The First Trial in a Neurodegenerative Disease
In April 2025, Ellen Bradley, Joshua Woolley and colleagues at the University of California, San Francisco published in Neuropsychopharmacology the first peer-reviewed trial of a psychedelic in patients with a neurodegenerative disease. Twelve adults with mild-to-moderate idiopathic Parkinson's disease and clinically significant depression or anxiety received one 10 mg and one 25 mg session of psilocybin under psychological support. The primary endpoint was feasibility and safety. The trial met it: no serious adverse events, no exacerbation of Parkinson's psychosis, no worsening of motor symptoms. The secondary signals were larger than the team's own pre-trial expectations. The Montgomery–Åsberg Depression Rating Scale fell by 9.3 points and stayed there at three months. The clinician-rated MDS-UPDRS Part III motor exam fell by 4.6 points and stayed below baseline at one month. The non-motor experiences subscale fell by 13.8 points with a Hedges' g of 3.0. CANTAB testing showed gains in paired associates learning, spatial working memory, and probabilistic reversal learning. "This is the first time a psychedelic has been tested on patients with any neurodegenerative disease," Bradley said in the UCSF press release. The trial was small, open-label, single-arm. It was also a turning point.
The context that turn arrives into is severe. The GBD 2016 Parkinson's Disease Collaborators documented that cases doubled from 2.5 million in 1990 to 6.2 million in 2015. Dorsey, Sherer, Okun and Bloem's 2018 review in the Journal of Parkinson's Disease called it "the fastest growing neurological disorder in the world" and projected a further doubling — to more than 12 million globally and potentially 17 million — by 2040. The U.S. economic burden, modelled at $51.9 billion in 2017 and projected to reach $79 billion by 2037, instead hit $82.2 billion in 2024, a decade ahead of projection (Parkinson's Foundation, 2024). Roughly 930,000 Americans live with the disease today (Marras et al., 2018); 1.2 million by 2030. There is, as of June 2026, no disease-modifying therapy approved anywhere in the world. The most recent serious attempts — prasinezumab (Roche, PASADENA) and cinpanemab (Biogen, SPARK) — both failed their primary endpoints. The molecular event that defines Parkinson's (α-synuclein aggregation) and the molecular event that defines psilocybin's effect on neurons (direct TrkB binding) have recently been characterised in detail. The two mechanisms converge on the same protein. That convergence is what the rest of this article examines.
The Two Diseases Inside Parkinson's
Most readers picture Parkinson's as a movement disorder. The tremor and the shuffle are the public signature. The honest clinical picture is two diseases running in the same patient. The first is the motor disorder produced by the selective loss of dopaminergic neurons in the substantia nigra pars compacta, with depletion of dopaminergic input to the striatum, the bradykinesia and rigidity that follow, and the levodopa responsiveness that has anchored treatment since 1967. The second is the non-motor disorder that often precedes the first by a decade or more — depression, anxiety, apathy, REM sleep behaviour disorder, hyposmia, cognitive decline, autonomic dysfunction (Schapira, Chaudhuri & Jenner, 2017). Standard pharmacology addresses the first, indifferently. It does not address the second.
Reijnders, Ehrt, Weber, Aarsland and Leentjens' 2008 systematic review in Movement Disorders, drawing on 51 prevalence studies, found clinically significant depression in 35–40 percent of patients with Parkinson's disease — major depressive disorder by DSM criteria in roughly 17 percent, minor depression in 22 percent, dysthymia in 13 percent. Aarsland and colleagues' 2011 review in Nature Reviews Neurology extended the picture: anxiety in 31 percent, apathy in 40 percent, both persistent, and crucially, "Symptoms of depression can be evident at the time of diagnosis and may develop in the premotor stage of the disease." Depression is not a reaction to the diagnosis. It is part of the diagnosis. It is in the substrate before the tremor begins. Motor Parkinson's is a disorder of dopaminergic loss in a defined nucleus. Mood Parkinson's is a disorder of multi-system monoaminergic loss — raphe serotonergic neurons degenerate (Politis et al., 2010), locus coeruleus noradrenergic neurons degenerate, limbic dopamine projections degenerate, and microglial activation overlays the whole picture.
