Walsh, Carol T.McKnight, C. JamesPoullette, Thomas Kenneth2024-11-182024-11-182023https://hdl.handle.net/2144/49488Posttraumatic stress disorder (PTSD) is a debilitating and prevalent psychiatric pathology across the world and highly effective treatments for it are lacking. PTSD is characterized by frequent and intrusive memories of trauma that arise several months after experiencing or witnessing a traumatic event. These memories elicit strong emotional responses in PTSD patients and initiate many somatic and psychiatric comorbidities. Treatments for PTSD exist, but the clinical trials evaluating them have produced inconsistent results including highly variable data on effect sizes and tolerability. Recent meta-analyses on these randomized clinical studies, comparing the effects of the approved treatments on PTSD symptom severity with control groups (employing inactive placebos or intent-to-treat groups), have shown similar safety profiles and low-to-medium effects sizes. Treatments currently approved for use in PTSD include manualized, trauma-focused psychotherapies (cognitive processing therapy (CPT) and prolonged exposure therapy) and pharmacotherapies that employ selective serotonin reuptake inhibitors (SSRIs). Conclusive data comparing the efficacy and tolerability of these therapies must be derived from head-to-head comparisons in randomized clinical trials. These studies are not yet available for 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy for the treatment of PTSD; the first phase 3 clinical trial of this treatment was published in early 2021. The development, and history of the treatment is also discussed. MDMA is a commonly used drug of abuse. In the context of its illicit use, it is often referred to as ecstasy or molly, where it is used in dance-party and music festival settings. It is a Drug Enforcement Agency (DEA) schedule I substance. The DEA scheduling of drugs under the controlled substance act is discussed to explain MDMA’s legal status relative to other drugs of abuse. MDMA’s legal designation has slowed research on this treatment and is therefore an important aspect of the history and development of the treatment. In MDMA-assisted psychotherapy, MDMA is administered to the participant prior to an eight-hour manualized therapy session. In this context, “manualized” refers to the strict adherence to a protocol and methodology of psychotherapeutic treatment by the therapist. Consistent with phase 2 clinical trials, the first and only published phase 3 trial for MDMA-assisted psychotherapy has shown it to be a highly efficacious and safe treatment for PTSD. There are many common subjective psychological effects of MDMA that have been reported in the literature, but its ability to enhance sociability, self-esteem, trust in others (especially the therapist), and reduce anxiety and defensiveness during the therapy session have long been thought to be the primary benefit in therapy. These behavioral traits are characteristically impaired in trauma-related disease states, which adversely affects the therapeutic processes. Acute cessation of some PTSD symptoms due to the subjective effects of MDMA may provide a “window of tolerance”, in which the patient can discuss traumatic memories without shutting down socially and mentally, which is common in psychotherapeutic treatment for PTSD. This thesis will also discuss MDMA pharmacology, chemistry, its role as a drug of abuse, and some of its molecular mechanisms of action that may confer its psychiatric subjective effects that have been reported in humans. Early studies on the toxicity of MDMA indicated adverse public health implications due to safety concerns and largely led to this designation of the molecule as a schedule I material. Further research has brought the validity of this early research into question, although serotonergic neurotoxicity seems to be the most prevalent. In short, single-dose MDMA administration in normal dosing ranges of MDMA used in illicit contexts has been shown to elicit some of the same histological and cellular changes produced by long-term SSRI use, further calling the toxicity of MDMA into question. An overview of PTSD will follow this discussion on MDMA. Specifically, this section will discuss the pathology, symptoms, diagnosis, comorbidities, risk factors, and the underlying neurobiology of PTSD and stress-related disease states. Resilience is an important feature of PTSD risk; more resilient people tend to develop PTSD less frequently upon exposure to trauma. Resilience is correlated with one’s capacity for regulating his or her own emotions, which is characteristically impaired in stress-related disease states and strongly contributes to many of the symptoms involved in this pathology. Understanding resilience and emotional regulation, their neurological basis, and role in PTSD pathology is therefore important for understanding these aspects of the disease state and are discussed thoroughly. The information presented in the MDMA and PTSD sections will then be discussed together in the following section on MDMA-assisted psychotherapy as it relates to the treatment and its proposed therapeutic mechanisms of action. The treatment methods in the stage 2 and 3 clinical trials of MDMA-assisted psychotherapy for PTSD are discussed and compared, the major focus of this section, however, will be the methods used in the first phase 3 clinical trial, as well as the results and limitations of this study. In short, the first stage 3 trial for the treatment showed a significantly improved efficacy in treating PTSD and its comorbid psychiatric pathologies as compared to both the current FDA-approved pharmaceutical and psychotherapeutic treatments for PTSD. Three main mechanisms of action that may account for the efficacy of MDMA-assisted psychotherapy for PTSD treatment have been discussed in the literature. These are not necessarily mutually exclusive and may all partly explain the treatment effects. These include the “window of tolerance” mechanism discussed above, the critical-period reopening mechanism, and the fear extinction facilitation mechanism. MDMA-assisted psychotherapy is a novel and creative approach to treating psychiatric pathologies. It is also the first treatment regime approved for investigation by the US Food and Drug Administration (FDA) in which a psychedelic or psychedelic-like agent is employed therapeutically or in which a psychoactive agent is employed alongside psychotherapeutic treatments. Other clinical trials of drug-assisted psychotherapy treatments using similar methods while employing different psychoactive drugs for the treatment of many psychiatric diseases are currently ongoing, MDMA- assisted psychotherapy has been the first of this novel method of therapy to be stringently studied under modern scientific randomized, placebo-controlled clinical is now being investigated for applications in other psychiatric pathologies. Further research into this treatment is critical for finding new ways for improving the treatment protocol, therefore improving treatment efficacy and safety. Such research will include addressing the limitations of the first published phase 3 clinical trial, investigating the mechanisms of action by which the treatment works, and conducting clinical trials in larger or more specific populations.en-USPharmacologyMDMAPTSDThesis/Dissertation2024-11-08