Post Traumatic Stress DisorderPhase 1NCT03752918
The Effects of MDMA on Prefrontal and Amygdala Activation in PTSD.
A Phase 1 study testing MDMA and Niacin in people with Post Traumatic Stress Disorder, run by Yale University at 1 site in United States.
Trial summary
This study aims to investigate the effects of MDMA on prefrontal and amygdala activation, and to explore the relationship between these MDMA-induced neural changes and the acute behavioral effects of the drug in patients with PTSD. Read more about this study
- Who is it for?
- Ages 21 to 55 years
- Conditions the study is for
- Post Traumatic Stress Disorder
- What is being tested?
- MDMA and Niacin
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 0 participants
- Where
- 1 siteUnited States
- Study dates
- May 2024to Jan 2028
- Phase
- Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 21 to 55 years
- All sexes
- No healthy volunteers
- Adult
Who may be able to join
- Males or females between the ages of 21-55 years. Females will be included if they are not pregnant and agreed to utilize a medically (non-hormonal)* accepted birth control method (to include implant birth control, condom, diaphragm with spermicide, intrauterine device, tubal ligation, abstinence, or partner with vasectomy) or if post-menopausal for at least 1 year, or surgically sterile.
- Able to provide written informed consent according to Yale HIC guidelines.
- Able to read and write English as a primary language.
- Diagnosis of PTSD, as determined by the Clinician Administered PTSD Scale (CAPS-5).
- Must have a score of 23 or higher on the Clinician-Administered PTSD Scale (CAPS-5) at screening.
- No more than mild TBI according to a modified version of the Brief TBI Screen.
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- Must not have a medical/neurological problem or use medication that would render MDMA unsafe by history or medical evaluation.
- No prior exposure to MDMA.
- Are willing to remain overnight at the study site after each experimental session.
- Are willing to be driven home the day after the experimental sessions.
- Not currently taking any of the listed medications at the time of the study.
- Are willing to sign a medical release for the investigators to communicate directly with their therapist and doctors.
- Are willing to abstain from alcohol, street drugs, and tobacco products while in the study.
Who cannot join
- Patients with a diagnostic history of bipolar disorder, schizophrenia or schizoaffective disorder or currently exhibiting psychotic features as determined by the MINI 7.0 for the DSM-5.
- Serious suicide or homicide risk, as assessed by evaluating clinician.
- Substance abuse or dependence during the 6 months prior to screening; or a positive pre-study (screening) urine drug screen.
- Any significant history of serious medical or neurological illness.
- Any signs of major medical or neurological illness on examination or as a result of ECG screening or laboratory tests (e.g. positive urine tox, positive HIV/AIDS tests ).
- Abnormality on physical examination. A participant with a clinical abnormality may be included only if the study physician considers the abnormality will not introduce additional risk factors and will not interfere with the study procedure.
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- Pregnant or lactating women or a positive urine pregnancy test for women of child-bearing potential at screening or prior to any imaging day.
- Any history indicating learning disability, mental retardation, or attention deficit disorder.
- Family history of cardiovascular diseases. History of hypertension with baseline blood pressure above 140 mmHg (systolic) and over 90 mmHg (diastolic). Any history of syncope and/or baseline blood pressure below 100mmHg (systolic).
- History of claustrophobia.
- BMI > 30 kg/m2 or >250 pounds.
- Anxiolytic, neuroleptic and SRI medications (off SRIs for 4 weeks, fluoxetine 5 weeks).
- Females taking hormonal contraceptives will not be able to participate in the study *(Hormonal contraceptives are exclusionary because MDMA increases production of oxytocin which is heavily modulated by other hormones (e.g. estrogen). Therefore, women need to be naturally cycling/ovulating and not taking any hormonal medications to participate in this study).
- Any metal or electromagnetic implants, including: (Cardiac pacemaker, artificial heart valve, defibrillator, aneurysm clip, cochlear implants, shrapnel, neurostimulators, history of metal fragments in eyes or skin, significant hearing loss or other severe sensory impairment, a history of seizures or current use of anticonvulsants.
Trial locations and contacts
1 site in 1 country.
United States1 site
Enact Research Collaborative
New Haven, Connecticut, 06510
About this study
Official title: The Effects of MDMA on Prefrontal and Amygdala Activation in Posttraumatic Stress Disorder
This study aims to investigate the effects of MDMA on prefrontal and amygdala activation, and to explore the relationship between these MDMA-induced neural changes and the acute behavioral effects of the drug in patients with PTSD.
