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1.
Transl Psychiatry ; 11(1): 506, 2021 10 02.
Artigo em Inglês | MEDLINE | ID: mdl-34601495

RESUMO

Serotonergic psychedelics are recently gaining a lot of attention as a potential treatment of several neuropsychiatric disorders. Broadband desynchronization of EEG activity and disconnection in humans have been repeatedly shown; however, translational data from animals are completely lacking. Therefore, the main aim of our study was to assess the effects of tryptamine and phenethylamine psychedelics (psilocin 4 mg/kg, LSD 0.2 mg/kg, mescaline 100 mg/kg, and DOB 5 mg/kg) on EEG in freely moving rats. A system consisting of 14 cortical EEG electrodes, co-registration of behavioral activity of animals with subsequent analysis only in segments corresponding to behavioral inactivity (resting-state-like EEG) was used in order to reach a high level of translational validity. Analyses of the mean power, topographic brain-mapping, and functional connectivity revealed that all of the psychedelics irrespective of the structural family induced overall and time-dependent global decrease/desynchronization of EEG activity and disconnection within 1-40 Hz. Major changes in activity were localized on the large areas of the frontal and sensorimotor cortex showing some subtle spatial patterns characterizing each substance. A rebound of occipital theta (4-8 Hz) activity was detected at later stages after treatment with mescaline and LSD. Connectivity analyses showed an overall decrease in global connectivity for both the components of cross-spectral and phase-lagged coherence. Since our results show almost identical effects to those known from human EEG/MEG studies, we conclude that our method has robust translational validity.


Assuntos
Dietilamida do Ácido Lisérgico , Mescalina , Animais , Eletroencefalografia , Dietilamida do Ácido Lisérgico/farmacologia , Psilocibina/análogos & derivados , Psilocibina/farmacologia , Ratos
2.
Neuron ; 109(16): 2535-2544.e4, 2021 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-34228959

RESUMO

Psilocybin is a serotonergic psychedelic with untapped therapeutic potential. There are hints that the use of psychedelics can produce neural adaptations, although the extent and timescale of the impact in a mammalian brain are unknown. In this study, we used chronic two-photon microscopy to image longitudinally the apical dendritic spines of layer 5 pyramidal neurons in the mouse medial frontal cortex. We found that a single dose of psilocybin led to ∼10% increases in spine size and density, driven by an elevated spine formation rate. The structural remodeling occurred quickly within 24 h and was persistent 1 month later. Psilocybin also ameliorated stress-related behavioral deficit and elevated excitatory neurotransmission. Overall, the results demonstrate that psilocybin-evoked synaptic rewiring in the cortex is fast and enduring, potentially providing a structural trace for long-term integration of experiences and lasting beneficial actions.


Assuntos
Dendritos/efeitos dos fármacos , Espinhas Dendríticas/efeitos dos fármacos , Lobo Frontal/efeitos dos fármacos , Plasticidade Neuronal/efeitos dos fármacos , Psilocibina/farmacologia , Animais , Córtex Cerebral/efeitos dos fármacos , Dendritos/fisiologia , Espinhas Dendríticas/fisiologia , Feminino , Masculino , Camundongos , Plasticidade Neuronal/fisiologia , Células Piramidais/fisiologia , Transmissão Sináptica/efeitos dos fármacos
3.
Molecules ; 26(10)2021 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-34063505