Why SSRIs Fail in Parkinson's
The default move when a Parkinson's patient screens positive for depression is the same as outside Parkinson's: an SSRI, usually sertraline. Bomasang-Layno, Fadlon, Murray and Himelhoch's 2015 systematic review in Parkinsonism and Related Disorders aggregated the trial data and found modest, inconsistent benefit. The NIH-funded SAD-PD trial (Richard et al., Neurology 2012) compared paroxetine, venlafaxine and placebo in 115 Parkinson's patients with depression. Both active arms separated from placebo, but effect sizes were small relative to non-Parkinson's depression — roughly 30 percent response at twelve weeks against 14 percent placebo, far below the ~50 percent typically seen in psychiatrically isolated MDD trials.
The mechanistic reason is direct. SSRIs increase synaptic serotonin by blocking the serotonin transporter on serotonergic axon terminals. In Parkinson's, those terminals are themselves the dying tissue. Politis and colleagues' 2010 PET study using the SERT radioligand [11C]DASB documented substantial loss of serotonergic innervation in raphe nuclei and downstream cortical and limbic targets in early Parkinson's, with the loss correlating with depression severity. Asking a transporter inhibitor to amplify signalling on a denervated projection is a structural mismatch — the neurons being asked to release more serotonin are partly the neurons that are no longer there. Compounding this, the dopaminergic loss in mesocorticolimbic projections contributes a hedonic and motivational component SSRIs cannot reach; the noradrenergic loss contributes an arousal-regulation component SSRIs touch only indirectly; the microglial activation contributes an inflammation component SSRIs do not address at all. The standard of care is not failing through incompetence. It is failing because it is treating one component of a four-component disorder with a single-mechanism drug whose own substrate is partly missing.
The Bradley 2025 Trial — What It Actually Showed
The Bradley/Woolley UCSF pilot (NCT04932434) was registered as an open-label, single-arm Phase IIa feasibility study. Twelve participants enrolled (ten completers), mean age 63.2, five women. Inclusion required mild-to-moderate idiopathic Parkinson's (Hoehn & Yahr ≤3) with clinically significant depression and/or anxiety. Exclusion criteria included history of psychotic disorder, active Parkinson's psychosis, first-degree family history of psychotic illness, and concurrent pimavanserin therapy. Parkinson's medications continued at stable doses; SSRIs and SNRIs were tapered at least two weeks before dosing. Each participant received one 10 mg session and, two weeks later, one 25 mg session, with three preparatory sessions, two dosing sessions of approximately eight hours each, and four integration sessions.
The primary endpoint was met. No serious adverse events occurred. No participant required medical intervention during dosing. Ten of twelve experienced treatment-emergent adverse events — transient anxiety, nausea, blood pressure elevation — all mild-to-moderate, all resolving without intervention. No participant developed emergent psychosis beyond the expected acute drug effects. Motor symptoms did not worsen during or after dosing. At three months, MADRS had fallen 9.3 ± 2.7 points (p = 0.001, Hedges' g = 1.0). HAM-A fell 3.8 points (p = 0.031, g = 0.7). BDI scores showed parallel sustained reductions. At one month, MDS-UPDRS Part I (non-motor experiences of daily living) had fallen 13.8 points (p < 0.001, g = 3.0); Part II by 7.5 (g = 1.2); Part III (clinician-rated motor exam) by 4.6 (g = 0.3). CANTAB showed significant improvements on paired associates learning, spatial working memory and probabilistic reversal learning.
The authors' own caveat was the trial's central piece of intellectual hygiene. This was a feasibility study, open-label, no placebo. Sham surgery trials in Parkinson's have produced 30 percent UPDRS improvement in placebo arms, and pre-trial cultural priming in psychedelic trials may exceed that. A Hedges' g of 3.0 in n=10 is a signal worth investigating; it is not an estimate of true population effect. None of the reported improvements distinguishes symptomatic relief from disease modification. The trial was not powered or instrumented for the latter — no DaTscan, no plasma neurofilament light, no α-synuclein seeding amplification assay. What the trial established is that the intervention can be given to people with this disease, in this stage, on this medication background, without making anything worse, with mood and motor signals strong enough to justify a randomised follow-on. The Phase 2 expansion (NCT06455293), now enrolling across UCSF and Yale under Benjamin Kelmendi, is built to deliver that follow-on.