Read the detailed description
The investigators intend to utilize state-of-the-art validated Human Connectome Project (HCP) style approaches to determine the effects of MDMA on prefrontal and amygdala activation, and to explore the relationship between these MDMA-induced neural changes and the acute behavioral effects of the drug in patients with PTSD. In addition, the investigators will collect preliminary data on the MDMA effects on large-scale intrinsic functional connectivity using novel graph-based network analyses.
Specifically, the investigators will measure medial prefrontal cortex (mPFC) and amygdala activation in response to negative stimuli in patients with PTSD. The investigators hypothesize that MDMA will increase mPFC, but decrease amygdala, activation in response to negative stimuli.
The investigators will also explore the relationship between the MDMA-induced mPFC and amygdala activation, and performance on Ekman's Emotional Facial Expression task. This task is modulated by the mPFC and amygdala and as well as trauma severity in participants with PTSD. And finally, to explore the effects of MDMA on resting-state functional connectivity (rs-fcMRI) the investigators will use Coupled Intrinsic Connectivity Distribution (Coupled-ICD); an innovative, graph-based, fully data-driven approach that is particularly sensitive to paired rs-fcMRI data (e.g. pre/post-treatment).
Adult participants with PTSD will be recruited for a double-blind, placebo-controlled, within-subjects, crossover-dose neuroimaging study in which they will initially receive either a single dose of MDMA 1.5mg/kg or a placebo (niacin 250mg), with a crossover dose to follow. Doses will be separated by 2 weeks.
- Conditions
- Post Traumatic Stress Disorder
- Being tested
- MDMA, Niacin
- Keywords
- MDMA
- Medical subject headings
- Stress Disorders, Post-Traumatic
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
MDMADrug
Also called 3,4-Methylenedioxymethamphetamine
A single dose of 1.5mg/kg will be administered once orally.
NiacinDrug
Also called Nicotinic acid
A single dose of 250mg will be administered once orally.
| Study group | Role | What they receive |
|---|---|---|
| MDMA | Experimental | MDMA (1.5mg/kg) Receives: Drug: MDMA |
| Niacin | Placebo comparator | Niacin (250mg) Receives: Drug: Niacin |
What is being measured
The primary outcome is the main question the study is designed to answer.
Changes in activation of mPFC, amygdala, and nucleus accumbens upon presentation of emotional faces.
This will be assessed using mixed effects regression models, with group, time, and group X time effects modeled to examine the effect of MDMA on region of interests (ROI) activation. We will also assess the functional connectivity of between these ROIs.
Measured: Initial Drug Dose, 2 weeks post drug dose (second drug dose).
Secondary outcomes (17)
Changes in PTSD symptoms, which will be measured by The Clinician-Administered PTSD Scale 5 (CAPS-5).
Assesses PTSD symptoms. It is a structured interview that consists of 30 items. Items are rated using a 0 to 4 severity scale. In addition to assessing the 20 DSM-5 PTSD symptoms, questions target the onset and duration of symptoms, subjective distress, impact of symptoms on social and occupational functioning, improvement in symptoms since a previous CAPS administration, overall response validity, overall PTSD severity, and specifications for the dissociative subtype (depersonalization and derealization. Higher scores indicate more severe PTSD symptoms.
Measured: Baseline, Initial Drug Dose and Second Drug Dose, 24 hours and 1 week after initial and second drug dose.
Changes in depression symptoms, which will be measured by The Beck Depression Inventory II (BDI-II).
Assesses depression symptoms. Consists of 21 items and uses a 0 to 3 severity scale. Total scores range from 0 to 63, with higher scores indicating more severe depression.
Measured: Baseline, Initial Drug Does and Second Drug Dose, 24 hours after initial and second drug dose, 3 and 5 days after initial and second drug dose (by phone), 1 week after initial and second drug dose, 15, 17, 19, and 21 days after second drug dose (phone).
Changes in sleep patterns, which will be measured by The Pittsburgh Sleep Quality Index (PSQI).
Assesses the quality and patterns of sleep in adults. It differentiates "poor" from "good" sleep quality by measuring seven areas (components): subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleeping medications, and daytime dysfunction over the last month. Items are rated using a 0 to 3 scale. The component scores are summed to produce a global score (range 0 to 21). Higher scores indicate worse sleep quality.
Measured: Baseline, 24 hours after first and second drug dose, 1 week after initial and second drug dose.
Changes in PTSD symptoms, which will be measured by The Posttraumatic Stress Disorder Checklist for the DSM-5 (PCL-5).
