Ignite Creation Date:
2024-05-06 @ 5:10 PM
Last Modification Date:
2024-10-26 @ 2:23 PM
Study NCT ID:
NCT05219175
Status:
ACTIVE_NOT_RECRUITING
Last Update Posted:
2024-05-01
First Post:
2022-01-02
Brief Title:
MDMA for Co-occurring PTSD and OUD After Childbirth
Sponsor:
University of New Mexico
Organization:
University of New Mexico
Study Overview
Official Title:
MDMA-Assisted Therapy 6 to 12 Months After Childbirth for People With Co-occurring Opioid Use and Post Traumatic Stress Disorders
Status:
ACTIVE_NOT_RECRUITING
Status Verified Date:
2024-04
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
This is an open-label study of the use of MDMA Assisted Therapy for postpartum people with co-occurring Post Traumatic Stress Disorder PTSD and Opioid Use Disorder OUD The study protocol has been adapted from the Phase 3 studies sponsored by the Multidisciplinary Association for Psychedelic Studies MAPS for PTSD Due to the high rate of concurrence of PTSD and OUD people with OUD may experience great benefit from the treatment of their PTSD with MDMA-assisted therapy based on the phase 2 and 3 studies for PTSD Use of MDMA-assisted therapy in this population has the potential to be of benefit for their OUD and maternal- infant attachment
This study will serve to explore the feasibility and safety of offering MDMA-assisted therapy for treatment of PTSD in postpartum people with opioid use disorder The CAPs 5 PTSD is the primary outcome the Timeline Follow-Back TLFB for opioid use is the secondary outcome and other assessments of opioid use disorder effects on maternal-infant attachment social connectedness and other mental health outcomes are exploratory The study will be conducted at the University of New Mexico Health Sciences Center located in Albuquerque New Mexico In addition to northern New Mexico being an epicenter of the current opioid use disorder epidemic in the United States there is a long-standing history of multigenerational use of illicit opioids in many communities of northern New Mexico There are high rates of opioid use disorder on pregnancy and accompanying Neonatal Opioid Use Withdrawal Syndrome NOWS in Albuquerque Santa Fe and surrounding communities
This study will serve to explore the feasibility and safety of offering MDMA-assisted therapy for treatment of PTSD in postpartum people with opioid use disorder The CAPs 5 PTSD is the primary outcome the Timeline Follow-Back TLFB for opioid use is the secondary outcome and other assessments of opioid use disorder effects on maternal-infant attachment social connectedness and other mental health outcomes are exploratory The study will be conducted at the University of New Mexico Health Sciences Center located in Albuquerque New Mexico In addition to northern New Mexico being an epicenter of the current opioid use disorder epidemic in the United States there is a long-standing history of multigenerational use of illicit opioids in many communities of northern New Mexico There are high rates of opioid use disorder on pregnancy and accompanying Neonatal Opioid Use Withdrawal Syndrome NOWS in Albuquerque Santa Fe and surrounding communities
Detailed Description:
Protocol Synopsis MDMA-Assisted Therapy 6 to 12 months After Childbirth for People with Co-occurring Opioid Use and Post Traumatic Stress Disorders
Protocol IUSOU1
Rationale Introduction
Background and Previous Research Data
Opioid use disorder
Opioid use disorder has reached epidemic levels in the United States and is now common in pregnant and postpartum people From 1999 to 2014 the delivery-related hospital admissions of people with opioid use disorder more than quadrupled from 15 to 65 per 1000 delivery hospitalizations New Mexico is one of the epicenters of the opioid use epidemic 128 newborns per 1000 births in New Mexico were diagnosed with Neonatal Opioid Withdrawal Syndrome in 2018 The standard of care for Opioid Use Disorder OUD is the use of medication for opioid use disorder MOUD that was either initiated during the pregnancy or was already being taken at the time of conception MOUD is effective at improving maternal and neonatal outcomes however postpartum relapse is common and carries an increased risk of fatal overdose By having the use of MOUD as an inclusion criteria we are selecting for a group of people that has a greater chance of being stable throughout the study period and at lower risk for opioid overdose than individuals who relapse and are not on MOUD
Post-Traumatic Stress Disorder
Psychological trauma is a common antecedent of addiction and a trauma-informed approach is integral to substance misuse care The high rates of childhood sexual abuse and rape are factors resulting in high rates of Post Traumatic Stress Disorder PTSD among pregnant and postpartum people PTSD occurs in some individuals that are exposed to an event that is perceived to result in serious injury sexual violence or an actual or possible threat to life Intrusive symptoms such as nightmares flashbacks emotional distress or physical reactivity can then recur when the traumatic event is persistently re-experienced leading to avoidance of trauma-related thoughts feelings or reminders of the events which act as triggers of symptoms The individuals life is adversely affected by negative alterations in mood and thought including the somatic symptoms of increased arousal and reactivity eg hypervigilance heightened startle reaction and difficulty sleeping PTSD is a serious disorder that commonly has a negative impact on an individuals quality of life including impairing their ability to work and maintain relationships and it is associated with increased substance use depression and suicide Symptoms must persist for at least a month at sufficient intensity to be diagnosed as PTSD however they are often severe last for many years and can be resistant to treatment