RESUMO

The psychedelic effects of some plants and fungi have been known and deliberately exploited by humans for thousands of years. Fungi, particularly mushrooms, are the principal source of naturally occurring psychedelics. The mushroom extract, psilocybin has historically been used as a psychedelic agent for religious and spiritual ceremonies, as well as a therapeutic option for neuropsychiatric conditions. Psychedelic use was largely associated with the "hippie" counterculture movement, which, in turn, resulted in a growing, and still lingering, negative stigmatization for psychedelics. As a result, in 1970, the U.S. government rescheduled psychedelics as Schedule 1 drugs, ultimately ending scientific research on psychedelics. This prohibition on psychedelic drug research significantly delayed advances in medical knowledge on the therapeutic uses of agents such as psilocybin. A 2004 pilot study from the University of California, Los Angeles, exploring the potential of psilocybin treatment in patients with advanced-stage cancer managed to reignite interest and significantly renewed efforts in psilocybin research, heralding a new age in exploration for psychedelic therapy. Since then, significant advances have been made in characterizing the chemical properties of psilocybin as well as its therapeutic uses. This review will explore the potential of psilocybin in the treatment of neuropsychiatry-related conditions, examining recent advances as well as current research. This is not a systematic review.


Assuntos
Alucinógenos/uso terapêutico , Transtornos Mentais/tratamento farmacológico , Neoplasias/tratamento farmacológico , Psilocibina/uso terapêutico , Pesquisa Biomédica/legislação & jurisprudência , Estudos Clínicos como Assunto , Alucinógenos/química , Alucinógenos/farmacologia , Humanos , Estrutura Molecular , Psilocibina/química , Psilocibina/farmacologia
5.
Expert Rev Clin Pharmacol ; 14(9): 1133-1152, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34038314

RESUMO

Introduction: There is increasing interest in the potential for psychedelic drugs such as psilocybin, LSD and ketamine to treat several mental health disorders, with a growing number of randomized controlled trials (RCTs) being conducted to investigate the therapeutic effectiveness of psychedelics.Areas covered: We review previous literature on expectancy effects and blinding in the context of psychedelic RCTs - literature which strongly suggest that psychedelic RCTs might be confounded by de-blinding and expectancy. We conduct systematic reviews of psychedelic RCTs using Medline, PsychInfo and EMBASE (Jan 1990 - Nov 2020) and show that currently reported psychedelic RCTs have generally not reported pre-trial expectancy, nor the success of blinding procedures.Expert opinion: While psychedelic RCTs have generally shown promising results, with large effect sizes reported, we argue that treatment effect sizes in psychedelic RCTs are likely over-estimated due to de-blinding of participants and high levels of response expectancy. We suggest that psychedelic RCTs should routinely measure de-blinding and expectancy. Careful attention should be paid to clinical trial design and the instructions given to participants to allow these confounds to be reduced, estimated and removed from effect size estimates. We urge caution in interpreting effect size estimates from extant psychedelic RCTs.


Assuntos
Alucinógenos/administração & dosagem , Transtornos Mentais/tratamento farmacológico , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Fatores de Confusão Epidemiológicos , Alucinógenos/farmacologia , Humanos , Ketamina/administração & dosagem , Ketamina/farmacologia , Dietilamida do Ácido Lisérgico/administração & dosagem , Dietilamida do Ácido Lisérgico/farmacologia , Psilocibina/administração & dosagem , Psilocibina/farmacologia , Projetos de Pesquisa
7.
Neuroimage ; 225: 117456, 2021 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-33069863

RESUMO

Hallucinogenic agents have been proposed as potent antidepressants; this includes the serotonin (5-HT) receptor 2A agonist psilocybin. In human subjects, psilocybin alters functional connectivity (FC) within the default-mode network (DMN), a constellation of inter-connected regions that displays altered FC in depressive disorders. In this study, we investigated the effects of psilocybin on FC across the entire brain with a view to investigate underlying mechanisms. Psilocybin effects were investigated in lightly-anaesthetized mice using resting-state fMRI. Dual-regression analysis identified reduced FC within the ventral striatum in psilocybin- relative to vehicle-treated mice. Refinement of the analysis using spatial references derived from both gene expression maps and viral tracer projection fields revealed two distinct effects of psilocybin: it increased FC between 5-HT-associated networks and cortical areas, including elements of the murine DMN, thalamus, and midbrain; it decreased FC within dopamine (DA)-associated striatal networks. These results suggest that interactions between 5-HT- and DA-regulated neural networks contribute to the neural and therefore psychological effects of psilocybin. Furthermore, they highlight how information on molecular expression patterns and structural connectivity can assist in the interpretation of pharmaco-fMRI findings.