The α-Synuclein, TrkB and BDNF Hero Mechanism
The molecular signature of Parkinson's is α-synuclein. The Lewy bodies first described by Lewy in 1912 and characterised at the protein level by Spillantini and colleagues in 1997 are dense intraneuronal inclusions whose dominant component is misfolded α-synuclein. Aggregated α-synuclein is the protein the field has spent two decades trying to clear, neutralise, or prevent — the target of failed antibody trials (prasinezumab, cinpanemab) and active vaccine programs. What the field had not until recently characterised is what α-synuclein does at the receptor level to kill the neurons it accumulates in.
Kang, Zhang, Liu and colleagues published in PNAS in October 2017 the finding that re-organised the question. α-Synuclein binds directly to the kinase domain of TrkB — the receptor for brain-derived neurotrophic factor (BDNF), the principal trophic-support molecule for dopaminergic neurons. The binding suppresses TrkB lipid raft distribution, decreases receptor internalisation, reduces axonal trafficking, and downregulates TrkB protein via ubiquitination. The effect is a near-shutdown of BDNF/TrkB signalling in the cells where α-synuclein has accumulated. The dopamine metabolite DOPAL stimulates the α-synuclein/TrkB interaction, creating a vicious cycle in which the neurons most active in dopamine synthesis are the neurons most aggressively starved of trophic support. Kang's rescue experiment closed the logic: disrupting the interaction restored TrkB signalling, prevented dopaminergic neuron death, and restored motor function in mouse models. The mechanism α-synuclein uses to kill the cell is suppression of BDNF and TrkB signalling.
The second piece of the convergence was published six years later. Moliner, Girych, Brunello and colleagues' 2023 paper in Nature Neuroscience demonstrated that psychedelics — psilocin, LSD, DMT — bind directly to a transmembrane site on the TrkB receptor, acting as positive allosteric modulators of BDNF signalling. The binding is independent of 5-HT2A. The affinity, as the authors reported, is approximately 1,000-fold greater than ketamine, the prior canonical TrkB-engaging plastogen. Conformational coupling between psilocin and TrkB increases the receptor's responsiveness to ambient BDNF and produces the structural plasticity signature — dendritic spine growth, dendritic arbor elaboration, synapse formation — that defines the broader psilocybin neuroplasticity literature. α-Synuclein binds TrkB and suppresses BDNF signalling; psilocin binds TrkB and amplifies it. The molecules converge on the same receptor with opposite valences. Psilocin physically re-engages the receptor α-synuclein has been trying to silence. The disease-modifying hypothesis is not a downstream inference from a clinical signal; it is a direct read of the receptor pharmacology. It is also, important to say plainly, a hypothesis. No published study has yet demonstrated psilocybin reversing or arresting α-synuclein–driven dopaminergic neurodegeneration in any standard preclinical model — α-syn pre-formed fibril injection, A53T transgenic, MPTP, 6-OHDA. The molecular logic is unusually clean. The animal data is not yet published.
5-HT2A, Dopamine, and the Basal Ganglia
Psilocin is a 5-HT2A agonist, and a substantial part of its plasticity signal depends on 5-HT2A engagement. Vargas, Dunlap and Dong's 2023 Science paper resolved the paradox of how an agonist at a receptor for which serotonin is the endogenous ligand could produce plasticity serotonin itself does not. Serotonin is polar and does not readily cross neuronal membranes. Psychedelics are lipophilic and reach intracellular 5-HT2A receptors — the receptors Vargas and colleagues showed drive the structural plasticity signature. The pharmacology is not "more serotonin"; it is access to a receptor pool the endogenous ligand cannot reach — the distinction underpinning the entire 5-HT2A receptor literature.
For Parkinson's, anatomy matters. The substantia nigra pars compacta is among the densest 5-HT2A regions in the basal ganglia (Huot, Fox & Brotchie, 2011); 5-HT2A receptors localise on dopaminergic cell bodies in midbrain nuclei (Doherty & Pickel, 2000) and on GABAergic and glutamatergic neurons projecting into and out of the basal ganglia. McGuire and colleagues' 2023 Journal of Neuroscience paper characterised 5-HT2A modulation of basal ganglia output. Carta, Carlsson, Kirik and Björklund's 2007 paper in Brain added the Parkinson's-specific piece: when dopaminergic neurons die, serotonergic terminals co-innervating the striatum acquire the capacity to convert L-DOPA to dopamine — becoming "false transmitter" sites. The serotonergic system takes on larger functional weight in basal ganglia dynamics as dopaminergic supply collapses. A 5-HT2A agonist operates on a system the disease has functionally amplified.
