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MDMA-assisted therapy for severe PTSD: a randomized, double-blind, placebo-controlled phase 3 study.Nature Medicine Jun 2021Post-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 Controlled Trial)
Randomized Controlled Trial
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 severe PTSD, including those with common comorbidities such as dissociation, depression, a history of alcohol and substance use disorders, and childhood trauma. After psychiatric medication washout, participants (n = 90) were randomized 1:1 to receive manualized therapy with MDMA or with placebo, combined with three preparatory and nine integrative therapy sessions. PTSD symptoms, measured with the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5, the primary endpoint), and functional impairment, measured with the Sheehan Disability Scale (SDS, the secondary endpoint) were assessed at baseline and at 2 months after the last experimental session. Adverse events and suicidality were tracked throughout the study. MDMA was found to induce significant and robust attenuation in CAPS-5 score compared with placebo (P < 0.0001, d = 0.91) and to significantly decrease the SDS total score (P = 0.0116, d = 0.43). The mean change in CAPS-5 scores in participants completing treatment was -24.4 (s.d. 11.6) in the MDMA group and -13.9 (s.d. 11.5) in the placebo group. MDMA did not induce adverse events of abuse potential, suicidality or QT prolongation. These data indicate that, compared with manualized therapy with inactive placebo, MDMA-assisted therapy is highly efficacious in individuals with severe PTSD, and treatment is safe and well-tolerated, even in those with comorbidities. We conclude that MDMA-assisted therapy represents a potential breakthrough treatment that merits expedited clinical evaluation.
Topics: Adult; Combined Modality Therapy; Double-Blind Method; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Male; Middle Aged; N-Methyl-3,4-methylenedioxyamphetamine; Stress Disorders, Post-Traumatic; Treatment Outcome
PubMed: 33972795
DOI: 10.1038/s41591-021-01336-3 -
The Journal of Neuroscience : the... Feb 2021A revamped interest in the study of hallucinogens has recently emerged, especially with regard to their potential application in the treatment of psychiatric disorders.... (Review)
Review
A revamped interest in the study of hallucinogens has recently emerged, especially with regard to their potential application in the treatment of psychiatric disorders. In the last decade, a plethora of preclinical and clinical studies have confirmed the efficacy of ketamine in the treatment of depression. More recently, emerging evidence has pointed out the potential therapeutic properties of psilocybin and LSD, as well as their ability to modulate functional brain connectivity. Moreover, MDMA, a compound belonging to the family of entactogens, has been demonstrated to be useful to treat post-traumatic stress disorders. In this review, the pharmacology of hallucinogenic compounds is summarized by underscoring the differences between psychedelic and nonpsychedelic hallucinogens as well as entactogens, and their behavioral effects in both animals and humans are described. Together, these data substantiate the potentials of these compounds in treating mental diseases.
Topics: Animals; Brain; Hallucinogens; Humans; Ketamine; Lysergic Acid Diethylamide; Mental Disorders; Mental Health; N-Methyl-3,4-methylenedioxyamphetamine; Psilocybin; Randomized Controlled Trials as Topic
PubMed: 33257322
DOI: 10.1523/JNEUROSCI.1659-20.2020 -
Psychedelics: Alternative and Potential Therapeutic Options for Treating Mood and Anxiety Disorders.Molecules (Basel, Switzerland) Apr 2022The word "psychedelic" (psyche (i.e., the mind or soul) and delos (i.e., to show)) has Greek origin and was first coined by psychiatrist Humphry Osmond in 1956, who had... (Review)
Review
The word "psychedelic" (psyche (i.e., the mind or soul) and delos (i.e., to show)) has Greek origin and was first coined by psychiatrist Humphry Osmond in 1956, who had been conducting research on lysergic acid diethylamide (LSD) at the time. Psychedelic drugs such as ,-DMT/DMT (,-dimethyltryptamine), 5-MeO-DMT (5-methoxy-,-dimethyltryptamine), LSD (lysergic acid diethylamide), MDMA (3,4-methylenedioxymethamphetamine) and psilocybin have had significant value as an entheogen in spiritual, religious (shamanic) and sociocultural rituals in Central and South American cultures for thousands of years. In the 1960s, the globalization of these drugs and their subsequent spread outside of their indigenous, old-world cultures, led to the subsequent implementation of strict drug control laws in many Western countries. Even today, psychedelics are still classified as Schedule I drugs, resulting in a still lingering negative stigmatization/perception, vilification, and ultimate criminalization of psychedelics. This controversy still lingers and still limits scientific research and full medical acceptance. For many years up until recently, the spiritual, religious and medicinal value of these drugs could not be explored in a scientific context. More recently, a second wave of psychedelic research is now focusing on psychedelics