Assuntos
Encéfalo/efeitos dos fármacos , Rede de Modo Padrão/efeitos dos fármacos , Psilocibina/farmacologia , Agonistas do Receptor 5-HT2 de Serotonina/farmacologia , Animais , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Corpo Estriado/diagnóstico por imagem , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Rede de Modo Padrão/diagnóstico por imagem , Rede de Modo Padrão/metabolismo , Dopamina/metabolismo , Neuroimagem Funcional , Imageamento por Ressonância Magnética , Mesencéfalo/diagnóstico por imagem , Mesencéfalo/efeitos dos fármacos , Mesencéfalo/metabolismo , Camundongos , Vias Neurais/diagnóstico por imagem , Vias Neurais/efeitos dos fármacos , Vias Neurais/metabolismo , Descanso , Serotonina/metabolismo , Tálamo/diagnóstico por imagem , Tálamo/efeitos dos fármacos , Tálamo/metabolismo
9.
Sci Rep ; 10(1): 22314, 2020 12 18.
Artigo em Inglês | MEDLINE | ID: mdl-33339902

RESUMO

Prevalence of major depression in people with chronic heart failure is higher than in normal populations. Depression in heart failure has become a major issue. Psilocybin-containing mushrooms commonly known as magic mushrooms, have been used since ancient times for their mind healing properties. Their safety in cardiovascular disease conditions is not fully known and may pose as a risk for users suffering from these illnesses. Study investigates the effects and safety of Psilocybe cubensis and Panaeolus cyanescens magic mushrooms use from genus Psilocybe and Panaeolus respectively, in a pathological hypertrophy conditions in which endothelin-1 disorder is a contributor to pathogenesis. We examined the effects of the mushrooms extracts on endothelin-1-induced hypertrophy and tumor necrosis factor-α (TNF- α)-induced cell injury in H9C2 cardiomyocytes. Mushrooms were oven dried and extracted with cold and boiling-hot water. H9C2 cardiomyocytes were induced with endothelin-1 prior to treatment with extracts over 48 h. Cell injury was stimulated with TNF-α. Results proposed that the water extracts of Panaeolus cyanescens and Psilocybe cubensis did not aggravate the pathological hypertrophy induced by endothelin-1 and also protected against the TNF-α-induced injury and cell death in concentrations used. Results support medicinal safe use of mushrooms under controlled conditions and cautioned use of higher concentrations.


Assuntos
Agaricales/química , Endotelina-1/genética , Hipertrofia/tratamento farmacológico , Psilocybe/química , Receptor de Endotelina A/genética , Animais , Antagonistas do Receptor de Endotelina A/farmacologia , Alucinógenos/química , Alucinógenos/farmacologia , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/patologia , Humanos , Hipertrofia/induzido quimicamente , Hipertrofia/patologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/patologia , Fenilpropionatos/farmacologia , Psilocibina/química , Psilocibina/farmacologia , Piridazinas/farmacologia , Ratos , Receptor de Endotelina A/efeitos dos fármacos , Fator de Necrose Tumoral alfa/genética
10.
Int J Mol Sci ; 21(18)2020 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-32906643

RESUMO

Depression impacts the lives and daily activities of millions globally. Research into the neurobiology of lateral habenula circuitry and the use of psychedelics for treating depressive states has emerged in the last decade as new directions to devise interventional strategies and therapies. Several clinical trials using deep brain stimulation of the habenula, or using ketamine, and psychedelics that target the serotonergic system such as psilocybin are also underway. The promising early results in these fields require cautious optimism as further evidence from experiments conducted in animal systems in ecologically relevant settings, and a larger number of human studies with improved spatiotemporal neuroimaging, accumulates. Designing optimal methods of intervention will also be aided by an improvement in our understanding of the common genetic and molecular factors underlying disorders comorbid with depression, as well as the characterization of psychedelic-induced changes at a molecular level. Advances in the use of cerebral organoids offers a new approach for rapid progress towards these goals. Here, we review developments in these fast-moving areas of research and discuss potential future directions.


