom additional or complementary treatments are urgently needed. In building our pilot study, several key decisions were made in the design based on regulatory, practical, clinical, and scientific knowledge surrounding the implementation of MDMA-AT with a comorbid population. Here, we present a detailed overview of start-up procedures, participant recruitment, selection, and treatment within our pilot trial of MDMA-AT for PTSD-AUD. We share the rationale behind several strategic protocol decisions and discuss safety considerations, determination of dosing parameters, specification of a psychotherapy platform, alternative design options and knowledge gaps.

1.2. Research objectives and hypothesis

There were several start-up activity objectives for this project including: 1) secure support from Lykos in the form of study drug provision by applying to their Investigator-Initiated Trial program; 2) assemble a multidisciplinary research team; 3) train six MDMA-AT therapists (training provided by Lykos Investigator Initiated Trial program); 4) apply for an Investigational New Drug Application (IND) from the FDA; 5) obtain a Schedule I license from the Drug Enforcement Administration (DEA) and procure the study medication; 6) set up appropriate psychedelic laboratory space; and 7) provide psychoeducation to the Brown University Institutional Review Board (IRB).

The primary objective of this project is to examine the effectiveness of MDMA-AT in veterans with PTSD-AUD (N = 12) to reduce PTSD and AUD severity. The aims of the trial are to collect pilot data on 1) the amount of alcohol consumed, 2) PTSD symptom severity; and 3) to determine the safety and tolerability of MDMA-AT in this comorbid population.

There are three directional hypotheses: 1) MDMA-AT will demonstrate significant reduction in alcohol consumption from baseline; 2) MDMA-AT will demonstrate significant reduction in PTSD symptom severity from baseline, and 3) the study design will be feasible, and MDMA-AT will be safe and well-tolerated.

To shed light on the potential mechanisms of MDMA-AT in veterans with PTSD-AUD, we will test the hypothesis that neural and peripheral biomarkers will improve post-treatment. Our exploratory aims include: 1) evaluating changes in neuroimaging data pertaining to neuroinflammation, white matter integrity, and cortico-limbic functional connectivity as measured by anatomical imaging, magnetic resonance spectroscopy (MRS) and a task-free functional MRI (fMRI), respectively; 2) evaluating pro- and anti-inflammatory cytokines as measured by enzyme-linked immunosorbent assay (ELISA); and 3) evaluating stress-related measures including an indirect adrenergic marker (α-amylase), a hypothalamic-pituitary-adrenal (HPA) axis marker (cortisol), and a neurotransmitter and hormone (oxytocin).

2. Materials and methods

2.1. Preliminary logistics and regulatory process

The initiation of the study required: 1) an IND from the FDA, 2) protocol approval from Lykos, 3) DEA license for a Schedule I drug, 4) Brown University IRB approval, 5) separate approval for the Magnetic Resonance Imaging (MRI) protocol, 6) the training of six study therapists in MDMA-AT, 7) registration of the clinical trial (NCT05943665), and 8) setup of appropriate laboratory space.

2.2. Trial design

Our study is a Stage 2, non-randomized, longitudinal, open pilot trial of MDMA-AT for veterans who are seeking treatment for PTSD-AUD (See Fig. 1) and is registered on clinicaltrials.gov (NCT05943665). Participants complete an in-person baseline assessment including a physical exam, undergo optional MRI protocols (if participant is agreeable and medically safe to do so), engage in MDMA-AT with trained clinicians, and complete assessments at the post-treatment follow-up. All assessments are completed by independent raters (e.g., Project Coordinator – baseline, Nurse Practitioner-medical exam, and Postdoctoral Fellows-post-treatment follow-up). Safety data are collected throughout. The open label trial design was chosen to limit the difference between the well-known expectation of the altered state of consciousness associated with MDMA compared to placebo administration. This design will allow us to mitigate considerable response bias, improve internal validity, and improve participant retention [55].

Fig. 1.

Flow Diagram of projected participants.

2.3. Participants and setting

Enrollment for this trial opened in January 2024. Participants (N = 12) are US military veterans, at least 18 years of age, who meet current DSM-5 criteria for PTSD and AUD and are willing to participate in an 11-week MDMA-AT protocol. This study follows the Lykos Phase 3 protocol guidelines for inclusion and exclusion criteria. In brief, Inclusion criteria: 1) able to provide proof of veteran status; 2) meet DSM-5 current criteria (past 30 days) for PTSD as assessed by the Clinician Administered PTSD Scale for DSM-5 (CAPS-5); 3) current diagnosis of AUD within the past month as confirmed by the Structured Clinical Interview for DSM Disorders (SCID). Exclusion criteria: 1) currently engaged in trauma-focused psychotherapy or are currently in a treatment program for SUD; 2) lack a stable living situation; 3) history of, or a current psychotic disorder, dissociative disorder, or bipolar affective disorder; and 4) have an active SUD (with the exception of mild or moderate cannabis use disorder). In addition, participants are required to comply with lifestyle modifications, including a medically supervised discontinuation of antidepressant medications (e.g., SSRIs) for a minimum of five half-lives plus one additional week before the first preparatory session. The complete list of inclusion/exclusion criteria can be found in Table 1.

