MM120 (Lysergide) May Enhance Neuroplasticity by Post-Dose Upregulation of TrkB
G. Smagin, J. TrippIntroduction
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 (EC 50 ) 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 (EC
50
0.2 pM). LSD, 25B-NBOMe, and fluoxetine activated TrkB (EC
50
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 (EC
50
0.06 pM) and reduced the activation efficacy to 60%. Other drugs reduced the activation potency, as well as the maximal receptor activation.
Image 1: Long description.