as neuropharmaceuticals to treat alcohol and tobacco addiction, general mood and anxiety disorders and cancer-related depression. There is now a vast array of promising evidence-based data to confirm the years of anecdotal evidence of the medicinal values of psychedelics. Natural therapeutic alternatives such as psychedelic drugs may provide a safe and efficacious alternate to conventional drugs used to treat mood and anxiety disorders. In a Western context in particular, psychedelic drugs as therapeutic agents for mood and anxiety disorders are becoming increasingly of interest amidst increasing rates of such disorders globally, changing social constructions, the implementation of government regulations and increasing investment opportunities, that ultimately allow for the scientific study to generate evidenced-based data. Alternative psychotherapeutic interventions are gaining interest also, because of their low physiological toxicity, relatively low abuse potential, safe psychological effects, and no associated persisting adverse physiological or psychological effects during and after use. On the other hand, conventional psychotic drugs and anti-depressants are becoming less favorable because of their adverse side effects. Psychedelic neuropharmaceutical interventions may with medical oversight be the solution to conventional psychiatric disorders such as depression and anxiety, and an alternative to conventional psychiatric treatment options. This paper will review the therapeutic potential of psychedelic drugs as alternative therapeutic options for mood and anxiety disorders in a controlled, clinical setting, where the chances of adverse psychological episodes occurring are mitigated.
Topics: Anxiety Disorders; Hallucinogens; Humans; Lysergic Acid Diethylamide; N,N-Dimethyltryptamine; N-Methyl-3,4-methylenedioxyamphetamine; Psilocybin
PubMed: 35458717
DOI: 10.3390/molecules27082520 -
Psychopharmacology Jun 2022± 3,4-Methylenedioxymethamphetamine (MDMA) and psilocybin are currently moving through the US Food and Drug Administration's phased drug development process for... (Review)
Review
RATIONALE & OBJECTIVES
± 3,4-Methylenedioxymethamphetamine (MDMA) and psilocybin are currently moving through the US Food and Drug Administration's phased drug development process for psychiatric treatment indications: posttraumatic stress disorder and depression, respectively. The current standard of care for these disorders involves treatment with psychiatric medications (e.g., selective serotonin reuptake inhibitors), so it will be important to understand drug-drug interactions between MDMA or psilocybin and psychiatric medications.
METHODS
In accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we queried the MEDLINE database via PubMed for publications of human studies in English spanning between the first synthesis of psilocybin (1958) and December 2020. We used 163 search terms containing 22 psychiatric medication classes, 135 specific psychiatric medications, and 6 terms describing MDMA or psilocybin.
RESULTS
Forty publications were included in our systematic review: 26 reporting outcomes from randomized controlled studies with healthy adults, 3 epidemiologic studies, and 11 case reports. Publications of studies describe interactions between MDMA (N = 24) or psilocybin (N = 5) and medications from several psychiatric drug classes: adrenergic agents, antipsychotics, anxiolytics, mood stabilizers, NMDA antagonists, psychostimulants, and several classes of antidepressants. We focus our results on pharmacodynamic, physiological, and subjective outcomes of drug-drug interactions.
CONCLUSIONS
As MDMA and psilocybin continue to move through the FDA drug development process, this systematic review offers a compilation of existing research on psychiatric drug-drug interactions with MDMA or psilocybin.
Topics: Adult; Drug Interactions; Hallucinogens; Humans; N-Methyl-3,4-methylenedioxyamphetamine; Psilocybin; Psychotherapy; Stress Disorders, Post-Traumatic
PubMed: 35253070
DOI: 10.1007/s00213-022-06083-y -
Psychopharmacology Bulletin Jun 2021Post-traumatic stress disorder (PTSD) has become one of the most common psychiatric diagnosis in the United States specifically within the veteran population. The... (Review)
Review
Post-traumatic stress disorder (PTSD) has become one of the most common psychiatric diagnosis in the United States specifically within the veteran population. The current treatment options for this debilitating diagnosis include trauma-focused psychotherapies along with selective serotonin reuptake inhibitors (SSRI) and serotonin-norepinephrine reuptake inhibitors (SNRI). MDMA has recently been shown as a novel therapeutic agent with promisingly results in the treatment of PTSD. MDMA is a psychoactive compound traditionally categorized as a psychedelic amphetamine that deemed a Schedule I controlled substance in the 1980s. Prior to its status as a controlled substance, it was used by psychotherapists for an array of psychiatric issues. In more recent times, MDMA has resurfaced as a potential therapy for PTSD and the data produced from randomized, controlled trials back the desire for MDMA to be utilized as an effective pharmacologic therapy in conjunction with psychotherapy..
