Neural Attunement

The post acute period following psychedelic exposure is theorized through afterglow, canalization, critical period, and recalibrative plasticity accounts; none of those compared here jointly requires a prospectively identifiable, outcome independent construct whose response dynamics are tested under perturbation and whose timing is compared against elapsed time since dosing. Ibogaine is an informative case, since its human neurophysiological evidence falls almost entirely in the post acute window: magnesium ibogaine delivered alongside complementary therapies has been associated with reductions in spatiotemporal neural signal complexity and slowing of peak alpha frequency persisting at least one month. Comparable longitudinal data from classical psychedelics indicate that persistent post acute change extends across compounds, although prospective Level 1 and Level 2 validation and convergence on a shared response architecture remain untested. Here I introduce the Neural Attunement Model, which separates three analytic levels. Level 1 is a person specific, persistent, and reproducibly occupied physiological configuration, identified from resting markers after acute effects resolve, and does not yet establish a shared cross person phenotype or equivalence class. Level 2 is the Neural Attunement phenotype, formed from those Level 1 configurations showing a preregistered alteration of response dynamics under standardized perturbation that covaries with expression of the configuration; whether those phenotypes share one cross person mapping is tested separately. Level 3 classifies functional outcome independently as adaptive, neutral, or maladaptive, and remains indeterminate where evidence is insufficient, so a reproducible state carries no presumption of benefit. Each claim carries a prespecified failure consequence, so a failed scope or auxiliary claim narrows the framework rather than rejecting it. The framework predicts baseline dependent, individual specific expression, tested against a fixed direction model out of sample, and treats state, plasticity, and functional outcome as unfolding across non identical timescales. Its central translational claim is that the interval of heightened susceptibility may be readable from the nervous system rather than inferred from a calendar, so that using candidate configuration probability to schedule structured intervention is justified only if it adds information beyond elapsed time since dosing. Ibogaine is the current empirical anchor, where CYP2D6-dependent parent exposure and the longer lived metabolite noribogaine may extend pharmacological influence into the post acute interval.

Keywords: neural attunement; ibogaine; post acute plasticity; metaplasticity; predictive processing; EEG complexity; adaptive tuning; individualized biomarkers.

Introduction

Psychedelic class compounds produce acute perturbational effects that have been extensively characterized. A synthesis of 48 studies and 1,774 participants characterized subacute effects from one day to one month after classical psychedelic exposure and identified consolidation and psychotherapy during that interval as open questions (Evens et al., 2023). Less attention has focused on the neurophysiological configuration of that period and whether it can be identified prospectively. Ibogaine is an informative case because its anti withdrawal effects have been documented for decades, its delayed clinical trajectory is accompanied by post acute human neurophysiological change, and its existing human data fall almost entirely within the post acute window (Alper et al., 1999; Alper, 2001; Lissemore et al., 2025). Early medically supervised case reports recorded conventional EEG around ibogaine administration and reported no abnormality (reviewed in Köck et al., 2022), but modern quantitative acute human EEG and neuroimaging data suitable for comparison with post acute findings are lacking, and quantitative human evidence is restricted to the sub acute and post acute periods (Lissemore et al., 2025; Cherian et al., 2024). The comparisons developed here therefore concern temporal regimes, not compound classes. The Neural Attunement Model incorporates the acute state, for which entropy based accounts are well established (Carhart Harris et al., 2014; Schartner et al., 2017), as an input condition without proposing an alternative theory of it. Its novelty lies in how it treats that period: as an individually detectable state regime rather than a time interval, one that does not earn phenotype status from resting physiology alone, that must show altered response dynamics under perturbation coupled within person to its own expression, whose functional value is classified separately from its identity, and whose translational worth depends on whether it improves intervention timing beyond elapsed time. Reduced to its questions, the framework asks whether a reproducible state exists, whether it carries altered response dynamics, and whether knowing it improves what is done next.

Two recent accounts cover adjacent ground. Carhart Harris et al. (2026) propose that an acute state of heightened context sensitivity favors a downstream recalibrative shift away from phenotypic canalization, with neuroplastic change entrenching rigidity where that shift fails. The Allostatic Reset Model proposes that acute sympathetic activation and destabilization are followed by a compensatory plasticity associated phase spanning several levels of description (Lawrence et al., 2026, preprint). Neural Attunement converges with the first on context dependent directionality and possible maladaptive outcome, and with the second on a distinct period of recalibrative change after acute perturbation, but its claim is narrower than either and differs on the points set out in Table 1. The terms used throughout are defined in Table 2. The phenotype name is earned rather than assumed, applying only after Prediction 4 shows that challenge response dynamics change and that the change is coupled to the configuration, and it is used in the state phenotype sense, an observable, dynamically validated expression of the system rather than a stable trait.

Claims are of three kinds, each with a different consequence on failure: constitutive claims, scope claims, and auxiliary hypotheses. Candidate implementations are mechanisms rather than claims. Two claims are constitutive: that a reproducible post acute configuration exists at a nontrivial prespecified prevalence, and that it demonstrates altered response dynamics under standardized challenge that covary with expression of that configuration. The existence claim, tested by Prediction 1a, is anchored to magnesium ibogaine as delivered in the derivation protocol and is established before any perturbational domain is chosen. It has two subcriteria, reported separately: detection, in which post acute observations separate from repeated individual pretreatment observations beyond expected variability and the named nonspecific comparators, and occupancy, in which an occupancy model explains them better than prespecified trajectory alternatives. Detection without occupancy establishes post acute reorganization but not a state. Individual existence and population level support are distinct, so study level support additionally requires the proportion meeting both subcriteria to exceed a registered population support criterion. Predictions 4A and 4B are domain specific constitutive tests of phenotype status. The full hierarchy, including what each failure rejects, the anchor replication and transport study classes, and the multi domain rule, is set out with Table 3.

Four claims are scope claims, tested by Predictions 1b, 3, 4C, and 6: cross person transport of the configuration, individualized rather than fixed direction modeling, a shared cross person response law, and timing information beyond elapsed time. Each defines how far the model extends and what can be built from the candidate configuration or the validated phenotype, and failure of any narrows what the framework claims without rejecting it. Prediction 2 is a supporting empirical prediction of the individualized scope claim rather than a separate claim. Two auxiliary hypotheses concern the post acute trajectory and its upstream determinants rather than the phenotype: that the trajectory stabilizes rather than merely persisting, and that acute context alignment contributes to subsequent reorganization (Prediction 5); failure of either removes a proposed feature and leaves the configuration and phenotype intact. Candidate implementations are the mechanisms that might realize any of these claims, including glutamatergic and excitation inhibition changes, calcium signaling, neurotrophic and monoaminergic modulation, predictive relaxation, and myelin remodeling; none is required. Table 3 states each prediction and its failure consequence in full.

The Neural Attunement Model describes a mechanistically informed process in which neural activity, starting from the individual's pretreatment operating regime, progresses through perturbation, transition, and candidate stabilization, yielding a candidate post acute configuration as defined in Table 2. Stability is not sufficient to establish therapeutic benefit: pathological priors, compulsive motivational states, and trauma related threat configurations can themselves be highly stable, so persistence and adaptiveness are separate properties requiring separate measurement (Davidson & McEwen, 2012; Lüscher & Malenka, 2011). The electrophysiological expression of the configuration is hypothesized to depend partly on pretreatment state, individual neurophysiology, and the functional domain under study, including pretreatment dysfunction where present (Gao et al., 2017; Davidson & McEwen, 2012).

Table 1 sets out the relationship to each neighboring framework; three points require statement. First, brain entropy is not a single quantity: fourteen published fMRI entropy metrics were weakly intercorrelated and did not index a single construct, so claims about entropy hold only for the metric used (McCulloch et al., 2026). Second, REBAS already names the post acute extension of the entropic and REBUS accounts (Zeifman et al., 2025); the present framework addresses the state in which such revision may consolidate rather than its content. Third, predictive processing accounts of psychopathology as failed precision weighting extend to trauma as a collapse of metastability (Huys et al., 2016; Kotler et al., 2026); the evidence on post acute predictive suppression is set out below (West et al., 2026b, preprint). What separates the present framework from the frameworks compared here is methodological rather than mechanistic, and several of its individual requirements have precedent: mediational and recalibrative plasticity already specifies markers in advance, separates upstream from downstream constructs, classifies outcome categories, and states explicit weakening and falsification conditions. The conjunction is what differs: among the frameworks compared here, none jointly requires that the state be identified independently of outcome, that resting identification be insufficient for phenotype status, that altered dynamics be demonstrated under perturbation and coupled within person, that functional valence be classified separately, that cross person equivalence be demonstrated, and that timing value exceed elapsed time.

Table 1

Relationship of Neural Attunement to Existing Psychedelic Frameworks

Note. Each framework addresses a different temporal phase or level of description. Core claims, temporal focus, and key citations for every row are given in full in Supplementary Table S2. The annealing row describes a metaphor used within canalization accounts rather than a separately named formal framework. Recent evidence indicates that acute desegregation on conventional measures can coexist with structured, context aligned organization on temporally resolved measures (Stoliker et al., 2026). The Neural Attunement Model is positioned as complementary, specifying candidate properties and tests of a candidate post acute configuration in electrophysiological terms, with the neurophysiological expression of that state hypothesized to be partly individual specific and its functional tuning outcome classified independently as adaptive, neutral, maladaptive, or indeterminate. ARM = Allostatic Reset Model; MR P = mediational and recalibrative plasticity; REBAS = revised beliefs after psychedelics; REBUS = relaxed beliefs under psychedelics.

