European journal of psychotraumatology • December 1, 2026 • Philip Gerrans, Hugh McGovern, Jakob Hohwy et al.
Complex post-traumatic stress disorder (C-PTSD) involves lasting difficulties with emotions, self-concept, and relationships, beyond typical PTSD symptoms. This review proposes a neurocognitive explanation based on predictive processing and self-modelling, focusing on how the brain's insula integrates bodily signals, emotions, and self-awareness. The authors suggest that C-PTSD arises from maladaptive predictions shaped by prolonged interpersonal trauma, leading to unstable self-regulation. They examine MDMA-assisted psychotherapy as one intervention that may temporarily alter emotional salience, trust, and self-related thinking. The framework generates testable hypotheses about self-modelling in C-PTSD and offers guidance for developing treatments that target affective regulation and self-referential processing.
Scientific reports • July 11, 2026 • Monnica T Williams, Sonya C Faber, Jordan Sloshower et al.
A small preliminary study of five diverse individuals found that MDMA-assisted therapy significantly reduced trauma symptoms related to discrimination. Scores on the Trauma Symptoms of Discrimination Scale dropped by an average of 38% after treatment, a large effect. All participants, who had experienced multiple forms of discrimination including gender, racial, and sexual orientation bias, reported marked improvement. The results suggest MDMA-assisted therapy may help alleviate discrimination-related trauma in marginalized populations, though the small sample size calls for cautious interpretation and further research with larger, more diverse groups.
Journal of the European Academy of Dermatology and Venereology • July 11, 2026 • Pablo Balado-simó, E Gimeno, Josep Riera‐monroig et al.
Chemsex—the use of psychoactive substances to enhance sexual activity, especially among gay, bisexual, and other men who have sex with men—is linked to a range of skin and mucosal complications. Dermatologists often encounter these manifestations first. Lesions vary by substance and route of administration: poppers dermatitis is common and frequently misdiagnosed as impetigo; MDMA causes oral mucositis and painful aphthous-like ulcers from bruxism and xerostomia; injection-related lesions from mephedrone and ketamine can resemble infections or vasculitis, leading to delayed diagnoses; cocaine with levamisole can cause cutaneous necrosis and vasculitis; GHB/GBL may lead to traumatic genital injuries due to reduced pain sensitivity; and constricting devices can cause mechanical trauma and penile deformities. Increased awareness of these signs supports earlier recognition and non-stigmatizing risk-reduction advice.
Translational Psychiatry • July 11, 2026 • Moira G. Semple, Sarah E. Mennenga, Ryan Smith et al.
Ketamine and MDMA, compounds known as psychoplastogens, show therapeutic potential for mood and trauma-related disorders, but their molecular mechanisms are not fully understood. In a study analyzing blood samples from 20 ketamine-treated participants and saliva samples from 16 MDMA-treated participants, DNA methylation changes were examined using a Brain-Epigenome-Wide Association Study targeting brain-relevant genes. Ketamine was associated with 405 significantly altered genes and 169 functional networks, while MDMA was linked to 346 altered genes and 183 networks. Both compounds converged on pathways related to neuroplasticity and neuroimmune regulation, suggesting they induce peripheral epigenetic changes that engage molecular pathways relevant to psychiatric health.
Mol Psychiatry • July 7, 2026
Psilocybin and MDMA are both psychedelic drugs but produce different behavioral effects. MDMA, but not psilocybin, raises both serotonin and norepinephrine in the medial prefrontal cortex. Blocking norepinephrine release reveals head-twitch responses (a rodent correlate of psychedelic effects) from MDMA, suggesting that noradrenergic signaling opposes serotonin 2A receptor effects. Artificially raising norepinephrine also reduces psilocybin-induced head-twitch responses. Activating the noradrenergic alpha-2 receptor alone suppresses these responses, even in mice lacking the locus coeruleus, indicating action via heteroreceptors. Importantly, alpha-2 receptor activation does not block psilocybin's antidepressant-like effects in the forced swim test. This suggests that side effects of serotonin 2A activation can be reduced without losing therapeutic benefits.