Table 1.

- Inclusion and exclusion criteria.

Inclusion Criteria
Participants are eligible to be included in the study if all the following criteria apply: Age 1Are at least 18 years old at the time of signing the informed consent. Type of Participant and Disease Characteristics 2Are able to provide proof of veteran status. 3Are fluent in speaking and reading English. 4At Baseline, meet criteria for Alcohol Use Disorder as measured by the SCID-5. 5Able to safely abstain from alcohol for at least 48 h without requiring medical detox. 6At Baseline meet DSM-5 criteria for current PTSD with a symptom duration of at least 6 months. 7At Baseline, have a PCL-5 score of 33 or greater. 8At Baseline, have a confirmed PTSD diagnosis per the CAPS-5 and a Total Severity Score of 28 or greater. 9Are able to swallow pills. 10Agree to have study visits recorded, including Experimental Sessions, assessments, and non-drug therapy sessions. 11Able to provide a contact (relative, spouse, close friend, or other support person) who is willing and able to be reached by the investigators in the event of a participant becoming unwell or unreachable. 12Able to identify appropriate support person(s) to stay with the participant on the evenings of the Experimental Sessions, see Section Support Person. Weight 13Body weight of at least 45 kg (kg). Sex and Contraceptive/Barrier Requirements 14 For participants assigned female sex at birth: • A participant is eligible to participate if not pregnant, not planning to become pregnant, or is not breastfeeding and one of the following conditions applies: o Is not able to become pregnant. OR o Is a person able to be pregnant (PABP) and using a contraceptive method that is highly effective, with a failure rate of <1 %. The investigator will evaluate the potential for contraceptive method failure (e.g., noncompliance, recently initiated) in relationship to the first dose of study intervention. •A PABP must have a highly sensitive negative urine pregnancy test at study entry and prior to each Experimental Session, see Schedule of Activities. •The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a participant with an early undetected pregnancy. Informed Consent 15Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the ICF and in this protocol. Other Inclusions 16Agree to inform the investigators within 48 h of any medical conditions and procedures. 17May have asymptomatic Hepatitis C virus (HCV) that has previously undergone evaluation and treatment as needed. 18Participants must have a plan, agreed upon by investigator, therapy team, and study clinician, to reduce use of substances and to manage symptoms without self-medicating. Enrollment will require that, in the judgment of the investigator, therapy team, and study physician, the plan for decreasing substance use is realistic and has a good chance of succeeding to prevent substance use from impacting the safety or efficacy of the investigational treatment. 19May have a history of or current Diabetes Mellitus (Type 2) if additional screening measures rule out underlying cardiovascular disease, if the condition is judged to be stable on effective management, and with approval by the study clinician. 20May have hypothyroidism if taking adequate and stable thyroid replacement medication. 21May have a history of, or current, glaucoma if approval for study participation is received from an ophthalmologist.
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply: Medical Conditions 1 Have symptomatic liver disease or have significant liver enzyme elevations. a) Alanine transaminase (ALT) or aspartate transaminase (AST) > 3 x upper limit of normal (ULN). b) Total bilirubin ≥1.5 x ULN or direct bilirubin <35 %. 2Current unstable liver or biliary disease per investigator assessment defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, persistent jaundice, or cirrhosis. a) Note: Stable chronic liver disease (including Gilbert's syndrome, asymptomatic gallstones, and chronic stable hepatitis B (e.g., the presence of hepatitis B surface antigen or positive hepatitis C antibody test result without evidence of active infection at screening or within 3 months prior to starting study intervention) is acceptable if the participant otherwise meets entry criteria. 3Have a history of seizures or delirium tremens (DTs). 4Significant alcohol withdrawal symptoms, defined as a Clinical Institute Withdrawal Assessment of alcohol scale, revised (CIWA-Ar) >10. 5Have a recent history of clinically significant hyponatremia or hyperthermia. 