Assuntos
Depressão/tratamento farmacológico , Habenula/efeitos dos fármacos , Alucinógenos/farmacologia , Encefalopatias/tratamento farmacológico , Encefalopatias/fisiopatologia , Comorbidade , Depressão/metabolismo , Depressão/fisiopatologia , Transtorno Depressivo/metabolismo , Transtorno Depressivo/fisiopatologia , Habenula/metabolismo , Alucinógenos/metabolismo , Humanos , Psilocibina/metabolismo , Psilocibina/farmacologia , Neurônios Serotoninérgicos/efeitos dos fármacos
11.
Psychopharmacology (Berl) ; 237(10): 3161-3171, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32700023

RESUMO

Ayahuasca is a psychoactive plant brew containing dimethyltryptamine (DMT) and monoamine oxidase inhibitors (MAOIs). It originates from the Amazon basin, where it is used primarily for ceremonial purposes. Ayahuasca tourists are now entering certain communities seeking alternative physical or psychological healing, as well as spiritual growth. RATIONALE: Recent evidence has shown that the similar acting psychedelic compound, psilocybin, facilitated long-term increases in trait openness following a single administration. OBJECTIVES: This paper assesses the impact of ayahuasca on personality in a traditional framework catering for ayahuasca tourists. METHOD: Within a mixed design, we examined the effect of ayahuasca on participants' personality (measured by the NEO Personality Inventory 3 questionnaire) across time (pre- to post-ayahuasca administration, and 6-month follow-up), relative to a comparison group (who did not ingest ayahuasca). RESULTS: The results demonstrated significant increases in agreeableness pre- and post-ayahuasca administration and significant reductions in neuroticism in 24 participants, relative to the comparison group. Both of these changes were sustained at 6-month follow-up, and trait level increases were also observed in openness at this stage. Additionally, greater perceived mystical experience (measured using the Mystical Experience Questionnaire 30) was associated with increased reductions in neuroticism. CONCLUSIONS: These findings, which indicate a positive mediating effect of ayahuasca on personality, support the growing literature suggesting potential therapeutic avenues for serotonergic psychedelics.


Assuntos
Banisteriopsis , Alucinógenos/farmacologia , Turismo Médico/psicologia , Neuroticismo/efeitos dos fármacos , Personalidade/efeitos dos fármacos , Extratos Vegetais/farmacologia , Adulto , Banisteriopsis/química , Feminino , Seguimentos , Alucinógenos/isolamento & purificação , Humanos , Masculino , Turismo Médico/tendências , Inibidores da Monoaminoxidase/isolamento & purificação , Inibidores da Monoaminoxidase/farmacologia , Misticismo/psicologia , N,N-Dimetiltriptamina/isolamento & purificação , N,N-Dimetiltriptamina/farmacologia , Neuroticismo/fisiologia , Personalidade/fisiologia , Peru/epidemiologia , Extratos Vegetais/isolamento & purificação , Psilocibina/isolamento & purificação , Psilocibina/farmacologia , Inquéritos e Questionários
12.
Neuroimage ; 220: 117049, 2020 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-32619708