Zenodo (CERN European Organization for Nuclear Research) • July 7, 2026
Combined use of MDMA and SSRIs may increase the risk of serotonin syndrome, though evidence is limited or indirect. Healthcare providers are advised to remain alert for symptoms of this condition and to discourage such drug interactions.
Asclepius International Journal of Scientific Health Science • July 5, 2026 • Pedro Martins Rabelo
A systematic review of eight randomized controlled trials found that psilocybin (25 mg) produced clinically significant reductions in depressive symptoms on the MADRS and QIDS-SR‑16 scales in treatment-resistant depression, while MDMA‑assisted therapy reduced CAPS‑5 scores in post‑traumatic stress disorder, with 67–71% of participants no longer meeting diagnostic criteria after treatment. Both substances had acceptable safety profiles with mostly transient adverse events. Direct comparative meta‑analysis was not possible due to clinical and methodological heterogeneity. Limitations include small samples, blinding difficulties, and lack of long‑term follow‑up.
July 5, 2026 • Mark Groeneveld
preprint
A practical manual for solo and guided MDMA therapy, grounded in a mechanistic framework of memory reconsolidation, predictive processing, complex system dynamics, and the defense cascade model, explains how MDMA therapy can durably improve mental illnesses by enabling the unlearning of inaccurate mental models. It provides evidence-based guidance on safety, session preparation, troubleshooting, and long-term healing, extending beyond clinical illness to address mental models that hinder community relationships, cognitive flexibility, and ethical reasoning. The manual emphasizes scientific rigor, transparency, and respect for autonomy, and includes discussion of tradeoffs between practitioner- and self-guidance.
Research Square • July 2, 2026
Among a nationally representative U.S. sample, the associations between lifetime use of MDMA/ecstasy or psilocybin and mental health outcomes differ by sexual identity. For heterosexual individuals, lifetime use of either substance was linked to higher odds of past-year major depressive episode and serious psychological distress, whereas for sexual minority individuals (lesbian, gay, bisexual), these associations were weaker or absent. The findings suggest that sexual identity moderates the relationship between psychedelic use and mental health, highlighting the need for identity-informed research in this area.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology • July 1, 2026 • Denis Arikci, Joran Borgulya, Isabelle Straumann et al. • 1 citation
In a double-blind, randomized, placebo-controlled crossover trial, 24 healthy adults received three doses of 2C-B (10, 20, and 30 mg), 125 mg MDMA, and 25 mg psilocybin. The 30 mg dose of 2C-B produced subjective effects comparable to MDMA but weaker than psilocybin, and increased emotional empathy similarly to MDMA. Only psilocybin caused bad drug effects and anxiety. MDMA produced the greatest cardiovascular stimulation, followed by psilocybin and then 2C-B. Only MDMA raised plasma oxytocin and neurophysin I. The average subjective effect duration of 30 mg 2C-B was 4.9 hours, similar to MDMA (4.8 h) and shorter than psilocybin (6.1 h). 2C-B had a plasma elimination half-life of about 1.3 hours.
Nature medicine • October 1, 2023 • 400 citations
In a phase 3 trial, MDMA-assisted therapy reduced PTSD symptoms and functional impairment more than placebo with therapy in 104 participants with moderate to severe PTSD. The average decrease in PTSD symptom severity was 23.7 points with MDMA-assisted therapy versus 14.8 points with placebo, and functional disability improved by 3.3 versus 2.1 points. Participants were ethnoracially diverse, with 27% identifying as Hispanic/Latino and 34% as other than White. Severe side effects occurred in 9.4% of the MDMA group and 3.9% of the placebo group; no deaths or serious adverse events were reported. The treatment was generally well tolerated.
Nature medicine • June 1, 2021 • Jennifer M Mitchell, Michael Bogenschutz, Alia Lilienstein et al. • 965 citations
A phase 3 clinical trial tested MDMA-assisted therapy against placebo for severe PTSD. Participants received manualized therapy with either MDMA or placebo alongside preparatory and integrative sessions. At two months after the last session, the MDMA group showed a significantly greater reduction in PTSD symptoms (average 24.4-point drop on the CAPS-5 scale) compared to the placebo group (13.9-point drop), with a large effect size. Functional impairment also improved more with MDMA. No serious safety issues such as abuse potential, suicidality, or heart rhythm problems were observed. The findings suggest MDMA-assisted therapy is highly effective and safe for severe PTSD, including in people with common co-occurring conditions.