6Have a marked Baseline QTcF interval >450 ms demonstrated on repeated ECG assessments. Participants whose QTcF exceeds this value during screening may be initially enrolled if a pre-study concomitant medication is suspected to be prolonging the QT-interval. ECGs should be repeated after initial enrollment and tapering off the pre-study concomitant medication to ensure the participant meets eligibility criteria prior to enrollment confirmation and to IMP dosing. a) Note: The QTcF is the QT interval corrected for heart rate according to Fridericia's formula. It is either machine-read or manually over-read. 7 Have a history of any medical condition that could make receiving a sympathomimetic drug harmful because of increases in blood pressure and heart rate. This includes, but is not limited to, a history of myocardial infarction, cerebrovascular accident, heart failure, severe coronary artery disease, or aneurysm. a) Participants with other mild, stable chronic medical problems may be enrolled if the study clinician and principal investigators agree the condition would not significantly increase the risk of MDMA administration or be likely to produce significant symptoms during the study that could interfere with study participation or be confused with side effects of the IMP. b) Examples of stable medical conditions that could be allowed include, but are not limited to, Diabetes Mellitus (Type 2), Human Immunodeficiency Virus (HIV) infection, Gastroesophageal Reflux Disease (GERD), hypothyroidism (if taking adequate and stable thyroid replacement medication), glaucoma (if approval for study participation is received from an ophthalmologist). Any medical disorder judged by the investigator to significantly increase the risk of MDMA administration by any mechanism would require exclusion. 8Have a diagnosis of controlled or uncontrolled hypertension, defined as repeated blood pressure readings of ≥140 mm of Mercury [mmHg] systolic or ≥ 90 mmHg diastolic. The diagnosis may be confirmed by repeated clinic measurements or home blood pressure monitoring if clinically indicated. 9Have a history of ventricular arrhythmia at any time, other than occasional premature ventricular contractions (PVCs) in the absence of ischemic heart disease. 10Have Wolff-Parkinson-White syndrome or any other accessory pathway that has not been successfully eliminated by ablation. 11Have a history of arrhythmia, other than premature atrial contractions (PACs) or occasional PVCs in the absence of ischemic heart disease, within 12 months of screening. a) Participants with a history of atrial fibrillation, atrial tachycardia, atrial flutter or paroxysmal supraventricular tachycardia or any other arrhythmia associated with a bypass tract may be enrolled only if they have been successfully treated with ablation and have not had recurrent arrhythmia for at least one year off all antiarrhythmic drugs or are under adequate and stable pharmacologic treatment for atrial fibrillation for at least a year, as confirmed by a cardiologist. 12Have a history of additional risk factors for Torsade de pointes (e.g., heart failure, hypokalemia, family history of Long QT Syndrome). 13Exclusion criteria specific to MRI: non-removable ferromagnetic materials; claustrophobia; history of head trauma or injury. Psychiatric Conditions 14Have engaged in a new form of psychiatric or mental health care within 12 weeks of enrollment, including Electroconvulsive Therapy (ECT) and ketamine-assisted therapy. 15Are currently prescribed antidepressant medications (e.g., selective serotonin reuptake inhibitors) requiring a medication taper. 16Are likely, in the investigator's opinion and via observation during the Preparatory Period, to be re-exposed to their index trauma or other significant trauma or other significant trauma during the study. 17Have a current moderate (not in early remission in the 3 months prior to enrollment and meets at least 5 of 11 diagnostic criteria per DSM-5) or severe cannabis use disorder within the 12 months prior to enrollment (meets at least 6 of 11 diagnostic criteria per DSM-5). a) May have current mild cannabis use disorder (meets 3 of 11 diagnostic criteria per DSM-5) or moderate cannabis use disorder in early remission for the 3 months prior to enrollment (meets 4 or 5 of 11 diagnostic criteria per DSM-5). 18Have an active substance use (other than cannabis) disorder at any severity within 12 months prior to enrollment. 