bioRxiv (Cold Spring Harbor Laboratory) • Scott A. Ford, Rob W. Ness, Moonhyuk Kwon et al.
preprint
A chromosome-level genome assembly of the diviners sage plant, which produces the hallucinogen salvinorin A, has been produced. The genome is about 541 million base pairs, diploid, and comparable to other sage species. Two gene clusters involved in diterpene biosynthesis were identified, including a gene that forms the dihydrofuran ring early in the salvinorin A pathway. Other enzyme classes likely involved in later steps are scattered across the genome. Most of these genes are not activated by methyl jasmonate treatment. This high-quality genome sequence will help uncover the remaining steps in salvinorin A biosynthesis and support exploration of its medical potential for chronic pain, addiction, and post-traumatic stress disorder.
Viviana D. Evans, Alejandro Arenas, Kenneth Shinozuka et al.
preprint
Ketamine, originally a dissociative anesthetic, is now used for treatment-resistant depression and major depressive disorder with suicidal ideation. A single intravenous infusion shows antidepressant effects within hours, with a large effect size on depression scores. It also reduces PTSD symptom severity and suicidal ideation in emergency settings. However, therapeutic effects often subside within weeks, requiring repeated doses. Risks include temporary or persistent memory impairment, cardiovascular issues, liver toxicity, and bladder inflammation. Ketamine's opioid-sparing effect improves postoperative pain management.
Preprints.org • Kainat Riaz, Sejal Suneel, Mohammad Hamza Bin Abdul Malik et al. • 1 citation
preprint
Half of patients with post-traumatic stress disorder (PTSD) do not respond to standard pharmacotherapy or psychotherapy. A review of six phase II randomized controlled trials indicates that MDMA-assisted psychotherapy can reduce PTSD symptoms, even in treatment-resistant cases, by increasing neurohormones such as dopamine, serotonin, norepinephrine, and oxytocin and by modulating brain regions involved in fear and anxiety. The FDA has granted MDMA-assisted psychotherapy a "Breakthrough Therapy" designation. Further research is needed to determine whether the benefits outweigh the risks and whether this approach can be integrated into existing treatment options.
medRxiv • W. M. Green, S.b. Raut, F.l.j. James et al. • 4 citations
preprint
MDMA-assisted psychotherapy improves dissociation, depression, and functional impairment in people with post-traumatic stress disorder (PTSD), but does not improve sleep quality. A systematic review and meta-analysis of randomized controlled trials found that the therapy reduces core PTSD symptoms and enhances quality of life. The evidence is limited by small sample sizes in available trials, but supports further development of MDMA-assisted psychotherapy for PTSD.
Kenneth Shinozuka, Burton J. Tabaac, Alejandro Arenas et al.
preprint
MDMA, known as a party drug in the 1980s, is emerging as a powerful treatment for PTSD. Phase III FDA trials show MDMA-assisted psychotherapy has an effect size of 0.7-0.91, two to three times larger than existing antidepressants. Within 18 weeks, 67 to 71% of patients no longer meet PTSD diagnostic criteria. The literature is biased: animal studies used doses far above human levels, and human samples often involve recreational users of multiple substances. Only six clinical trials, all by MAPS, have been conducted, but preliminary evidence suggests MDMA is much more effective than current antidepressants for PTSD.
Philip Gerrans, Hugh Mgovern, Jakob Hohwy et al. • 1 citation
preprint
Complex post-traumatic stress disorder (C-PTSD) involves additional symptoms beyond those of PTSD, including emotional instability, negative self-concept, and interpersonal difficulties, often from prolonged trauma like childhood maltreatment or domestic violence. A novel model based on active inference and self-modelling explains these differences and identifies the insula's role in affective regulation. The model suggests that MDMA-assisted therapy may help recalibrate emotional regulation and strengthen self-model, offering a potential treatment avenue. Theoretical and clinical implications are discussed, with emphasis on further empirical research.
Balazs Szigeti, Ellen Bradley, Joshua Woolley
preprint
Unmasking bias—where participants or researchers can guess who received a treatment due to its noticeable effects—may account for the reported benefits of MDMA-assisted therapy for PTSD. Analyzing data from trials of ketamine and escitalopram, the authors found that the magnitude of unmasking bias is larger than the treatment-versus-control effect size observed for MDMA. This indicates that MDMA-AT's effect sizes are not too large to be explained by unmasking alone, though the findings do not prove that the effects are entirely or partially due to this bias.
L. J. Flameling, Jacob S. Aday, Michiel van Elk • 1 citation
preprint
A commentary on a phase 3 trial of MDMA-assisted therapy for PTSD raises concerns about expectancy effects. The trial reported positive results, but most participants correctly guessed their treatment assignment, and expectations were not measured. The authors argue these effects were minimal, but the commentary contends that without measuring expectations, it remains possible that placebo or nocebo effects contributed to the observed outcomes.
SSRN Electronic Journal • Vincent Joralemon
The Drug Enforcement Administration (DEA) classifies MDMA as a Schedule I controlled substance, the most restrictive category under the Controlled Substances Act. However, Lykos Therapeutics (formerly MAPS PBC) has submitted a New Drug Application for MDMA-assisted therapy for PTSD. If the FDA approves this drug, it would provide the 'accepted medical use' that Schedule I drugs are statutorily denied, triggering a rescheduling process. Based on precedents like XYWAV and cannabis-derived medications, the DEA would likely reschedule only the specific FDA-approved drug product—likely to be marketed as RENSANSE—to Schedule II or III, while raw MDMA remains on Schedule I. This mechanism offers a model for incrementally relaxing federal restrictions on psychedelic substances and expanding research access.
Noam Goldway, Taly Markovits, Naomi Fine et al.
preprint
Dissociation—feeling detached from one's body, surroundings, or self—is common in PTSD but its neural basis is poorly understood. Using network control theory, researchers examined brain dynamics during dissociative states in two contexts: ketamine-induced dissociation in 30 healthy volunteers and therapeutic interventions in 78 PTSD patients. Ketamine produced brain dynamics similar to those seen in PTSD patients before treatment, with increased dominance of a default mode network meta-state and decreased dominance of a somatomotor meta-state. Ketamine did not significantly alter the brain's energetic landscape, but transition energies increased after PTSD treatment, suggesting more organized, less entropic brain dynamics.