Table 2

Terms and Their Referents

Note. Terms are defined for use in this manuscript. Level 1, Level 2, and Level 3 refer to the three levels of evidence set out in Figure 1 and in Operational Criteria.

The initial human electrophysiological evidence derives primarily from a single open label observational cohort of 30 male Special Operations Forces veterans receiving magnesium ibogaine alongside complementary therapies. The functional neuroimaging, structural morphometric, and frequency resolved network analyses come from that same cohort, which is within cohort multimodal triangulation and not independent convergence (Lissemore et al., 2025; Cherian et al., 2024; Geoly et al., 2026; Sridhar et al., 2026; Shinozuka et al., 2026, preprint). Structural imaging in those participants found increased cortical thickness, subcortical volumetric expansion, and predicted brain age reduced by 1.3 years at one month, with the authors noting that T1-weighted measures are sensitive to nonstructural change and that no control condition was included (Geoly et al., 2026). It is additional measured brain change in the derivation cohort, not independent replication, evidence of synaptic remodeling, or validation of the proposed state. Clinical improvement therefore cannot be attributed to magnesium ibogaine independently of psychotherapeutic, environmental, expectancy, and procedural influences. Because that cohort also supplied several of the observations used to construct the framework, associations within it are derivation evidence rather than independent validation, and replication, prospective prediction, and out of sample model comparison are required before the proposed markers can be considered validated.

Three kinds of ordering are distinguished. Acquisition order is fixed: acute exposure precedes any post acute observation. Evidentiary order is fixed by the framework: Level 1 must be established before Level 2 phenotype status can be granted. Biological causal order is not assumed, since plasticity, resting reorganization, learning, pharmacology, and environmental input may overlap. The framework therefore treats the candidate configuration as the product of processes ordered in the first two senses, preceded by an acute perturbational phase (Figure 1) during which large scale organization becomes less modular on time averaged measures while becoming more tightly aligned to experiential context on temporally resolved measures (Stoliker et al., 2026). These are one state at two analytical scales, and neither alone establishes anything durable. The system then passes through a transition in which context aligned organization may consolidate, redirect, weaken, or be replaced. The acute resolution criterion sets the operational start of post acute measurement; the biological processes that contribute to the later state may begin earlier, during acute exposure.

Figure 1

The Neural Attunement Process: Acute Input, Continued Tuning Susceptibility, Three Levels of Evidence, and Functional Classification

Note. The acute phase is an input condition rather than a component of the post acute state, represented at two analytical scales because conventional aggregate and temporally resolved measures of the same state diverge (Stoliker et al., 2026); the acute features shown are empirical examples and are measure-, context-, and compound dependent, not universal. The three shaded levels correspond to the three levels of evidence in the Operational Criteria. Level 1 identifies a candidate configuration from persistent resting markers and establishes nothing about its response dynamics. Level 2 licenses the Neural Attunement phenotype only when reproducibly altered response dynamics under standardized challenge covary within person with expression of the Level 1 configuration; covariation licenses the claim that the configuration indexes those dynamics, not that it produces them. Level 3 is determined by independently measured outcome and may remain indeterminate where functional measurements are insufficient or conflicting. The components operate across overlapping but non identical timescales. Durable markers were observed at 3.5 days and 1 month and early markers at 3.5 days; timepoints are provisional, and marker directions are group level findings in the magnesium ibogaine anchor cohort, not specifications of individual trajectories.

The framework distinguishes two candidate biological process components and one independently measured functional classification. These are separate from the evidentiary levels in Figure 1: the process components describe candidate biological operations, whereas the levels specify what evidence is required to identify the configuration, validate the phenotype, and classify functional consequence. The first is a reproducible post acute reorganization persisting beyond expected measurement variability, measured through aperiodic slope, oscillatory power, neural complexity, and peak alpha frequency (Lissemore et al., 2025; Gao et al., 2017; Donoghue et al., 2020). The second is altered thresholds for subsequent synaptic change, a reopened social reward learning critical period in mice (Nardou et al., 2023), and activity dependent consolidation in which contemporaneous activity and experiential salience may bias which trajectories are reinforced (Jiang et al., 2026; He & Ron, 2006; Marton et al., 2019). The third is functional outcome, assessed independently of state identification through the measures set out in Operational Criteria (Huys et al., 2016; Kotov et al., 2017; Reynolds & Berridge, 2008).

The three differ in epistemic status. The reorganization markers are measured directly in longitudinal human EEG. Stabilization is an interpretation of those markers that current sampling density cannot establish. Directional tuning rests on causal preclinical and associative human evidence. Functional outcome has been measured in humans, but Level 3 classification in relation to a prospectively validated configuration or phenotype remains untested, and is prospectively classified as adaptive, neutral, or maladaptive, with classification remaining indeterminate where the available evidence is insufficient or conflicting.

The acute state enters the framework as an input condition rather than as a component of the post acute state. Three propositions organize the subsections that follow, and none of them is a constitutive claim of the framework: that acute reconfiguration is structured rather than uniformly disintegrative, that what the acute state is aligned to may bias what is subsequently consolidated, and that predictive constraint may remain relaxed once the acute state has resolved.

Acute Network Reconfiguration as a Precursor to Post Acute Reorganization

Acute states involve structured reconfiguration of large scale organization rather than uniform disintegration: across multiple agents, transmodal unimodal connectivity increases, within network reductions are most consistent in visual and somatomotor subnetworks, and dorsal striatal coupling with unimodal cortex increases, interpreted as a flattening of the cortical processing hierarchy (Girn et al., 2026). That reconfiguration is not uniform across compounds or measurement domains. In awake rats, mescaline produced cerebellar selective BOLD suppression despite widespread hyperconnectivity, with altered evoked responses to rewarding olfactory input (Cavallaro et al., 2026); that study is acute, in rats, and its relevance here is methodological, since resting connectivity and evoked response gave different pictures of the same state. Modeling aligns psilocybin's shaping of slow cortical propagation with 5-HT2A distribution (Mäki Marttunen, 2026), but the acute oscillatory profile is not uniform across studies either.

Reported acute effects range across increases in beta and gamma power (Ip et al., 2026), decreases in beta with modest frontal gamma increases (Stoliker et al., 2026), a biphasic beta pattern (Sutherland et al., 2026), and an acute gamma increase (Lyons et al., 2026), so the acute to post acute contrast is drawn most confidently for signal complexity and peak alpha frequency. Time averaged descriptions such as reduced modularity do not exhaust what is organized about the acute state: in a large single site acute dataset, per participant modularity fell under psilocybin in all four contexts yet predicted neither mystical experience scores nor next day mindset change, while trajectory structure recovered from the same data by contrastive embedding predicted both, with stronger subjective effects accompanied by tighter within condition clustering rather than the diffuse trajectories increased random variability would produce (Stoliker et al., 2026). Desegregation on conventional measures and structured, context sensitive organization on temporally resolved measures therefore coexist in the same acute state.

The distinction from acute reconfiguration is one of function rather than order versus disorder: the acute phase reveals and may bias context dependent organization, while the post acute phase concerns whether and how that organization relates to subsequent consolidation.

From Acute Context Alignment to Post Acute Consolidation

The transition can be described more specifically, though the available human evidence is associative rather than causal. Three results converge at three timescales. The degree to which acute neural trajectories differentiate experiential contexts correlates with next day psychological change, selectively with self dissolving and boundary dissolving effects rather than sensory hallucinogenic effects or anxiety (Stoliker et al., 2026). Acute cortical signal entropy predicts one month well being improvement, mediated by next day psychological insight (Lyons et al., 2026). In naturalistic group psilocybin sessions, high dose participants given a compassion imagery task before dosing reported higher absorption at 30, 90, and 180 days than those given a breathing task, with imagery related connectivity distinguishing conditions only at high dose (Pallavicini et al., 2026).

These findings are consistent with a specific transition mechanism: what the acute state is aligned to may constrain or bias what the post acute window subsequently consolidates. Two limits should be noted. First, the Stoliker imaging is entirely acute and its brain behavior relationships are correlational, so it is a conceptual bridge to the post acute claim and not evidence for it: it establishes neither a persistent resting representation, nor stabilization, nor a post acute window. Secondly, the Pallavicini study was naturalistic, unrandomized, not preregistered, and its authors described it as exploratory. Causal evidence that experiential context directs consolidation is therefore absent in humans, and the strongest causal evidence for activity dependent directionality is preclinical: silencing a presynaptic region during psilocybin administration disrupts the expected pattern of activity dependent rewiring (Jiang et al., 2026). This is why Prediction 5 is stated at two levels, observational and causal.

The transition is therefore more continuous than a strict partition implies. The hypothesis is not that organization begins in the post acute period, but that durable stabilization may emerge there, biased upstream by context and experience during the acute phase.