19Have used Ecstasy (material represented as containing MDMA) more than 10 times within the last 10 years or at least once within 6 months of the first Experimental Session 20 Any participant presenting current serious suicide risk, as determined through psychiatric interview, responses to C-SSRS, and clinical judgment of the investigator will be excluded; however, history of suicide attempts is not an exclusion. Any participant who is likely to require hospitalization related to suicidal ideation and behavior, in the judgment of the investigator, will not be enrolled. Any participant presenting with the following on the Baseline C-SSRS will be excluded: a) Suicidal ideation score of 4 or greater within the last 6 months of the assessment at a frequency of once a week or more b) Suicidal ideation score of 5 within the last 6 months of the assessment c) Any suicidal behavior, including suicide attempts or preparatory acts, within the last 6 months of the assessment. Participants with non-suicidal self-injurious behavior may be included if approved by the study clinician. 21Would present a serious risk to others as established through clinical interview and contact with treating psychiatrist. Prior/Concomitant Therapy 22Require ongoing concomitant therapy with a psychiatric medication with exceptions described in protocol section on Concomitant Medications. 23Current use of pharmacotherapies (i.e., naltrexone or disulfiram) to treat alcohol use. 24Require use of concomitant medications that could prolong the QT interval during Experimental Sessions. 25Are currently engaged in trauma-focused psychotherapy or are currently in a treatment program for SUD (self-help programs are not an exclusion). Prior/Concurrent Clinical Study Experience 26Current enrollment in any other clinical study involving an investigational study treatment or any other type of medical research, unless approved by the study clinician. Diagnostic Assessments 27Have a history of or a current primary psychotic disorder, bipolar affective disorder type I or dissociative identity disorder assessed via the DDIS and clinical interview. 28Have a current eating disorder with compensatory behaviors. 29Have current major depressive disorder with psychotic features. 30Have current Personality Disorders (paranoid, schizoid, schizotypal, antisocial, borderline, histrionic, narcissistic, avoidant, dependent, obsessive-compulsive) assessed via the SCID-5-PD. Diagnoses will be confirmed by clinical interview. Other Exclusions 31Are not able to provide adequate informed consent. 32Sensitivity to any of the study interventions, or components thereof, or drug or other allergy that, in the opinion of the sponsor-investigator or study clinician, contraindicates participation in the study. 33Are currently engaged in compensation litigation whereby financial gain would be achieved from prolonged symptoms of PTSD or any other psychiatric disorders. 34Lack of social support or lack a stable living situation. 35Previous participation in a Lykos-sponsored MDMA clinical trial. 36Employees (and their immediate family members) Lykos; or individuals in a personal relationship with the sponsor investigator. 37Have any current problem which, in the opinion of the sponsor-investigator or study clinician, might interfere with study participation. Lifestyle Considerations All participants must agree to the following lifestyle modifications at time of signing the Informed Consent Form (ICF) and throughout the study. •Are willing to complete all activities described in the ICF, which include MDMA dosing, therapy sessions, follow-up sessions, completing evaluation instruments, and all necessary telephone contact. •Agree to not participate in any other interventional clinical trials during the duration of this study, without prior approval of the study clinician. • Agree not to take any new or prohibited medications or recreational drug substances during the course of the study without first discussing with the sponsor-investigator in consultation with the study clinician. • Agree to not begin a new form of mental healthcare during the screening or treatment phases of the trial, without first discussing with the sponsor-investigator in consultation with the study clinician. o It is acceptable for participants to continue ongoing mental healthcare, if it is not increased in frequency or specifically excluded by the study protocol. o All ongoing therapies should be documented by the study team and discussed with the study clinician prior to enrolment to avoid confounding treatment effects. In some instances, the study clinician may request that the participant delay enrolment until their planned course of therapy is complete, and an integration period has elapsed. •Agree to inform the investigators within 48 h of any new medical conditions and procedures.

