Alex Jinich-Diamant
preprint
Mystical states induced by psychedelics, meditation, or fasting all converge on the same brain state: a transient near-critical regime. Serotonergic psychedelics relax top-down priors by sensitizing layer 5 pyramidal neurons; open-monitoring meditation elevates cortical entropy through altered thalamocortical connectivity; caloric restriction destabilizes the default mode network by attenuating metabolic support for high-level attractors. The depth of the mystical state, not the method of induction, predicts lasting therapeutic benefit, suggesting conscious experience itself is the mechanistic agent of change. This framework proposes that near-critical dynamics may allow field-theoretic and quantum-coherent contributions to consciousness to become detectable.
Preprints.org • Enzo Tagliazucchi • 2 citations
preprint
Serotonergic psychedelics alter conscious awareness, perception, mood, emotion, and cognition, but their effects resist simple classification like stimulant or sedative. Their defining feature is temporarily inducing an altered state of consciousness. Because only humans can explicitly report conscious experiences, studying these compounds requires non-invasive neuroimaging techniques in healthy subjects. This review examines how neuroimaging has been applied to investigate the neural correlates of altered consciousness caused by serotonergic psychedelics.
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.
Research Square • Ulrich Gergs, Hannes Jacob, Pauline Braekow et al. • 1 citation
LSD increases the force and rate of heart muscle contraction by activating H2-histamine receptors in humans, and also acts as a partial agonist at 5-HT4 serotonin receptors in mice. In human atrial tissue from heart surgery patients, LSD's contractile effects were blocked by cimetidine, an H2-receptor antagonist. These findings clarify the cardiac effects of LSD, which is being studied again for psychiatric uses.
Research Square • Taqwa B. Thanoon, Zeina A. Althanoon
Depression during pregnancy can harm offspring brain development and behavior. Common antidepressants like SSRIs carry risks because they cross the placenta. Ketamine is being explored as an alternative. This study in mice examined the effects of ketamine on offspring of mothers that experienced stress. Female mice were divided into groups: control, maternal stress, stress plus fluoxetine, and stress plus ketamine. Behavioral tests measured anxiety, anhedonia, and despair in the offspring. Maternal stress increased anxiety-like behaviors, and both ketamine and fluoxetine reversed some effects. However, fluoxetine was more effective at reducing despair. Ketamine moderately reduced anhedonia compared to controls. More research on dose and timing is needed to optimize ketamine treatment.
Tony Montgomery
A simple endogenous tryptamine can profoundly alter perception and self-modeling. The Birth Echo Hypothesis proposes that during a narrow perinatal window around delivery, a convergence of stress, sensory novelty, and neuromodulators biases encoding of high-salience sensorimotor templates. In adulthood, exogenous DMT may reconfigure brain dynamics via 5-HT2A and sigma-1 receptors, making these preverbal templates accessible as archetypal, emotionally intense, synesthetic content. DMT is framed as a co-modulator within an evolved perinatal regulatory ensemble. Testable predictions include adult DMT phenomenology showing perinatal-consistent motifs, neonatal EEG/fMRI state-space similarity to adult DMT states, and peri-parturient biospecimens revealing DMT-pathway marker co-variation. The hypothesis reframes psychedelic phenomenology as structural re-expression of early sensorimotor templates.
Burton J. Tabaac, Kenneth Shinozuka, Anne Weisman et al.
preprint
5-MeO-DMT, a psychedelic found in toad venom and some plants, shows rapid antidepressant effects in early clinical trials. A Phase 2b trial reported that 57.5% of participants with treatment-resistant depression achieved remission within eight days. Other Phase 2a and 2b trials suggest it may reduce depressive symptoms more effectively than existing treatments like SSRIs. The substance appears low-risk in controlled settings, though most studies are small and only two double-blind randomized controlled trials have been conducted in clinical populations. Long-term effects need further study, and its possible link to near-death experiences remains debated.
Kenneth Shinozuka, Burton J. Tabaac, Alejandro Arenas et al.
preprint
DMT, the psychedelic in ayahuasca, is being studied for depression. In a double-blind, placebo-controlled trial, ayahuasca led to remission in 36% of patients with treatment-resistant depression within one week. A Phase IIa trial reported that 57% of patients with major depressive disorder experienced remission 12 weeks after a single dose of DMT. DMT is naturally produced in the body, but likely at insignificant levels. The idea that DMT is released during death remains unproven. Ayahuasca can cause temporary vomiting but appears generally safe. More research is needed on DMT's therapeutic and biological roles.
ChemRxiv • Vito Federico Palmisano, Claudio Agnorelli, Andrea Fagiolini et al.
The ability of classic psychedelics to permeate neuronal membranes and reach intracellular 5-HT2A receptors is critical for their therapeutic effects. Using molecular dynamics simulations, this computational study examined how structural modifications to tryptamines affect membrane permeability. Dimethylation of the primary amine group and adding a methoxy group at position 5 increased permeability. In contrast, substitutions at other positions on the indole ring and protonation of the molecules raised the energy barrier at the bilayer center, making the compounds highly impermeable. These findings can guide future drug design to develop psychedelics with enhanced activity.
bioRxiv (Cold Spring Harbor Laboratory) • Hanna M. Tolle, Andrea I Luppi, Timothy Lawn et al. • 1 citation
preprint
A geometric deep learning model called graphTRIP predicts post-treatment depression severity from pretreatment clinical and brain imaging data. Trained on a clinical trial comparing psilocybin and escitalopram, it achieves strong predictive accuracy (r = 0.75) and generalizes to an independent dataset. The model links better outcomes to reduced functional coupling within serotonin systems and broader serotonergic integration with sensory-motor networks. Causal analysis shows a group-level advantage of psilocybin over escitalopram but identifies individuals with specific stress-related neuromodulatory profiles who may benefit more from escitalopram, advancing precision medicine and biomarker discovery in depression.