Persistent Predictive Relaxation as a Candidate Mechanism of Post Acute Tuning Susceptibility

West et al. (2026b) report reduced predictive suppression in individuals who had used psilocybin or LSD within the preceding three weeks relative to matched controls, expressed as fewer fast saccades and as reduced suppression of delta and theta power to predictively presented stimuli, with convergent findings after 5-MeO DMT. In mice, reduced predictive suppression remained evident 24 hr after 1 mg/kg psilocybin alongside weakened anterior cingulate modulation of primary visual cortex and spine growth in that projection population. This supplies a candidate mechanism linking acute perturbation to later consolidation: the post acute interval may remain unusually susceptible to tuning under persistently reduced top down predictive constraint. The human findings are cross sectional and associative, the causal circuit evidence is preclinical, and neither establishes that post acute predictive relaxation produces therapeutic improvement or maladaptive change. The interpretation therefore remains provisional, and what it motivates is the testable proposition that subsequent experience and activity remain mechanistically relevant after the acute state has ended.

Why Ibogaine Anchors the Model

Ibogaine anchors the framework empirically rather than theoretically, providing a detailed longitudinal post acute electrophysiological dataset, though the framework itself is not ibogaine specific. Its parent half life is strongly CYP2D6-dependent rather than uniformly long: at a single 20 mg dose it was 2.5 hr in placebo pretreated and 10.2 hr in paroxetine pretreated subjects, with noribogaine at 13.0 and 20.1 hr respectively (Glue et al., 2015), so post acute pharmacological influence rests on the metabolite and on metabolizer status rather than on the parent compound, and exposure at therapeutic doses was not characterized in the anchor cohort. The sigma-2 affinity on which the sigma pathway rests was characterized for parent ibogaine (Mach et al., 1995); the metabolite was profiled separately and its binding is similar but not identical (Staley et al., 1996). Ibogaine engages NMDA receptors, sigma receptor pathways, and downstream neurotrophic systems including GDNF and BDNF in mesocorticolimbic circuits (Popik et al., 1995; Glick & Maisonneuve, 1998; He & Ron, 2006; Iyer et al., 2021; Marton et al., 2019).

Ibogaine and noribogaine inhibited VMAT2 with submicromolar potency, and noribogaine also inhibited SERT with comparable potency, identifying it as a prototype reuptake inhibitor defined by dual modulation of vesicular and plasma membrane monoamine transport (Hwu et al., 2026). Because VMAT2 and SERT shape monoamine dynamics involved in reward valuation, salience assignment, and affective regulation, this multi target profile is relevant to the valuation processes described below. It is not offered as a basis for the extended post acute signatures, because in vitro potency cannot be bridged to an electrophysiological change at one month without an exposure to potency comparison that has not been made. The absence of acute monitoring in the available cohorts also prevents comparison with ibogaine's own acute profile, and the post acute signatures observed after magnesium ibogaine have been less extensively characterized in classical psychedelic datasets.

The Post Acute Phase as a Distinct Temporal Regime

Entropy based models propose that therapeutic change arises in part from acute increases in neural disorder, signal diversity, and selective network disintegration (Carhart Harris et al., 2014; Schartner et al., 2017), though mega analytic evidence indicates that acute within network disintegration is more selective than originally proposed and better characterized as structured cross network reconfiguration (Girn et al., 2026). The claim advanced here concerns a different interval. The three subsections below set out what has been measured after the acute state resolves: reduced spatiotemporal complexity, an oscillatory profile that differs from the acute one, and partial convergence across compounds.

Post acute reductions in neural signal complexity

Human electrophysiological studies indicate that magnesium ibogaine administration, in an open label protocol delivered alongside complementary therapies, is associated with sustained reductions in spatiotemporal Lempel Ziv complexity at 3.5 days and one month (Lissemore et al., 2025), in contrast to the acute increases reported during the drug state with classical psychedelics (Lyons et al., 2026). The reduction is specific to complexity computed across electrodes: after accounting for spectral power, within electrode temporal complexity was unchanged, so the effect was a change in the diversity of activity patterns across cortical sites rather than in the irregularity of activity at any one site (Lissemore et al., 2025). Reduced complexity is neither inherently pathological nor by itself therapeutic, since comparable reductions occur under general anesthesia (Schartner et al., 2015), and Carhart Harris et al. (2026) propose increased complexity as the acute marker of heightened phenotypic plasticity. The two claims concern different intervals and are compatible, but a post acute complexity reduction must be shown not to be a reduction in vigilance, which the discriminant validity condition in Prediction 1 requires; in the anchor cohort the reductions co occurred with preserved or improved cognitive inhibition.

Post acute oscillatory signatures differ from acute entropic profiles

Acute psychedelic states increase signal diversity (Schartner et al., 2017), with psilocybin at peak effects decreasing theta and alpha and increasing beta and gamma (Ip et al., 2026). Following the magnesium ibogaine treatment package, theta and alpha power increased and frontal beta and posterior and frontal gamma decreased at 3.5 days (Lissemore et al., 2025); at one month only the posterior gamma reduction remained significant in the primary normalized analysis, while after removal of the aperiodic component the theta and alpha increases and delta and gamma decreases were significant. The alpha finding requires caution, because a comparable left parietal alpha increase appeared in an age matched external EMBARC reference that the original authors read as a possible placebo contribution. After single dose psilocybin in major depressive disorder, auditory evoked theta power approximately doubled at two weeks and correlated with improvement (Skosnik et al., 2023), making post acute theta increase a candidate recurring feature, although the psilocybin theta literature is not uniform.

Persistent psychedelic effects are not restricted to electrophysiological measures: diffusion tensor imaging one month after a single 25 mg dose of psilocybin shows decreased axial diffusivity in prefrontal striatal and prefrontal thalamic tracts, surviving correction in the left hemisphere only, correlating with decreased network modularity over the same month (Lyons et al., 2026).

Post acute neurophysiological change extends across psychedelic class compounds

Delayed effects are not unique to ibogaine: classical psychedelics exhibit an afterglow window during which connectivity, mood, and behavioral measures continue to evolve for days to weeks. Entropy based, REBUS, and canalization accounts already contemplate such a window (Carhart Harris et al., 2014, 2023; Carhart Harris & Friston, 2019); the present framework adds operational markers for it, and ibogaine's pharmacology may make the window unusually prolonged. Persistent circuit level change follows psilocybin, including lasting hippocampal default mode alterations (Siegel et al., 2024), and EEG from veterans with traumatic brain injury after a psilocybin retreat shows comparable post acute oscillatory normalization in a population overlapping the anchor cohort (Blest Hopley et al., 2025). Convergence is incomplete and measure dependent. In one naturalistic cohort of long term users abstinent at least 30 days, two analyses of the same sample found no group differences in oscillatory power or Lempel Ziv complexity (Wójcik et al., 2026, preprint; West et al., 2026a, preprint). In a double blind placebo controlled crossover study of psilocybin, acute alpha and beta reductions and increased gamma diversity had resolved by six hours, while reduced delta and theta power at 24 hours correlated with positive life changes at four weeks independently of acute intensity (Nikolič et al., 2026), a sub acute window carrying long term signal that contrasts directionally with the post acute theta increase in the anchor cohort. Observed post acute marker expression is therefore measure specific and compound sensitive, leaving open whether different implementations converge on a shared higher order response architecture.

The generalizability claims are ordered and the evidence weakens at each step: that a persistent group level anchor signature follows magnesium ibogaine, which the anchor cohort supports as derivation evidence and which motivates the candidate configuration; that components persist when magnesium is removed, with population held comparable (protocol transport); that they persist outside the derivation population under a comparable anchor protocol (population transport), the only evidence on either axis being one small cohort that changed both at once; that homologous response architectures occur across other psychedelics despite different measured implementations, which is untested; and that the architecture extends beyond psychedelics, which is speculative. A controlled ibogaine study holding population comparability is required before protocol transport can be claimed, a comparable protocol study outside the derivation population before population transport, and cross compound validation before homologous architectures.

Candidate Process 1. Persistent Electrophysiological Reorganization and Candidate Stabilization

Because the post acute period may contain both residual flexibility and emerging stabilization, an account of its evolution must consider systems governing excitation, plasticity thresholds, predictive constraint, and network communication. Glutamate regulates synaptic plasticity, large scale network communication, and excitation inhibition balance, and dysregulated glutamatergic signaling contributes to altered excitability and learning across several psychiatric conditions (Lüscher & Malenka, 2011; Volkow & Morales, 2015; Yizhar et al., 2011). Convergent NMDA, sigma, and neurotrophic actions may shift the operating regime of circuits disproportionately involved in addiction and trauma, and classical psychedelics engage overlapping pathways through distinct receptor profiles. The molecular routes are unsettled and are treated as competing or interacting candidates: direct binding to TrkB has been reported (Moliner et al., 2023), and broad receptor and kinase profiling indicates that multiple targets contribute (Jain et al., 2025). Neither result is required by the framework.

Glutamatergic Signaling as a Candidate Systems Substrate

Glutamatergic signaling is one candidate substrate. The candidate configuration is hypothesized to involve altered excitatory and inhibitory dynamics across distributed networks (Deco et al., 2011; Isaacson & Scanziani, 2011; Davidson & McEwen, 2012), and ibogaine engages those systems through NMDA receptor interactions, sigma receptor modulation, and downstream neurotrophic induction: both GDNF and BDNF are modulated by ibogaine and noribogaine, each linked to lasting mesocorticolimbic change (Popik et al., 1995; Glick & Maisonneuve, 1998; He & Ron, 2006; Carnicella et al., 2010; Marton et al., 2019). Peripheral BDNF currently lacks support as a biomarker of these mechanisms: a meta analysis found no evidence that psychoplastogens elevate blood BDNF (Calder et al., 2025). The cellular level convergence with classical psychedelics is set out in Supplementary Note S3 (Salerno et al., 2026; Dölen & Wilkinson, 2026).

