Psilocybin and Psilocin: Neuropharmacology, Clinical Potential, and Risks

Introduction

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Psilocybin (4-phosphoryloxy-N,N-dimethyltryptamine) and its active metabolite psilocin (4-hydroxy-N,N-dimethyltryptamine) are hallucinogenic indolealkylamine compounds found in more than 200 species of mushrooms in the genera Psilocybe, Panaeolus, Copelandia, and others [1]. The most well-known species include Psilocybe cubensis, P. semilanceata (liberty cap), P. cyanescens, and P. azurescens [2].

The history of psilocybin-containing mushroom use spans millennia. Archaeological evidence indicates their ritual use in Mesoamerica (modern-day Mexico and Central America) at least 3,500 years ago [3]. The Mazatec people traditionally used “teonanácatl” mushrooms (“flesh of the gods”) in religious and healing ceremonies [4].

Modern scientific interest in psilocybin began in 1957 when American banker and amateur mycologist R. Gordon Wasson published an article in LIFE magazine about his experience participating in a Mazatec ceremony with shaman María Sabina [5]. This led to the isolation and synthesis of psilocybin by Albert Hofmann (Laboratoires Sandoz) in 1958-1959 [6].

After a period of active research in the 1950s-1960s and subsequent prohibition as part of the “War on Drugs” (Controlled Substances Act, 1970, USA), psilocybin was classified as Schedule I—a substance with high potential for abuse and no recognized medical value [7]. Nevertheless, starting in the 2000s, a “psychedelic renaissance” emerged—a revival of scientific research into psilocybin’s therapeutic potential [8].

Neuropharmacology

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5-HT2A Agonism and the Serotonergic System

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Psilocybin is a prodrug that, after oral ingestion, is rapidly dephosphorylated by alkaline phosphatases into psilocin [9]. Psilocin acts as a partial agonist of serotonin 5-HT2A receptors, located predominantly on the apical dendrites of layer V pyramidal neurons in the prefrontal cortex [10].

Mechanism of action:

1. Activation of 5-HT2A receptors leads to increased serotonin (5-HT) release and enhanced excitability of layer V cortical pyramidal cells [11].
2. This, in turn, leads to increased extracellular glutamate in the neocortex [12].
3. Elevated glutamate levels stimulate AMPA receptors, which can enhance BDNF (brain-derived neurotrophic factor) secretion [13].
4. BDNF stimulates TrkB receptors and the mTOR pathway, leading to further BDNF production and sustained AMPA activation [13].

Relationship with plasma psilocin levels: The level of active metabolite psilocin in blood plasma is closely related to both cerebral 5-HT2A receptor occupancy and the intensity of the psychedelic experience [14]. PET (positron emission tomography) studies demonstrate dose-dependent 5-HT2A receptor occupancy by psilocin [15].

Default Mode Network (DMN) and Brain Entropy

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Default Mode Network (DMN) is a network of brain regions (including medial prefrontal cortex, posterior cingulate cortex, and precuneus) that is active during resting state and associated with self-reflection, autobiographical memory, and “mental wandering” [16]. DMN hyperactivity is associated with depression, anxiety, and rumination [17].

Effects of psilocybin on DMN: A systematic review of neuroimaging studies showed that psychedelics induce DMN modulation characterized by:

• Decreased functional connectivity within DMN [18].
• Increased connectivity between DMN and other networks typically functionally segregated [19].
• Disintegration and desegregation of the brain’s functional architecture [14].

Brain Entropy Hypothesis: Robin Carhart-Harris and colleagues proposed that psychedelics increase the “entropy” (degree of disorder) of neural activity, leading to more desynchronized patterns of brain activity and loss of oscillatory power [20]. This state of increased entropy correlates with the subjective intensity of the psychedelic experience and mystical experiences [21].

REBUS and the Anarchic Brain: A development of the entropy hypothesis was the theory of “Relaxed Beliefs Under Psychedelics” (REBUS) and the “anarchic brain” [22]. According to this model:

• Psychedelics disrupt the function of DMN and other high-level networks, reducing the precision of “priors” (prior beliefs) in Bayesian inference.
• This leads to temporary relaxation of rigid cognitive and perceptual models, allowing new information to update entrenched pathological thought patterns.
• Result: a more plastic, less ordered (more entropic), and more desegregated functional brain state [22].

Neuroplasticity and Structural Changes

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Psilocybin and other 5-HT2A receptor agonist psychedelics are called “psychoplastogens” for their ability to induce neuroplasticity [23].