Assesses PTSD symptoms. It is a 20-item self-report measure that assesses the 20 DSM-5 symptoms of PTSD. Items are rated using a 0 to 4 scale. Total scores range from 0 to 80, with higher scores indicating more severe PTSD symptoms.
Measured: Baseline, 24 hours after initial and second drug dose, 3 and 5 days after initial and second drug dose (phone), 1 week after initial and second drug dose, 15, 17, 19, and 21 days after second drug dose (phone).
Changes in personality traits, which will be measured by The NEO Personality Inventory - Revised (NEO PI-R).
Assesses changes in personality traits. It is a personality inventory that examines a person's Big Five personality traits. It consist of 240 items that assess 30 specific traits, which in turn define the five factors: Neuroticism (N), Extraversion (E), Openness to Experience (O), Agreeableness (A), and Conscientiousness (C). Items are rated on a five-point Likert scale, from strongly disagree to strongly agree.
Measured: Baseline, 1 week after initial and second drug dose.
Changes in mental states, which will be measured The 5-Dimensional Altered States of Consciousness Scale (5D-ASC).
Assesses different mental states induced by the interventions. Consists of 94 items which are rated by placing marks on a horizontal visual analogue scale (100 millimeters in length). The scale ranges from no, not more than usual (on the left) to yes, very much more than usual (on the right). The items are scored by measuring the millimeters from the low end of the scale to the participant's mark (from 0 to 100).
Measured: Initial and second drug dose.
Changes in growth following a traumatic event, which will be measured by The Post traumatic Growth Inventory (PTGI).
Assesses positive outcomes reported by persons who have experienced traumatic events. It is a 21-item scale that includes factors of New Possibilities, Relating to Others, Personal Strength, Spiritual Change, and Appreciation of Life. Participants are asked to rate the degree to which this change occurred in their life as a result of the crisis/disaster. Each item is rated from 0 (I did not experience this change as a result of my crisis) to 5 (I experienced this change to a very great degree as a result of my crisis). Total score is calculated by summing all items. Individual factors are scored by adding responses to items on each factor. Higher scores indicate greater growth.
Measured: Baseline, 24 hours after initial and second drug dose, 1 week after initial and second drug dose.
Changes in well-being, which will be measured by The Well-Being Inventory (WBI).
Assesses well-being across life domains and such as work, finances, health, and social relationships. Participants are first asked questions about their level of functioning in each domain. Items are rated from 1 (never) to 5 (most or all of the time). Then they are asked questions about their satisfaction in each domain. Items are rated from 1 (very dissatisfied) to 5 (very satisfied). Higher total scores indicate greater well-being.
Measured: Baseline, 1 week after initial and second drug dose.
Changes in psychological inflexibility/experiential avoidance, which will be measured by The Acceptance and Action Questionnaire II (AAQ-II).
Assesses psychological inflexibility/experiential avoidance. Participants are asked to rate how true each statement is for them. Items are rated from 1 (never true) to 7 (always true). Higher scores equal greater levels of psychological inflexibility.
Measured: Baseline, 1 Week after initial and second drug dose.
Changes in emotional regulation, which will be measured by The Emotion Regulation Questionnaire (ERQ).
Assesses emotional regulation. A 10-item scale designed to measure respondents' tendency to regulate their emotions in two ways: (1) Cognitive Reappraisal and (2) Expressive Suppression. Participants answer each item on a 7-point Likert scale ranging from 1 (strongly disagree) to 7 (strongly agree). The higher the scores the greater the use of the emotion regulation strategy.
Measured: Baseline, 1 week after initial and second drug dose.
Changes in cognitive and emotional empathy, which will be measured by the Multifaceted Empathy Test (MET).
Measures cognitive and emotional empathy simultaneously and independently using a series of photorealistic stimuli computer based tasks.
Measured: Baseline, Initial and Second Drug Dose, 24 hours after initial and second drug dose, 1 week after initial and second drug dose.
Changes in the quality of specific relationships in terms of supportive and conflictual dynamics will be assessed with the Quality of Relationships Inventory (QRI)
The 25 question task assesses the contemporary quality of specific relationships (between the patient and a specific individual, such as a family member) at a particular point in time in terms of conflict, support, and depth. It uses a Likert-type 4 point scale going from "1" indicating the item does not apply at all, while "4" indicates the item applies quite a lot.
Measured: Baseline, Initial and Second Drug Dose, 1 week after initial and second drug dose.
