Two cryo-EM papers offer a design recipe; the efficacy evidence is still mice only.
Weekly Science Digest, 12 Sep 2026 to 18 Sep 2026. 23 papers read, 8 preprints, 4 new trials.
1. Engineering out the 5-HT2B problem
Two cryo-EM studies built 5-HT2A agonists that actively antagonise 5-HT2B.
Comparing the binding pockets of the two receptors gave design rules — steric and conformational constraints in the side-extended and extended pockets — that were then used to make tryptamine and phenethylamine derivatives with the split profile. Selected compounds, including IHCH-2330, showed antidepressant-like effects in rodents.
Blocking 5-HT2A failed to abolish psilocybin's fear-extinction and BDNF effects in mice.
Pretreatment with ketanserin or the selective antagonist MDL100907 left psilocybin's facilitation of extinction, hippocampal and prefrontal BDNF, and dentate doublecortin counts largely intact. Separately, a single 1 mg/kg dose restored novel-mouse investigation in SAPAP3 knockouts seven days later — in males only.
Three papers go after blinding, the word "plasticity", and the main outcomes scale.
A JAMA Psychiatry viewpoint proposes UMBRAA — unidentifiable multidrug blinding with reduced, authorized awareness — to attack the masking problem head-on. Carhart-Harris and colleagues argue that popular neuroplasticity biomarkers often index canalization, the opposite of plasticity proper. And the Persisting Effects Questionnaire, used for decades, turns out not to support its assumed factor structure: it collapses to positive and negative, now with a validated short form.
The week's human data are hypothesis-generating: six interviews and a clinician workshop.
In treatment-resistant OCD, qualitative interviews with three responders and three non-responders from an RCT suggest surrender versus control, and disidentification versus overidentification with OCD, tracked outcome. In a separate study, 48 mental health professionals did a high-ventilation breathwork workshop and rated the induced states as comparable in intensity to moderate psychedelic doses, judging clinical potential to exceed risk.