The importance of set and setting cannot be overstated when conducting MDMA-AT. Careful attention and effort are brought to the setup of the clinical laboratory space to include comfortable furnishings in which the participant can recline; blankets, pillows, eye shades and headphones are also provided.

2.4. Procedures

The IRB of Brown University approved this study (approval number: STUDY00000023). Potential participants for the trial are being recruited via advertisements placed on the internet (e.g., Brown University webpages). Following phone screening for preliminary eligibility, participants complete a baseline assessment (Table 1). Participants are given a full description of the study procedures and an IRB-approved informed consent form before any study procedures occur.

2.5. MDMA-assisted therapy (MDMA-AT)

All participants receive an 11 week treatment cycle which consists of three preparatory sessions (Sessions 1–3; 90-min each), a MDMA-AT experimental session (Session 4; 8 h), three integration sessions (Sessions 5–7; 90-min each), a second MDMA-AT experimental session (Session 8; 8 h), followed by three integration sessions (Sessions 9–11; 90-min each; Fig. 2). The therapy model includes a therapist pair that is present at each session.

Fig. 2.

Flow of the laboratory sessions.

MDMA-AT utilizes a non-directive approach designed to invite inquiry and provide suggestion. During the preparatory sessions, the therapist pair works with the participant to prepare for MDMA-AT, begin building therapeutic alliance, and promote a safe setting for confronting trauma-related memories, emotions, and thoughts. During the two experimental sessions, the therapy pair offers the first part of the split dose of MDMA. The participant sits or reclines on comfortable furnishings. Eyeshades and a program of music are provided for the participant. Fluids are provided throughout the session and vitals are monitored. About 90–120 min after the initial dose, participants are offered the second part of the split dose (half the amount of the first dose) to extend the effects of MDMA. At the end of each experimental session, participants are instructed to call/text a member of the therapy pair when they arrive where they will be staying for the night. If the therapy pair has not received a call/text within 2 h after the participant has left the site, the therapists will call the participant and support person to confirm arrival. During this call/text conversation, the therapy pair will ask about the participant's well-being and invite them to begin the process of integration through self-reflection, journaling, meditation, or other quiet activities. Of note, if needed, emergency/rescue medications may be prescribed by the study physician during or at the end of the experimental sessions (e.g., benzodiazepines or zolpidem) to help manage overwhelming anxiety or concerns about sleep disturbance.

After each experimental session, three integration sessions take place in which the therapy pair discusses and reviews with the participant experiences that occurred during the experimental session. The therapy pair encourage the transfer of states of acceptance, feelings of closeness, and reduced fear experienced in the experimental sessions to emotionally threatening everyday situations.

Project therapists are licensed clinicians (5 clinical psychologists and 1 clinical social worker) who are extensively trained through the Lykos MDMA Therapy Training Program. Study therapists received specific training in the MDMA-AT method, protocol, and latest version of the Investigational Brochure (IB). Training consists of completing online training modules, and participating in an in-person or online training that includes watching and discussing videos of experimental sessions (equating to approximately 100 h of training). The final part of training includes consultation from the Lykos-qualified independent consultants to provide the therapists with additional feedback and support. In addition to this specific training, the study requires that participating therapists have the proper education, experience, and licensure. The therapists in this study have a range of 8–25 years of experience of delivering trauma-informed psychotherapy to veterans.

2.6. Study medication

The medication is secured in a safe in a Brown University vault. This open-label study includes two experimental sessions of therapy assisted by flexible divided doses of MDMA. The initial dose is expected to produce all commonly reported effects of MDMA. The supplemental dose prolongs subjective effects of MDMA without producing physiological effects much greater than peak effects occurring after the initial dose, and will be administered unless there is a reason to withhold it. Total amounts of MDMA to be administered per experimental session range from 68 mg to 150 mg MDMA.

Similar MDMA doses to those planned in this study have been safely used in previous Phase 2 and 3 studies sponsored by Lykos. Phase 2 studies using 63, 84, and 105 mg MDMA initial doses followed by a supplemental half-dose reduced PTSD symptomology following two to three experimental sessions and supported further clinical evaluation [49,56].

Larger doses have been safely administered in Lykos sponsored trials (125 initial and 62 mg supplemental MDMA; 80–180 mg initial and 40–60 mg supplemental MDMA) [57,58]. The results of the Lykos sponsored Phase 2 studies led to the selection of 68 mg and 100 mg MDMA as the initial active doses.

2.6.1. Medication administration procedures

Medication is offered by a member of the therapy pair to the participant during the experimental sessions. In the first experimental session, the initial dose is 68 mg MDMA. In the second experimental sessions, the initial dose is increased to 100 mg MDMA unless tolerability issues emerge with the first dose, or the participant declines. In each experimental session, 1.5–2 h after the initial dose is given, the participant will be administered a supplemental half-dose unless tolerability issues emerge with the first dose or the participant declines.

2.7. Measures

2.7.1. Primary outcome (AUD)

The primary outcome is alcohol consumption as measured by: 1) drinks per drinking day, 2) number of heavy drinking days (defined as 4+ drinks per occasion for women and 5+ drinks for men), and 3) percent days abstinent as measured by the Timeline Follow Back [59] (a self-report measure that utilizes a calendar format to obtain estimates of daily alcohol and other substance use over the previous 90 days).

2.7.2. Secondary outcome (PTSD)

The secondary outcome measure is PTSD symptom severity as measured by the CAPS-5 [60]. The CAPS-5 is a semi-structured interview that assesses history of trauma exposure and PTSD symptoms to produce a diagnostic score (presence or absence) and a PTSD Total Severity score.

2.7.3. Other outcomes: feasibility, safety and tolerability

Measures of feasibility of MDMA-AT in this population of veterans is measured by: 1) ability to reach recruitment targets, 2) enrollment, 3) retention, 4) dropout, and 5) satisfaction with treatment.

Safety assessments include: monitoring vital signs, withdrawal syndrome [61], cardiovascular, respiratory, gastrointestinal, and neurological systems and use of concomitant medications. Suicidal ideation and behavior will be assessed by the Columbia-Suicide Severity Rating Scale (C-SSRS [62]), a clinician-administered measure of suicidal behavior devised to detect potential suicidal thoughts or behaviors during a clinical trial.

