Psychedelics Early Online Release

MDMA, 3,4-methylenedioxymethamphetamine (“ecstasy,” “molly”), is a distinctive entactogen that reverses the serotonin (5-HT) transporter to increase synaptic 5-HT, while also engaging catecholaminergic and oxytocinergic pathways. In clinical trials, MDMA-assisted psychotherapy has yielded substantial improvements in treatment-resistant posttraumatic stress disorder (PTSD), although regulatory approval has been delayed over concerns about functional unblinding and protocol rigor. Early randomized, placebo-controlled studies also suggest benefits in autism spectrum disorder, eating disorders with comorbid PTSD, and anxiety related to life-threatening illness. Large epidemiological and naturalistic studies associate MDMA use with lower rates of depression, reduced suicidal ideation, and improved posttrauma coping, though causal inference is limited. MDMA-associated hyponatremia appears primarily linked to oxytocin-mediated antidiuresis (elevated plasma oxytocin without a copeptin rise), with arginine vasopressin potentially contributing under hyperthermia or polydipsia. In rodents, MDMA pretreatment enhances stress resilience and preserves adaptive neuroplasticity via a vagus-dependent gut–brain axis. This review traces MDMA's history; synthesizes evidence on acute risks (hyperthermia, hyponatremia, sympathomimetic overstimulation, and transient cognitive effects); and evaluates long-term outcomes and putative resilience mechanisms. Future work should standardize dosing and psychotherapeutic protocols, incorporate biomarkers to guide patient selection, and conduct adequately powered trials across emerging indications, alongside long-term safety monitoring and multidisciplinary collaboration.

Psychiatric illness, particularly stress-related disorders including depression, anxiety and posttraumatic stress disorder, presents a considerable health burden worldwide with high prevalence, disabling symptoms, and scant efficacy of available treatments. Chronic stress is a major contributor to the origin and development of these conditions, to the detriment of both individual and, by extension, public health. More recently, psychedelics such as psilocybin, lysergic acid diethylamide, and 3,4-methylenedioxymethamphetamine (MDMA) have gained attention as potential therapeutic tools, mainly because of their ability to elicit altered states of consciousness and their impact on neuroplasticity, emotional processing, and serotonin pathways. This perspective paper discusses the mechanisms underlying the therapeutic effects of these substances, their potential utility for treating stress-related psychiatric disorders, and the need for a paradigm shift in the prevailing view of the intricate relationship between psychedelics, stress, and mental well-being.

Professor Gregor Hasler stands at the forefront of revolutionary psychedelic research and neuroplasticity studies, transforming our understanding of mental health treatment through groundbreaking scientific discoveries. As Chair of Psychiatry at the University of Fribourg, Switzerland, where he directs the Molecular Psychiatry Lab, Hasler has pioneered research on how psychedelics like LSD, psilocybin, and MDMA reshape brain function to treat depression, PTSD, and addiction. His Genomic Press Interview reveals a career dedicated to uncovering rapid antidepressant mechanisms and developing innovative treatments that offer hope to millions suffering from psychiatric conditions. His interdisciplinary team investigates how psychedelics rapidly enhance neuroplasticity, with clinical improvements lasting months or years after treatment. Hasler's groundbreaking discovery of mGluR5 as a biomarker for nicotine dependence represents his greatest scientific success, demonstrating his ability to translate complex molecular research into practical clinical applications. Honored with prestigious awards including the NARSAD Independent Investigator Award and the Robert Bing Award from the Swiss Academy of Medical Sciences, he bridges rigorous neuroscience with compassionate clinical practice. His influential book Higher Self: Psychedelics in Psychotherapy captures decades of research wisdom, proposing bold visions for psychiatry's future. As former President of the Swiss Society for Drug Safety in Psychiatry and a member of the American College of Neuropsychopharmacology, Hasler ensures the safe integration of psychedelic therapies into mainstream medicine. His work on glutamate and GABA neurotransmitter systems has fundamentally changed how we understand mood disorders, offering new pathways for treatment-resistant conditions and establishing him as a transformative leader in modern psychiatry.

Introduction

Launching a new journal is rarely the beginning people imagine it to be. It is not the first word, but the latest entry in a conversation already unfolding; in fits, in fragments, and in contradictions. Psychedelics enters the scholarly domain not with a thesis, but with a question: How should we think, write, and research consciousness in a landscape where definitions erode faster than they are drawn?

From the outset, our journal's indexed title, Psychedelics, has served a practical purpose. It signaled the core of our focus: compounds that alter perception, interrogate the self, and

Heart rate modulation and clinical improvement in major depression: A randomized clinical trial with accelerated intermittent theta burst stimulation

Jonas Wilkening,

Henrike M. Jungeblut,

Ivana Adamovic,

Vladimir Belov,

Peter Dechent,

Lara Eicke,

Niels Hansen,

Vladislav Kozyrev,

Lara E. Marten,

Yonca Muschke,

Caspar Riemer,

Knut Schnell,

Asude Tura,

Melanie Wilke,

Fabian Witteler,

Jens Wiltfang,

Anna Wunderlich,

Valerie Zimmeck,

Anna Zobott,

Carsten Schmidt-Samoa,

Tracy Erwin-Grabner, and

Roberto Goya-Maldonado

MDMA in Psychiatry: From PTSD to emerging indications, safety, and future directions

Psychedelics in the context of stress and psychiatric disorders: A new horizon in mental health treatment

Gregor Hasler: Three Guiding Questions — How do psychedelics shape the brain? How can they heal psychiatric disorders such as depression and PTSD? How can we ensure their safe and responsible use?

Harriet de Wit: What can we learn about behavior and brain processes by studying psychoactive drugs in humans? How can we harmonize behavioral research in humans and nonhuman species?

Claire Foldi: Unravelling the neurobiology of eating disorders to inform effective treatments

Stephen Ross: Psychedelic-assisted therapies for difficult-to-treat psychiatric and medical disorders

Deanna M. Kaplan: Listening to daily life: exploring speech data, shared meaning, and generative artificial intelligence (AI) in clinical science

Erin Mauney: Psychedelics as modulators of the gut-brain interaction

Michael A. Wheeler: Psychedelics and neuroimmune circuits—what a strange trip, indeed

Psychedelics, Yes—but Not Only: Redefining the boundaries of consciousness research as part of humanity's ongoing attempt to transcend our incompleteness

Introduction

Single-dose psychedelic enhances cognitive flexibility and reversal learning in mice weeks after administration

Katarina Leão: Links between the auditory and limbic systems, with a focus on the effects of unconventional novel treatment options, such as psychedelics and cannabis extract

Najaf Amin: Rare coding genetic variation and downstream omics hold the key to understanding the pathogenesis of depression

Cardiac rhythms as windows into brain stimulation response: Promise and pitfalls in precision psychiatry

MDMA in Psychiatry: From PTSD to emerging indications, safety, and future directions

Psychedelics in the context of stress and psychiatric disorders: A new horizon in mental health treatment

Heart rate modulation and clinical improvement in major depression: A randomized clinical trial with accelerated intermittent theta burst stimulation

Cover-to-Cover

Counting the uncountable: The critical quest to quantify psychedelic medicine's reach

Bernard Lerer: Pre-clinical, translational and clinical research focused on the use of psychedelic drugs and their derivatives to treat psychiatric disorders

Charles L. Raison: Elucidating the role of conscious experience in the therapeutic effects of psychedelics as a means to optimize clinical outcomes

Table of Contents