Lancet Psychiatry • May 1, 2018 • 443 citations
A randomized, double-blind, phase 2 clinical trial tested MDMA-assisted psychotherapy for post-traumatic stress disorder in military veterans, firefighters, and police officers. Participants were randomly assigned to receive different doses of MDMA during psychotherapy sessions. The findings revealed that the active dose of MDMA led to significant and lasting reductions in PTSD symptoms compared to the lower dose, indicating that this innovative therapeutic approach can effectively treat this condition and provide significant relief for individuals with profound trauma.
Journal of Psychopharmacology • October 31, 2012 • Peter Oehen, Rafael Traber, Verena Widmer et al. • 407 citations
MDMA-assisted psychotherapy for treatment-resistant PTSD can be safely administered in a clinical setting. In a randomized, double-blind, active-placebo controlled pilot trial, 12 patients received either a low dose (25 mg plus 12.5 mg supplemental) or a full dose (125 mg plus 62.5 mg supplemental) of MDMA during three experimental sessions, combined with weekly non-drug psychotherapy. No serious drug-related adverse events occurred. While clinician-rated PTSD symptoms (CAPS) did not show statistically significant reductions (p = 0.066), self-reported improvement (PDS) was clinically and statistically significant (p = 0.014). CAPS scores further improved at one-year follow-up, and three MDMA sessions were more effective than two (p = 0.016).
J Psychopharmacol • July 19, 2010 • 672 citations
In a pilot randomized controlled trial, MDMA-assisted psychotherapy reduced PTSD symptoms more than placebo therapy in people with chronic, treatment-resistant posttraumatic stress disorder. The treatment was well tolerated, with no serious adverse events. These results suggest that MDMA-assisted psychotherapy may be a safe and effective intervention for this difficult-to-treat population, warranting further investigation.
BMC Pharmacology • March 3, 2006 • Dawn D. Han, Howard H. Gu • 419 citations
Cocaine blocks all three monoamine transporters (DAT, NET, SERT) at similar concentrations (KI values 0.2–0.7 μM). Methylphenidate inhibits DAT and NET around 0.1 μM but requires about 1000-fold higher concentration to inhibit SERT. Amphetamine and methamphetamine are most potent at NET (KI 0.07–0.1 μM), 5- to 9-fold less potent at DAT (KI ≈ 0.6 μM), and 200- to 500-fold less potent at SERT (KI 20–40 μM). MDMA shows higher potency at SERT than at DAT. Human and mouse transporters respond similarly to each drug, with KI values within 4-fold. These relative potencies indicate which neurotransmitter systems each stimulant disrupts most.
Therapeutic Drug Monitoring • March 19, 2004 • Rafael de la Torre, Magı́ Farré, Pere N. Roset et al. • 445 citations
MDMA (ecstasy) is a widely misused psychostimulant that increases energy, euphoria, and sociability while also producing distinctive 'entactogen' effects such as feeling close to others and increased empathy. It works by promoting the release and blocking the reuptake of serotonin, dopamine, and norepinephrine. Acute toxic effects include serotonin syndrome, characterized by muscle rigidity, hyperreflexia, and hyperthermia. MDMA metabolism involves two main pathways; one is partially regulated by the polymorphic enzyme CYP2D6, but mechanism-based inhibition after two consecutive doses limits the impact of CYP2D6 genetics on acute toxicity. Metabolism may also contribute to long-term neurotoxic effects through progressive degeneration of the serotonergic system.
Synapse • January 1, 2000 • Richard B. Rothman, Michael H. Baumann, Christina M. Dersch et al. • 933 citations
Stimulants like amphetamine, MDMA, and methamphetamine are known to produce reinforcing effects in animals through the brain chemical dopamine. However, their subjective effects in humans—such as euphoria or alertness—may rely more on norepinephrine. Using lab tests, the authors measured how several stimulants affect the release of norepinephrine and dopamine. They found that all tested drugs were most potent at releasing norepinephrine. Crucially, the oral doses that produce amphetamine-like subjective effects in people correlated with the drugs' ability to release norepinephrine, not dopamine, and did not lower prolactin levels (a marker of dopamine release). These findings suggest norepinephrine may play a key role in the subjective experience of stimulants in humans.