The pimavanserin paradox sits at the centre. Pimavanserin (Nuplazid, ACADIA) is a selective 5-HT2A inverse agonist (Ki ≈ 0.087 nM), FDA-approved in 2016 for Parkinson's psychosis. If blocking 5-HT2A treats Parkinson's psychosis, how can activating it be safe in Parkinson's patients? Three pieces reconcile this. Mechanism: Hacksell and colleagues (2014) noted pimavanserin's effect is most pronounced where there is basal constitutive 5-HT2A activity — it silences chronic, low-grade aberrant cortical signalling driven by levodopa exposure and receptor upregulation. Psilocin produces an acute four-to-six-hour pulse on a different time scale. Downstream consequence: acute 5-HT2A activation is followed by days to weeks of altered cortical excitability and post-acute reductions in 5-HT2A density. A single pulsed agonism event can leave the receptor system in a less aberrantly excitable state than it started in. Trial design: Bradley excluded patients with active psychosis, history of psychotic disorder, family history of psychotic illness, and concurrent pimavanserin use; none of the enrolled twelve developed psychotic symptoms. Agonism and inverse agonism at 5-HT2A on different schedules are not opposite interventions on the same biology.
Neuroinflammation in the Substantia Nigra
McGeer, Itagaki, Boyes and McGeer's 1988 Neurology paper documented the foundational finding: activated, HLA-DR-positive microglia surround dying dopaminergic neurons in the substantia nigra of Parkinson's patients post-mortem. The decades since have built out the mechanism. Aggregated α-synuclein is itself a microglial activator: it engages microglial TLR2 and TLR4, drives NF-κB-dependent transcription, assembles the NLRP3 inflammasome, and triggers IL-1β, IL-18, TNF-α and IL-6 release (Haque et al., 2021). Gordon, Albornoz and Christie's 2018 paper in Science Translational Medicine showed pharmacological NLRP3 inhibition (MCC950) protects dopaminergic neurons in both α-synuclein PFF and 6-OHDA mouse models — confirming the inflammasome as a non-redundant driver of neurodegeneration. TNF-α is elevated in Parkinson's substantia nigra and CSF (Mogi et al., 1994). PET imaging with TSPO ligands has documented in-vivo microglial activation in patient substantia nigra that precedes overt motor symptoms in prodromal cases.
Psilocybin's anti-inflammatory pharmacology is now well characterised. Flanagan and Nichols' 2018 International Review of Psychiatry review summarised the foundational finding: sub-behavioural doses of the 5-HT2A agonist DOI suppressed TNF-α–driven inflammation in rodent models with potency approximately ten-fold greater than dexamethasone. Kozłowska and colleagues' 2024 paper in Molecules extended the picture to microglia specifically: psilocin reduced microglial phagocytic activity, reactive oxygen species production, and nitric oxide release — three signatures of the over-activated Parkinson's microglial phenotype — in a 5-HT2-receptor-dependent manner. The 2025 paper in International Immunopharmacology mapped the dual mechanism. Psilocin engages both serotonergic (5-HT2A/2B/7) and aryl hydrocarbon receptor (AhR) signalling. AhR activation is specifically required for BDNF upregulation; the serotonergic and TrkB axis drives TNF-α suppression. The two arms converge inside the same microglial population: psilocin simultaneously suppresses inflammatory cytokine release and amplifies neurotrophic factor secretion in the cells whose dysregulation is a major driver of substantia nigra neuron death. This is the bridging paper that links the neuroinflammation literature to the BDNF/TrkB mechanism. In Parkinson's the two effects are not parallel — they are convergent on the same pathology.
Neuroplasticity and the Synaptic Re-Bloom
Parkinson's pathology, viewed across years rather than across symptoms, is a slow erasure of synaptic architecture. Dopaminergic axons in the striatum retract before cell bodies die in the substantia nigra. Cortico-striatal synapses lose strength. Dendritic spines on medium spiny neurons disappear. The cognitive component — executive dysfunction, working-memory degradation, eventual dementia in 30–40 percent of long-survival cases — reflects an extension of the same process into cortical and hippocampal circuits. Standard symptomatic treatment does not address this layer. Levodopa substitutes for the dopamine the cells can no longer make; it does not rebuild the synapses the cells have lost.