PTSD can be treated with behavioral or medication therapies however the treatments for PTSD are often not included in the services offered by perinatal substance use programs The 2020 Guidelines from International Society for Traumatic Stress Studies include strong recommendations for the use of cognitive processing therapy cognitive therapy EMDR Eye Movement Desensitization and Reprocessing prolonged exposure and cognitive behavioral therapy with a trauma focus for adults with PTSD Selective Serotonin Reuptake Inhibitors SSRIs have a modest effect on symptom reduction however they are often used long term without achieving a resolution of PTSD
MDMA
MDMA 3 4-Methylenedioxymethamphetamine has received breakthrough drug status from the FDA for the treatment of PTSD MDMA is a monoamine releaser and re-uptake inhibitor with indirect effects on neurohormone release MDMA has a more complex neurochemical mechanism than classical psychedelics involving increased release of serotonin dopamine noradrenaline and oxytocin Activation of the 5-hydroxytryptamine receptor 1A 5-HT1a and 5-hydroxytryptamine receptor 1B 5-HT1b receptors decreases feeling of anxiety and depression and reduces amygdala mediated fear response These effects are accompanied by increased empathy emotional closeness and compassion Effects on the alpha-2 receptor are potentially beneficial in psychotherapy by reducing trauma associated hypervigilance mitigated by norepinephrine The release of oxytocin the hormone promoting maternal infant bonding is hypothesized to increase empathy feelings of closeness and decrease the fear activity activated in the amygdala1516 The neurocognitive effects of MDMA- assisted therapy have been proposed to be mediated via memory reconsolidation and fear extinction by reducing activation in the insula and amygdala which are involved with the expression and fear and anxiety A functional Magnetic Resonance Imaging MRI study of subjects administered MDMA demonstrated a decrease in insula network connectivity lending support to the hypothesis that this is a mechanism for the effects of MDMA
The combined neurobiological effects of MDMA reduce defenses and fear of emotional injury enhance communication and introspection And can increase empathy and compassion allowing for a psychological state that enhances successful trauma processing during psychotherapy MDMA has demonstrated benefit for treatment resistant PTSD in a series of phase 2 studies of MDMA-assisted therapy sponsored by the Multidisciplinary Association for Psychedelic Studies In pooled analysis of six phase 2 randomized controlled trials of MDMA-assisted therapy for long term PTSD more participants in the active group 542 did not meet DSM-IV Diagnostic Manual of Mental Disorders PTSD diagnostic criteria than the control group 226 after two MDMA sessions Based on historical comparison MDMA appears to be more effective than the two FDA approved Selective Serotonin Reuptake Inhibitor SSRI medications sertraline and paroxetine The processing of trauma during MDMA-assisted therapy may produce additional lasting changes by increasing the individuals personality trait of openness
MDMA may be of benefit to people for opioid use disorder secondary to resolving or improving PTSD symptoms or by a pathway independent of PTSD Although published research regarding the use of MDMA for substance use disorders is limited to a single small study involving alcohol use disorder described below20 there is a growing literature involving the use of classic psychedelics eg psilocybin and LSD Psilocybin has shown promise in the treatment of tobacco and alcohol use disorders and is being studied for opioid and cocaine use disorders A novel psychedelic ibogaine has been reported as a specific treatment for opioid use disorder however there have not been any randomized controlled trials Lysergic Acid Diethylamide LSD was extensively studied as a treatment for alcohol use disorder in the 1960s and 1970s A meta-analysis of six randomized controlled trials including 536 subjects demonstrated a beneficial effect of LSD on alcohol misuse OR 196 95 Confidence Interval CI 136-284 p 00003 Although rigorous prospective trials are lacking the use of plant derived psychedelics for substance use disorders additionally includes peyote in the Native American church for alcohol use disorder in the United States and Ayahuasca for cocaine and other substance use disorders in Peru and Brazil
The classic psychedelics work primarily at the level of the 5-HT2A receptor where they decrease activity in the brains default mode network which is correlated with ego dissolution Although classic psychedelics are showing benefit for addiction there are postpartum people with opioid use disorder who may not desire the experiences of ego dissolution and mystical experience during the postpartum period MDMA has psychedelic effects however it does not usually lead to the profound states of ego dissolution and mystical experiences that are associated with the positive effects of the classic psychedelics and detected by the Mystical Experience Questionnaire MEQ-30 The first study of MDMA for a substance use disorder is the Bristol Imperial MDMA in Alcoholism Study BIMA which demonstrated the feasibility of MDMA treatment after community based alcohol detoxification A follow-up study of alcohol consumption after MDMA treatment for PTSD demonstrated that alcohol consumption since study enrollment decreased among 22 participants 400 stayed the same for 17 participants 309 and increased for 2 participants 36 compared to prior to study enrollment