Calcium Dependent Excitability as a Candidate Intermediate Mechanism

Calcium signaling is a candidate transduction layer linking iboga alkaloid pharmacology to excitability and activity dependent plasticity, not an established component of the framework. Two points bear on the framework itself. State dependent calcium responsiveness may be more informative than resting calcium activity as a challenge measure, which places calcium inside the perturbational architecture set out below. Evoked calcium engagement is not a surrogate for durable plasticity, because acute dendritic calcium activity under psilocybin dissociates from subsequent spine formation (Savalia et al., 2026, preprint). No single receptor pathway is posited as sufficient to generate the candidate configuration. The findings, their concentrations, and their limits are set out in Supplementary Note S2.

Downstream neurotrophic systems have been implicated in behavioral effects that outlast acute exposure (He et al., 2005; Carnicella et al., 2008, 2010; Nicolas, 2025), though no direct human measurement of glutamatergic dynamics after ibogaine has been reported. Under psilocybin, 7T magnetic resonance spectroscopy shows regionally specific acute glutamate modulation, increased in medial prefrontal and decreased in hippocampal regions (Mason et al., 2020).

Oscillatory and Network Reconfiguration

Following magnesium ibogaine, reductions in beta and gamma power and increases in theta and alpha power were observed alongside improved cognitive inhibition at the early post acute timepoint. Lissemore et al. (2025) also reported a steeper aperiodic exponent. Excitation inhibition rebalancing is one unconfirmed candidate explanation for this pattern and is not established by it. The exponent is treated here as a descriptive spectral measure whose relation to synaptic excitation and inhibition remains unresolved (Gao et al., 2017; Donoghue et al., 2020): it moves as expected under ketamine and thiopental (Cortes Briones et al., 2025, preprint) but not under GABA A antagonism, parvalbumin suppression (Salvatore et al., 2024), or midazolam (Sutherland et al., 2026). It is retained in the multivariate representation on descriptive grounds alone.

Frequency resolved analysis of the same cohort reports persistent reorganization of high beta (24-25 Hz) networks, shifting activation from left frontal toward posterior cortex at both post acute timepoints, and corticothalamic neural field modeling estimated decreased cortico cortical gain with unchanged cortico thalamic gain, which the authors describe as reduced effective excitatory coupling across cortex (Shinozuka et al., 2026, preprint). The same shift appeared in an independent open label opioid use disorder sample of 10 analyzed participants recorded a median of 12 days after ibogaine without magnesium, reaching cluster level significance in the 25 Hz network only. That sample is small and partially electrode limited, but it is the one piece of the anchor signature not subject to the magnesium confound. Functional neuroimaging of the cohort reports increased regional cerebral blood flow in cortical, limbic, and striatal subregions, with left insula and anterior cingulate perfusion tracking improvement in disability (Sridhar et al., 2026); its relationship to post acute oscillatory change is unresolved.

Persistent electrophysiological reorganization is hypothesized to shape or constrain the conditions under which enhanced plastic capacity with directional tuning is expressed. The two overlap in time, and their causal ordering is an empirical question rather than a framework assumption, since reopened susceptibility to social reward learning does not require the resting trajectory to have settled first (Nardou et al., 2023). Current evidence does not establish that any of this is achieved through a uniform reduction in excitatory drive across individuals, regions, or circuits.

Candidate Process 2. Enhanced Plastic Capacity and Directional Tuning

Across psychedelic class compounds, psychological and physiological effects continue to emerge over days and weeks after the acute drug state, a trajectory particularly well documented for ibogaine (Alper et al., 1999; Brown & Alper, 2018; Noller et al., 2018), and long term follow up of the magnesium ibogaine cohort found reductions in disability, PTSD, depression, and anxiety sustained through 12 months, with Cohen's d of at least 2.18 (Faerman et al., 2026), subject to the limits set out in Limitations.

This delayed trajectory is consistent with metaplasticity, activity dependent change in the rules governing subsequent synaptic plasticity (Lüscher & Malenka, 2011). The direct preclinical evidence is Nardou et al. (2023): psychedelics, including ibogaine, reopen the social reward learning critical period in adult mice through metaplastic restoration of oxytocin mediated long term depression in the nucleus accumbens, with the duration of the reopened period proportional to the duration of acute subjective effects and ibogaine producing the longest open state tested, still open at four weeks, which was the last interval assessed rather than a demonstrated point of closure. A second preparation shows the same interaction in sensory cortex: a single dose of ibogaine in adult mice did not alter visual acuity or dendritic spine density on its own, but when followed 24 hr later by four days of monocular deprivation, the adult visual cortex again showed juvenile like experience dependent plasticity, alongside reduced parvalbumin staining energy, a whole cortex reduction in perineuronal net staining energy that did not reach conventional significance, and fewer vGAT positive inhibitory puncta (Acuña et al., 2026). Monocular deprivation is not psychotherapy, but this is direct causal evidence for the conjunction this candidate process asserts: ibogaine induced a condition in which subsequent sensory experience shaped the expressed plastic response, and the substrate includes the structural and inhibitory brakes associated with critical period closure.

Human EEG supplies candidate post acute correlates overlapping that window without demonstrating metaplasticity. Complexity reduction and peak alpha slowing persist to one month and are treated as durable anchor markers; the oscillatory power effects and the theta/beta ratio increase that tracked improved cognitive inhibition were not significant at one month in the primary normalized analysis and are treated as early markers. Primary findings survived sensitivity analyses for moderate TBI and alcohol use (Lissemore et al., 2025), and post acute BOLD connectivity change in the same cohort (Sridhar et al., 2026) partially overlaps with that reported after a DMT harmine formulation (Egger et al., 2025). Because the relationship between neural variability and function is not monotonic (McDonnell & Ward, 2011; Garrett et al., 2011), the proposal is narrower: in the cohort studied to date, reduced diversity of activity patterns across cortical sites accompanies improved cognitive inhibition and reduced arousal related symptoms, and that conjunction, rather than reduced variability as such, characterizes the anchor pattern that motivates the candidate regime. Whether it alters the selectivity or durability of subsequent learning is untested.

Mystical type experiences during magnesium ibogaine are associated both with PTSD improvement and with persistent decreases in peak alpha frequency, linking acute subjective experience to a persistent post acute marker (Brown, T. K., et al., 2019; Brown, R. E., et al., 2026; Lissemore et al., 2025). Acute mystical experience and post acute physiology are each associated with aspects of subsequent outcome in the available cohort, but their independent and potentially mediating contributions have not been established within a common prospective model. Acute experience may influence which material becomes a candidate for consolidation, while post acute physiological conditions influence which of those changes is retained; these are temporally distinct contributions, and current human evidence establishes the causal necessity of neither (Alper, 2001; Popik et al., 1995; Cherian et al., 2024).

Experience dependent plasticity provides mechanistic precedent, but the specific interaction has not been demonstrated prospectively in humans (Lüscher & Malenka, 2011; Huys et al., 2016), and subjective experience is not proposed as the sole initiator: pharmacological mechanisms alter plasticity capacity and learning thresholds through GDNF induction and downstream dopaminergic remodeling (He & Ron, 2006; Carnicella et al., 2010; Marton et al., 2019) while ongoing activity drives plastic change independently. The directional function is what matters for Candidate Process 2. Experiential salience may bias which available plastic trajectories are consolidated; that bias is not assumed to be therapeutic since the same mechanism permits consolidation of maladaptive reorganization, and which occurs is an empirical question rather than a property of the window.

Activity Dependent Consolidation During the Evolving Post Acute State

Rodent evidence supports the principle that plasticity operates under directional constraint, and it does so with cell type specificity: psilocybin rewires subcortical projecting and intracortical projecting pyramidal populations in opposing directions, and only the subcortical projecting population is required for the behavioral effect (Jiang et al., 2026; Shao et al., 2025). Acute activation is not itself evidence of durable remodeling, because acute dendritic calcium activity under psilocybin dissociates from subsequent spine formation (Savalia et al., 2026, preprint), so engagement and downstream plasticity require independent measurement. The tracing, silencing, and knockout results and their limits are set out in Supplementary Note S3.

Experiential salience is distinct from emotional intensity or generalized arousal: it is the degree to which information is tagged as relevant for future behavior, whether generated internally or shaped by therapeutic context (Volkow & Morales, 2015; Gillan et al., 2016). It may act at more than one point in the therapeutic arc, under different physiological conditions whose relative contribution has not been established in humans (Lüscher & Malenka, 2011; Huys et al., 2016).

