Psychoplastogen compounds such as ketamine and MDMA have shown therapeutic promise for mood and trauma-related disorders, yet the molecular mechanisms underlying their effects remain poorly understood. Here, we applied a Brain-Epigenome-Wide Association Study (BEWAS) targeting brain-relevant genes to examine DNA methylation changes following treatment. Pre- and post-treatment blood (ketamine, N...
Psychedelic compounds such as ketamine and MDMA have shown therapeutic promise for mood and trauma-related disorders, yet their molecular mechanisms remain unclear. This study applied a Brain-Epigenome-Wide Association Study (BEWAS) to assess DNA methylation changes in brain-enriched genes following treatment. Pre- and post-treatment blood (ketamine, N = 20) and saliva (MDMA, N = 16) samples...
Midomafetamine (3,4-methylenedioxymethamphetamine [MDMA]) is under the U.S. Food and Drug Administration review for treatment of post-traumatic stress disorder in adults. MDMA is metabolized by CYP2D6 and is a strong inhibitor of CYP2D6, as well as a weak inhibitor of renal transporters MATE1, OCT1, and OCT2. A pharmacokinetic phase I study was conducted to evaluate the effects of food on MDMA...
In the version of the article initially published, some members of the MAPP2 Study Collaborator Group were listed only in the Supplementary Information. Charlotte Harrison, Berra Yazar-Klosinski, Wael Garas, Darrick May, Cole Marta, Susan Walker, Elizabeth Nielson, Gregory Wells, Randall Brown, Revital Amiaz, Yair Wallach, Ray Worthy, Alia Lilienstein and Amy Emerson have now been added to the...
Introduction There is a resurgence of interest in the therapeutic potential of psychedelic substances such as 3,4-methylenedioxymethamphetamine (MDMA). Primary findings from our randomized, double-blind, placebo-controlled, multi-site Phase 3 clinical trial of participants with severe PTSD (NCT03537014) showed that MDMA-assisted therapy induced significant attenuation in the...
This multi-site, randomized, double-blind, confirmatory phase 3 study evaluated the efficacy and safety of 3,4-methylenedioxymethamphetamine-assisted therapy (MDMA-AT) versus placebo with identical therapy in participants with moderate to severe post-traumatic stress disorder (PTSD). Changes in Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) total severity score (primary endpoint) and...
This multi-site, randomized, double-blind, confirmatory phase 3 study evaluated the efficacy and safety of 3,4-methylenedioxymethamphetamine-assisted therapy (MDMA-AT) versus placebo with identical therapy in participants with moderate to severe post-traumatic stress disorder (PTSD). Changes in Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) total severity score (primary endpoint) and...
Post-traumatic stress disorder (PTSD) presents a major public health problem for which currently available treatments are modestly effective. We report the findings of a randomized, double-blind, placebo-controlled, multi-site phase 3 clinical trial (NCT03537014) to test the efficacy and safety of 3,4-methylenedioxymethamphetamine (MDMA)-assisted therapy for the treatment of patients with...
Unsuccessfully treated posttraumatic stress disorder (PTSD) is a serious and life-threatening disorder. Two medications, paroxetine hydrochloride and sertraline hydrochloride, are approved treatments for PTSD by the Food and Drug Administration (FDA). Analyses of pharmacotherapies for PTSD found only small to moderate effects when compared with placebo. The Multidisciplinary Association for...
BackgroundPrevious research has demonstrated that epigenetic changes in specific hypothalamic-pituitary-adrenal (HPA) genes may predict successful psychotherapy in post-traumatic stress disorder (PTSD). A recent Phase 3 clinical trial reported high efficacy of 3,4-methylenedioxymethamphetamine (MDMA)-assisted therapy for treating patients with severe PTSD compared to a therapy with placebo...
IntroductionIncreasing evidence demonstrates 3,4-methylenedioxymethamphetamine (MDMA)-assisted therapy (MDMA-AT) may be a safe and effective treatment for post-traumatic stress disorder (PTSD). There is growing interest in MDMA-AT to address a range of other health challenges. Chronic pain and PTSD are frequently comorbid, reciprocally interdependent conditions, though the possible role of...
3,4-methylenedioxymethamphetamine-assisted therapy (MDMA-AT) for post-traumatic stress disorder (PTSD) has demonstrated promise in multiple clinical trials. MDMA is hypothesized to facilitate the therapeutic process, in part, by decreasing fear response during fear memory processing while increasing extinction learning. The acute administration of MDMA in healthy controls modifies recruitment...