Cognitive schemas about oneself and others, will be assessed by the Trauma and Attachment Beliefs Scale (TABS)
The 84 item self-report scale, which measures responses on a 1-6 scale (1 = "Disagree Strongly, 6 = Agree Strongly) the degree to which respondents believe the statements correspond with their own beliefs. The measures of these beliefs relate to self-safety, other-safety, self-trust, other-trust, self-esteem, other-esteem, self-intimacy, other-intimacy, self-control, and other control.
Measured: Baseline
Brain injury will be assessed for with the CogState Neuropsychological Test
Brain injuries associated with traumatic events, such as concussions, will be screened for in the CogState Neuropsychological Test, a standard computerized test used to assess neuropsychological deficits associated with brain injury.
Measured: Baseline, 1 week after initial and second drug dose.
Moral injury, or the sense of distress due to contradiction of deeply-held beliefs due to a traumatic event, will be measured by the Moral Injury Events Scale (MIES)
This 9 item self-report scale measures the moral injury, or distress due to the contradiction to a deeply-held belief about the world that often accompanies a traumatic incident. The injury is assessed in terms of "perceived transgression" and "perceived betrayal." Items are assessed with a Likert-type Scale (1 to 6, 1 = "strongly disagree," 6 = "strongly agree," with no neutral option). Higher scores indicate greater severity of associated event.
Measured: Baseline, Initial and Second Drug Dose, 24 hours after initial and second drug dose, 1 week after initial and second drug dose.
Changes in concept and sense of existential meaning will be measured with the Purpose and Meaning scale (PIL)
Measures evaluation of the sense of existential purpose and enthusiasm for life in a three part self-report survey. Part A is a 20 point scale test which uses a 1-7 scale in which low number answers correspond attitudes such as boredom and directionless-ness. Parts B and C are not empirically useful, but ask for participants to completes sentences and compose a paragraph respectively. Higher scores indicate a greater existential sense of purpose, with scores above 113 indicate a high degree of purpose, scores below 92 suggesting a lack of purpose, and scores between 92 and 112 indicate moderate levels of purpose.
Measured: Baseline, 1 week after second drug dose.
Changes in depression symptoms, which will be measured Montgomery-Asberg Depression Rating Scale (MADRS).
Assesses depression symptoms. Consists of 10 items and uses a 0 to 6 severity scale. Total scores range from 0 to 60, with higher scores indicating more severe depression.
Measured: Baseline, Initial and Second Drug Dose, 24 hours after initial and second drug dose, 1 week after initial and second administration.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted26 Nov 2018
- Study startMay 2024 (estimated)
- Primary completionJan 2028 (estimated)
- Study completionJan 2028 (estimated)
Why it stopped: Funding ended.
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (40)Papers the sponsor has linked to this study.
- Other trials for Post Traumatic Stress DisorderStudies of the same condition, open and under way.
- More trials run by Yale UniversityThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Model description
- This study will be a double-blind, placebo-controlled, within-subjects, crossover-dose neuroimaging study in which participants will initially receive either a single dose of MDMA 1.5mg/kg or a placebo (niacin 250mg), with a crossover dose to follow. Doses will be separated by 2 weeks.
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 0 participants (actual)
Sponsor and investigators
- Lead sponsor
- Yale University
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Benjamin Kelmendi, MD, Yale University
- Investigators
- Benjamin Kelmendi, MD, Principal investigator, Yale University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03752918
- Sponsor's protocol ID
- 2000020348
- Status last verified
- May 2024
- First submitted
- 16 Nov 2018
- Last updated
- 19 May 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Haagen JF, Smid GE, Knipscheer JW, Kleber RJ. The efficacy of recommended treatments for veterans with PTSD: A metaregression analysis. Clin Psychol Rev. 2015 Aug;40:184-94. doi: 10.1016/j.cpr.2015.06.008. Epub 2015 Jun 27.
PubMed 26164548Kessler RC, Sonnega A, Bromet E, Hughes M, Nelson CB. Posttraumatic stress disorder in the National Comorbidity Survey. Arch Gen Psychiatry. 1995 Dec;52(12):1048-60. doi: 10.1001/archpsyc.1995.03950240066012.
PubMed 7492257Pitman RK, Rasmusson AM, Koenen KC, Shin LM, Orr SP, Gilbertson MW, Milad MR, Liberzon I. Biological studies of post-traumatic stress disorder. Nat Rev Neurosci. 2012 Nov;13(11):769-87. doi: 10.1038/nrn3339. Epub 2012 Oct 10.