The closest empirical precedent for this separation is a randomized placebo controlled crossover study of 100 micrograms of LSD in 45 healthy adults (Calder et al., 2026). Offline motor learning improved the day after LSD and auditory evoked potentials remained modulated one week later, but tetanization and paired associative stimulation produced no reliable potentiation like effect, peripheral BDNF was unchanged, and learning did not correlate with the neurophysiological measures. Persistent physiology, plasticity probes, and improved learning therefore do not cohere by default, which is why the three levels are separated. Experienceless analogs may still produce durable plasticity related change (Cameron et al., 2021, 2023), but whether they alter the rules governing subsequent plasticity has not been shown. A prophylactic chemotherapy model extends the dissociation: psilocybin before cisplatin prevented mechanical hypersensitivity across six cycles, 5-HT2A antagonists abolished the protection, and non hallucinogenic tabernanthalog conferred comparable protection (Heles et al., 2026). The difference appeared in the response to a subsequent insult rather than at rest, precedent for latent change becoming evident only under perturbation, and required no structured input; where the targeted outcome depends on learning, structured input may assume a larger directional role (Supplementary Prediction S2).

The functional domains used throughout this component are illustrative, selected because they are represented in the anchor literature, and are not defining domains of the framework; the Level 3 architecture applies unchanged to depression, obsessive compulsive disorder, chronic pain, or other transdiagnostic contexts. Directional tuning operates within circuits dysregulated in addiction and trauma, where threat related or compulsive cues acquire exaggerated motivational value while adaptive rewards lose influence (Volkow & Morales, 2015; Volkow et al., 2016; Nawijn et al., 2015; Gillan et al., 2016; Lokshina et al., 2021).

An intracranial precedent in male rats, set out in Supplementary Note S3, establishes two propositions relied on here: that dopamine can act as a permissive gain signal, and that environmental and neurochemical conditions can retune which mode a circuit occupies (Reynolds & Berridge, 2008; Faure et al., 2008; Richard & Berridge, 2011). Recalibration is a change in the conditions governing mode selection, not an increase in reward signaling.

A predictive processing account frames this dysregulation as failed precision weighting: hypervigilance as overweighted threat prediction error, anhedonia as underweighted positive prediction error, and addiction as distorted precision assignment to reward cues (Huys et al., 2016; Gillan et al., 2016; Kotler et al., 2026). Adaptive tuning would involve restored context appropriate prediction error scaling, for which the post acute oscillatory profile is a candidate correlate and not evidence of correction (Skosnik et al., 2023; Blest Hopley et al., 2025). The high beta redistribution correlates with PTSD improvement at both post acute timepoints, most strongly on the intrusion criterion (Shinozuka et al., 2026, preprint), so adaptive tuning may involve network level reorganization beyond broadband power, though the functional role of that redistribution is unresolved.

Individual spectral and complexity measures are not specific readouts of threat, salience, or executive control circuitry. Associations between peak alpha frequency, the aperiodic exponent, and PTSD improvement in the anchor cohort motivate circuit level hypotheses but do not establish that any of these directly index normalization of a particular system (Cavanagh & Frank, 2014; Gao et al., 2017; Lissemore et al., 2025; Shinozuka et al., 2026, preprint).

The framework therefore hypothesizes that adaptive tuning may involve improved discrimination between behaviorally relevant and maladaptive signals, weaker compulsive dominance, and more context appropriate valuation (Volkow & Morales, 2015; Gillan et al., 2016). Preclinical reward learning evidence is consistent but disagrees on duration (Hinchcliffe et al., 2026, preprint; Thomas et al., 2026; Supplementary Note S3), and post acute reward effects are compound- and paradigm dependent and, in at least one well powered paradigm, shorter lived than the electrophysiological changes described here. Plasticity induction, reward responsiveness, and clinical change may follow distinct temporal functions, as two recent syntheses support. A systematic review of 62 associative learning studies concludes that learning enhancement extends into the post acute phase and appears to depend on environmental engagement during it, though only two of the studies were human (Caulfield et al., 2026), and a reward learning review argues that learning from reward receipt is enhanced acutely and learning from reward omission more prominently post acutely (Kosted et al., 2026).

Functional Tuning Outcomes: Adaptive, Neutral, and Maladaptive

Plasticity, consolidation, and persistence are not intrinsically therapeutic. A reopened window increases susceptibility to change without specifying direction, and a reproducible configuration may itself be pathological, so state identification is silent on functional value and outcome is classified independently as adaptive, neutral, or maladaptive. Adaptive tuning requires prespecified improvement in relevant functional or clinical measures. Maladaptive tuning requires prespecified worsening or reinforcement of dysfunctional salience, threat, compulsive, or behavioral patterns. Neutral requires positive evidence of practical equivalence rather than a failed significance test: the confidence interval for change must fall entirely inside a prespecified region of practical equivalence, whose boundaries may be informed by a minimal clinically important difference, a smallest effect size of interest, or a reliable change index, none of which is itself evidence of equivalence. Classification remains indeterminate when the available measurements are insufficient to place the result inside or outside that region, or when domains conflict. Classifications are specific to a domain and to a time horizon. The primary classification timepoint or interval is preregistered, and a later reversal, such as reduced threat responsiveness that first lowers distress and later impairs threat discrimination, is reported as a separate classification at that horizon rather than retroactively redefining the earlier one.

The question of when a plasticity related process is adaptive rather than maladaptive is not new; canalization and recalibrative plasticity accounts treat the same learning mechanisms as capable of either outcome depending on context (Carhart Harris et al., 2023, 2026). The contribution here is the separation of state identification from outcome classification, which permits the two to be measured independently and makes therapeutic context mechanistically relevant without assuming that experience alone determines outcome. The probability of adaptive versus maladaptive tuning is predicted to depend on interactions among pretreatment state, altered plasticity, ongoing activity, salient experience, environmental input, and their timing. The clinical objective is therefore to identify a period of increased susceptibility to tuning and to bias that process toward independently validated adaptive functional change, rather than to induce plasticity or stabilization as such.

Three terms are used distinctly throughout and are not interchangeable. Persistence means the configuration remains detectably different from pretreatment across separated observations. Stabilization means the longitudinal trajectory itself demonstrates settling or constrained evolution rather than arbitrary fluctuation, transient excursion, or return toward baseline. Altered response dynamics means that the mapping from perturbational input through response to recovery is reproducibly changed under standardized challenge; regulation is not used here, because it denotes performance against a defined target and the framework specifies none. Independently measured function then classifies the resulting trajectory as adaptive, neutral, or maladaptive. Maladaptive tuning is not a default explanation for absent therapeutic response. It is supported only when a candidate post acute configuration is independently identified and prespecified measures demonstrate worsening or reinforcement of maladaptive function; failure to improve without such evidence is neutral or indeterminate.

Discussion

Four points orient what follows. The anchor evidence establishes group level persistence of selected post acute electrophysiological effects. Level 1, reliable separation of an individual's post acute observations from that person's own pretreatment distribution together with reproducible occupancy, has not been prospectively validated in any cohort. Level 2 has not been tested: the anchor cohort completed standardized cognitive assessment, but no standardized perturbation with the response and recovery measurements Level 2 requires has been administered after ibogaine. The claim that distinguishes the framework in translation is Prediction 6, that measured state carries information about sensitivity to structured intervention beyond elapsed time.

The model predicts that post acute stabilization, if it occurs, would involve reproducible multivariate organization not reducible to signal amplitude. Specific cross frequency, phase coupling, and timing relationships can be evaluated electrophysiologically, but assigning them to particular circuits would require source resolved or invasive methods (Cavanagh & Frank, 2014; Gao et al., 2017).

In the anchor cohort, reduced high frequency activity, shifts toward low frequency dominance, and decreased signal complexity jointly indicate a reproducible post acute reorganization, but no single directional change indexes response dynamics or functional value (Gao et al., 2017; Lissemore et al., 2025). Source estimates overlap default mode territories, though EEG spatial resolution precludes network specific conclusions (Lissemore et al., 2025, Supplementary Information), and network modeling supports an intracortical contribution to the high beta reorganization without establishing that the treatment's broader effects are primarily intracortical (Shinozuka et al., 2026, preprint).

Clinical reports of lasting shifts in self regulation, craving, trauma reactivity, and goal directed behavior are consistent with adaptive tuning but do not establish that salience and reward circuitry has been recalibrated (Alper et al., 1999; Brown & Alper, 2018; Noller et al., 2018).

An allostatic interpretation, in which neural systems adapt their operating state to changing demands rather than returning to a fixed setpoint, is compatible with the model but is not among its claims. Under that interpretation, reduced overshoot, faster recovery, and a smaller post stimulus offset for equivalent behavioral demands could constitute adaptive regulation at Level 3, where a target for the system has been independently defined.

The model does not require convergence on an identical electrophysiological endpoint across individuals. Stable person specific structure is established in functional connectivity, precision functional mapping, and the aperiodic component of the power spectrum (Finn et al., 2015; Gordon et al., 2017; Demuru & Fraschini, 2020), and neural degeneracy permits similar functional outcomes to arise from different underlying configurations (Noppeney et al., 2004). A transdiagnostic account of psychotic symptoms argues similarly, proposing that disturbances across several neurotransmitter systems converge on shared computational vulnerabilities expressed as abnormal integration and segregation dynamics and unstable attractor states (Braun et al., 2026). That is precedent in another clinical domain, not evidence for a post acute psychedelic state. Widely divergent parameter combinations can produce closely comparable network output (Prinz et al., 2004), and homeostatic tuning rules generate correlated ion channel expression while individual conductances vary substantially (O'Leary et al., 2013).