MDMA is increasingly used in clinical research, but no cGMP process has yet been reported. We describe here the first fully validated cGMP synthesis of up to 5 kg (≈30 000 patient doses) of MDMA in a four-step process beginning with a noncontrolled starting material. The overall yield was acceptable (41-53%, over four steps), and the chemical purity of the final product was excellent, exceeding...
3,4 Methylenedioxymethamphetamine (MDMA)-assisted therapy has been recently found to be highly effective for treatment of posttraumatic stress disorder (PTSD). Previous studies have been inconclusive in elucidating potential MDMA genotoxicity. We performed three regulatory compliant studies to investigate the potential of genotoxic effects of MDMA treatment in humans: (1) an in vitro bacterial...
Sleep disturbances (SDs) are among the most distressing and commonly reported symptoms in posttraumatic stress disorder (PTSD). Despite increased attention on sleep in clinical PTSD research, SDs remain difficult to treat. In Phase 2 trials, 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy has been shown to greatly improve PTSD symptoms. We hypothesized that MDMA-assisted...
Background: Posttraumatic stress disorder (PTSD) is a debilitating mental health condition associated with serious adverse health outcomes and functional impairment. Previous MDMA–assisted therapy (MDMA-AT) studies have shown promising results in single site studies. Two open-label studies tested this modality in multisite clinical trials to assess the feasibility of scaling this manualized...
Post-traumatic stress disorder (PTSD) presents a major public health problem for which currently available treatments are modestly effective. We report the findings of a randomized, double-blind, placebo-controlled, multi-site phase 3 clinical trial (NCT03537014) to test the efficacy and safety of 3,4-methylenedioxymethamphetamine (MDMA)-assisted therapy for the treatment of patients with...
IMPORTANCE: There is a pressing need for development of novel pharmacology for the treatment of Posttraumatic Stress Disorder (PTSD). Given increasing use of medical cannabis among US military veterans to self-treat PTSD, there is strong public interest in whether cannabis may be a safe and effective treatment for PTSD. OBJECTIVE: The aim of the present study was to collect preliminary data on...
Cognitive-behavioural conjoint therapy (CBCT) for PTSD has been shown to improve PTSD, relationship adjustment, and the health and well-being of partners. MDMA (3,4-methylenedioxymethamphetamine) has been used to facilitate an individual therapy for PTSD. This study was an initial test of the safety, tolerability, and efficacy of MDMA-facilitated CBCT. Six couples with varying levels of...
Abstract The success of modern medicine creates a growing population of those suffering from life-threatening illnesses (LTI) who often experience anxiety, depression, and existential distress. We present a novel approach; investigating MDMA-assisted psychotherapy for the treatment of anxiety in people with an LTI. Participants with anxiety from an LTI were randomized in a double-blind study to...
Posttraumatic stress disorder (PTSD) is a chronic condition that has wide-ranging negative effects on an individual's health and interpersonal relationships. Treatments with long-term benefits are needed to promote the safety and well-being of those suffering from PTSD. To examine long-term change in PTSD symptoms and additional benefits/harms after 3,4-methylenedioxymethamphetamine...
Abstract 3,4‐Methylenedioxymethamphetamine (MDMA)–assisted psychotherapy for posttraumatic stress disorder (PTSD) has been shown to significantly reduce clinical symptomatology, but posttraumatic growth (PTG), which consists of positive changes in self‐perception, interpersonal relationships, or philosophy of life, has not been studied with this treatment. Participant data ( n = 60) were pooled...
Unsuccessfully treated posttraumatic stress disorder (PTSD) is a serious and life-threatening disorder. Two medications, paroxetine hydrochloride and sertraline hydrochloride, are approved treatments for PTSD by the Food and Drug Administration (FDA). Analyses of pharmacotherapies for PTSD found only small to moderate effects when compared with placebo. The Multidisciplinary Association for...
Posttraumatic stress disorder is a prevalent mental health condition with substantial impact on daily functioning that lacks sufficient treatment options. Here we evaluate six phase 2 trials in a pooled analysis to determine the study design for phase 3 trials of MDMA-assisted psychotherapy for PTSD. Six randomized, double-blind, controlled clinical trials at five study sites were conducted...
Posttraumatic stress disorder often does not resolve after conventional psychotherapies or pharmacotherapies. Pilot studies have reported that 3,4-methylenedioxymethamphetamine (MDMA) combined with psychotherapy reduces posttraumatic stress disorder symptoms. This pilot dose response trial assessed efficacy and safety of MDMA-assisted psychotherapy across multiple therapy teams. Twenty-eight...