EPV932
MM120 (Lysergide) May Enhance Neuroplasticity by Post-Dose Upregulation of TrkB
G. Smagin 1,*, J. Tripp 1
1Non-Clinical, MindMed, New York, United States
Introduction: MM120 (lysergide D-tartrate, a formulation of LSD) is under development as a potential treatment for generalized anxiety and major depressive disorders. How psychedelic drugs interact at the TrkB receptor, a key target of neuroplasticity, is not reported.
Objectives: The study evaluated binding and functional activity of known serotonergic psychedelic compounds and SRI fluoxetine at the TrkB receptor.
Methods: Activation of TrkB by brain-derived neurotrophic factor (BDNF) was assessed by measuring inositol monophosphate 1 (IP1) accumulation. NIH/3T3 cells stably expressing human TrkB were used. BDNF was added, followed by incubation with Anti-IP1-Cryptate and IP1-d2. IP1 formation was determined by Homogeneous Time-Resolved Fluorescence (HTRF). We tested LSD, psilocin, N,N-dimethyltryptamine (DMT), mescaline, 2,5-dimethoxy-4-iodoamphetamine (DOI),N-2-methoxybenzyl-phenethylamine (25B-NBOMe), 4-bromo-2,5-dimethoxyphenethylamine (2C-B), methylenedioxyamphetamine (MDA), and the selective serotonin reuptake inhibitor fluoxetine. Activation potencies (EC50) were derived from the concentration-response curves using nonlinear regression.
Results: BDNF was highly potent at the TrkB receptor, activating it in the sub-picomolar range (EC50 0.2 pM). LSD, 25B-NBOMe, and fluoxetine activated TrkB (EC50 of 811, 26370, and 6040 pM respectively) with low maximal efficacies (40, 57, and 60% respectively). All remaining drugs did not activate the TrkB at concentrations <1 mM. Cotreatment with BDNF and a fixed concentration of LSD increased the BDNF-induced TrkB activation potency (EC50 0.06 pM) and reduced the activation efficacy to 60%. Other drugs reduced the activation potency, as well as the maximal receptor activation.
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Conclusions: LSD, 25B-NBOMe, and fluoxetine activated TrkB at pharmacologically relevant concentrations as partial agonists, while psilocin, DMT, DOI, MDA, and 2C-B did not. Induced TrkB upregulation may underly and provide evidence for the neuroplastic effects of LSD.
Disclosure of Interest: G. Smagin Shareolder of: 100%, Employee of: 100%, J. Tripp Shareolder of: 100%, Employee of: 100%