2.7.4. Exploratory outcomes (neuroimaging and inflammation)

2.7.4.1. Neuroimaging component

A preliminary investigation of brain networks involved in MDMA-AT in veterans endorsing PTSD-AUD will be conducted, and changes in network function after psychotherapy will be evaluated. Brain correlates of therapeutic and peripheral biomarker change will be evaluated using structural, MRS, and task-free fMRI methods. Participants will undergo MRI scanning at baseline and again after the completion of psychotherapy (Fig. 3).

Fig. 3.

– Neuroimaging design.

Markers of neuroinflammation will be assessed using magnetic resonance spectroscopy (MRS). MRS data will be acquired in pre-frontal and limbic regions in separate scans and the same subject-specific regions will be assessed before and after treatment. Non-specific MRS markers known to be sensitive to levels of neuroinflammation, including N-acetyl aspartate (NAA), myo-inositol, choline and total creatine, will be assessed. In addition, diffusion weighted imaging (DWI) will be used to characterize white matter tracts and tract-based spatial statistics (TBSS) will be used to assess changes in derivative measures, including fractional anisotropy (FA), axial diffusivity (AD) and radial diffusivity (RD). Task-free resting-state fMRI will be used to assess differences in cortico-limbic network functional connectivity before vs after MDMA-AT using a within-subjects approach. All MRI scanning will be conducted at the Brown MRI Research Facility. Although each participant is encouraged to partake, all MRI procedures will be optional for study participants.

MR Spectroscopy. Single-voxel MR Spectroscopy (MRS, ∼10 min) will be used to assess relative levels of compounds previously shown to be affected by neuroinflammation, including choline, myo-inositol, NAA and total creatine.

Anatomical Imaging by diffusion-weighted imaging (DWI). DWI imaging will characterize whole-brain white matter microstructure, which is informative regarding potential changes in structural connectivity after treatment. High-resolution (1 mm) T1 structural imaging (∼6 min) is acquired with a ME-MPRAGE sequence to provide anatomical references for seed-based functional connectivity analysis and placement of MRS regions of interest. DWI (99 directions, AP and PA directions, plus field maps; ∼15 min) provides characterization of white matter tracts and derivative measures (FA, RD, AD) provide characterization of whole-brain white matter microstructure, which is informative regarding potential changes in structural connectivity.

Functional Imaging. A task-free fMRI will be conducted to assess changes in network connectivity. Changes in cortico-limbic functional connectivity will be assessed using task-free resting-state fMRI (2 mm voxels, TR 1500 ms, ∼10 min). Seed-based functional connectivity analysis will be used to assess cortico-limbic networks. Limbic seed regions (e.g., the amygdala) will be anatomically specified using the high-resolution ME-MPRAGE data.

2.7.4.2. Peripheral biomarkers

We will quantify peripheral salivary biomarkers as follows: an indirect adrenergic marker (α-amylase) and an HPA-axis marker (cortisol). We also will measure blood biomarkers as follows: pro/anti-inflammatory level interleukin-6/10/17A (IL-6, IL-10 and IL-17A) cytokines [63,64]; monocyte chemoattractant protein 1 (MCP-1), a chemokine that regulates migration and infiltration of monocytes/macrophages and is involved in various neuroinflammatory disorders [65,66]; and brain-derived neurotrophic factor (BDNF), a protein that plays an important role in neuronal survival [65,67].

Peripheral inflammatory response is assessed by measuring cytokines (pro and anti-inflammatory). BDNF was selected as a biomarker of neuroplasticity as psychedelics have shown to interact with neurogenic pathways (mTOR and Trk-B) [39]. Peripheral biomarkers are measured over time (four timepoints) before treatment, at each of the two MDMA-AT sessions, and at the end of the treatment.

2.8. Data analysis plan

Data will be summarized to provide descriptive information on safety, tolerability, and efficacy. Descriptive and summary statistics will be generated for demographic, clinical, and behavioral data. Statistics will include number of observations, means, standard deviation, median, range, and interquartile range for continuous variables, and the number and percent for categorical variables; 95 % or 90 % confidence intervals will be presented where appropriate. The explanation for all discontinuations will be tabulated and grouped by major reason. All deviations related to study inclusion or exclusion criteria, conduct of the study, or subject assessment will be tabulated.

As a pilot study with a small sample, statistical analyses will focus on the direction of effects from pre-to post-treatment and whether there is evidence of clinically meaningful change. Effect sizes will be examined, recognizing the inherent difficulties in relying on effect sizes generated from pilot studies to power larger trials and expecting that confidence intervals will be large. Preliminary analyses will include examining patterns of missing data, nonnormality of outcome variables, and univariate statistics on all key variables. In this study, clinically meaningful change will be measured on indices of alcohol use and PTSD symptoms using the standard error of measurement (SEM), operationally defined as a reduction in scores by at least one SEM. Unless otherwise specified, t-tests will be conducted pre-post treatment for all relevant variables. P values of < 0.05 will be considered statistically significant.