Mechanisms of neuroplasticity:

1. Dendritic growth and increased spine density:

   • Psilocybin (1 mg/kg) caused a 10-fold increase in dendritic spine density and size in the medial prefrontal cortex (mPFC) of mice, persisting 7 days and, though somewhat diminished, still detectable 34 days after administration [24].

2. Synaptic proteins and BDNF-mTOR signaling:

   • Psilocybin increases levels of synaptic proteins (p-GluA1, PSD95, synapsin-1), activates the BDNF-mTOR signaling pathway (BDNF, TrkB, mTOR), and promotes neurogenesis [25].

3. Glutamate and AMPA:

   • Psychedelics lead to excitation of layer 5 pyramidal neurons and increased extracellular glutamate levels, which enhances AMPA receptor stimulation. AMPA receptor stimulation can enhance BDNF secretion, which stimulates TrkB and mTOR receptors, which in turn stimulates further BDNF production and sustained AMPA activation [13].

4. Rapidity of effects:

   • Psychoplastogens induce changes such as increased dendritic length, spine density, synapse number, and intrinsic excitability, typically within 24-72 hours after a single dose [26].

Studies on human cells: A study on iPSC-derived human cortical neurons showed that psilocin:

• Increases BDNF expression.
• Activates gene expression programs associated with neuromodulation and plasticity.
• Increases neuronal complexity, synaptogenesis, and changes in neural network function [27].

These data confirm that psilocybin activates widespread neuroplastic programs in human neurons.

Clinical Studies

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Depression (Treatment-Resistant Depression, TRD)

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Definition: Treatment-resistant depression (TRD) is depression that does not respond to two or more courses of antidepressants from different classes [28].

Key studies:

Carhart-Harris et al. (2017), Imperial College London:

• Design: Open-label study, 12 patients with TRD, two doses of psilocybin (10 mg and 25 mg) one week apart.
• Results: At week 1 post-treatment, all 19 patients (later expanded sample) showed reduction in depressive symptoms, 47% met response criteria at week 5 [29].
• fMRI data: Reduced amygdala blood flow correlated with reduced depressive symptoms, confirming mechanistic link between neurobiological changes and clinical effect [29].

Davis et al. (2021), Johns Hopkins:

• Design: Randomized double-blind study, patients with major depression, 2 psilocybin sessions (20 mg/70 kg and 30 mg/70 kg) vs. immediate treatment group vs. delayed treatment.
• Results: Rapid and sustained reduction in depressive symptoms. At 4 weeks post-treatment, 67% of immediate treatment group participants demonstrated clinically significant response, and 58% achieved remission [30].

Goodwin et al. (2022), NEJM—largest randomized controlled trial:

• Design: Phase 2, double-blind, multicenter study, 233 participants with TRD, three groups: 25 mg psilocybin, 10 mg, 1 mg (control).
• Results: At week 3 (primary endpoint), remission rates were 29% (25 mg), 9% (10 mg), 8% (1 mg)—approximately 20% remission above placebo rate [31].
• Safety: Treatment generally safe, adverse events (headache, nausea, dizziness) noted in 77% of participants (179 of 233), no serious adverse effects reported [31].

Meta-analysis (2024): A systematic review of 8 studies including 524 adult patients showed:

• Pooled remission rates: 45% for psilocybin vs. 22% for comparators.
• Large effect size favoring psilocybin (Hedge’s g = -0.89) [32].

Long-term outcomes: A study of U.S. military veterans with severe TRD showed that at month 6, 80% met response criteria and 50% remission, but at month 9 effects began to wane, and at month 12 only 40% maintained response and 30% remission [33]. This indicates that psilocybin’s effects may diminish over time, requiring repeated sessions or maintenance therapy.

Anxiety and Depression in Life-Threatening Illness

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Griffiths et al. (2016), Johns Hopkins:

• Design: Randomized double-blind crossover study, 51 patients with cancer and symptoms of depression and/or anxiety. Two sessions: low dose (1 or 3 mg/70 kg) vs. high dose (22 or 30 mg/70 kg) 5 weeks apart [34].
• Results:
  • High-dose psilocybin led to significant reductions in depression and anxiety on clinical and self-report scales, as well as increases in quality of life, life meaning, and optimism [34].
  • At 6 months after the last session, approximately 80% of participants continued to demonstrate clinically significant reductions in depression and anxiety, approximately 60% achieved remission into the normal range [34].
  • Role of mystical experience: Significant association between intensity of mystical experience (on the MEQ30 scale) on session day and long-term therapeutic outcomes at 5 weeks and beyond. This association persisted even when overall psilocybin effect intensity was controlled in partial correlation analysis, indicating that mystical experience itself plays an important role beyond the overall drug effect intensity [34].

