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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 2019Psychedelic plants and fungi have been used in indigenous medicinal traditions for millennia. Modern psychedelic research began when Albert Hofmann first synthesized...
Psychedelic plants and fungi have been used in indigenous medicinal traditions for millennia. Modern psychedelic research began when Albert Hofmann first synthesized lysergic acid diethylamide (LSD-25) in 1938. Five years later, became the first person to ingest LSD. Hofmann was unaware of the significance of his actions, and the effects they would set in motion. After a burgeoning period of scientific and cultural exploration in the1950s and '60s, psychedelic research was slowed to a near halt. Throughout the 1970s and '80s governmental interventions severely hampered global psychedelic research, despite evidence of the limited medical risks and therapeutic potential of psychedelics. After decades of persistent education and advocacy, rigorous research employing psychedelics as tools of discovery and healing are abundant today. Studies are taking place in research institutions and in private practice sites supported by non-profit and for-profit organizations, as well as individual investigators. This research includes clinical trials with MDMA-assisted therapy for the treatment of PTSD, alcoholism, and social anxiety, and psilocybin clinical studies for depression and addiction, as well as the ability of psychedelics to catalyze spiritual or mystical experiences and inspire creativity, and into the neuroscientific understanding the effects of psychedelic substances on our nervous system.
Topics: Biomedical Research; Hallucinogens; History, 20th Century; History, 21st Century; Humans; Lysergic Acid Diethylamide; Mental Disorders; N-Methyl-3,4-methylenedioxyamphetamine; Psilocybin
PubMed: 31132970
DOI: 10.1080/02791072.2019.1606472 -
Journal of Psychopharmacology (Oxford,... May 2021
Topics: Humans; N-Methyl-3,4-methylenedioxyamphetamine; Psychotherapy; Substance-Related Disorders
PubMed: 33938311
DOI: 10.1177/02698811211012604 -
The American Journal of Drug and... Sep 2023A drug concoction called tusi has emerged in Latin America and in Europe and is now beginning to acquire popularity in the United States. "Tusi" is a phonetic...
A drug concoction called tusi has emerged in Latin America and in Europe and is now beginning to acquire popularity in the United States. "Tusi" is a phonetic translation of "2C," a series of psychedelic phenethylamines. The concoction is also sometimes referred to as "pink cocaine" as it typically comes in the form of pink powder. However, despite its name, the concoction rarely contains 2C series drugs. Multiple drug checking studies have found that the majority of tusi samples contain ketamine, often combined with 3,4-methylenedioxymethamphetamine (MDMA), methamphetamine, cocaine, opioids, and/or new psychoactive substances. The tusi phenomenon complicates the drug landscape because it has the potential to confuse both people who use it and researchers alike. People using may think the drug is 2C/2C-B, and they may also be unaware that the concoction tends to consist of ketamine and a wide variety of other drugs. Unintentional exposure to its contents can lead to increased risk of adverse effects. The tusi phenomenon also has the potential to complicate drug research as unknown exposure to drugs like ketamine and MDMA will lead to underreporting of use. A combination of self-report and toxicological testing may be needed to inform the most accurate estimates of use. Both researchers and people at risk for use need to be informed about this new concoction. Drug researchers need to be cognizant about the way they query use, and people at risk for using need to be educated about the possible contents of tusi and associated dangers.
Topics: Humans; N-Methyl-3,4-methylenedioxyamphetamine; Ketamine; Hallucinogens; Methamphetamine; Cocaine; Substance-Related Disorders
PubMed: 37162319
DOI: 10.1080/00952990.2023.2207716 -
Nature May 2019A critical period is a developmental epoch during which the nervous system is expressly sensitive to specific environmental stimuli that are required for proper circuit...
A critical period is a developmental epoch during which the nervous system is expressly sensitive to specific environmental stimuli that are required for proper circuit organization and learning. Mechanistic characterization of critical periods has revealed an important role for exuberant brain plasticity during early development, and for constraints that are imposed on these mechanisms as the brain matures. In disease states, closure of critical periods limits the ability of the brain to adapt even when optimal conditions are restored. Thus, identification of manipulations that reopen critical periods has been a priority for translational neuroscience. Here we provide evidence that developmental regulation of oxytocin-mediated synaptic plasticity (long-term depression) in the nucleus accumbens establishes a critical period for social reward learning. Furthermore, we show that a single dose of (+/-)-3,4-methylendioxymethamphetamine (MDMA) reopens the critical period for social reward learning and leads to a metaplastic upregulation of oxytocin-dependent long-term depression. MDMA-induced reopening of this critical period requires activation of oxytocin receptors in the nucleus accumbens, and is recapitulated by stimulation of oxytocin terminals in the nucleus accumbens. These findings have important implications for understanding the pathogenesis of neurodevelopmental diseases that are characterized by social impairments and of disorders that respond to social influence or are the result of social injury.