2.8.1. Primary outcome (AUD) analysis

The primary endpoint is the change in mean alcohol use variables derived from the Timeline Followback (TLFB) from baseline to post-treatment follow-up. Specifically, we will examine changes in drinks per drinking day, number of heavy drinking days and percent days abstinent. T-tests will be conducted to examine changes in the primary endpoint variables. The primary endpoint analyses will be based on an intent to treat sample.

2.8.2. Secondary outcome (PTSD) analysis

The key secondary endpoint is the change in mean total severity CAPS-5 Total Severity Score from Baseline to Post-treatment follow-up. T-tests will be conducted to examine changes in the secondary outcome variable.

2.8.3. Other outcomes: feasibility, safety and tolerability analyses

Measures used to evaluate feasibility of delivering MDMA-AT in this population of veterans include: 1) ability to reach recruitment targets, 2) enrollment, 3) retention, 4) dropout, and 5) satisfaction with treatment.

Safety and tolerability will be assessed measuring adverse events (AEs). AEs that begin after the first administration of study drug or existing AEs that worsen after the first dose of study medication are considered Treatment Emergent Adverse Events (TEAE)s. The number and percentage of participants reporting TEAEs will be summarized by system organ class, severity, and by relationship to study drug. The number and percentage of participants with SAEs, and/or with AEs leading to treatment discontinuation will also be summarized. Clinically significant changes in physical examination, laboratory parameters, vital signs, electrocardiogram (ECG), psychiatric health, withdrawal, and suicidality will be reported as AEs.

Concomitant medications will be coded using the WHO Drug Dictionary and will be classified by Anatomical Therapeutic Chemical classification and preferred term for the Safety Analysis Set. Frequencies and percentages of participants using will be presented.

Vital signs will be summarized using descriptive statistics of actual values and changes from baseline over time. Continuous laboratory data will be examined for trends using descriptive statistics of actual values and changes from baseline over time.

For each participant, C-SSRS data will be categorized into 1) suicidal ideation, and 2) suicidal behavior at each visit. An increase in suicidality (from baseline) in a participant will be reported as an AE. The percentage of participants with passive suicidal ideation and active suicidal behavior will be presented by visit.

2.8.4. Exploratory outcome (neuroimaging and inflammation) analyses

For the neuroimaging analysis, change from baseline to post-treatment in markers of neuroinflammation via MRS, white matter tracks via DWI and network connectivity via fMRI in prefrontal and limbic regions will be evaluated by t-test. The magnitude of change will predict alcohol use (TLFB) and PTSD severity (CAPS-5 score) post-treatment.

For the salivary biomarkers (cortisol, α-amylase), generalized estimating equation (GEE) models will be used allowing characterization and comparison of changes in the response over time (four timepoints: baseline, at each of the two MDMA-AT sessions, and at posttreatment follow-up).

For the blood cytokine analysis (IL-10, IL-6, IL-17A, MCP-1; INFγ, TNFα, BDNF), a t-test will be conducted to assess the change from pre-to post-therapy.

Finally, we will conduct a correlation analysis (bivariate) between changes in central (brain) and peripheral (blood) biomarkers.

3. Discussion

Current treatment options for comorbid PTSD-AUD have limited efficacy and high dropout rates [8,9]. Given the well-documented impairment in psychosocial functioning, poor quality of life, and increased risk for suicide [3,4], additional treatment options are urgently needed. This paper presents the design and methodology for a cutting-edge project that aims to improve the lives of veterans with PTSD-AUD by examining a promising intervention with a growing evidence base for treatment of PTSD [14,49,56] and favorable preliminary data on alcohol use [52,54]. To our knowledge, this the first study to evaluate MDMA-AT for co-occurring PTSD-AUD among veterans. Furthermore, this study's use of neuroimaging procedures will gather data that furthers our understanding of the underlying mechanisms leading to clinical change when combining MDMA with psychotherapy.