Psilocybin's effect on synaptic architecture is now characterised in striking detail. Ly, Olson and colleagues' 2018 paper in Cell Reports established the broad principle that psychedelics — LSD, DMT, DOI, psilocin — promote rapid and persistent structural and functional plasticity, increasing dendritic spine density, dendritic arbor complexity, and synapse number in vitro and in vivo, with potency in several assays equal to or exceeding ketamine. Shao, Liston and colleagues' 2021 paper in Neuron used two-photon imaging in awake mice to show that a single dose of psilocybin produced an approximately 10 percent increase in dendritic spine size and density in layer V pyramidal neurons of medial frontal cortex within 24 hours, persisting at least one month. Catlow, Sanchez-Ramos and colleagues' 2013 paper in Experimental Brain Research showed low-dose psilocybin increased hippocampal BrdU-positive cell counts — a marker of psilocybin-driven neurogenesis — and facilitated extinction of trace fear conditioning, with ketanserin blocking the effect. Hesselgrave and colleagues' 2021 PNAS paper documented an increased hippocampal AMPA/NMDA ratio in CA1 pyramidal neurons after a single psilocybin dose. For Parkinson's, the relevant question is whether this plasticity surge can reach the basal ganglia and the dying nigro-striatal projection. The 5-HT2A receptor distribution argues that it can, structurally. The TrkB mechanism argues that it should, biochemically. The direct preclinical demonstration is missing. What is present is a compound whose plasticity signature is among the strongest in contemporary neuropharmacology, applied to a disease whose pathology is, at the cellular level, the inverse of plasticity.
The Clinical Pipeline Beyond Bradley 2025
The UCSF pilot is the first published trial. It is not the only one in motion. The Phase 2 expansion (NCT06455293), titled "Psilocybin Therapy for Depression in Parkinson's Disease," is recruiting across UCSF and Yale, with Ellen Bradley and Joshua Woolley as UCSF principal investigators and Benjamin Kelmendi at Yale as the second-site PI. Target enrolment is approximately 60 participants. The design is randomised and controlled. Each participant receives two 25 mg psilocybin sessions with therapy support. The trial adds transcranial magnetic stimulation in a stratified arm, structural and functional neuroimaging including fMRI, peripheral inflammation markers, and neuroplasticity-relevant biomarkers — endpoints the open-label pilot did not include.
The broader pipeline relevant to Parkinson's is sparser than the depression and PTSD pipelines but is moving. COMPASS Pathways' COMP005 and COMP006 Phase 3 trials in treatment-resistant depression both hit primary endpoints in 2025, with MADRS differences against placebo of −3.6 and −3.8, establishing that synthetic psilocybin is scalable at Phase 3 in the depression population. COMPASS has not announced a Parkinson's-specific program. Johns Hopkins' psilocybin for depression in mild cognitive impairment and early Alzheimer's trial (NCT04123314), under Albert Garcia-Romeu and Paul Rosenberg, is the closest cross-trial in the neurodegeneration corpus — a parallel question in a parallel disease, covered in the OOTW Journal companion piece on psilocybin in Alzheimer's disease. Mass General Brigham has launched a psychedelic research centre; no public Parkinson's program is yet disclosed. The academic groups most likely to deliver the next Parkinson's-specific data sit at UCSF and Yale (the Bradley/Woolley/Kelmendi triangle), at UC Davis (David Olson's psychoplastogen programme, including the non-hallucinogenic TrkB-engaging tabernanthalog described in Cameron et al., Nature 2021), at Imperial College London / UCSF (Carhart-Harris group; Szigeti co-authored Bradley 2025), and at Johns Hopkins. The number of registered psilocybin-Parkinson's trials remains, as of June 2026, two.