OUD PTSD and MDMA
OUD and PTSD are strongly associated comorbid disorders The association between these conditions may be due to traumatic life events leading to PTSD which are self-medicated with the opioid however the lifestyle of individuals with opioid use disorder may also predispose to an increased likelihood of traumatic events In pregnant woman with high rates of adverse childhood events it is these traumatic events that usually precede the development of OUD However trauma that occurs after they have OUD may intensify their PTSD symptoms An Australian study of individuals with heroin dependence demonstrated that 90 had serious trauma in the life history and 40 had PTSD The US National Comorbidity Survey of the general population estimated a lifetime prevalence rate of PTSD of 68 and current past year PTSD prevalence of 35The lifetime prevalence of PTSD among men was 36 and among women was 97 Woman have higher 12 month prevalence rates of PTSD of 52 compared to 18 among men
Racial trauma may contribute to PTSD either due to a major life event occurring directly due to racism including hate crimes or workplace harassment or due to a series of subtler lifelong occurrences that are the result of micro aggressions and implicit racial bias To identify these sources of trauma newer assessment instruments have been developed including the UConn RacialEthnic Stress and Trauma Survey and a short version which has been used by MDMA therapists A culturally informed approach to MDMA assisted therapy for PTSD includes cultural diversity on the treatment team outreach to communities of color and development of a setting including music and artwork that is culturally sensitive and appropriate This can include conveying an appreciation that most psychedelic therapies have their roots in the plant medicine of indigenous healers eg psilocybin peyote and ayahuasca and that the approach to using synthesized psychedelics that are not plant derived eg MDMA and ketamine can still integrate learning from these indigenous practices
Maternal PTSD and substance use disorders have been proposed as mechanisms of intergenerational trauma transmission through their effect on maternal infant bonding The disruption of maternal attachment leads to an increased risk of the child developing substance use disorder Treating maternal PTSD during pregnancy or postpartum has the theoretical potential to decrease the likelihood of the infant developing a substance use disorder during adolescence or adulthood As MDMA appears to be effective in the treatment of PTSD in other populations a feasibility study of the use of MDMA-assisted therapy in postpartum people with OUD has great potential to benefit the infant as well as the mother Use of MDMA during pregnancy or during breastfeeding presents an unacceptable level of maternal and neonatal risk due to the lack of safety data however studies of postpartum people at the University of New Mexico have demonstrated that the average time for stopping breastfeeding in this group was three weeks postpartum therefore offering MDMA- assisted therapy for PTSD at 6-12 months of age would only exclude a small proportion of people due to ongoing breastfeeding
Although the likelihood of benefit for opioid use disorder from MDMA experimental sessions may not be associated with higher scores on the MEQ-30 there are other instruments that can assess the effect of the experience on the participant The Challenging Experience Questionnaire has been used to assess the effects of challenging emotions such as fear or paranoia which may be a negative predictor of a positive response from the sessionsThe CEQ does not address the issue of how the challenging experience was resolved Challenging experiences may potentially facilitate transformation through a pivotal state that may increase neuroplasticity and deep learning Stanislav Grof a founder of transpersonal psychology and author of LSD Psychotherapy felt that challenging psychedelic experiences were of benefit in supporting psychological transformationThe recently developed Emotional Breakthrough Inventory EBI was developed to complement the MEQ-30 and CEQ and to look at the participants ability to achieve a breakthrough experience by overcoming challenging emotions and memoriesUnderstanding the psychological processes that support positive change such as resolution of PTSD or maintenance of remission for opioid use disorder is an exploratory objective
Indications being studied
Co-occurring Post Traumatic Stress Disorder and Opioid User Disorder
Treatment Proposal and Rationale
Due to the high rate of concurrence of PTSD and OUD these people may experience great benefit from the treatment of their PTSD with MDMA-assisted therapy based on the phase 2 and 3 studies for PTSD Use of MDMA-assisted therapy in this population has the potential to be of benefit for their OUD and maternal- infant attachment This open-label study will serve to explore the feasibility and safety of offering MDMA-assisted therapy for treatment of PTSD in postpartum people with opioid use disorder The CAPs 5 PTSD is the primary outcome the Timeline Follow-Back TLFB for opioid use is the secondary outcome and other assessments of opioid use disorder effects on maternal-infant attachment social connectedness and other mental health outcomes are exploratory