PubMed 23047775Abad S, Camarasa J, Pubill D, Camins A, Escubedo E. Adaptive Plasticity in the Hippocampus of Young Mice Intermittently Exposed to MDMA Could Be the Origin of Memory Deficits. Mol Neurobiol. 2016 Dec;53(10):7271-7283. doi: 10.1007/s12035-015-9618-z. Epub 2015 Dec 21.
PubMed 26687233Mithoefer MC, Wagner MT, Mithoefer AT, Jerome L, Doblin R. The safety and efficacy of +/-3,4-methylenedioxymethamphetamine-assisted psychotherapy in subjects with chronic, treatment-resistant posttraumatic stress disorder: the first randomized controlled pilot study. J Psychopharmacol. 2011 Apr;25(4):439-52. doi: 10.1177/0269881110378371. Epub 2010 Jul 19.
PubMed 20643699Mithoefer MC, Wagner MT, Mithoefer AT, Jerome L, Martin SF, Yazar-Klosinski B, Michel Y, Brewerton TD, Doblin R. Durability of improvement in post-traumatic stress disorder symptoms and absence of harmful effects or drug dependency after 3,4-methylenedioxymethamphetamine-assisted psychotherapy: a prospective long-term follow-up study. J Psychopharmacol. 2013 Jan;27(1):28-39. doi: 10.1177/0269881112456611. Epub 2012 Nov 20.
PubMed 23172889Shin LM, Rauch SL, Pitman RK. Amygdala, medial prefrontal cortex, and hippocampal function in PTSD. Ann N Y Acad Sci. 2006 Jul;1071:67-79. doi: 10.1196/annals.1364.007.
PubMed 16891563Shin LM, Liberzon I. The neurocircuitry of fear, stress, and anxiety disorders. Neuropsychopharmacology. 2010 Jan;35(1):169-91. doi: 10.1038/npp.2009.83.
PubMed 19625997Lanius RA, Bluhm R, Lanius U, Pain C. A review of neuroimaging studies in PTSD: heterogeneity of response to symptom provocation. J Psychiatr Res. 2006 Dec;40(8):709-29. doi: 10.1016/j.jpsychires.2005.07.007. Epub 2005 Oct 7.
PubMed 16214172Etkin A, Wager TD. Functional neuroimaging of anxiety: a meta-analysis of emotional processing in PTSD, social anxiety disorder, and specific phobia. Am J Psychiatry. 2007 Oct;164(10):1476-88. doi: 10.1176/appi.ajp.2007.07030504.
PubMed 17898336Carhart-Harris RL, Wall MB, Erritzoe D, Kaelen M, Ferguson B, De Meer I, Tanner M, Bloomfield M, Williams TM, Bolstridge M, Stewart L, Morgan CJ, Newbould RD, Feilding A, Curran HV, Nutt DJ. The effect of acutely administered MDMA on subjective and BOLD-fMRI responses to favourite and worst autobiographical memories. Int J Neuropsychopharmacol. 2014 Apr;17(4):527-40. doi: 10.1017/S1461145713001405. Epub 2013 Dec 17.
PubMed 24345398Hysek CM, Domes G, Liechti ME. MDMA enhances "mind reading" of positive emotions and impairs "mind reading" of negative emotions. Psychopharmacology (Berl). 2012 Jul;222(2):293-302. doi: 10.1007/s00213-012-2645-9. Epub 2012 Jan 27.
PubMed 22277989Kirkpatrick MG, Lee R, Wardle MC, Jacob S, de Wit H. Effects of MDMA and Intranasal oxytocin on social and emotional processing. Neuropsychopharmacology. 2014 Jun;39(7):1654-63. doi: 10.1038/npp.2014.12. Epub 2014 Jan 22.
PubMed 24448644Hysek CM, Schmid Y, Simmler LD, Domes G, Heinrichs M, Eisenegger C, Preller KH, Quednow BB, Liechti ME. MDMA enhances emotional empathy and prosocial behavior. Soc Cogn Affect Neurosci. 2014 Nov;9(11):1645-52. doi: 10.1093/scan/nst161. Epub 2013 Oct 4.
PubMed 24097374Wardle MC, de Wit H. MDMA alters emotional processing and facilitates positive social interaction. Psychopharmacology (Berl). 2014 Oct;231(21):4219-29. doi: 10.1007/s00213-014-3570-x. Epub 2014 Apr 12.