Multidimensional brain health indexing provides a measurement precedent, evaluating longitudinal change against an individual's own baseline rather than a population average (Cook et al., 2026; Honea et al., 2026). These are precedents from systems and cognitive neuroscience, not evidence about post acute psychedelic states, and they establish only that individual specific implementation of a shared function is an ordinary property of the nervous system.

The framework therefore distinguishes a generalizable response architecture from its individual neurophysiological expression. Pharmacological responsiveness may itself be state dependent. Across three independent event related potential studies, baseline mismatch negativity amplitude predicted both the direction and the magnitude of ketamine induced change, a disordinal effect estimated against regression to the mean using a separate drug free test retest dataset (Cecchi et al., 2026). That is a human demonstration, in a different compound class, of the baseline dependent directionality Prediction 2 asserts. The magnesium ibogaine cohort therefore provides an anchor group level pattern rather than a universal template.

This individualized formulation is falsifiable only if tested by prediction rather than description. Models built from person specific baseline state and within person change must predict the perturbational parameters of Prediction 4 more accurately than a fixed directional group signature in held out or external data. The target is the perturbational parameters rather than the Level 1 configuration, because both competing models are built from the same resting features: Prediction 1 freezes the predictor representation and Prediction 4 supplies a target neither model helped build, with the cross fitting requirement given in Supplementary Note S1. The result supports individualized Neural Attunement phenotype architecture only where the nominated Prediction 4 target has shown adequate reliability, post acute alteration under 4A, and coupling under 4B. If 4A fails, better prediction of ordinary response variation is an individual differences finding and neither rescues nor validates the individualized formulation. If 4A succeeds while 4B fails, the configuration has not earned phenotype status, and a superior individualized model establishes individual differences prediction from Level 1 features rather than individualized phenotype architecture. Prediction of independently measured functional trajectory is external validation reported separately. Baseline dependent moderation of marker direction is secondary rather than necessary, since an individualized model may outperform a fixed signature through multivariate weighting, interactions, or nonlinear baseline relationships without any marker changing sign. If it does not outperform the fixed direction model out of sample, the simpler cohort level signature is preferred and the individualized formulation rejected.

The current magnesium ibogaine dataset provides an empirical anchor signature rather than a universal endpoint. It demonstrates group level persistence of selected post acute effects across the sampled timepoints, but not Level 1 individual persistence, which requires repeated pretreatment recordings the study did not collect, and not stabilization, since measurements at baseline, approximately 3.5 days, and one month cannot distinguish approach to a stable configuration from oscillation, transient excursion, or early return toward baseline. Stabilization requires denser sampling with repeated pretreatment recordings (Supplementary Note S1). At the group level, durable anchor markers are reduced spatiotemporal signal complexity, computed across recording sites, and slowing of peak alpha frequency; early markers include a steepened aperiodic slope, reduced beta and gamma power, and increased or preserved theta and alpha organization, the alpha finding limited by placebo confounding. Candidate resting markers are persistent resting electrophysiological changes in spatiotemporal complexity, peak alpha frequency, periodic and aperiodic spectral properties, and network topography, which become Level 1 features only once Prediction 1a succeeds.

Response Dynamics as the Constitutive Property

Response dynamics, as defined in Table 2, are the constitutive property, and regulation is not used constitutively. Candidate estimands include gain, damping, latency, recovery constant, post stimulus offset from the pre stimulus baseline, habituation, and trial to trial variability under standardized challenge, selected where the registered model family defines them; the requirement is altered recovery or adaptation architecture rather than estimation of every parameter in every paradigm. These are not self defining, and Supplementary Note S1 specifies the input, response model, estimands and units, identifiability assumptions, sampling, and rival models, together with one complete reference implementation so that the proposal can be evaluated concretely rather than as a set of registration requirements. In it the primary domain is threat reactivity under a graded aversive cue delivered at three or more intensities, the primary parameter is the recovery constant of the evoked response, configuration expression is the frozen Level 1 classifier probability for that session, and the registered expectations are separated: 4A asks whether the recovery constant departs from that participant's pretreatment dynamics by more than the registered threshold, 4B whether the occasion specific component of configuration expression predicts it within person, and 4C whether the sign and magnitude of that relationship across people obey the frozen baseline dependent mapping. Shared vigilance, residual pharmacological exposure, and session level arousal are the competing accounts that must be excluded, and the implementation fails if the dynamic model containing recovery and adaptation terms does not outperform the restricted reactivity model out of sample by the registered margin. Altered amplitude alone is changed reactivity. Level 2 validation is domain specific in the first instance: altered dynamics under reward challenge but not under threat demonstrate reward domain alteration only, and each validation study nominates one primary perturbational domain before data collection, preferably the cleanest available, together with the primary response parameter or multivariate dynamic signature, the dynamical model family, the reference condition, the smallest meaningful departure from pretreatment dynamics, and the criterion by which the full dynamic model must outperform the restricted reactivity model, so that Prediction 4A is a constrained test rather than a two sided test of any change. Prediction 4A asks whether that registered aspect of recovery or adaptation architecture changes beyond pretreatment variability and control variation. It does not require a common sign across the sample, and the cross person baseline dependent mapping is not among its success criteria, because that mapping is what Prediction 4C tests; conditioning 4A on it would create the dependency the claim hierarchy denies. A fixed signed direction is registered only where theory or independent literature predicts one for the whole sample. Because individual departures may legitimately differ in sign, population support for 4A is not read from a group mean, which can approach zero when real departures cancel; the protocol registers one non directional population estimand in advance, such as a hierarchical magnitude criterion or a prevalence of meaningful individual departures (Supplementary Note S1). Nothing in this definition requires improvement. Better, worse, or differently tuned dynamics all satisfy Level 2, valence is assigned at Level 3, and the requirement is formalized as Prediction 4.

Establishing Coupling Without Reusing the Endpoint

Coupling measured within a single session is not sufficient, because rest and challenge recorded at one visit share transient causes, so Level 2 requires cross session coupling with configuration expression remeasured and stable across both sessions, repeated rest and challenge blocks with a preregistered protection against challenge induced carryover, or an explicit latent measurement model. Because configuration expression is itself estimated, its uncertainty is propagated into the coupling and mapping models rather than treated as observed. Covariation does not establish that the configuration produces those dynamics, because arousal, sleep, residual exposure, autonomic state, symptom change, or treatment context could produce both; the designs, the validation sequence that prevents the coupling test from reusing its own endpoint, and the designs that would license a causal claim are specified in Supplementary Note S1. Functional consequences are independently measured reward, threat, salience, control, behavioral, and clinical outcomes, and these classify the direction of tuning. Resting markers can identify a candidate configuration without demonstrating altered response dynamics, because comparable resting output can arise from different underlying configurations.

What Is Meant by a State

State here does not mean a discrete category. It means a reproducibly occupied region of an individual's multivariate neural state space, occupied after acute drug effects resolve, whose properties are reproducible across observations within that person. This manuscript adopts occupancy as a deliberately stronger operational criterion because it distinguishes a reproducibly occupied regime from continuous trajectory change and supplies a prospective failure condition. Other dynamical frameworks may define a state more broadly, including coherent regimes whose state vectors continue to evolve. In estimation, Level 1 is ordinarily represented continuously, as configuration probability or distance from the individual's pretreatment distribution, and categorical membership is used only after a threshold has been independently calibrated and frozen. Two estimands must be distinguished and only the first is constitutive. Within person detection asks whether the procedure separates a post acute observation from that individual's own baseline distribution at prespecified reliability, and Level 1 membership requires detection together with reproducible occupancy. Across person transportability asks whether a shared estimator performs that separation in held out participants; the framework predicts it but does not require it. Prediction 1a is a state identification claim rather than a causal treatment effect claim: repeated baselines and nonspecific comparators establish that a state is present after treatment, not that the intervention produced it, since concurrent psychotherapy, expectancy, spontaneous symptom change, and recovery from sleep disruption occur over the same interval. A claim that magnesium ibogaine induces the state requires an appropriate longitudinal comparison or randomized design. Two people at Level 1 may differ in feature weights, spatial pattern, and even the direction of change, and what each must demonstrate is reliable departure from their own pretreatment baseline together with reproducible occupancy. Because Level 1 is defined through resting physiology, failure to detect it rejects this resting biomarker formulation under the conditions tested and does not establish that post acute learning susceptibility or latent reorganization is absent; the degeneracy that motivates individualized estimation also permits altered responses to input without an altered resting output.