Study Design This is a single site open-label feasibility study to assess the safety and effectiveness of MDMA-assisted therapy in 15 people who are between six to twelve months after childbirth with co-existing opioid use disorder OUD and postt-raumatic stress disorder PTSD The therapy teams will have received training in MDMA-assisted therapy provided by the Multidisciplinary Association for Psychedelic Studies MAPS
For the first medication sessions participants will receive a dose of 100 mg MDMA Hydrochloric acid HCL 80 mg MDMA followed by a supplemental 40 mg MDMA HCL 35 mg MDMA dose two hours after receiving the initial dose unless tolerability issues emerge with the first dose or the participant declines MDMA is administered during the Treatment Period with manualized therapy in three open-label monthly Experimental Sessions This 12-week Treatment Period is preceded by two three Preparatory Sessions During the Treatment Period each Experimental Session is followed by three Integrative Sessions of non-drug therapy The second and third medication sessions may use 120 mg MDMA Hydrochloric acid HCL 100 mg MDMA followed by a supplemental 60 mg MDMA HCL 50 mg MDMA dose two hours after receiving the initial dose unless tolerability issues emerge with the first dose or the participant declines
For each participant the study will consist of
Screening Period phone screen informed consent eligibility assessment and enrollment if eligible
Preparatory Period with Enrollment Confirmation medication tapering Preparatory Sessions and Baseline assessments
Treatment Period three monthly Medication Sessions and associated Integrative Sessions over 12 weeks
Follow-up Period and Study Conclusion
The 1-month Primary Outcome visit will occur 4 weeks - 2 weeks after the last study session
At 6 months after the last study session a final assessment will occur for the PTSD and OUD outcomes
Psychotherapeutic Model for MDMA Assisted therapy for PTSD and OUD
The manual for MDMA-assisted therapy of PTSD uses a nondirective approach with a focus on using empathetic presence and listening The approach is person centered therapy where the participant uses their own inner healing intelligence to guide their therapy In this study the participants have opioid use disorder which has been stable on MOUD buprenorphine or methadone for at least three months The study will use motivational interviewing MI techniques to guide the initiation of the therapy for opioid use disorder MI is also a patient centered approach rooted in empathic listening and can address the common issue of ambivalence of entering a trauma centered therapy Therapists may choose approaches that use the tools of acceptance and commitment therapy ACT motivational enhancement therapy and mindfulness among other approaches that have been used with psychedelic assisted therapies The investigators are following the approach of MDMA-assisted therapy manual for PTSD which allows for elements of other therapeutic approaches to be applied as long as they are done so within the guidelines of the Manual The study will not attempt to manualize the additional elements of opioid use disorder therapy The investigators will maintain a record of the psychotherapeutic context of the preparatory and integration sessions
Recruitment and Participant Population Subject Recruitment People using buprenorphine will primarily be recruited during pregnancy from the Milagro Perinatal Substance Use Program at the University of New Mexico UNM and the GRACE Program at Lovelace Womens Hospital in Albuquerque New Mexico These two programs care for almost all the pregnant people using buprenorphine or methadone for MOUD during pregnancy in the greater Albuquerque area The Milagro program cares for approximately 150 pregnant people per year of which about 90 n120 have opioid use disorder on MOUD and about 60 are using methadone n72 and 40 buprenorphine n48 The people in the Milagro program are about 90 Hispanic 10 non-Hispanic White with an occasional Native American woman The Grace program cares for about 25 pregnant people a year who are using buprenorphine A third recruitment site in Albuquerque will be the University of New Mexico UNM FOCUS program which collaborates with Milagro by providing well-child and developmental care to infants born to the people in Milagro as well as other people with substance use disorders and offers ongoing buprenorphine to people after childbirth The PI for this study Larry Leeman MD is the Medical Director for Milagro Participation in the study will also be offered to pregnant and postpartum people prescribed buprenorphine who receive care in Santa Fe sixty miles north of Albuquerque Information regarding the study will be provided to physicians offering prenatal care in Santa Fe however screening and all study procedures will occur at UNM The research team will carefully assess the potential participants willingness and motivation to make the sixty-mile drive to Albuquerque and back for all required in-person study visits prior to enrollment in the study
Statistical Analysis The primary outcome is the change from baseline in the Total Severity Score from the CAPS 5 until 1 month after the 3rd medication visit The investigators will perform paired T tests for the two assessment periods to see if the confidence interval overlaps between the two groups The investigators will also compare the effect size as measured by CAPS 5 in this cohort with OUD compared to the MAPP1 and MAPP2 cohorts which had OUD as an exclusion criteria