Topics: Aging; Animals; Conditioning, Classical; Critical Period, Psychological; Female; Learning; Long-Term Synaptic Depression; Male; Mice; Mice, Inbred C57BL; N-Methyl-3,4-methylenedioxyamphetamine; Nucleus Accumbens; Oxytocin; Reward; Signal Transduction
PubMed: 30944474
DOI: 10.1038/s41586-019-1075-9 -
The Lancet. Diabetes & Endocrinology Jul 2023Disruptions of the hypothalamic-pituitary axis can cause an arginine vasopressin deficiency, also known as central diabetes insipidus. Patients with this condition are... (Randomized Controlled Trial)
Randomized Controlled Trial
Oxytocin in response to MDMA provocation test in patients with arginine vasopressin deficiency (central diabetes insipidus): a single-centre, case-control study with nested, randomised, double-blind, placebo-controlled crossover trial.
BACKGROUND
Disruptions of the hypothalamic-pituitary axis can cause an arginine vasopressin deficiency, also known as central diabetes insipidus. Patients with this condition are at high risk of additional oxytocin deficiency owing to the close anatomical proximity of oxytocin-producing neurons; however, no conclusive evidence for such a deficiency has been reported. We aimed to use 3,4-methylenedioxymethamphetamine (MDMA, also known as ecstasy), a strong activator of the central oxytocinergic system, as a biochemical and psychoactive provocation test to investigate oxytocin deficiency in patients with arginine vasopressin deficiency (central diabetes insipidus).
METHODS
This single-centre, case-control study with nested, randomised, double-blind, placebo-controlled crossover trial included patients with arginine vasopressin deficiency (central diabetes insipidus) and healthy controls (matched 1:1 by age, sex, and BMI) and was conducted at the University Hospital Basel, Basel, Switzerland. We used block randomisation to assign participants to receive either a single oral dose of MDMA (100 mg) or placebo in the first experimental session; patients received the opposite treatment at the next session, with a wash-out period of at least 2 weeks between the two sessions. Participants and investigators assessing the outcomes were masked to assignment. Oxytocin concentrations were measured at 0, 90, 120, 150, 180, and 300 min after MDMA or placebo. The primary outcome was the area under the plasma oxytocin concentration curve (AUC) after drug intake. The AUC was compared between groups and conditions using a linear mixed-effects model. Subjective drug effects were assessed throughout the study using ten-point visual analogue scales. Acute adverse effects were assessed before and 360 min after drug intake using a 66-item list of complaints. This trial is registered with ClinicalTrials.gov, NCT04648137.
FINDINGS
Between Feb 1, 2021, and May 1, 2022, we recruited 15 patients with arginine vasopressin deficiency (central diabetes insipidus) and 15 healthy controls. All participants completed the study and were included in the analyses. In healthy controls, median plasma oxytocin concentration was 77 pg/mL (IQR 59-94) at baseline and increased by 659 pg/mL (355-914) in response to MDMA, resulting in an AUC of 102 095 pg/mL (41 782-129 565); in patients, baseline oxytocin concentration was 60 pg/mL (51-74) and only slightly increased by 66 pg/mL (16-94) in response to MDMA, resulting in an AUC of 6446 pg/mL (1291-11 577). The effect of MDMA on oxytocin was significantly different between groups: the AUC for oxytocin was 82% (95% CI 70-186) higher in healthy controls than in patients (difference 85 678 pg/mL [95% CI 63 356-108 000], p<0·0001). The increase in oxytocin in healthy controls was associated with typical strong subjective prosocial, empathic, and anxiolytic effects, whereas only minimal subjective effects were observed in patients, in agreement with the lack of increase in oxytocin concentrations. The most frequently reported adverse effects were fatigue (eight [53%] healthy controls and eight [53%] patients), lack of appetite (ten [67%] healthy controls and eight [53%] patients), lack of concentration (eight [53%] healthy controls and seven [47%] patients), and dry mouth (eight [53%] healthy controls and eight [53%] patients). In addition, two (13%) healthy controls and four (27%) patients developed transient mild hypokalaemia.