RESUMO

Psychedelic drugs, such as psilocybin and LSD, represent unique tools for researchers investigating the neural origins of consciousness. Currently, the most compelling theories of how psychedelics exert their effects is by increasing the complexity of brain activity and moving the system towards a critical point between order and disorder, creating more dynamic and complex patterns of neural activity. While the concept of criticality is of central importance to this theory, few of the published studies on psychedelics investigate it directly, testing instead related measures such as algorithmic complexity or Shannon entropy. We propose using the fractal dimension of functional activity in the brain as a measure of complexity since findings from physics suggest that as a system organizes towards criticality, it tends to take on a fractal structure. We tested two different measures of fractal dimension, one spatial and one temporal, using fMRI data from volunteers under the influence of both LSD and psilocybin. The first was the fractal dimension of cortical functional connectivity networks and the second was the fractal dimension of BOLD time-series. In addition to the fractal measures, we used a well-established, non-fractal measure of signal complexity and show that they behave similarly. We were able to show that both psychedelic drugs significantly increased the fractal dimension of functional connectivity networks, and that LSD significantly increased the fractal dimension of BOLD signals, with psilocybin showing a non-significant trend in the same direction. With both LSD and psilocybin, we were able to localize changes in the fractal dimension of BOLD signals to brain areas assigned to the dorsal-attenion network. These results show that psychedelic drugs increase the fractal dimension of activity in the brain and we see this as an indicator that the changes in consciousness triggered by psychedelics are associated with evolution towards a critical zone.


Assuntos
Córtex Cerebral/efeitos dos fármacos , Rede de Modo Padrão/efeitos dos fármacos , Alucinógenos/farmacologia , Dietilamida do Ácido Lisérgico/farmacologia , Psilocibina/farmacologia , Córtex Cerebral/diagnóstico por imagem , Estado de Consciência/efeitos dos fármacos , Rede de Modo Padrão/diagnóstico por imagem , Humanos , Imageamento por Ressonância Magnética
13.
Neuroimage ; 218: 116980, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32454209

RESUMO

Psychedelic drugs, including the serotonin 2a (5-HT2A) receptor partial agonist psilocybin, are receiving renewed attention for their possible efficacy in treating a variety of neuropsychiatric disorders. Psilocybin induces widespread dysregulation of cortical activity, but circuit-level mechanisms underlying this effect are unclear. The claustrum is a subcortical nucleus that highly expresses 5-HT2A receptors and provides glutamatergic inputs to arguably all areas of the cerebral cortex. We therefore tested the hypothesis that psilocybin modulates claustrum function in humans. Fifteen healthy participants (10M, 5F) completed this within-subjects study in which whole-brain resting-state blood-oxygenation level-dependent (BOLD) signal was measured 100 â€‹min after blinded oral administration of placebo and 10 mg/70 â€‹kg psilocybin. Left and right claustrum signal was isolated using small region confound correction. Psilocybin significantly decreased both the amplitude of low frequency fluctuations as well as the variance of BOLD signal in the left and right claustrum. Psilocybin also significantly decreased functional connectivity of the right claustrum with auditory and default mode networks (DMN), increased right claustrum connectivity with the fronto-parietal task control network (FPTC), and decreased left claustrum connectivity with the FPTC. DMN integrity was associated with right-claustrum connectivity with the DMN, while FPTC integrity and modularity were associated with right claustrum and left claustrum connectivity with the FPTC, respectively. Subjective effects of psilocybin predicted changes in the amplitude of low frequency fluctuations and the variance of BOLD signal in the left and right claustrum. Observed effects were specific to claustrum, compared to flanking regions of interest (the left and right insula and putamen). This study used a pharmacological intervention to provide the first empirical evidence in any species for a significant role of 5-HT2A receptor signaling in claustrum functioning, and supports a possible role of the claustrum in the subjective and therapeutic effects of psilocybin.


Assuntos
Claustrum/efeitos dos fármacos , Alucinógenos/farmacologia , Vias Neurais/efeitos dos fármacos , Psilocibina/farmacologia , Adulto , Idoso , Atenção/efeitos dos fármacos , Atenção/fisiologia , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Memória/efeitos dos fármacos , Memória/fisiologia , Pessoa de Meia-Idade , Percepção/efeitos dos fármacos , Percepção/fisiologia
14.
Biol Psychiatry ; 88(2): 197-207, 2020 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-32111343