The secondary outcome is to evaluate the effect of MDMA-assisted therapy for PTSD on the Opioid Use by the TLFB assessment of the number of days of illicit opioid use in the baseline thirty-day period compared to the thirty-day period preceding the 6-month follow-up visit As a normal a distribution curve is not anticipated the nonparametric Wilcoxon signed rank test will be used
For the exploratory outcomes the investigators will collect estimates of Hedges g effect size for continuous measures to determine the sample size of a powered study for any of the measures studied
An exploratory objective is to evaluate the effect of MDMA assisted therapy on maternal-infant-bonding attachment and parenting as measured by multiple questionnaires assessments and use of the Still Face Paradigm SFP a well-known objective measure of bonding and attachment to obtain video assessment of the mother as she is interacting with her baby The SFP videos are recorded prior to study initiation on the morning after each MDMA session and after completion of the study Participants may decide not to participate in the SFP video assessments without affecting their participation in the primary study of MDMA-AT for OUD and PTSD
A qualitative analysis will be included based on a structured interview that will occur with all participants between 4-8 weeks after the 3rd experimental session The investigators will work with a UNM social scientist which may be a PhD Psychologist who has previously collaborated with this team in prior PTSD in pregnancy research
Protocol IUSOU1
Rationale Introduction
Background and Previous Research Data
Opioid use disorder
Opioid use disorder has reached epidemic levels in the United States and is now common in pregnant and postpartum people From 1999 to 2014 the delivery-related hospital admissions of people with opioid use disorder more than quadrupled from 15 to 65 per 1000 delivery hospitalizations New Mexico is one of the epicenters of the opioid use epidemic 128 newborns per 1000 births in New Mexico were diagnosed with Neonatal Opioid Withdrawal Syndrome in 2018 The standard of care for Opioid Use Disorder OUD is the use of medication for opioid use disorder MOUD that was either initiated during the pregnancy or was already being taken at the time of conception MOUD is effective at improving maternal and neonatal outcomes however postpartum relapse is common and carries an increased risk of fatal overdose By having the use of MOUD as an inclusion criteria we are selecting for a group of people that has a greater chance of being stable throughout the study period and at lower risk for opioid overdose than individuals who relapse and are not on MOUD
Post-Traumatic Stress Disorder
Psychological trauma is a common antecedent of addiction and a trauma-informed approach is integral to substance misuse care The high rates of childhood sexual abuse and rape are factors resulting in high rates of Post Traumatic Stress Disorder PTSD among pregnant and postpartum people PTSD occurs in some individuals that are exposed to an event that is perceived to result in serious injury sexual violence or an actual or possible threat to life Intrusive symptoms such as nightmares flashbacks emotional distress or physical reactivity can then recur when the traumatic event is persistently re-experienced leading to avoidance of trauma-related thoughts feelings or reminders of the events which act as triggers of symptoms The individuals life is adversely affected by negative alterations in mood and thought including the somatic symptoms of increased arousal and reactivity eg hypervigilance heightened startle reaction and difficulty sleeping PTSD is a serious disorder that commonly has a negative impact on an individuals quality of life including impairing their ability to work and maintain relationships and it is associated with increased substance use depression and suicide Symptoms must persist for at least a month at sufficient intensity to be diagnosed as PTSD however they are often severe last for many years and can be resistant to treatment
PTSD can be treated with behavioral or medication therapies however the treatments for PTSD are often not included in the services offered by perinatal substance use programs The 2020 Guidelines from International Society for Traumatic Stress Studies include strong recommendations for the use of cognitive processing therapy cognitive therapy EMDR Eye Movement Desensitization and Reprocessing prolonged exposure and cognitive behavioral therapy with a trauma focus for adults with PTSD Selective Serotonin Reuptake Inhibitors SSRIs have a modest effect on symptom reduction however they are often used long term without achieving a resolution of PTSD
MDMA
MDMA 3 4-Methylenedioxymethamphetamine has received breakthrough drug status from the FDA for the treatment of PTSD MDMA is a monoamine releaser and re-uptake inhibitor with indirect effects on neurohormone release MDMA has a more complex neurochemical mechanism than classical psychedelics involving increased release of serotonin dopamine noradrenaline and oxytocin Activation of the 5-hydroxytryptamine receptor 1A 5-HT1a and 5-hydroxytryptamine receptor 1B 5-HT1b receptors decreases feeling of anxiety and depression and reduces amygdala mediated fear response These effects are accompanied by increased empathy emotional closeness and compassion Effects on the alpha-2 receptor are potentially beneficial in psychotherapy by reducing trauma associated hypervigilance mitigated by norepinephrine The release of oxytocin the hormone promoting maternal infant bonding is hypothesized to increase empathy feelings of closeness and decrease the fear activity activated in the amygdala1516 The neurocognitive effects of MDMA- assisted therapy have been proposed to be mediated via memory reconsolidation and fear extinction by reducing activation in the insula and amygdala which are involved with the expression and fear and anxiety A functional Magnetic Resonance Imaging MRI study of subjects administered MDMA demonstrated a decrease in insula network connectivity lending support to the hypothesis that this is a mechanism for the effects of MDMA
