Obsessive Compulsive Disorder (OCD) affects 2-3% of people, causing intrusive thoughts and repetitive behaviors that impair quality of life. Current treatments like cognitive behavioral therapy and SSRIs leave many patients unresponsive. Psilocybin, a psychedelic acting on serotonin receptors, may break rigid neural patterns and reset hyperactive brain networks. In a randomized placebo-controlled trial, participants with severe treatment-resistant OCD received up to 8 doses of psilocybin weekly, with doses varying from low to high. Psilocybin reduced OCD symptoms by 23% to 100%, with improvements lasting weeks to months. Higher doses produced stronger mystical experiences linked to greater symptom reduction. No severe side effects occurred. Despite clinical improvement, no changes in error-related brain activity were observed. Psilocybin appears promising for treatment-resistant OCD in a supportive setting.
Photoswitchable ligands for two class A G protein-coupled receptors (GPCRs) were designed, synthesized, and characterized. For the serotonin 2A receptor (5-HT2AR), a photoswitchable derivative of the psychedelic N,N-dimethyltryptamine (photo-DMT) was created that binds with similar affinities in its cis- and trans-configurations but produces different levels of receptor activation, acting as an efficacy switch. For the muscarinic acetylcholine receptor 1 (M1R), photoswitchable derivatives of the agonist xanomeline, called xanoswitches, were optimized for two-photon near-infrared light activation, enabling bidirectional modulation of neuronal activity in vivo, and for one-photon amber-light activation, allowing control of calcium oscillations and zebrafish motility. The work also presents the first allosteric photoswitch for class A GPCRs, using the M1 positive allosteric modulator BQCA to create Photo-BQCAs that dynamically modulate cooperativity.