RESUMO

BACKGROUND: The use of psilocybin in scientific and experimental clinical contexts has triggered renewed interest in the mechanism of action of psychedelics. However, its time-dependent systems-level neurobiology remains sparsely investigated in humans. METHODS: We conducted a double-blind, randomized, counterbalanced, crossover study comprising 23 healthy human participants who received placebo and 0.2 mg/kg of psilocybin orally on 2 different test days. Participants underwent magnetic resonance imaging at 3 time points between administration and peak effects: 20 minutes, 40 minutes, and 70 minutes after administration. Resting-state functional connectivity was quantified via a data-driven global brain connectivity method and compared with cortical gene expression maps. RESULTS: Psilocybin reduced associative, but concurrently increased sensory, brain-wide connectivity. This pattern emerged over time from administration to peak effects. Furthermore, we showed that baseline connectivity is associated with the extent of psilocybin-induced changes in functional connectivity. Lastly, psilocybin-induced changes correlated in a time-dependent manner with spatial gene expression patterns of the 5-HT2A (5-hydroxytryptamine 2A) and 5-HT1A (5-hydroxytryptamine 1A) receptors. CONCLUSIONS: These results suggest that the integration of functional connectivity in sensory regions and the disintegration in associative regions may underlie the psychedelic state and pinpoint the critical role of the serotonin 2A and 1A receptor systems. Furthermore, baseline connectivity may represent a predictive marker of the magnitude of changes induced by psilocybin and may therefore contribute to a personalized medicine approach within the potential framework of psychedelic treatment.


Assuntos
Alucinógenos , Psilocibina , Encéfalo , Mapeamento Encefálico , Estudos Cross-Over , Método Duplo-Cego , Alucinógenos/farmacologia , Humanos , Psilocibina/farmacologia
15.
Neuroimage ; 209: 116462, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-31857204

RESUMO

Neuroimaging studies of the psychedelic state offer a unique window onto the neural basis of conscious perception and selfhood. Despite well understood pharmacological mechanisms of action, the large-scale changes in neural dynamics induced by psychedelic compounds remain poorly understood. Using source-localised, steady-state MEG recordings, we describe changes in functional connectivity following the controlled administration of LSD, psilocybin and low-dose ketamine, as well as, for comparison, the (non-psychedelic) anticonvulsant drug tiagabine. We compare both undirected and directed measures of functional connectivity between placebo and drug conditions. We observe a general decrease in directed functional connectivity for all three psychedelics, as measured by Granger causality, throughout the brain. These data support the view that the psychedelic state involves a breakdown in patterns of functional organisation or information flow in the brain. In the case of LSD, the decrease in directed functional connectivity is coupled with an increase in undirected functional connectivity, which we measure using correlation and coherence. This surprising opposite movement of directed and undirected measures is of more general interest for functional connectivity analyses, which we interpret using analytical modelling. Overall, our results uncover the neural dynamics of information flow in the psychedelic state, and highlight the importance of comparing multiple measures of functional connectivity when analysing time-resolved neuroimaging data.


Assuntos
Córtex Cerebral/efeitos dos fármacos , Conectoma , Alucinógenos/farmacologia , Ketamina/farmacologia , Dietilamida do Ácido Lisérgico/farmacologia , Magnetoencefalografia/efeitos dos fármacos , Rede Nervosa/efeitos dos fármacos , Psilocibina/farmacologia , Adulto , Anticonvulsivantes/farmacologia , Córtex Cerebral/fisiologia , Feminino , Alucinógenos/administração & dosagem , Humanos , Ketamina/administração & dosagem , Dietilamida do Ácido Lisérgico/administração & dosagem , Masculino , Rede Nervosa/fisiologia , Psilocibina/administração & dosagem , Tiagabina/farmacologia , Adulto Jovem
16.
Aust N Z J Psychiatry ; 54(3): 225-231, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31752499

RESUMO

In the quest for new treatment options for depression, attention is being paid to the potential role of psychedelic drugs. Psilocybin is of particular interest given its mechanism of action, its benefits in early trials and its relatively low side effects burden. This viewpoint outlines a number of key issues that remain to be elucidated about its potential use in the clinical environment, including clarification of the profile of people most likely to benefit and those who might experience adverse effects, longer-term outcomes and the role of psychotherapeutic input alongside the drug itself. There are also opportunities to understand better, the neurobiology underpinning its effects.