3.1. Rationale and design considerations

For many veterans with co-occurring PTSD-AUD, the significant impacts on psychosocial functioning and quality of life are not fully addressed by existing treatments and patients continue to report clinically significant symptoms. MDMA-AT may lead to significant improvements in functioning as well as a reduction in PTSD-AUD symptoms. In our efforts to gather further data with this population, there were many challenges and questions surrounding its implementation and evaluation. During this process, our team grappled with several key issues related to safety considerations, rationale for dosing strategy, regulatory processes, and psychotherapy framework. For example, we briefly considered conducting a small, randomized controlled trial. However, we elected to conduct an open label trial given that MDMA-AT has not been studied in a comorbid sample previously. We were also very aware of the significant challenges inherent in attempting to blind participants and research staff to condition in psychedelic research [55]. Additionally, we considered including three MDMA-AT experimental sessions rather than two. However, given the nature of a small, time-limited study, and the evidence that two MDMA-AT experimental sessions can produce significant clinical change, we elected to include two MDMA-AT experimental sessions.

3.2. Safety considerations

We incorporated several safety elements into the design of this trial, including extensive screening procedures, stringent inclusion/exclusion criteria, repeated ECG, monitoring alcohol withdrawal [61] and vital sign assessments, ample psychotherapeutic support, Lykos trained dyadic therapy pairs, and emergency/rescue medications. As in most clinical trials, these measures serve to align the study sample with categorical diagnoses, limit the heterogeneity of the sample, exclude certain situations and conditions that might affect outcome independent of any treatment effect, ensure that participants are likely to be able to adhere to the protocol, and maximize safety. Nonetheless, these rigorous safety measures may render many prospective participants ineligible. Some of these parameters were inflexible due to medical and psychiatric concerns. The psychiatric criterion of most concern is suicidality. It is well documented that veterans are at high risk of suicidality, approximately 1.5 times more likely to die by suicide than non-veterans, with this risk compounded by PTSD and substance use disorders [68]. In order to ensure safety in light of this risk, suicidality is measured continuously at the start of all preparatory, experimental, and integrative sessions.

We also considered the abuse potential of MDMA in designing safety mitigation strategies. Findings from previous research indicate that single doses of MDMA have not produced discontinuation symptoms. Some adverse reactions have been reported during the seven days following an MDMA dose (e.g., anxiety, dizziness, depressed mood, fatigue, headache, jaw clenching, reduced appetite, nausea, and panic attack); however symptoms were mild to moderate in severity and nearly all resolved within 7 days of dosing [14]. A meta-analysis [14] of pooled Phase 2 data concluded that MDMA, given in the context of psychotherapy, does not have a high abuse liability [46,47,69,70] This study offers MDMA in single doses spaced a month apart in a controlled setting under the supervision of a trained therapist team.

3.3. Selection of study drug

Although classic psychedelic research is growing in popularity, the selection of the non-classic psychedelic, MDMA, was made based on its potential as a treatment for PTSD [71]. While MDMA may have a growing evidence in the literature as a potential treatment for PTSD, this study drug selection also addresses a gap in literature between PTSD and alcohol use [72]. Despite the frequency and risk factors associated with AUD as a comorbidity to PTSD, AUD is a generally unexplored topic within MDMA-AT. By selecting MDMA-AT for this trial we are able to operate in a domain that is well grounded while also expanding knowledge for further treatment potentials.

Funding

This study is supported by funds from the Brown University Office of the Vice President for Research (OVPR) and from the National Institute of General Medical Sciences (NIGMS), Center of Biomedical Research Excellence (COBRE, P20 GM130414). Dr. Haass-Koffler is also supported by the National Institute on Alcohol Abuse and Alcoholism (R01 AA030888; R01 AA027760).

CRediT authorship contribution statement

Erica Eaton: Writing – review & editing, Writing – original draft, Project administration, Methodology, Investigation, Funding acquisition, Conceptualization. Christy Capone: Writing – review & editing, Writing – original draft, Project administration, Methodology, Investigation, Funding acquisition, Conceptualization. Brian J. Gully: Writing – review & editing, Project administration, Methodology. Zoe E. Brown: Writing – review & editing, Project administration, Methodology. Mollie Monnig: Writing – review & editing, Project administration, Methodology, Investigation, Data curation, Conceptualization. Michael S. Worden: Writing – review & editing, Methodology, Investigation, Data curation, Conceptualization. Robert M. Swift: Writing – review & editing, Project administration, Methodology, Investigation, Conceptualization. Carolina L. Haass-Koffler: Writing – review & editing, Writing – original draft, Project administration, Methodology, Investigation, Funding acquisition, Data curation, Conceptualization.

Declaration of competing interest

The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:

CLH-K received mifepristone and matching placebo for another trial and travel support to CA to present the data at the Corcept Therapeutic Conference (September 2022), holds two patents for the development of negative allosteric modulators targeting the stress system and one patent application on the development of a compound for noradrenergic blockade. All is unrelated to this work. The other authors have no conflict of interest to disclose.