PubMed 24728603
Study at a glance
From the registry record, last updated by the sponsor on 19 May 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- The Effects of MDMA on Prefrontal and Amygdala Activation in Posttraumatic Stress Disorder
- ClinicalTrials.gov ID
- NCT03752918
- Acronym / sponsor ID
- 2000020348
- Conditions
- Post Traumatic Stress Disorder
- Keywords
- MDMA
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- WithdrawnReason stopped: Funding ended.
- Enrolment
- 0 participants (actual)
- Lead sponsor
- Yale UniversityUniversity, hospital or other
- Study start
- May 2024 (estimated)
- Primary completion
- Jan 2028 (estimated)
- Study completion
- Jan 2028 (estimated)
- First posted
- 26 Nov 2018 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This study aims to investigate the effects of MDMA on prefrontal and amygdala activation, and to explore the relationship between these MDMA-induced neural changes and the acute behavioral effects of the drug in patients with PTSD.
Detailed description
The investigators intend to utilize state-of-the-art validated Human Connectome Project (HCP) style approaches to determine the effects of MDMA on prefrontal and amygdala activation, and to explore the relationship between these MDMA-induced neural changes and the acute behavioral effects of the drug in patients with PTSD. In addition, the investigators will collect preliminary data on the MDMA effects on large-scale intrinsic functional connectivity using novel graph-based network analyses.
Specifically, the investigators will measure medial prefrontal cortex (mPFC) and amygdala activation in response to negative stimuli in patients with PTSD. The investigators hypothesize that MDMA will increase mPFC, but decrease amygdala, activation in response to negative stimuli.
The investigators will also explore the relationship between the MDMA-induced mPFC and amygdala activation, and performance on Ekman's Emotional Facial Expression task. This task is modulated by the mPFC and amygdala and as well as trauma severity in participants with PTSD. And finally, to explore the effects of MDMA on resting-state functional connectivity (rs-fcMRI) the investigators will use Coupled Intrinsic Connectivity Distribution (Coupled-ICD); an innovative, graph-based, fully data-driven approach that is particularly sensitive to paired rs-fcMRI data (e.g. pre/post-treatment).
Adult participants with PTSD will be recruited for a double-blind, placebo-controlled, within-subjects, crossover-dose neuroimaging study in which they will initially receive either a single dose of MDMA 1.5mg/kg or a placebo (niacin 250mg), with a crossover dose to follow. Doses will be separated by 2 weeks.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
- Model description
- This study will be a double-blind, placebo-controlled, within-subjects, crossover-dose neuroimaging study in which participants will initially receive either a single dose of MDMA 1.5mg/kg or a placebo (niacin 250mg), with a crossover dose to follow. Doses will be separated by 2 weeks.
| Arm | Type | Receives |
|---|---|---|
| MDMA | Experimental | Drug: MDMAMDMA (1.5mg/kg) |
| Niacin | Placebo comparator | Drug: NiacinNiacin (250mg) |
Who may qualify
- Ages
- 21 to 55 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult
Key inclusion criteria (13 listed)
- Males or females between the ages of 21-55 years. Females will be included if they are not pregnant and agreed to utilize a medically (non-hormonal)* accepted birth control method (to include implant birth control, condom, diaphragm with spermicide, intrauterine device, tubal ligation, abstinence, or partner with vasectomy) or if post-menopausal for at least 1 year, or surgically sterile.
- Able to provide written informed consent according to Yale HIC guidelines.
- Able to read and write English as a primary language.
- Diagnosis of PTSD, as determined by the Clinician Administered PTSD Scale (CAPS-5).
- Must have a score of 23 or higher on the Clinician-Administered PTSD Scale (CAPS-5) at screening.
Key exclusion criteria (14 listed)
- Patients with a diagnostic history of bipolar disorder, schizophrenia or schizoaffective disorder or currently exhibiting psychotic features as determined by the MINI 7.0 for the DSM-5.
- Serious suicide or homicide risk, as assessed by evaluating clinician.
- Substance abuse or dependence during the 6 months prior to screening; or a positive pre-study (screening) urine drug screen.
- Any significant history of serious medical or neurological illness.
- Any signs of major medical or neurological illness on examination or as a result of ECG screening or laboratory tests (e.g. positive urine tox, positive HIV/AIDS tests ).
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| MDMAAlso: 3,4-MethylenedioxymethamphetamineA single dose of 1.5mg/kg will be administered once orally. | Drug | MDMA |
| NiacinAlso: Nicotinic acidA single dose of 250mg will be administered once orally. | Drug | Niacin |
Primary outcome
Changes in activation of mPFC, amygdala, and nucleus accumbens upon presentation of emotional faces.