Assuntos
Transtorno Depressivo/tratamento farmacológico , Alucinógenos/farmacologia , Psilocibina/farmacologia , Psicoterapia , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto
17.
Med Hypotheses ; 134: 109406, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31634774

RESUMO

We introduce a novel hypothesis which states that the therapeutic utilisation of psilocybin has beneficial effects on genetic aging. Ex hypothesi, we predict a priori that controlled psilocybin interventions exert quantifiable positive impact on leucocyte telomere length (telomeres are a robust predictor of mortality and multifarious aging-related diseases). Our hypothesising follows the Popperian logic of scientific discovery, viz., bold (and refutable) conjectures form the very foundation of scientific progress. The 'psilocybin-telomere hypothesis' is formalised as a logically valid deductive (syllogistic) argument and we provide substantial evidence to support the underlying premises. Impetus for our theorising derives from a plurality of converging empirical sources indicating that psilocybin has persistent beneficial effects on various aspects of mental health (e.g., in the context of depression, anxiety, PTSD, OCD, addiction, etc.). Additional support is based on a large corpus of studies that establish reliable correlations between mental health and telomere attrition (improved mental health is generally correlated with longer telomeres). Another pertinent component of our argument is based on recent studies which demonstrate that "meditative states of consciousness" provide beneficial effects on genetic aging. Similarly, psilocybin can induce states of consciousness that are neurophysiologically and phenomenologically significantly congruent with meditative states. Furthermore, prior research has demonstrated that a single dose of psilocybin can occasion life-changing transformative experiences (≈ 70% of healthy volunteers rate their experience with psilocybin amongst the five personally most meaningful lifetime events, viz., ranked next to giving birth to a child or losing a loved one). We postulate that these profound psychological events leave quantifiable marks at the molecular genetic/epigenetic level. Given the ubiquitous availability and cost effectiveness of telomere length assays, we suggest that quantitative telomere analysis should be regularly included in future psilocybin studies as an adjunctive biological marker (i.e., to facilitate scientific consilience via methodological triangulation). In order to substantiate the 'psilocybin-telomere hypothesis' potential neuropsychopharmacological, endocrinological, and genetic mechanisms of action are discussed (e.g., HPA-axis reactivity, hippocampal neurogenesis, neurotropic growth factors such as BDNF, 5-HT2A receptor agonism, neuroplasticity/synaptoplasticity, brain-wide alterations in neuronal functional connectivity density, involvement of the SLC6A4 serotonin transporter gene, inter alia). The proposed research agenda is thus intrinsically highly interdisciplinary, and it has deep ramifications from a philosophy of science perspective as it connects the epistemic level (qualitative experiential phenomenology) with the ontic level (quantitative molecular genetics) of analysis. In the long term, multidisciplinary and innovative investigations of the 'psilocybin-telomere hypothesis' could contribute to the improvement of senotherapeutic psychological interventions and the identification of novel geroprotective and neuroprotective/restorative pharmaceutical targets to decelerate genetic aging and improve well-being and quality of life during the aging process.