The combined neurobiological effects of MDMA reduce defenses and fear of emotional injury enhance communication and introspection And can increase empathy and compassion allowing for a psychological state that enhances successful trauma processing during psychotherapy MDMA has demonstrated benefit for treatment resistant PTSD in a series of phase 2 studies of MDMA-assisted therapy sponsored by the Multidisciplinary Association for Psychedelic Studies In pooled analysis of six phase 2 randomized controlled trials of MDMA-assisted therapy for long term PTSD more participants in the active group 542 did not meet DSM-IV Diagnostic Manual of Mental Disorders PTSD diagnostic criteria than the control group 226 after two MDMA sessions Based on historical comparison MDMA appears to be more effective than the two FDA approved Selective Serotonin Reuptake Inhibitor SSRI medications sertraline and paroxetine The processing of trauma during MDMA-assisted therapy may produce additional lasting changes by increasing the individuals personality trait of openness
MDMA may be of benefit to people for opioid use disorder secondary to resolving or improving PTSD symptoms or by a pathway independent of PTSD Although published research regarding the use of MDMA for substance use disorders is limited to a single small study involving alcohol use disorder described below20 there is a growing literature involving the use of classic psychedelics eg psilocybin and LSD Psilocybin has shown promise in the treatment of tobacco and alcohol use disorders and is being studied for opioid and cocaine use disorders A novel psychedelic ibogaine has been reported as a specific treatment for opioid use disorder however there have not been any randomized controlled trials Lysergic Acid Diethylamide LSD was extensively studied as a treatment for alcohol use disorder in the 1960s and 1970s A meta-analysis of six randomized controlled trials including 536 subjects demonstrated a beneficial effect of LSD on alcohol misuse OR 196 95 Confidence Interval CI 136-284 p 00003 Although rigorous prospective trials are lacking the use of plant derived psychedelics for substance use disorders additionally includes peyote in the Native American church for alcohol use disorder in the United States and Ayahuasca for cocaine and other substance use disorders in Peru and Brazil
The classic psychedelics work primarily at the level of the 5-HT2A receptor where they decrease activity in the brains default mode network which is correlated with ego dissolution Although classic psychedelics are showing benefit for addiction there are postpartum people with opioid use disorder who may not desire the experiences of ego dissolution and mystical experience during the postpartum period MDMA has psychedelic effects however it does not usually lead to the profound states of ego dissolution and mystical experiences that are associated with the positive effects of the classic psychedelics and detected by the Mystical Experience Questionnaire MEQ-30 The first study of MDMA for a substance use disorder is the Bristol Imperial MDMA in Alcoholism Study BIMA which demonstrated the feasibility of MDMA treatment after community based alcohol detoxification A follow-up study of alcohol consumption after MDMA treatment for PTSD demonstrated that alcohol consumption since study enrollment decreased among 22 participants 400 stayed the same for 17 participants 309 and increased for 2 participants 36 compared to prior to study enrollment
OUD PTSD and MDMA
OUD and PTSD are strongly associated comorbid disorders The association between these conditions may be due to traumatic life events leading to PTSD which are self-medicated with the opioid however the lifestyle of individuals with opioid use disorder may also predispose to an increased likelihood of traumatic events In pregnant woman with high rates of adverse childhood events it is these traumatic events that usually precede the development of OUD However trauma that occurs after they have OUD may intensify their PTSD symptoms An Australian study of individuals with heroin dependence demonstrated that 90 had serious trauma in the life history and 40 had PTSD The US National Comorbidity Survey of the general population estimated a lifetime prevalence rate of PTSD of 68 and current past year PTSD prevalence of 35The lifetime prevalence of PTSD among men was 36 and among women was 97 Woman have higher 12 month prevalence rates of PTSD of 52 compared to 18 among men