Ross et al. (2016), NYU: A parallel study with similar design in 29 patients with cancer and existential distress showed rapid and sustained reductions in anxiety and depression symptoms after psilocybin-assisted therapy [35].

PTSD (Post-Traumatic Stress Disorder)

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Although MDMA (methylenedioxymethamphetamine) has received more attention in PTSD research, psilocybin is also being studied as a potential treatment. Johns Hopkins is conducting studies to determine psilocybin’s efficacy as a novel PTSD therapy [36].

Status: Studies are in early phases, large randomized controlled trials have not yet been completed.

Addictions

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Nicotine dependence:

• Johnson et al. (2014), Johns Hopkins—pilot study:

  • Design: Open-label pilot study, 15 participants dependent on tobacco, 2-3 psilocybin sessions combined with cognitive-behavioral therapy (CBT) for smoking cessation [37].
  • Results: Unprecedented outcomes—80% of participants remained abstinent at 6 months, more than double conventional success rates (~35% for varenicline, the most effective pharmacological agent) [37].

• NIH grant (2021): Johns Hopkins Medicine received a grant from the National Institutes of Health (NIH) to study psilocybin’s effects on tobacco addiction—the first NIH grant in more than half a century awarded directly for research on therapeutic effects of a classical psychedelic [38]. Multicenter three-year study in collaboration with University of Alabama at Birmingham and New York University [38].

Alcohol dependence:

• Bogenschutz et al. (2022)—phase 2:
  • Design: Double-blind placebo-controlled study, participants with alcohol dependence, two doses of psilocybin vs. diazepam (active placebo) combined with psychotherapy [39].
  • Results: Participants receiving psilocybin had heavy drinking days only 10% of the time during the 32-week study period, compared to 24% for the control group [39].

Opioid dependence: Upcoming Johns Hopkins studies will determine psilocybin’s efficacy as a novel therapy for opioid dependence [36].

FDA Breakthrough Therapy Designation

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In 2018, FDA granted psilocybin “Breakthrough Therapy” status for treatment-resistant depression (TRD) [40].

In 2019, FDA granted a second Breakthrough Therapy status for psilocybin for treatment of major depressive disorder (MDD) [40].

This status accelerates drug development and review when preliminary clinical evidence indicates the drug may demonstrate substantial improvement over existing treatments [41].

Current status (2026): Psilocybin is in phase 3 clinical trials, with integration into mainstream psychiatry expected in coming years [40].

Legal Status

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USA—Federal Level

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Psilocybin is classified as a Schedule I controlled substance under the Controlled Substances Act, meaning it is considered to have high potential for abuse and dependence and no recognized medical value [42].

Decriminalization and Legalization in USA

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Oregon:

• In 2020, Oregon voters approved Measure 109, legalizing medical psilocybin for supervised therapeutic use in licensed facilities [43].
• Operational start: Residents over 21 were able to access supervised psilocybin treatments in government-approved facilities starting in 2023 [43].
• Oregon became the first state to legalize medical psilocybin treatment [43].

Colorado:

• In 2022, Colorado voters approved Proposition 122, legalizing psilocybin for supervised therapeutic use in licensed facilities, similar to Oregon [44].

Local-level decriminalization: Several U.S. cities have decriminalized possession of psilocybin for personal use, including:

• Denver, Colorado (2019)
• Oakland and Santa Cruz, California (2019-2020)
• Washington, D.C. (2020)
• Seattle, Washington (2021)
• Detroit, Michigan (2021) [45]

Important: Decriminalization does not mean legalization. Possession remains a violation at the federal level but is not a priority for local law enforcement.

Netherlands

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• Psilocybin-containing mushrooms have been banned since 2008 [46].
• Psilocybin-containing truffles (sclerotia) remain legal—they are sold in licensed smart shops and can be used recreationally or therapeutically [46].
• Legal loophole: After the mushroom ban in 2008, the law specified prohibition only on mushroom fruiting bodies, creating a loophole allowing people to legally possess and consume psilocybin truffles [46].
• Netherlands is one of the few countries where truffle use is openly permitted and regulated [46].

Portugal

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• Portugal became the first country in the world to decriminalize all drugs for personal use in 2001, including psilocybin [47].
• Possession of small quantities is not a criminal offense and is instead handled through public health services [47].
• While sales are not legalized, individuals are not prosecuted for possession or use of mushrooms in small quantities [47].

Other Jurisdictions

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Brazil: Cultivation and possession for personal use are not formally prohibited, though sale is illegal [48].