The Invariant That Defines the Equivalence Class

Level 2 is reached by a Level 1 configuration that demonstrates a preregistered alteration of response dynamics under challenge, coupled to its own expression, and only such configurations constitute the Neural Attunement phenotype. Whether those individually validated phenotypes also form one cross person equivalence class is a further, scope defining claim, and because different individuals may reach a candidate configuration through different electrophysiological implementations, the class is defined by a prespecified higher order property of the response architecture rather than by shared coordinates in raw feature space or shared clinical outcome. Population validation of 4A and 4B is distinct from individual phenotype assignment, which requires an evidential threshold registered in advance (Supplementary Note S1). The property has three parts. First, in observations belonging to or probabilistically expressing the Level 1 configuration, a preregistered primary subset of the response parameters, or a multivariate signature over them, is reproducibly altered relative to each person's own pretreatment estimate and beyond control variation; a generic treatment associated challenge effect does not qualify. Second, the within person component of configuration expression, separated from the between person component, predicts those dynamics in the preregistered domain, in a preregistered form of dependence that may be graded, threshold, nonlinear, or latent. The two parts establish different things: 4A establishes conditional dynamic alteration during the candidate state, and 4B establishes state specificity, that the alteration tracks expression of the configuration rather than merely co occurring with treatment. This is why 4A alone is insufficient and why both are constitutive. Third, and scope defining, the direction of change follows a shared baseline dependent mapping from pretreatment position to the direction and magnitude of parameter change, so that a person entering with higher pretreatment threat gain and a person entering with lower pretreatment threat gain satisfy one rule through opposite movement in the same parameter, with Level 3 determining whether either movement is improvement. Because that is also the geometry regression to the mean produces unaided, the mapping is estimated from repeated pretreatment measurements with baseline measurement error modeled explicitly, and a raw change score regressed on the same observed baseline is not an admissible confirmatory test (Supplementary Note S1). Individual intercepts and loadings may vary within a random effect structure frozen in advance; the mapping parameters may not. This is Prediction 4C: the mapping must outperform no change and fixed direction models and meet a preregistered parsimony aware noninferiority criterion against a higher capacity cross person model under participant held out validation, with the same allowable pretreatment information, and its failure leaves individually validated phenotypes standing. Where a class is claimed, the requirement is a shared mapping rather than a beneficial one: a restorative mapping carries functional content and belongs to Level 3, and a reproducible rule that moves the system away from an adaptive region satisfies Level 2 and is classified as maladaptive. Prediction 3 asks a different question, whether individualized modeling of the Level 1 configuration outperforms a fixed group signature.

Operational Definition of the Candidate Configuration

A monotonic approach alone without subsequent bounded occupancy does not satisfy the definition, because a trajectory with no region of reproducible occupancy is a course rather than a state, and Prediction 1a tests this by comparing an occupancy model against prespecified trajectory alternatives. After a preregistered acute resolution point, the candidate configuration is a reproducible multivariate neural configuration that differs from the individual's pretreatment configuration beyond expected test retest variability, persists across repeated post acute measurements, and is specified independently of clinical outcome. It must survive three identification threats: temporal leakage, in which a classifier learns when a recording was made rather than the state of the person recorded, sleep and circadian phase, and feature provenance, addressed by design. Biological time locking is not among them, since it limits Prediction 6 rather than falsifying Level 1, and neither is residual pharmacology, since a configuration maintained by drug or metabolite can exist. Exposure bears on incremental information: before the configuration serves as an independent biomarker, as the coupling index in Prediction 4B, or as a timing signal in Prediction 6, it must add information beyond pharmacokinetic exposure, compared as a rival predictor rather than partialled out. The resolution criteria, adjustments, and prospective detection sequence are specified in Supplementary Note S1.

Measurement Requirements

Preserved basic cognitive function is necessary evidence against gross generalized suppression but insufficient for discriminant validity, since a vigilance shift large enough to move these markers need not impair task performance; improvement in function is reserved for external validation. State identification is therefore silent on whether the tuning it reflects is adaptive. The individual baseline distribution must be estimable, which two or three pretreatment recordings cannot provide for a high dimensional representation, and reliability must be estimated for each feature at the timescale of use rather than assumed from the literature. The permissible covariance strategies, the reference distributions against which single measure change is evaluated, and the outcome reliability ceiling on Level 3 prediction are given in Supplementary Note S1 (Dominicus et al., 2025; Uudeberg et al., 2025; Gell et al., 2024).

Two constraints prevent this formulation from accommodating any observed change. A global reduction in complexity accompanied by reduced consciousness, generalized psychomotor suppression, or inability to perform the assessment is excluded as nonspecific suppression. Domain specific functional worsening does not invalidate identification of the phenotype and may instead contribute to classification as maladaptive tuning. The aperiodic exponent is retained as a descriptive spectral marker whose relation to synaptic excitation and inhibition remains unresolved. Functional tuning outcome is assessed independently through reward learning performance, salience and threat measures, and validated clinical instruments, and classification is made separately within each domain, because a participant may improve in one domain, not change in another, and worsen in a third; a global designation requires a preregistered aggregation rule. In adaptive cases, recalibration is hypothesized to emerge over days to weeks, but the timing and direction of functional change are empirical variables rather than components of state identification.

The post acute window begins only once both criteria in Table 2 are satisfied, the prespecified end of the principal acute pharmacodynamic phase and resolution of the principal acute subjective and behavioral state, a state criterion rather than a clock criterion, so elapsed time is recorded continuously and modeled rather than used to define onset. Intervals of approximately 24 to 72 hours for ibogaine, and shorter for classical psychedelics, describe existing protocols rather than boundaries of the framework. The boundary combines a prespecified end of the principal acute pharmacodynamic phase, which does not mean elimination of parent compound or metabolite, with a common subjective or behavioral resolution criterion, and the primary analysis is repeated under alternative cutoffs. When expression peaks, how long individual markers last, and when the window closes remain unknown, and the last bounds predicted intervention sensitivity (Prediction 6).

Table 3

Core Predictions, Tests, and Failure Consequences

Note. These six predictions discriminate Neural Attunement from simpler alternatives. Decisive applies to Predictions 1a, 4A, and 4B; a failed 4A or 4B is decisive for the nominated domain and population, and framework level rejection follows the multi domain rule stated below; for the others the failure column states what is lost, a narrowing of scope or the removal of an auxiliary hypothesis. Predictions 1 through 3 concern configuration identification and individual expression, Prediction 4 dynamic validation, Prediction 5 acute to post acute trajectory formation, and Prediction 6 state dependent intervention sensitivity. Within Prediction 4, 4A is altered response dynamics, 4B is within person coupling of those dynamics to configuration expression, 4C is the scope claim of a shared baseline dependent mapping, and the secondary hypothesis that challenge measures add information beyond resting markers is not decisive. Full specifications, secondary and utility criteria, evidence, status, and design requirements are given in Supplementary Table S3 and Supplementary Note S1. The post acute window is provisional and may vary by compound, dose, population, and outcome domain. Each prediction resolves to support, to rejection under the tested conditions, or to an inconclusive result where the interval spans the registered criterion; a nonsignificant result in an adequately powered study is not by itself a rejection. EEG = electroencephalography.

Each prediction resolves to support, to rejection under the tested conditions, or to an inconclusive result where the interval spans both, and a nonsignificant result in an adequately powered study is not by itself a rejection. Prediction 1a is decisive for the magnesium ibogaine anchor: failure of either detection or occupancy rejects the proposed configuration, identification below the registered prevalence criterion limits support to a subgroup, and a negative magnesium free study tests protocol transport rather than retrospectively rejecting the anchor. Predictions 4A and 4B are decisive for phenotype status in the nominated domain and population; failure in one preregistered domain cannot be rescued through post hoc domain substitution, and broader rejection requires failure across the frozen multi domain program specified in Supplementary Note S1.

Predictions 1b, 3, 4C, and 6 are scope claims, and Prediction 5 and the stabilization criterion are auxiliary; the failure consequence of each is given in Table 3 and in full in Supplementary Note S1, and Prediction 2 remains subordinate to Prediction 3. Because Prediction 6 does not require Prediction 4, it tests translational utility rather than validating the phenotype, and a positive result cannot rescue a failed 4A or 4B. Evidence for a scope claim, auxiliary hypothesis, or candidate mechanism does not substitute for constitutive validation. The licensing structure branches rather than ascending, and what each surviving version licenses is set out in Supplementary Note S1.

A biomarker defined post acute state as a candidate intervention window

If the candidate configuration can be detected prospectively using an independently validated classifier, the model predicts that it may define a window of heightened sensitivity to structured intervention (Prediction 6), consistent with metaplasticity (Lüscher & Malenka, 2011) and with state dependent learning and consolidation (Davidson & McEwen, 2012). Afterglow and critical period accounts already propose such a window; the translational claim here is that it may be readable from the nervous system rather than inferred from elapsed time, so the test is whether candidate configuration probability moderates intervention response beyond days since administration. If it does not, there is no justification for using the biomarker to schedule that intervention rather than time alone, although it may retain value in the other contexts of use described below. Because Prediction 6 does not require Prediction 4, its moderator is candidate configuration probability unless a classifier has been calibrated against individual Level 2 labels (Supplementary Note S1). A positive result would establish differential response to structured input, not that metaplasticity explains the interaction, since engagement, attention, tolerability, and motivation could contribute, and not that scheduling by the biomarker improves outcomes. Scheduling value requires a subsequent comparison of decision policies that accounts for measurement burden, classification error, and missed opportunities relative to time based scheduling.

Oscillatory and complexity based biomarkers may guide individualized protocols

Neural signal complexity, beta and gamma power, theta beta ratio, and peak alpha frequency are candidate biomarkers for tracking the configuration and testing whether its trajectory overlaps independently established markers of a metaplastic window. Perturbational and input state output methods have distinguished brain states that resting measures do not separate (Casali et al., 2013; Friston et al., 2003), which is the basis of Prediction 4. A pilot combining EEG and heart rate variability under brief auditory perturbation found no group level effects in ten healthy participants but substantial inter individual variability in response direction and magnitude, which its authors treat as preliminary (Hauber et al., 2026). Frontal theta beta ratio has high test retest reliability (Angelidis et al., 2016), and a multivariate latent signature from resting EEG predicted antidepressant response and generalized to two independent samples (Wu et al., 2020). These are methodological precedents for individualized electrophysiological prediction, not validation of the markers proposed here.

