The microtubule normalization framework (Leicht, 2026a,b,c) proposes that therapeutic intervention in schizophrenia and Alzheimer’s disease should target the restoration of correct microtubule dynamic instability rather than unidirectional stabilization or destabilization. This addendum presents converging evidence from psychedelic and cannabinoid research demonstrating that psychotogenic substances disrupt microtubule dynamics in both directions: ∆9-THC directly inhibits tubulin polymerization and alters tubulin secondary/tertiary structure (Mohammadkhani et al., 2020, 2025), while psilocybin shifts α-tubulin post-translational modifications toward increased dynamic instability via elevated tyrosination (Maltby et al., 2026). Phenethylamine hallucinogens show structural homology to the microtubule inhibitor colchicine and bind the colchicine pocket on tubulin (Craddock et al., 2023). Critically, MAP6/STOP knockout mice — which lack the primary microtubule-stabilizing protein — display schizophrenia-like behaviors that respond to antipsychotics and to the microtubule-stabilizing agent Epothilone D (Andrieux et al., 2002). Together, these findings support the normalization principle: psychosis can be triggered by deviation from optimal microtubule dynamics in either direction, and the therapeutic goal is not to push the system toward a fixed endpoint but to restore the conditions for self-regulated dynamic instability.
Marko Leicht (Wed,) studied this question.