What We Don't Know
The case rests on a mechanism convergence supported by independent peer-reviewed papers, on a coherent 5-HT2A and neuroinflammatory pharmacology aligned with Parkinson's pathology, and on a single 12-patient open-label feasibility trial. It does not rest on what would be required to call psilocybin disease-modifying. The sample size in Bradley 2025 is small. N = 12, no placebo, no blinding. Sham surgery trials in Parkinson's have produced 30 percent UPDRS improvement in placebo arms; expectancy in psychedelic trials may exceed that. A Hedges' g of 3.0 on non-motor UPDRS in n=10 is not an estimate of population effect. The disease-modification question was not addressed by the trial. No DaTscan, no plasma neurofilament light, no α-synuclein seeding amplification assay, no longitudinal imaging beyond three months. All reported improvements are symptomatic and time-limited.
The preclinical evidence in Parkinson's-specific animal models is, in published peer-reviewed form, absent. As of June 2026, no paper combines psilocybin (or close analogues) with the standard Parkinson's models: α-synuclein PFF injection, A53T transgenic, MPTP-lesioned, or 6-OHDA-lesioned animals. The 5-HT2A agonist DOI has been tested in 6-OHDA models for L-DOPA-induced dyskinesia, but the agonist arm of that pharmacology runs in the opposite mechanistic direction from where any disease-modifying claim would need to run. The TrkB-rescue logic implied by Kang 2017 and Moliner 2023 has not been directly tested with psilocybin in a Parkinson's pathology model. This is the most surprising feature of the contemporary literature: the molecular logic is unusually clean, and the animal experiments that would test it are not yet done.
REM sleep behaviour disorder is present in up to 70 percent of Parkinson's patients (Postuma et al., 2013), itself an early synucleinopathy marker. The Bradley pilot did not specifically exclude RBD; no exacerbations were reported in the published data. The interaction of psilocybin with RBD at scale is essentially untested. Drug interactions with the major Parkinson's medications are equally under-studied. MAO-B inhibitors (selegiline, rasagiline) interact in principle with serotonergic agents; the Bradley trial allowed concurrent levodopa but did not characterise MAO-B inhibitor interactions in detail. Cardiovascular and orthostatic considerations in elderly Parkinson's patients — many of whom have autonomic dysfunction and orthostatic hypotension — are flagged by the transient blood pressure elevations the trial documented, but not yet characterised across larger samples. Disease stage matters. The Hoehn & Yahr ≤3 cap excluded patients with severe motor fluctuations, dyskinesia, or dementia. What happens in stage 4–5 disease is unknown.
Where the Pair Piece Sits
This article is the second in OOTW Journal's neurodegeneration pillar. The first, on psilocybin in Alzheimer's disease, covered the parallel mechanism case: BDNF restoration in a disease defined by trophic-factor decline, microglial quieting in a disease defined by neuroinflammation, and acute plasticity surge in a disease defined by the slow loss of synaptic architecture. The diseases differ at the surface: Alzheimer's is amyloid-β plaques and tau tangles, Parkinson's is α-synuclein Lewy bodies; Alzheimer's begins in hippocampus and entorhinal cortex, Parkinson's in substantia nigra and dorsal motor nucleus of the vagus; the cognitive phenotype dominates one, the motor phenotype the other. They converge at the cellular level. Both involve a protein-aggregation–driven shutdown of neurotrophic signalling. Both involve sustained microglial activation. Both are losses of synaptic real estate that accumulate over years. The therapeutic logic that follows is the same regardless of which protein is doing the damage upstream: restore BDNF/TrkB signalling, quiet the microglial phenotype, drive a plasticity window patients and therapists can use.
That framework is what the Kang 2017 and Moliner 2023 papers, taken together, make pharmacologically concrete for Parkinson's specifically. α-Synuclein binds the receptor; psilocin binds the same receptor with opposite valence. The molecular mismatch resolves in a single direction. Whether it resolves clinically — whether the receptor convergence translates into a slowing or arrest of dopaminergic neuron death across years — is the empirical question the next decade of trials has to answer. The Bradley pilot opened the door. The Phase 2 expansion will narrow the range of plausible answers. The animal-model studies the field has not yet published will, when they arrive, anchor or unsettle the mechanistic case. Two articles into the neurodegeneration pillar, the same mechanisms keep arriving with new clothes on. The Bradley pilot was not a proof of disease modification. The Kang/Moliner convergence is not a proof that what works in cells works in patients. What we have is a hypothesis whose mechanism is more aligned with the disease than any pharmacology Parkinson's has seen in fifty years, and the first published evidence that the drug can be given to these patients without making them worse. That is where the case stands. It is enough to keep going. It is not enough to stop being careful.
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