Assuntos
Envelhecimento/efeitos dos fármacos , Modelos Genéticos , Modelos Psicológicos , Psilocibina/uso terapêutico , Psicotrópicos/uso terapêutico , Encurtamento do Telômero/efeitos dos fármacos , Envelhecimento/genética , Envelhecimento/psicologia , Senilidade Prematura/tratamento farmacológico , Senilidade Prematura/genética , Senilidade Prematura/prevenção & controle , Animais , Ansiedade/tratamento farmacológico , Ansiedade/genética , Fator Neurotrófico Derivado do Encéfalo/fisiologia , Estado de Consciência/efeitos dos fármacos , Metilação de DNA/efeitos dos fármacos , Depressão/tratamento farmacológico , Depressão/genética , Modelos Animais de Doenças , Sistema Endócrino/fisiopatologia , Humanos , Neurotransmissores/fisiologia , Estresse Oxidativo/efeitos dos fármacos , Personalidade/efeitos dos fármacos , Psilocibina/farmacologia , Psicotrópicos/farmacologia , Projetos de Pesquisa , Proteínas da Membrana Plasmática de Transporte de Serotonina/fisiologia , Estresse Psicológico/tratamento farmacológico , Estresse Psicológico/genética , Encurtamento do Telômero/fisiologia
18.
Swiss Med Wkly ; 149: w20124, 2019 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-31568558

RESUMO

Lysergic acid diethylamide (LSD) is a potent hallucinogenic substance that was extensively investigated by psychiatrists during the 1950s and 1960s. Researchers were interested in the unique effects induced by this substance, some of which resemble symptoms seen in schizophrenia. Moreover, during that period LSD was studied and used for the treatment of several mental disorders such as depression, anxiety, addiction and personality disorders. Despite this long history of research, how LSD induces its specific effects on a neuronal level has been relatively unclear. In recent years there has been a revival of research in hallucinogenic drugs and their possible clinical applications. These contemporary studies in the UK and Switzerland include neuroimaging studies using functional magnetic resonance imaging (fMRI). In this review, we collect and interpret these recent neuroimaging findings. Overall, previous results across studies indicate that LSD administration is associated with extensive alterations in functional brain connectivity, measuring the correlated activities between different brain regions. The studies mostly reported increases in connectivity between regions and, more specifically, consistently found increased connectivity within the thalamocortical system. These latter observations are in agreement with models proposing that hallucinogenic drugs exert their effects by inhibiting cerebral filtering of external and internal data. However, studies also face several limitations, including potential biases of neuroimaging measurements.


Assuntos
Encéfalo/efeitos dos fármacos , Alucinógenos/farmacologia , Dietilamida do Ácido Lisérgico/farmacologia , Encéfalo/diagnóstico por imagem , Humanos , Psilocibina/farmacologia
19.
Sci Rep ; 9(1): 14914, 2019 10 24.
Artigo em Inglês | MEDLINE | ID: mdl-31649304

RESUMO

Meditation and psychedelics have played key roles in humankind's search for self-transcendence and personal change. However, neither their possible synergistic effects, nor related state and trait predictors have been experimentally studied. To elucidate these issues, we administered double-blind the model psychedelic drug psilocybin (315 µg/kg PO) or placebo to meditators (n = 39) during a 5-day mindfulness group retreat. Psilocybin increased meditation depth and incidence of positively experienced self-dissolution along the perception-hallucination continuum, without concomitant anxiety. Openness, optimism, and emotional reappraisal were predictors of the acute response. Compared with placebo, psilocybin enhanced post-intervention mindfulness and produced larger positive changes in psychosocial functioning at a 4-month follow-up, which were corroborated by external ratings, and associated with magnitude of acute self-dissolution experience. Meditation seems to enhance psilocybin's positive effects while counteracting possible dysphoric responses. These findings highlight the interactions between non-pharmacological and pharmacological factors, and the role of emotion/attention regulation in shaping the experiential quality of psychedelic states, as well as the experience of selflessness as a modulator of behavior and attitudes. A better comprehension of mechanisms underlying most beneficial psychedelic experiences may guide therapeutic interventions across numerous mental conditions in the form of psychedelic-assisted applications.


Assuntos
Alucinógenos/farmacologia , Meditação/psicologia , Atenção Plena , Psilocibina/farmacologia , Atenção/efeitos dos fármacos , Budismo , Emoções/efeitos dos fármacos , Feminino , Alucinógenos/efeitos adversos , Humanos , Masculino , Meditação/métodos , Pessoa de Meia-Idade , Psilocibina/efeitos adversos , Comportamento Social
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