The Lancet • October 1, 1998 • Ud Mccann, Z Szabò, Ursula Scheffel et al. • 664 citations
Using positron emission tomography (PET) with a ligand that selectively binds to serotonin transporters, researchers found direct evidence of a decrease in a structural component of brain serotonin neurons in people who use MDMA (ecstasy). This suggests MDMA use may damage or reduce serotonin neurons in the living human brain.
British Journal of Addiction • August 1, 1992 • Nadia Solowij, Wayne Hall, Nicole Lee • 417 citations
Ecstasy (MDMA) is a recreational drug gaining worldwide popularity, yet research on its use and effects is limited. A survey of 100 users recruited through peer networks found that Ecstasy is primarily used infrequently for fun at dance parties and social gatherings. The main effects reported were positive mood, intimacy, and closeness, along with stimulant and psychedelic properties. Side effects and residual effects were no more severe than those of amphetamines or hallucinogens. Tolerance to positive effects developed with frequent use, while negative effects increased. Animal research indicates neurotoxicity to serotonergic nerve terminals, warranting caution until human hazard levels are determined.
Proceedings of the National Academy of Sciences • March 1, 1992 • Gary Rudnick, S C Wall • 533 citations
MDMA (ecstasy) acts on serotonin transporters in both the plasma membrane and secretory vesicles. In plasma membrane vesicles from human platelets, MDMA inhibits serotonin transport and imipramine binding by directly interacting with the sodium-dependent serotonin transporter, and it stimulates serotonin efflux in a stereo-specific, sodium-dependent, and imipramine-sensitive manner via transporter-mediated exchange. In vesicles from bovine adrenal chromaffin granules containing the vesicular biogenic amine transporter, MDMA inhibits ATP-dependent serotonin accumulation and stimulates efflux by dissipating the transmembrane pH difference and directly interacting with the vesicular transporter.
Journal of Neuroscience • August 1, 1988 • Elizabeth O’hearn, Giuseppe Battaglia, Eb de Souza et al. • 546 citations
Two amphetamine derivatives, MDA and MDMA, cause lasting damage to serotonin-producing nerve fibers in the rat brain. Two weeks after repeated high doses, serotonin axons throughout the forebrain are profoundly lost, while dopamine and norepinephrine axons remain intact. The damage is selective to fine axon terminals; thicker fibers and the cell bodies in the raphe nuclei survive. Some brain regions, such as the hippocampus and parts of the neocortex, show partial sparing. Swollen and fragmented axons observed shortly after treatment confirm ongoing degeneration. MDA produces greater loss of serotonin axons than MDMA at the same dose. The findings establish that these drugs are toxic to serotonin axon terminals and cause long-term denervation of the forebrain.
Journal of Pharmacology and Experimental Therapeutics • September 1, 1987 • G. Battaglia, S. Yeh, E. O'hearn et al. • 459 citations
Repeated administration of MDMA and MDA to rats caused long-lasting damage to serotonin neurons. Two weeks after a four-day treatment, levels of the serotonin metabolite 5-hydroxyindoleacetic acid were reduced by 30-60% in several brain regions, and the density of serotonin uptake sites fell by 50-75%. No widespread changes occurred in norepinephrine or dopamine systems. The findings demonstrate that both drugs produce persistent neurotoxic effects on the structural and functional integrity of serotonergic neurons, and measuring serotonin uptake site density offers a way to quantify this damage.
Journal of Psychoactive Drugs • October 1, 1986 • George Greer, Requa Tolbert • 420 citations
In a clinical setting, individuals who took MDMA reported predominantly positive subjective effects, including enhanced communication, emotional openness, and introspection, with minimal adverse reactions. The drug appeared to facilitate therapeutic processes by reducing fear and defensiveness. Some participants experienced transient anxiety or discomfort, but overall the experience was described as valuable and conducive to personal insight. The authors suggest that MDMA may have potential as an adjunct to psychotherapy when used under controlled conditions.