INTERPRETATION
These findings are highly suggestive of clinically meaningful oxytocin deficiency in patients with arginine vasopressin deficiency (central diabetes insipidus), laying the groundwork for a new hypothalamic-pituitary disease entity.
FUNDING
Swiss National Science Foundation, Swiss Academy of Medical Sciences, and the G&J Bangerter-Rhyner Foundation.
Topics: Humans; N-Methyl-3,4-methylenedioxyamphetamine; Diabetes Insipidus, Neurogenic; Oxytocin; Cross-Over Studies; Case-Control Studies; Double-Blind Method; Arginine; Diabetes Mellitus
PubMed: 37192642
DOI: 10.1016/S2213-8587(23)00120-1 -
JAMA Psychiatry Aug 2019
Topics: Consciousness; Humans; Ketamine; Mental Disorders; N-Methyl-3,4-methylenedioxyamphetamine; Psilocybin; Psychopharmacology; Psychotropic Drugs
PubMed: 31241740
DOI: 10.1001/jamapsychiatry.2019.1145 -
Medicine, Health Care, and Philosophy Sep 2020In the present paper, we discuss the ethics of compassionate psychedelic psychotherapy and argue that it can be morally permissible. When talking about psychedelics, we... (Review)
Review
In the present paper, we discuss the ethics of compassionate psychedelic psychotherapy and argue that it can be morally permissible. When talking about psychedelics, we mean specifically two substances: psilocybin and MDMA. When administered under supportive conditions and in conjunction with psychotherapy, therapies assisted by these substances show promising results. However, given the publicly controversial nature of psychedelics, compassionate psychedelic psychotherapy calls for ethical justification. We thus review the safety and efficacy of psilocybin- and MDMA-assisted therapies and claim that it can be rational for some patients to try psychedelic therapy. We think it can be rational despite the uncertainty of outcomes associated with compassionate use as an unproven treatment regime, as the expected value of psychedelic psychotherapy can be assessed and can outweigh the expected value of routine care, palliative care, or no care at all. Furthermore, we respond to the objection that psychedelic psychotherapy is morally impermissible because it is epistemically harmful. We argue that given the current level of understanding of psychedelics, this objection is unsubstantiated for a number of reasons, but mainly because there is no experimental evidence to suggest that epistemic harm actually takes place.
Topics: Chronic Disease; Compassionate Use Trials; Hallucinogens; Humans; Mental Disorders; N-Methyl-3,4-methylenedioxyamphetamine; Psilocybin; Psychotherapy; Terminal Care
PubMed: 32468195
DOI: 10.1007/s11019-020-09958-z -
MMW Fortschritte Der Medizin Feb 2018
Review
Topics: Adult; Drug Overdose; Humans; Illicit Drugs; Male; N-Methyl-3,4-methylenedioxyamphetamine; Young Adult
PubMed: 29417511
DOI: 10.1007/s15006-018-0150-8 -
Current Psychiatry Reports Oct 2022Few treatments are available for patients with mood disorders or post-traumatic stress disorder (PTSD) who have already failed multiple interventions. After several... (Review)
Review
PURPOSE OF REVIEW
Few treatments are available for patients with mood disorders or post-traumatic stress disorder (PTSD) who have already failed multiple interventions. After several decades when research into psychedelics was effectively halted by federal legislation, the past several years have shown the re-emergence of thoughtful investigations studying the utility of compounds such as 3,4-methylenedioxymethamphetamine (MDMA) and psilocybin.
RECENT FINDINGS
Several studies have coupled the safe administration of psychedelic compounds in a controlled environment after several hours of preparation of study participants and followed by multiple sessions to integrate the psychedelic experience. The improvement participants experience appear related to the often profound perspective changes experienced and seem unlike the improvements seen in the currently available care paradigms. Studies cited include treatment resistant depression, end of life despair, and PTSD. Psychedelic psychotherapy, a unique remarriage of biological therapy and psychotherapy, has the potential to transform mental health care.
Topics: Hallucinogens; Humans; N-Methyl-3,4-methylenedioxyamphetamine; Psilocybin; Psychotherapy; Stress Disorders, Post-Traumatic
PubMed: 36129571
DOI: 10.1007/s11920-022-01363-y