Time frame: Initial Drug Dose, 2 weeks post drug dose (second drug dose).
This will be assessed using mixed effects regression models, with group, time, and group X time effects modeled to examine the effect of MDMA on region of interests (ROI) activation. We will also assess the functional connectivity of between these ROIs.
17 secondary outcomes
Changes in PTSD symptoms, which will be measured by The Clinician-Administered PTSD Scale 5 (CAPS-5).
Time frame: Baseline, Initial Drug Dose and Second Drug Dose, 24 hours and 1 week after initial and second drug dose.
Changes in depression symptoms, which will be measured by The Beck Depression Inventory II (BDI-II).
Time frame: Baseline, Initial Drug Does and Second Drug Dose, 24 hours after initial and second drug dose, 3 and 5 days after initial and second drug dose (by phone), 1 week after initial and second drug dose, 15, 17, 19, and 21 days after second drug dose (phone).
Changes in sleep patterns, which will be measured by The Pittsburgh Sleep Quality Index (PSQI).
Time frame: Baseline, 24 hours after first and second drug dose, 1 week after initial and second drug dose.
Changes in PTSD symptoms, which will be measured by The Posttraumatic Stress Disorder Checklist for the DSM-5 (PCL-5).
Time frame: Baseline, 24 hours after initial and second drug dose, 3 and 5 days after initial and second drug dose (phone), 1 week after initial and second drug dose, 15, 17, 19, and 21 days after second drug dose (phone).
Changes in personality traits, which will be measured by The NEO Personality Inventory - Revised (NEO PI-R).
Time frame: Baseline, 1 week after initial and second drug dose.
Changes in mental states, which will be measured The 5-Dimensional Altered States of Consciousness Scale (5D-ASC).
Time frame: Initial and second drug dose.
Changes in growth following a traumatic event, which will be measured by The Post traumatic Growth Inventory (PTGI).
Time frame: Baseline, 24 hours after initial and second drug dose, 1 week after initial and second drug dose.
Changes in well-being, which will be measured by The Well-Being Inventory (WBI).
Time frame: Baseline, 1 week after initial and second drug dose.
Changes in psychological inflexibility/experiential avoidance, which will be measured by The Acceptance and Action Questionnaire II (AAQ-II).
Time frame: Baseline, 1 Week after initial and second drug dose.
Changes in emotional regulation, which will be measured by The Emotion Regulation Questionnaire (ERQ).
Time frame: Baseline, 1 week after initial and second drug dose.
Changes in cognitive and emotional empathy, which will be measured by the Multifaceted Empathy Test (MET).
Time frame: Baseline, Initial and Second Drug Dose, 24 hours after initial and second drug dose, 1 week after initial and second drug dose.
Changes in the quality of specific relationships in terms of supportive and conflictual dynamics will be assessed with the Quality of Relationships Inventory (QRI)
Time frame: Baseline, Initial and Second Drug Dose, 1 week after initial and second drug dose.
Cognitive schemas about oneself and others, will be assessed by the Trauma and Attachment Beliefs Scale (TABS)
Time frame: Baseline
Brain injury will be assessed for with the CogState Neuropsychological Test
Time frame: Baseline, 1 week after initial and second drug dose.
Moral injury, or the sense of distress due to contradiction of deeply-held beliefs due to a traumatic event, will be measured by the Moral Injury Events Scale (MIES)
Time frame: Baseline, Initial and Second Drug Dose, 24 hours after initial and second drug dose, 1 week after initial and second drug dose.
Changes in concept and sense of existential meaning will be measured with the Purpose and Meaning scale (PIL)
Time frame: Baseline, 1 week after second drug dose.
Changes in depression symptoms, which will be measured Montgomery-Asberg Depression Rating Scale (MADRS).
Time frame: Baseline, Initial and Second Drug Dose, 24 hours after initial and second drug dose, 1 week after initial and second administration.
Results and safety
The study was withdrawn before enrolling participants, so there are no results.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 19 May 2026.
- Background: PubMed 26164548Haagen JF, Smid GE, Knipscheer JW, Kleber RJ. The efficacy of recommended treatments for veterans with PTSD: A metaregression analysis. Clin Psychol Rev. 2015 Aug;40:184-94. doi: 10.1016/j.cpr.2015.06.008. Epub 2015 Jun 27.
- Background: PubMed 7492257Kessler RC, Sonnega A, Bromet E, Hughes M, Nelson CB. Posttraumatic stress disorder in the National Comorbidity Survey. Arch Gen Psychiatry. 1995 Dec;52(12):1048-60. doi: 10.1001/archpsyc.1995.03950240066012.
