bioRxiv (Cold Spring Harbor Laboratory)
June 30, 2026
Blake A Fordyce, Yi-Ting Chiu, Nicholas A. Wright et al.
Activation of mGluR2, the primary presynaptic autoreceptor for glutamate in the brain, attenuates the behavioral and electrophysiological effects of psychedelics. The mechanisms behind this are debated, with two competing hypotheses: direct actions via mGluR2/5-HT2A heterodimers, or presynaptic inhibition of glutamate release. In mice expressing tagged receptors, mGluR2 agonist pretreatment reduced the head twitch response induced by the psychedelic DOI. Multiple orthogonal in vivo and in vitro approaches found no evidence for receptor colocalization or oligomerization under basal or agonist-exposed conditions, nor for mGluR2-mediated modulation of 5-HT2A ligand binding. The findings support models where mGluR2 signaling modulates 5-HT2A receptor activity in layer V pyramidal neurons rather than requiring mGluR2/5-HT2A multimers.
International Journal of Molecular Sciences
June 26, 2026
M. Fernández‐guarino, Nicolás Yagüe-septién, Laura Marín-ochoa et al.
Several psychoactive compounds produce biological effects on the skin through neurochemical and immune pathways. Topical cannabinoids like THC show anti-inflammatory, antipruritic, and anti-aging properties. The antidepressant fluoxetine regulates pro-inflammatory cytokines in keratinocytes, promotes wound healing and cell regeneration, and may benefit allergic skin conditions. Psychedelics that activate serotonin receptors (5-HTR) can influence cellular aging and immune modulation; 5-HT receptor agonists prevent UV-induced photocarcinogenesis, and psilocybin reduces aging markers in human fibroblasts. Psilocin may alleviate acute itch via the kynurenine pathway. These findings bridge neuropharmacology and dermatology for new therapeutic strategies.
Zenodo (CERN European Organization for Nuclear Research)
June 24, 2026
Ramiro Solis
The brain's ability to rewire itself declines with age, but why remains unclear. This paper examines whether the compound N,N-dimethyltryptamine (DMT) helps maintain neuroplasticity, and whether its decline contributes to age-related loss of cognitive flexibility. DMT promotes synaptic growth and neurogenesis in animals, and levels are reportedly highest during development. However, evidence is mixed: one study finds DMT concentrations comparable to serotonin, while another finds it undetectable in rat brain. DMT's affinity for the sigma-1 receptor is three orders of magnitude higher than physiological concentrations, and a key finding about intracellular 5-HT2A receptor binding has not been replicated. The paper does not claim the hypothesis is established, but proposes a research program to test whether DMT depletion causes lost plasticity or is incidental.
Zenodo (CERN European Organization for Nuclear Research)
June 24, 2026
Enkhamgalan Nasanjargal
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Figshare
June 23, 2026
Elena Bray, Grant C. Glatfelter, Alexander D. Maitland et al.
A new chemical synthesis of 4-bromo-N,N-dimethyltryptamine (4-Br-DMT) was developed, enabling the creation of novel tryptamine molecules with modifications at the C4 position via palladium cross-coupling reactions. This approach facilitates rapid development of a library of compounds for studying structure-activity relationships with serotonergic targets. Compared to psilocin and DMT, 4-Br-DMT exhibits a serotonergic profile but lacks psychedelic-like effects in mice, though it has a reduced safety profile.
Journal of Psychopharmacology
June 23, 2026
Lenka Seillier, Alexandre Seillier, Morgan A. Zvolska et al.
Psilocybin produces rapid and sustained antidepressant-like effects in rats, as measured by reduced immobility and increased climbing in the forced swim test. Blocking the 5-HT2B receptor with the antagonist RS-127445 dose-dependently reversed these behavioral effects, indicating that 5-HT2B receptors are necessary for psilocybin's antidepressant-like activity. However, the same antagonist did not affect psilocybin-induced head-twitch responses, a proxy for psychedelic effects, suggesting that the antidepressant-like and psychedelic effects of psilocybin can be dissociated via different serotonin receptor subtypes.
Zenodo (CERN European Organization for Nuclear Research)
June 22, 2026
Ramiro Solis
The human body has enzymes that both make and rapidly break down DMT, a molecule structurally nearly identical to serotonin that binds to the same serotonin receptors. This raises the question of whether DMT serves an endogenous physiological function or is merely a metabolic byproduct. Evidence is mixed: one report finds DMT concentrations in the nanomolar range comparable to serotonin and dopamine, while another finds DMT undetectable in rat brain. DMT's affinity for the sigma-1 receptor is far weaker than its likely physiological concentrations, and a key finding about intracellular 5-HT2A receptor binding has not been replicated.
medRxiv
June 22, 2026
Roi Basch, Maya Cohen, Leehe Peled‐avron
Serotonin-boosting treatments, such as SSRIs and psychedelics, consistently reduce repetitive negative thoughts like rumination, worry, and obsessions, but do not reliably improve performance on lab tests of cognitive flexibility. A meta-analysis of 2,030 participants across 45 effect sizes found that acute tryptophan depletion did not impair cognitive flexibility, and serotonin elevation did not enhance it. However, serotonin elevation produced a medium-to-large reduction in pathological perseverative thinking. The effect was stronger in samples with more female participants, and psilocybin showed a marginally larger reduction than SSRIs. The findings suggest serotonin's role in emotional and cognitive rigidity is distinct from its effects on objective executive function.