Topics: Adult; Hallucinogens; Humans; N-Methyl-3,4-methylenedioxyamphetamine; Psychotherapy; Stress Disorders, Post-Traumatic; Veterans
PubMed: 34421149
DOI: No ID Found -
Dialogues in Clinical Neuroscience 2019This article covers the renaissance of classical psychedelic drugs such as psilocybin and LSD plus 3,4-methylene dioxymethamphetamine (MDMA-ecstasy) in psychiatric... (Review)
Review
This article covers the renaissance of classical psychedelic drugs such as psilocybin and LSD plus 3,4-methylene dioxymethamphetamine (MDMA-ecstasy) in psychiatric research. These drugs were used quite extensively before they became prohibited. This ban had little impact on recreational use, but effectively stopped research and clinical treatments, which up to that point had looked very promising in several areas of psychiatry. In the past decade a number of groups have been working to re-evaluate the utility of these substances in medicine. So far highly promising preliminary data have been produced with psilocybin in anxiety, depression, smoking, alcoholism, and with MDMA for post-traumatic stress disorder (PTSD) and alcoholism. These findings have led to the European Medicines Agency approving psilocybin for a phase 3 study in treatment-resistant depression and the Food and Drug Administration for PTSD with MDMA. Both trials should read out in 2020, and if the results are positive we are likely to see these medicines approved for clinical practice soon afterwards. .
Topics: Hallucinogens; Humans; Ketamine; Lysergic Acid Diethylamide; Mental Disorders; N-Methyl-3,4-methylenedioxyamphetamine; Psilocybin; Psychiatry
PubMed: 31636488
DOI: 10.31887/DCNS.2019.21.2/dnutt -
Clinical Obstetrics and Gynecology Mar 2019Stimulant use, including cocaine, methamphetamines, ecstasy, and prescription stimulants, in pregnancy is increasingly common. In the United States, stimulants are the... (Review)
Review
Stimulant use, including cocaine, methamphetamines, ecstasy, and prescription stimulants, in pregnancy is increasingly common. In the United States, stimulants are the second most widely used and abused substances during pregnancy and pregnant women using stimulants in pregnancy are at increased risk of adverse perinatal, neonatal, and childhood outcomes. In this review, we describe the pharmacology, pathophysiology, and epidemiology of stimulants, summarize the maternal and neonatal effects of perinatal stimulant use, and outline treatment options for stimulant use disorders among pregnant women. Development of effective treatment strategies for stimulant use disorders identified among pregnant women are urgently needed.
Topics: Alkaloids; Central Nervous System Stimulants; Cocaine; Female; Humans; Methamphetamine; N-Methyl-3,4-methylenedioxyamphetamine; Pregnancy; Pregnancy Outcome; Prenatal Exposure Delayed Effects; Substance-Related Disorders; Systematic Reviews as Topic; United States
PubMed: 30601144
DOI: 10.1097/GRF.0000000000000418 -
Progress in Neuro-psychopharmacology &... Jun 2018MDMA-assisted psychotherapy for treatment of PTSD has recently progressed to Phase 3 clinical trials and received Breakthrough Therapy designation by the FDA. MDMA used... (Review)
Review
MDMA-assisted psychotherapy for treatment of PTSD has recently progressed to Phase 3 clinical trials and received Breakthrough Therapy designation by the FDA. MDMA used as an adjunct during psychotherapy sessions has demonstrated effectiveness and acceptable safety in reducing PTSD symptoms in Phase 2 trials, with durable remission of PTSD diagnosis in 68% of participants. The underlying psychological and neurological mechanisms for the robust effects in mitigating PTSD are being investigated in animal models and in studies of healthy volunteers. This review explores the potential role of memory reconsolidation and fear extinction during MDMA-assisted psychotherapy. MDMA enhances release of monoamines (serotonin, norepinephrine, dopamine), hormones (oxytocin, cortisol), and other downstream signaling molecules (BDNF) to dynamically modulate emotional memory circuits. By reducing activation in brain regions implicated in the expression of fear- and anxiety-related behaviors, namely the amygdala and insula, and increasing connectivity between the amygdala and hippocampus, MDMA may allow for reprocessing of traumatic memories and emotional engagement with therapeutic processes. Based on the pharmacology of MDMA and the available translational literature of memory reconsolidation, fear learning, and PTSD, this review suggests a neurobiological rationale to explain, at least in part, the large effect sizes demonstrated for MDMA in treating PTSD.