Jamaica: Psilocybin-containing mushrooms are not controlled, legal for cultivation, sale, and consumption [48].

Canada: Some patients with terminal illnesses have received compassionate exemptions for legal access to psilocybin therapy [48].

Russia and most EU countries: Psilocybin is classified as a controlled substance, its production, possession, and distribution are prosecuted by law.

Risks and Side Effects

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⚠️ Bad Trips (Severe Psychedelic Crises)

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Definition: A “bad trip” is an acutely negative psychological experience during a psychedelic session, characterized by intense fear, panic, paranoia, disorientation, or dysphoria [49].

Risk factors:

• Uncontrolled setting (set and setting).
• High dose without psychotherapeutic support.
• Predisposition to anxiety or unstable mental state.

Management: In clinical settings, bad trips are rare due to careful preparation, controlled setting, and presence of trained therapists [50]. In recreational settings, bad trips can lead to risky behavior or psychological trauma.

☠️ Psychosis and Risk for Predisposed Individuals

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Predisposition to psychosis: Psilocybin can precipitate psychotic episodes in individuals predisposed to schizophrenia or bipolar disorder [51]. Clinical studies typically exclude participants with family or personal history of psychotic disorders.

Mechanism: 5-HT2A receptor agonism can destabilize fragile mental states, leading to prolonged psychotic symptomatology in predisposed individuals [52].

⚠️ RECOMMENDATION: Individuals with family history of schizophrenia, bipolar disorder, or psychosis SHOULD NOT use psilocybin outside strictly controlled clinical settings.

HPPD (Hallucinogen Persisting Perception Disorder)

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Definition: HPPD is a disorder characterized by spontaneous recurrences of perceptual distortions (visual effects such as motion trails, halos around objects, object size changes) after discontinuation of hallucinogen use [53].

Prevalence: HPPD is rare but can be prolonged and debilitating for those who experience it. Exact prevalence is unknown, estimates range from 1% to 5% of psychedelic users [54].

Risk factors: Polypharmacy (use of multiple psychoactive substances), high doses, frequent use [54].

☠️ Serotonin Syndrome and Interactions with SSRIs

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Serotonin syndrome (serotonin toxicity): A potentially life-threatening condition arising from excessive serotonin accumulation in the brain. Symptoms include agitation, rapid heartbeat, muscle rigidity, high fever, and in severe cases, seizures [55].

⚠️ CRITICALLY IMPORTANT:

Recent studies (2025) showed encouraging data:

• 10 studies assessing safety of concurrent use of antidepressants and classical psychedelics showed no signs of serotonin toxicity or syndrome, including studies with psilocybin combined with SSRIs [56].
• Psilocybin, being a psychedelic partial agonist of the serotonin 5-HT2A receptor, appears to have the lowest risk of any type of serotonin syndrome [57].

HOWEVER:

Attenuation of psilocybin effects:

• Studies showed that when using mushrooms with SSRIs, the probability of weaker-than-expected drug effects was 0.47 (47%), with SNRIs—0.55 (55%) [58].
• SSRIs/SNRIs appear to attenuate psilocybin’s effects, and this attenuating effect may last up to 3 months after discontinuing antidepressants [58].

Dangerous user strategies: Study participants reported difficulties accessing reliable information about drug interactions, and some employed potentially unsafe strategies such as extreme dose escalation or abrupt antidepressant cessation [58].

⚠️ RECOMMENDATION:

• DO NOT abruptly stop SSRIs/SNRIs to use psilocybin.
• Consult a physician about safe dose reduction or alternative strategies.
• In clinical settings, psilocybin combined with SSRIs is considered relatively safe, but efficacy may be reduced [56].

Physiological Side Effects

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Acute effects (during session):

• Nausea and vomiting (15-30% of participants) [59].
• Headache (often within 24 hours of session) [31].
• Dizziness [31].
• Elevated blood pressure and heart rate (typically moderate and transient) [60].

Long-term safety:

• Studies have not identified serious long-term physical side effects with controlled psilocybin use [61].
• Psilocybin does not cause physical dependence or withdrawal syndrome [62].

Therapeutic Potential vs. Recreational Use

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Distinction Between Clinical and Recreational Context

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Clinical context (psilocybin-assisted therapy):

• Preparation: Several psychotherapy sessions before psilocybin intake to establish trust, discuss intentions, and prepare for the experience.
• Set and setting: Controlled, safe environment with two trained therapists present (often male and female), dim lighting, music, comfortable place to lie down [63].
• Integration: Several psychotherapy sessions after psilocybin intake to process the experience, extract insights, and integrate into daily life [63].
• Dosage: Standardized doses (typically 20-30 mg psilocybin for therapeutic sessions) [34].
• Monitoring: Continuous monitoring of vital functions and psychological state.

