The GABAergic Gateway: A Chemist's Hypothesis for Psychedelic Mechanisms

Background: Psychedelic-assisted therapies show promise for MDD, PTSD, and addiction, yet mechanisms are often framed as 5-HT2A-centric, despite evidence of GABAergic pathology in these conditions.Hypothesis (Author Perspective): As a chemist examining psychedelic pharmacology, I propose that inhibitory-circuit modulation acts as a necessary systems-level gate converting transient 5-HT2A activation into acute phenomenology and sustained plasticity.Evidence: (i) Provisional 1H-MRS indicates coordinated mPFC GABA-glutamate recalibration (GABA+ denotes macromolecule-containing edited signal; interpretation requires harmonized pipelines); (ii) critical-period reopening (2 days-4 weeks) outlasts receptor occupancy, implicating downstream gating; (iii) target disorders show robust GABAergic deficits.Predictions: This framework suggests ΔGABA+ should couple to network and gamma changes; post-acute GABA_A positive allosteric modulation (PAM) potentiation should truncate plasticity windows; baseline GABA+ may stratify response.Implications: This perspective suggests treating GABA as a potential gate, not the origin, and encourages integrating 7T MRS, PET, TMS-EEG, and pharmacological challenges.Disconfirmers: The hypothesis would be challenged by an absence of ΔGABA+-network coupling; failure of post-acute GABA_A PAMS to truncate plasticity windows; or no prognostic value of baseline GABA+ after harmonized analysis.Note: This hypothesis paper presents a cross-disciplinary perspective intended to stimulate neuroscience research. Empirical validation by systems neuroscience experts is required.