Future Directions: Compound Development and Protocol Design

The framework is compatible with dimensional transdiagnostic approaches that prioritize shared circuit dysfunction over categorical diagnosis (Insel et al., 2010; Kotov et al., 2017). Level 1 is initially a candidate monitoring biomarker, and becomes a candidate pharmacodynamic response biomarker when its change is attributable to exposure to the medical product. A drug induced sleep, learning, or homeostatic response would still be pharmacodynamic in that sense; whether the signal indexes the Neural Attunement configuration specifically, and by what mechanism, is a separate validation question. Pretreatment measures are candidate stratification or moderator variables until they demonstrate differential response to an intervention relative to a comparator, at which point they become predictive biomarkers; Prediction 6 is the experiment that could establish that context of use for configuration membership. Level 3 remains a clinical or functional outcome and should not be called a surrogate endpoint without substantially stronger validation. That vocabulary demands a predefined context of use, locked models, and external validation (Khalsa et al., 2026), and psychiatric drug development is being reframed around the same measures this framework uses (Etkin et al., 2026). The untested design implications for compounds and protocols optimized for controllable post acute tuning are set out in Supplementary Note S4.

Limitations and Boundary Conditions

The human electrophysiological evidence derives primarily from a single cohort (Lissemore et al., 2025) that was not randomized, included no healthy reference group, was demographically homogeneous, and had predominantly mild traumatic brain injury, with clinical response near ceiling, restricting the variance available for brain behavior correlation. Increased theta at the online reference electrode may have contributed to the regional theta increases, and increased alpha and reduced delta are consistent with normalization of injury related abnormality, whereas the core markers are not (Lissemore et al., 2025). The network analysis awaits peer review (Shinozuka et al., 2026, preprint). Until independent samples, including healthy reference, female, civilian, and magnesium free cohorts, are reported, all claims here are hypothesis generating. Should a shared estimator fail to transport, the framework falls back to individually estimated models, at the cost that detection may require enough post acute observations from a person to estimate their own configuration, which would constrain biomarker guided scheduling within a first exposure until a validated classifier permits single session detection (Supplementary Note S1). The reported 12-month clinical durability does not establish persistence of the configuration, because neurophysiology was not measured across that interval and most participants reported subsequent psychedelic use or other interventions (Faerman et al., 2026). The phenotype was not tested in that cohort, since no perturbational challenge with response and recovery measurement was administered, although standardized cognitive assessment was.

Temporal interpretation is constrained by the absence of modern quantitative acute electrophysiological data for ibogaine in humans suitable for direct comparison with the post acute findings. The post acute signature may prove distinctive to ibogaine, a class property expressed more durably under it, or an artifact of the protocol and cohort studied. The framework requires none of these, and studies capturing acute and post acute electrophysiology in the same participants will adjudicate among them (Table 3). The temporal architecture is also formulated for discrete exposures, and repeated low dose regimens may generate overlapping or recurrent states, requiring modeling of exposure history and re entry rather than a single assumed window (Tabaac et al., 2026).

The available data are correlational. The observed reorganization may be a downstream consequence of other processes rather than a cause of psychological change, and causation requires interventional designs that manipulate network dynamics directly (Gao et al., 2017). Sleep and circadian physiology are a named competing explanation: sleep deprivation alters periodic and aperiodic resting EEG (Bai et al., 2024), and spectral slope and Lempel Ziv complexity index sleep and wake states and sleep stage (Höhn et al., 2024; Aamodt et al., 2023), so both anchor markers have a documented alternative referent. Ibogaine sessions alter sleep timing, so a 3.5-day measurement may index sleep debt or rebound, and a one month measurement may index sleep improved secondary to reduced symptoms. Preserved cognition does not exclude this, because a vigilance shift sufficient to move these measures need not impair task performance. If generic sleep or vigilance state accounts for the anchor signature, the anchor does not support the framework as formulated; treatment induced sleep change that contributes to a larger configuration is instead a candidate mediator (Supplementary Note S1).

Homeostatic recovery is a second named rival. Acute perturbation can produce compensatory homeostatic and heterosynaptic restoration that yields persistent normalization of resting physiology without heightened learning susceptibility or directional tuning (Chen et al., 2013; Zenke et al., 2015), and homeostatic plasticity can itself act as metaplasticity (Li et al., 2019). Resting markers cannot distinguish the two accounts. Prediction 6 is what separates them: a pure homeostatic recovery account does not by itself predict that a measured post acute state will specifically moderate the effects of structured input beyond elapsed time.

The framework's descriptive premise requires greater measurement specificity than earlier formulations implied. The increased dynamic flexibility reported four weeks after psilocybin (Pasquini et al., 2026) concerns a different modality, scale, and compound and does not contradict the ibogaine findings, but it does rule out any general claim that therapeutic post acute states are characterized by reduced neural variability. Whether the electroencephalographic complexity reduction has a BOLD counterpart, or moves oppositely, is unknown and should be measured in a multimodal design.

EEG cannot localize circuit specific changes with anatomical precision. Beta gamma power, theta coherence, and peak alpha frequency index global network state rather than placing effects within salience, reward, or control circuits, so multimodal imaging and invasive electrophysiology will be needed. Degeneracy adds a further limit. A null result on a resting measure does not establish that the underlying process is uninvolved, because a mechanism may alter responsiveness to input without altering resting output, which applies directly to the calcium account. The proposed mechanism of persistent tuning susceptibility relies partly on West et al. (2026b), a preprint whose human evidence is cross sectional and does not establish that predictive relaxation precedes state formation or predicts outcome. The two West et al. reports draw on the same sample of 26 psychedelic users and 16 controls, so they are convergent measures within one cohort rather than independent replication.

Pharmacological and procedural confounds also constrain interpretation. Ibogaine carries a documented adverse event profile, including cardiac liability mediated partly by hERG channel inhibition (Koenig et al., 2014; Ona et al., 2022), and protocols frequently coadminister magnesium to mitigate it. Because magnesium was coadministered throughout the anchor protocol, the observed changes cannot be attributed to ibogaine alone (Cherian et al., 2024). CYP2D6 activity influences human ibogaine pharmacokinetics (Glue et al., 2015) and was not characterized in the anchor cohort, so exposure varied by an unmeasured amount. Resting markers cannot separate a pharmacologically maintained configuration, a pharmacologically initiated change no longer maintained, and a downstream learning or homeostatic change; all three are compatible with Level 1 existence, and plasma concentration does not establish brain target engagement (Supplementary Note S1). Calcium findings differ by preparation, concentration, species, sex, genotype, channel class, and compartment, none has been linked prospectively to the post acute human markers (Vilner & Bowen, 2000; Zhang & Cuevas, 2002; Villalba et al., 2025), and calcium modulation is not a required mechanism (Supplementary Note S2).

The higher order architecture may ultimately generalize beyond psychedelic or pharmacological interventions, but the operational criteria specified here were developed for discrete pharmacological exposures. Extension to neuromodulation, behavioral training, or contemplative practice would require intervention appropriate definitions of the acute input and of the state resolution boundary. Current evidence does not establish that these converge on a common directional spectral signature, a uniform reduction in variability, or a shared excitation inhibition shift; the untested prediction is convergence at the higher order level of reproducible response architecture, with functional value assessed independently (Davidson & McEwen, 2012).

Finally, the framework is conservative with respect to subjective experience. Experiential salience is incorporated as a plasticity directing signal, but the model does not attempt to explain phenomenology, meaning making, or spiritual interpretation, which may interact with attunement without being reducible to electrophysiological metrics.

Available human evidence demonstrates group level persistent post acute neurophysiological change following magnesium ibogaine, including reductions in spatiotemporal Lempel Ziv complexity and slowing of peak alpha frequency detectable at one month, with earlier oscillatory and aperiodic changes of shorter or analysis dependent duration. The Neural Attunement Model interprets these as the current empirical anchor for a candidate post acute configuration within which reopened plasticity, ongoing activity, and experiential context may interact to shape durable change.

Where tuning is adaptive, the framework predicts improvement in independently measured cognitive control, motivational salience, behavioral flexibility, and clinical function at the preregistered horizon. Evidence across psychedelic class interventions establishes that neurobiological and psychological change can persist beyond the acute drug state, but not that identical markers move in the same directions across compounds, populations, or modalities. The model is therefore offered first as a testable framework for the magnesium ibogaine derived candidate post acute configuration, despite heterogeneous neural implementation, and for classifying the resulting trajectories, with homologous architectures after other discrete pharmacological exposures treated as explicit generalization claims. Its claims and their failure consequences are set out in the Introduction and below Table 3, and failure of anything other than a constitutive claim leaves a smaller version of the framework standing. Its value will depend on longitudinal multimodal studies that obtain pretreatment, acute, and repeated post acute measurements in the same participants, and that compare neural trajectories with independently assessed behavioral and clinical outcomes.

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