Racial trauma may contribute to PTSD either due to a major life event occurring directly due to racism including hate crimes or workplace harassment or due to a series of subtler lifelong occurrences that are the result of micro aggressions and implicit racial bias To identify these sources of trauma newer assessment instruments have been developed including the UConn RacialEthnic Stress and Trauma Survey and a short version which has been used by MDMA therapists A culturally informed approach to MDMA assisted therapy for PTSD includes cultural diversity on the treatment team outreach to communities of color and development of a setting including music and artwork that is culturally sensitive and appropriate This can include conveying an appreciation that most psychedelic therapies have their roots in the plant medicine of indigenous healers eg psilocybin peyote and ayahuasca and that the approach to using synthesized psychedelics that are not plant derived eg MDMA and ketamine can still integrate learning from these indigenous practices
Maternal PTSD and substance use disorders have been proposed as mechanisms of intergenerational trauma transmission through their effect on maternal infant bonding The disruption of maternal attachment leads to an increased risk of the child developing substance use disorder Treating maternal PTSD during pregnancy or postpartum has the theoretical potential to decrease the likelihood of the infant developing a substance use disorder during adolescence or adulthood As MDMA appears to be effective in the treatment of PTSD in other populations a feasibility study of the use of MDMA-assisted therapy in postpartum people with OUD has great potential to benefit the infant as well as the mother Use of MDMA during pregnancy or during breastfeeding presents an unacceptable level of maternal and neonatal risk due to the lack of safety data however studies of postpartum people at the University of New Mexico have demonstrated that the average time for stopping breastfeeding in this group was three weeks postpartum therefore offering MDMA- assisted therapy for PTSD at 6-12 months of age would only exclude a small proportion of people due to ongoing breastfeeding
Although the likelihood of benefit for opioid use disorder from MDMA experimental sessions may not be associated with higher scores on the MEQ-30 there are other instruments that can assess the effect of the experience on the participant The Challenging Experience Questionnaire has been used to assess the effects of challenging emotions such as fear or paranoia which may be a negative predictor of a positive response from the sessionsThe CEQ does not address the issue of how the challenging experience was resolved Challenging experiences may potentially facilitate transformation through a pivotal state that may increase neuroplasticity and deep learning Stanislav Grof a founder of transpersonal psychology and author of LSD Psychotherapy felt that challenging psychedelic experiences were of benefit in supporting psychological transformationThe recently developed Emotional Breakthrough Inventory EBI was developed to complement the MEQ-30 and CEQ and to look at the participants ability to achieve a breakthrough experience by overcoming challenging emotions and memoriesUnderstanding the psychological processes that support positive change such as resolution of PTSD or maintenance of remission for opioid use disorder is an exploratory objective
Indications being studied
Co-occurring Post Traumatic Stress Disorder and Opioid User Disorder
Treatment Proposal and Rationale
Due to the high rate of concurrence of PTSD and OUD these people may experience great benefit from the treatment of their PTSD with MDMA-assisted therapy based on the phase 2 and 3 studies for PTSD Use of MDMA-assisted therapy in this population has the potential to be of benefit for their OUD and maternal- infant attachment This open-label study will serve to explore the feasibility and safety of offering MDMA-assisted therapy for treatment of PTSD in postpartum people with opioid use disorder The CAPs 5 PTSD is the primary outcome the Timeline Follow-Back TLFB for opioid use is the secondary outcome and other assessments of opioid use disorder effects on maternal-infant attachment social connectedness and other mental health outcomes are exploratory
Study Design This is a single site open-label feasibility study to assess the safety and effectiveness of MDMA-assisted therapy in 15 people who are between six to twelve months after childbirth with co-existing opioid use disorder OUD and postt-raumatic stress disorder PTSD The therapy teams will have received training in MDMA-assisted therapy provided by the Multidisciplinary Association for Psychedelic Studies MAPS
For the first medication sessions participants will receive a dose of 100 mg MDMA Hydrochloric acid HCL 80 mg MDMA followed by a supplemental 40 mg MDMA HCL 35 mg MDMA dose two hours after receiving the initial dose unless tolerability issues emerge with the first dose or the participant declines MDMA is administered during the Treatment Period with manualized therapy in three open-label monthly Experimental Sessions This 12-week Treatment Period is preceded by two three Preparatory Sessions During the Treatment Period each Experimental Session is followed by three Integrative Sessions of non-drug therapy The second and third medication sessions may use 120 mg MDMA Hydrochloric acid HCL 100 mg MDMA followed by a supplemental 60 mg MDMA HCL 50 mg MDMA dose two hours after receiving the initial dose unless tolerability issues emerge with the first dose or the participant declines
For each participant the study will consist of
Screening Period phone screen informed consent eligibility assessment and enrollment if eligible
Preparatory Period with Enrollment Confirmation medication tapering Preparatory Sessions and Baseline assessments
Treatment Period three monthly Medication Sessions and associated Integrative Sessions over 12 weeks