Pharmacological Reports
June 22, 2026
Magdalena Zaniewska
Serotonin (5-HT) is a key neuromodulator involved in mood, appetite, aggression, and impulse control. Dysregulation of central 5-HT function is implicated in alcohol use disorder (AUD) and comorbid depression. Reduced 5-HT activity increases the risk of developing AUD, particularly Cloninger's type II, characterized by early onset, violent, and antisocial behaviors. Tph2-deficient mice, which lack central 5-HT, exhibit increased ethanol consumption and behavioral features resembling type II alcohol dependence. Alcohol-preferring rat lines show reduced 5-HT levels, decreased serotonergic projections to the cortex, and reduced prefrontal 5-HT2A receptor binding. The efficacy of selective 5-HT reuptake inhibitors (SSRIs) is limited, with beneficial effects only in less severe, later-onset forms. Serotonergic psychedelic-assisted therapies may activate 5-HT2A receptors in the prefrontal cortex, a region dysfunctional in AUD.
June 21, 2026
Camille Racca, Cécilie Cordier
A systematic review and meta-analysis will assess the efficacy and safety of classic serotonergic psychedelics and related ergoline or lysergamide compounds—including psilocybin, LSD, DMT, mescaline, methysergide, and others—for cluster headache and migraine. The review will synthesize evidence on changes in headache burden, safety and tolerability, quality of life, and functional impact. If enough comparable data exist, random-effects meta-analyses will be performed separately by headache disorder and compound. The protocol outlines the planned methods but does not yet report results.
Progress in neuro-psychopharmacology & biological psychiatry
June 20, 2026
Zhen Xuen Brandon Low
Autism Spectrum Disorder involves social-communication deficits, cognitive rigidity, and atypical sensory processing, with current drugs providing only limited relief. Dysregulated serotonin signaling, impaired neuroplasticity, and chronic neuroimmune activation are central features. Serotonergic psychedelics like psilocybin and LSD, which act as 5-HT2A receptor agonists, may relax overly rigid cortical priors, reopen critical periods for social learning, and recalibrate neural circuits. They enhance synaptic plasticity via BDNF and mTOR signaling, modulate cortical oscillations, and suppress neuroinflammation. Systems-level frameworks suggest these compounds induce less constrained brain states that counteract hyper-segregated connectivity in ASD. Preclinical and early human studies report improvements in sociability, sensory responsiveness, and behavioral flexibility, but rigorous clinical trials are needed to establish safety and efficacy.
Research Square
June 19, 2026
Aline Frick, Grace Blest‐hopley, Manesh Grin et al.
In a reanalysis of a six-week randomized controlled trial comparing psilocybin with escitalopram for moderate-to-severe major depressive disorder, sex-related patterns emerged for anxiety and anhedonia. Women receiving psilocybin showed greater reductions in anxiety than men, while women receiving escitalopram showed greater reductions in anhedonia than men. For other depressive symptoms, thought suppression, and well-being, sex differences were small and uncertain. Sexual dysfunction severity was lower overall in the psilocybin group than in the escitalopram group and lower in women than in men, though the treatment-by-sex interaction was not significant. These preliminary findings suggest that responses to these serotonergic treatments may differ between women and men, supporting the need for adequately powered, sex-balanced trials.
Naunyn-Schmiedeberg's archives of pharmacology
June 18, 2026
Nicholas V. Cozzi
Deuterium substitution at the ring methoxy positions of the psychedelic drug 2C-B slightly increased its binding affinity at human 5-HT2A receptors, likely due to kinetic isotope effects that dampen molecular vibrations and rotations. However, deuteration did not alter the drug's ability to stimulate intracellular calcium release or recruit β-arrestin 2; all compounds showed similar low nanomolar potency and efficacy in these functional assays. No appreciable metabolism by human liver microsomes was observed for any compound during the experiment.
Cell reports. Medicine
June 12, 2026
Josh Allen, Bianca Jupp, Tamara L Baker et al.
One year after a fluid-percussion traumatic brain injury, male rats showed persistent sensorimotor, learning, memory, and affective deficits; reduced serotonin 2A receptor binding; and microglial changes in the medial prefrontal cortex, including decreased process branching and enlarged soma size. A single dose of psilocybin (1 mg/kg) improved sensorimotor function, restored serotonin 2A receptor binding, and reduced microglial cell counts. These results suggest psilocybin has therapeutic potential for chronic traumatic brain injury and support further investigation of psychedelic treatments.
Journal of pharmacological sciences
June 1, 2026
Daiki Masukawa, Rei Tajika, Yoshimi Ichimaru et al.
Hallucinogens like LSD act mainly through the 5-HT2A receptor, but how they are regulated is not fully understood. GPR143, a receptor for L-DOPA, modulates certain other receptors. In mice lacking GPR143, the hallucinogen DOI caused more hyperactivity and more c-Fos expression in the nucleus accumbens, indicating enhanced effects. In cells expressing the 5-HT2A receptor, adding GPR143 reduced DOI-induced signaling. These results suggest GPR143 dampens 5-HT2A receptor signaling and weakens behavioral responses to hallucinogens.