Recreational context:

• Lack of preparation and integration: Users may lack psychotherapeutic support before and after.
• Uncontrolled setting: Use at parties, festivals, unfamiliar places—increases risk of bad trips and risky behavior.
• Unknown dosage: Psilocybin content in mushrooms varies by species, cultivation method, mushroom part. Users often don’t know exact dose.
• Polypharmacy: Combination with alcohol, cannabis, other psychoactive substances—increases risk of side effects.
• Legal risks: In most jurisdictions, recreational psilocybin use is illegal and carries criminal liability.

Critically important distinction: The therapeutic effects of psilocybin observed in clinical studies are not simply the result of the drug’s chemical action, but the synergy of the drug, psychotherapeutic support, preparation, and integration [63]. Recreational use without these components is unlikely to produce therapeutic results and may be dangerous.

Conclusion

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Psilocybin represents one of the most promising tools in modern psychiatry, demonstrating unprecedented efficacy in treating treatment-resistant depression, anxiety in life-threatening illness, and addictions. Neurobiological mechanisms, including DMN modulation, increased brain entropy, and induction of neuroplasticity, provide a compelling basis for its therapeutic potential.

Key findings:

1. Efficacy: Psilocybin-assisted therapy shows remission rates ~45% in TRD, exceeding conventional treatments [32].

2. Mechanism: Acts through 5-HT2A receptor agonism, reduction of DMN hyperactivity, increased brain entropy, and induction of neuroplasticity through BDNF-mTOR signaling [13, 22, 24].

3. Safety: In clinical use, the safety profile is relatively favorable, without serious long-term physical side effects or dependence [61].

4. Risks: Bad trips, psychosis in predisposed individuals, HPPD (rare). Interaction with SSRIs reduces efficacy, but serotonin syndrome is unlikely [56, 58].

5. Legal status: Schedule I in most jurisdictions, but decriminalization and legalization for therapeutic use are expanding (Oregon, Colorado, Netherlands-truffles, Portugal-decriminalization) [43-47].

6. Context is critical: Therapeutic effects require psychotherapeutic support, preparation, controlled setting, and integration—recreational use is not equivalent [63].

7. FDA Breakthrough Therapy: Breakthrough Therapy status accelerates development, phase 3 studies underway, integration into mainstream psychiatry expected in coming years [40].

Limitations:

• Long-term effects diminish over time, requiring repeated sessions [33].
• Small sample sizes in most studies.
• Mechanisms of mystical experience and their relationship to therapeutic outcomes require further study.

Psilocybin-assisted therapy has the potential to transform treatment of mental disorders but requires responsible clinical application, further research, and thoughtful regulatory policy.

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[54] Recovered.org. Psilocybin-Assisted Therapy. https://recovered.org/hallucinogens/psilocybin/psilocybin-therapy

[55] Psychiatrist.com (2024). Case Study Ties Psilocybin to Serotonin Toxicity When Used with Antidepressants. https://www.psychiatrist.com/news/case-study-ties-psilocybin-to-serotonin-toxicity-when-used-with-antidepressants/

[56] PMC (2024). Concomitant use of antidepressants and classic psychedelics: A scoping review. https://pmc.ncbi.nlm.nih.gov/articles/PMC12572353/

[57] Pharmacy Times (2024). Assessing Risk for Serotonin Syndrome When Treating Patients on Antidepressants With Psychedelic Medicine. https://www.pharmacytimes.com/view/assessing-risk-for-serotonin-syndrome-when-treating-patients-on-antidepressants-with-psychedelic-medicine

[58] PubMed (2023). Attenuation of psilocybin mushroom effects during and after SSRI/SNRI antidepressant use. https://pubmed.ncbi.nlm.nih.gov/37291890/

[59] PMC (2016). Psilocybin produces substantial and sustained decreases in depression and anxiety. https://pmc.ncbi.nlm.nih.gov/articles/PMC5367557/

[60] Sage Journals (2016). Psilocybin produces substantial and sustained decreases in depression and anxiety. https://journals.sagepub.com/doi/full/10.1177/0269881116675513

[61] PubMed (2020). Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder. https://pubmed.ncbi.nlm.nih.gov/33146667/

[62] Recovered.org. Psilocybin-Assisted Therapy. https://recovered.org/hallucinogens/psilocybin/psilocybin-therapy

[63] PMC (2016). Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer. https://pmc.ncbi.nlm.nih.gov/articles/PMC5367557/

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