Follow-up Period and Study Conclusion
The 1-month Primary Outcome visit will occur 4 weeks - 2 weeks after the last study session
At 6 months after the last study session a final assessment will occur for the PTSD and OUD outcomes
Psychotherapeutic Model for MDMA Assisted therapy for PTSD and OUD
The manual for MDMA-assisted therapy of PTSD uses a nondirective approach with a focus on using empathetic presence and listening The approach is person centered therapy where the participant uses their own inner healing intelligence to guide their therapy In this study the participants have opioid use disorder which has been stable on MOUD buprenorphine or methadone for at least three months The study will use motivational interviewing MI techniques to guide the initiation of the therapy for opioid use disorder MI is also a patient centered approach rooted in empathic listening and can address the common issue of ambivalence of entering a trauma centered therapy Therapists may choose approaches that use the tools of acceptance and commitment therapy ACT motivational enhancement therapy and mindfulness among other approaches that have been used with psychedelic assisted therapies The investigators are following the approach of MDMA-assisted therapy manual for PTSD which allows for elements of other therapeutic approaches to be applied as long as they are done so within the guidelines of the Manual The study will not attempt to manualize the additional elements of opioid use disorder therapy The investigators will maintain a record of the psychotherapeutic context of the preparatory and integration sessions
Recruitment and Participant Population Subject Recruitment People using buprenorphine will primarily be recruited during pregnancy from the Milagro Perinatal Substance Use Program at the University of New Mexico UNM and the GRACE Program at Lovelace Womens Hospital in Albuquerque New Mexico These two programs care for almost all the pregnant people using buprenorphine or methadone for MOUD during pregnancy in the greater Albuquerque area The Milagro program cares for approximately 150 pregnant people per year of which about 90 n120 have opioid use disorder on MOUD and about 60 are using methadone n72 and 40 buprenorphine n48 The people in the Milagro program are about 90 Hispanic 10 non-Hispanic White with an occasional Native American woman The Grace program cares for about 25 pregnant people a year who are using buprenorphine A third recruitment site in Albuquerque will be the University of New Mexico UNM FOCUS program which collaborates with Milagro by providing well-child and developmental care to infants born to the people in Milagro as well as other people with substance use disorders and offers ongoing buprenorphine to people after childbirth The PI for this study Larry Leeman MD is the Medical Director for Milagro Participation in the study will also be offered to pregnant and postpartum people prescribed buprenorphine who receive care in Santa Fe sixty miles north of Albuquerque Information regarding the study will be provided to physicians offering prenatal care in Santa Fe however screening and all study procedures will occur at UNM The research team will carefully assess the potential participants willingness and motivation to make the sixty-mile drive to Albuquerque and back for all required in-person study visits prior to enrollment in the study
Statistical Analysis The primary outcome is the change from baseline in the Total Severity Score from the CAPS 5 until 1 month after the 3rd medication visit The investigators will perform paired T tests for the two assessment periods to see if the confidence interval overlaps between the two groups The investigators will also compare the effect size as measured by CAPS 5 in this cohort with OUD compared to the MAPP1 and MAPP2 cohorts which had OUD as an exclusion criteria
The secondary outcome is to evaluate the effect of MDMA-assisted therapy for PTSD on the Opioid Use by the TLFB assessment of the number of days of illicit opioid use in the baseline thirty-day period compared to the thirty-day period preceding the 6-month follow-up visit As a normal a distribution curve is not anticipated the nonparametric Wilcoxon signed rank test will be used
For the exploratory outcomes the investigators will collect estimates of Hedges g effect size for continuous measures to determine the sample size of a powered study for any of the measures studied
An exploratory objective is to evaluate the effect of MDMA assisted therapy on maternal-infant-bonding attachment and parenting as measured by multiple questionnaires assessments and use of the Still Face Paradigm SFP a well-known objective measure of bonding and attachment to obtain video assessment of the mother as she is interacting with her baby The SFP videos are recorded prior to study initiation on the morning after each MDMA session and after completion of the study Participants may decide not to participate in the SFP video assessments without affecting their participation in the primary study of MDMA-AT for OUD and PTSD
A qualitative analysis will be included based on a structured interview that will occur with all participants between 4-8 weeks after the 3rd experimental session The investigators will work with a UNM social scientist which may be a PhD Psychologist who has previously collaborated with this team in prior PTSD in pregnancy research
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
True
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None