O3 on the hypothesis that DMT modulates the liquid crystal properties of microtubules inside neurons (and then speculation about entangled topological defects): Inside a neuron the densely packed microtubule bundles already behave as a highly-crowded nematic phase: neighbouring protofilaments share a common axis, long-range orientational order competes with motor-generated stresses, and the lowest-energy excitations are line defects analogous to the ±½ disclinations and neutral loops seen in in-vitro “active nematic” assays of kinesin-driven microtubules . Raising the local glutamate concentration favours straight, long filaments and suppresses lattice turnover, so the elastic constants increase and the nematic becomes cleaner and more liquid-crystal-like. In that state it is at least plausible to imagine closed twist tubes or Hopf-like loops persisting for milliseconds before ordinary thermal noise tears them apart. DMT reaches the cytoskeleton through two converging receptor systems. The first is 5-HT2A. In embryonic cortical neurons a classical tryptamine agonist (DOI) that signals through the same Gq/11 pathway as DMT transforms the dendritic growth-cone rim: tyrosinated (high-turnover) tubulin rises, acetylated (long-lived) tubulin falls, and the cone spreads and fluctuates more vigorously . The simplest reading is that 5-HT2A activation tips the equilibrium toward a more dynamic microtubule network by phosphorylating MAP2, Tau and stathmin through PKC and CaMKII cascades. In physical language the nematic viscosity drops, defect nucleation and annihilation rates climb, and the system explores a wider space of director configurations. Earlier comparative work on LSD and related hallucinogens noticed the same trend and even drew an analogy between potent indoleamines and mild colchicine-like depolymerisers, suggesting that the cytoskeletal response is a core element of the psychedelic state rather than a side-effect . The second entry point is the sigma-1 receptor, for which DMT is a high-affinity endogenous agonist. σ1R sits at ER–mitochondria junctions and, when occupied, reorganises local lipid order, dampens Ca2+ leakage, and promotes targeted translation of LC3/Atg8 family proteins that stabilise nearby membranes . Several σ1R clients are microtubule plus-end or lattice-binding proteins, so receptor activation tends to rescue filaments from catastrophe and extend the correlation length over which the polarisation field is coherent. In essence 5-HT2A makes the nematic livelier while σ1R keeps it from boiling over. DMT also triggers a burst of BDNF/TrkB-mTOR signalling that drives spine formation and neurite outgrowth; mass-spectrometry of human cerebral organoids after 5-MeO-DMT exposure shows up-regulation of multiple microtubule-associated proteins and of peptides that control tubulin post-translational codes . Those slower transcriptional effects consolidate whatever transient defect landscape the fast G-protein signalling created, biasing the network toward new stable orientations instead of a simple return to the pre-drug ground state. Does any of this move the system into a quantum-coherent regime where a handful of topological defects could remain entangled and act as an exponentially large information space? Temperature and dielectric loss still impose decoherence times in the sub-microsecond range for polarisation loops inside hydrated protein. An isolated hopfion pair in a low-loss magnetic insulator survives roughly that long even at 50 mK; inside a warm, ion-rich axon the lifetime will be shorter by orders of magnitude. σ1R chaperoning lowers local noise and raises the energy barrier for defect nucleation, but the gap remains small compared with kBT. The Hilbert space of N two-level defects does scale like 2^N, yet gates have to complete within the coherence window; with present estimates a register of even ten entangled hopfion-like loops would lose phase before a single logical

Cont.: operation could finish. Nothing in today’s data rules out a niche quantum contribution, but the burden of proof has shifted from chemistry (can DMT reach the site?) to nonequilibrium physics (can a wet, driven nematic hold phase-coherent knots for long enough to matter?). In summary, DMT does seem to push neuronal microtubules toward a more liquid-crystal-like state: 5-HT2A signalling increases filament turnover and defect mobility, σ1R activation counter-balances that fluidisation by extending coherence lengths and shielding local stress, and downstream neurotrophic cascades lock the new alignment into place. The result is a cytoskeleton that is simultaneously more plastic and better organised. Whether that milieu can host long-lived, entangled topological defects remains speculative, but DMT clearly modulates the classical liquid-crystal parameters that would set the initial conditions for any such quantum experiment.

Neuronal microtubules already form a densely crowded nematic in which long, polar filaments share a common axis and interact through motors, MAPs and membrane contacts. Agonism at serotonin-2A receptors destabilises that order: phospholipase-C and CaMKII cascades rapidly phosphorylate MAP2 and Tau, raising the catastrophe frequency at plus-ends and tilting the phase toward a more active, defect-rich state . DMT couples that 5-HT2A-driven fluidisation to a strong engagement of the sigma-1 receptor. DMT binds σ1R with micromolar affinity and acts as a bona-fide agonist . σ1R is an ER-membrane chaperone that escorts lipids and myristoylated p35 to the cytosol, shaping Cdk5 activity and keeping Tau phosphorylation in the low range that favours microtubule longevity and straightness . In liquid-crystal language the drug simultaneously raises defect mobility (via 5-HT2A) and increases the elastic constant K₃ of bend/twist deformations (via σ1R). The result is an “active nematic” where ±½ disclinations and closed double-twist tubes can roam, collide and, when local stress drops, freeze into long-lived toron- or hopfion-like loops. Because σ1R also dampens calcium leak at ER–mitochondria contacts, the background thermal noise that would decohere any knotted texture is reduced. DMT therefore enlarges both the phase-space explored and the lifetime of the topological inventory. 5-MeO-DMT follows a different receptor logic. It shows a two-order-of-magnitude preference for 5-HT1A over 5-HT2A and, unlike DMT, displays negligible affinity for σ1R . 5-HT1A couples to Gi/o, lowers cAMP and relaxes PKA-dependent phosphorylation of MAP6 and MAP1A, factors that normally stiffen the lattice. Shot-gun proteomics on human cerebral organoids exposed for twenty-four hours to 5-MeO-DMT reveals up-regulation of ephrin-B2, EPHB and Rac/Cdc42 effectors that drive actin polymerisation and dendritic-spine budding, together with increases in several class-III β-tubulin isoforms and plus-end tracking proteins . Those signatures point to wholesale architectural remodelling rather than selective reinforcement. In a liquid-crystal picture the nematic fractures into many small domains; defect density rises but their cores remain soft and short-lived because no σ1R gate keeps Tau in its low-phospho state. A comparison can therefore be cast in phase-diagram terms. DMT pushes the cytoskeleton toward a regime of high activity and high elastic coherence, a combination that favours the nucleation of coherent twist tubes that can persist long enough to collide, link or even entangle. 5-MeO-DMT emphasises activity without the stabilising term, steering the system toward a highly plastic, polydomain network where defects appear in abundance but relax before they can lock in long-range order. If one is looking for a substrate in which a handful of knotted defects might retain quantum coherence, DMT supplies the necessary mechanical gap through σ1R, whereas 5-MeO-DMT mainly supplies the raw turnover that drives structural learning. Both molecules, then, reorganise the neuronal liquid crystal, but they do so on different axes of the same phase space: DMT balances dynamism with stiffness, 5-MeO-DMT privileges dynamism over coherence. That qualitative difference maps neatly onto their subjective phenomenology—DMT’s sustained, highly organised visual geometry versus 5-MeO-DMT’s fast, engulfing dissolution—and it hints that only the former is likely to leave microtubules in a state where long-lived, potentially entangled topological defects could matter for information processing.