- Background: PubMed 23047775Pitman RK, Rasmusson AM, Koenen KC, Shin LM, Orr SP, Gilbertson MW, Milad MR, Liberzon I. Biological studies of post-traumatic stress disorder. Nat Rev Neurosci. 2012 Nov;13(11):769-87. doi: 10.1038/nrn3339. Epub 2012 Oct 10.
- Background: PubMed 26687233Abad S, Camarasa J, Pubill D, Camins A, Escubedo E. Adaptive Plasticity in the Hippocampus of Young Mice Intermittently Exposed to MDMA Could Be the Origin of Memory Deficits. Mol Neurobiol. 2016 Dec;53(10):7271-7283. doi: 10.1007/s12035-015-9618-z. Epub 2015 Dec 21.
- Background: PubMed 20643699Mithoefer MC, Wagner MT, Mithoefer AT, Jerome L, Doblin R. The safety and efficacy of +/-3,4-methylenedioxymethamphetamine-assisted psychotherapy in subjects with chronic, treatment-resistant posttraumatic stress disorder: the first randomized controlled pilot study. J Psychopharmacol. 2011 Apr;25(4):439-52. doi: 10.1177/0269881110378371. Epub 2010 Jul 19.
- Background: PubMed 23172889Mithoefer MC, Wagner MT, Mithoefer AT, Jerome L, Martin SF, Yazar-Klosinski B, Michel Y, Brewerton TD, Doblin R. Durability of improvement in post-traumatic stress disorder symptoms and absence of harmful effects or drug dependency after 3,4-methylenedioxymethamphetamine-assisted psychotherapy: a prospective long-term follow-up study. J Psychopharmacol. 2013 Jan;27(1):28-39. doi: 10.1177/0269881112456611. Epub 2012 Nov 20.
- Background: PubMed 16891563Shin LM, Rauch SL, Pitman RK. Amygdala, medial prefrontal cortex, and hippocampal function in PTSD. Ann N Y Acad Sci. 2006 Jul;1071:67-79. doi: 10.1196/annals.1364.007.
- Background: PubMed 19625997Shin LM, Liberzon I. The neurocircuitry of fear, stress, and anxiety disorders. Neuropsychopharmacology. 2010 Jan;35(1):169-91. doi: 10.1038/npp.2009.83.
- Background: PubMed 16214172Lanius RA, Bluhm R, Lanius U, Pain C. A review of neuroimaging studies in PTSD: heterogeneity of response to symptom provocation. J Psychiatr Res. 2006 Dec;40(8):709-29. doi: 10.1016/j.jpsychires.2005.07.007. Epub 2005 Oct 7.
- Background: PubMed 17898336Etkin A, Wager TD. Functional neuroimaging of anxiety: a meta-analysis of emotional processing in PTSD, social anxiety disorder, and specific phobia. Am J Psychiatry. 2007 Oct;164(10):1476-88. doi: 10.1176/appi.ajp.2007.07030504.
- Background: PubMed 24345398Carhart-Harris RL, Wall MB, Erritzoe D, Kaelen M, Ferguson B, De Meer I, Tanner M, Bloomfield M, Williams TM, Bolstridge M, Stewart L, Morgan CJ, Newbould RD, Feilding A, Curran HV, Nutt DJ. The effect of acutely administered MDMA on subjective and BOLD-fMRI responses to favourite and worst autobiographical memories. Int J Neuropsychopharmacol. 2014 Apr;17(4):527-40. doi: 10.1017/S1461145713001405. Epub 2013 Dec 17.
- Background: PubMed 22277989Hysek CM, Domes G, Liechti ME. MDMA enhances "mind reading" of positive emotions and impairs "mind reading" of negative emotions. Psychopharmacology (Berl). 2012 Jul;222(2):293-302. doi: 10.1007/s00213-012-2645-9. Epub 2012 Jan 27.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Benjamin Kelmendi, MD principal investigator
Yale University
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing MDMA and Niacin in people with Post Traumatic Stress Disorder, run by Yale University at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 13 inclusion and 14 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: withdrawn, as of the sponsor's last update on 19 May 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study was withdrawn before enrolling participants, so there are no results.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Changes in activation of mPFC, amygdala, and nucleus accumbens upon presentation of emotional faces. (time frame: Initial Drug Dose, 2 weeks post drug dose (second drug dose).). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03752918, which also lists 40 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 19 May 2026.