Topics: Animals; Clinical Trials as Topic; Combined Modality Therapy; Humans; N-Methyl-3,4-methylenedioxyamphetamine; Psychotherapy; Psychotropic Drugs; Stress Disorders, Post-Traumatic
PubMed: 29524515
DOI: 10.1016/j.pnpbp.2018.03.003 -
Nature Medicine Oct 2023This multi-site, randomized, double-blind, confirmatory phase 3 study evaluated the efficacy and safety of 3,4-methylenedioxymethamphetamine-assisted therapy (MDMA-AT)... (Randomized Controlled Trial)
Randomized Controlled Trial
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 Sheehan Disability Scale (SDS) functional impairment score (key secondary endpoint) were assessed by blinded independent assessors. Participants were randomized to MDMA-AT (n = 53) or placebo with therapy (n = 51). Overall, 26.9% (28/104) of participants had moderate PTSD, and 73.1% (76/104) of participants had severe PTSD. Participants were ethnoracially diverse: 28 of 104 (26.9%) identified as Hispanic/Latino, and 35 of 104 (33.7%) identified as other than White. Least squares (LS) mean change in CAPS-5 score (95% confidence interval (CI)) was -23.7 (-26.94, -20.44) for MDMA-AT versus -14.8 (-18.28, -11.28) for placebo with therapy (P < 0.001, d = 0.7). LS mean change in SDS score (95% CI) was -3.3 (-4.03, -2.60) for MDMA-AT versus -2.1 (-2.89, -1.33) for placebo with therapy (P = 0.03, d = 0.4). Seven participants had a severe treatment emergent adverse event (TEAE) (MDMA-AT, n = 5 (9.4%); placebo with therapy, n = 2 (3.9%)). There were no deaths or serious TEAEs. These data suggest that MDMA-AT reduced PTSD symptoms and functional impairment in a diverse population with moderate to severe PTSD and was generally well tolerated. ClinicalTrials.gov identifier: NCT04077437 .
Topics: Humans; Stress Disorders, Post-Traumatic; N-Methyl-3,4-methylenedioxyamphetamine; Treatment Outcome; Combined Modality Therapy; Double-Blind Method
PubMed: 37709999
DOI: 10.1038/s41591-023-02565-4 -
Journal of Psychoactive Drugs 2020After a two-decade hiatus in which research on psychedelics was essentially halted, placebo-controlled clinical trials of psychedelic-assisted therapy for mental health...
After a two-decade hiatus in which research on psychedelics was essentially halted, placebo-controlled clinical trials of psychedelic-assisted therapy for mental health conditions have begun to be published. We identified nine randomized, placebo-controlled clinical trials of psychedelic-assisted therapy published since 1994. Studies examined psilocybin, LSD (lysergic acid diethylamide), ayahuasca (which contains a combination of N,N-dimethyltryptamine and harmala monoamine oxidase inhibitor alkaloids), and MDMA (3,4-methylenedioxymethamphetamine). We compared the standardized mean difference between the experimental and placebo control group at the primary endpoint. Results indicated a significant mean between-groups effect size of 1.21 (Hedges ), which is larger than the typical effect size found in trials of psychopharmacological or psychotherapy interventions. For the three studies that maintained a placebo control through a follow-up assessment, effects were generally maintained at follow-up. Overall, analyses support the efficacy of psychedelic-assisted therapy across four mental health conditions - post-traumatic stress disorder, anxiety/depression associated with a life-threatening illness, unipolar depression, and social anxiety among autistic adults. While study quality was high, we identify several areas for improvement regarding the conduct and reporting of trials. Larger trials with more diverse samples are needed to examine possible moderators and mediators of effects, and to establish whether effects are maintained over time.
Topics: Adult; Banisteriopsis; Hallucinogens; Humans; Lysergic Acid Diethylamide; N-Methyl-3,4-methylenedioxyamphetamine; Psilocybin
PubMed: 32529966
DOI: 10.1080/02791072.2020.1769878