RESUMEN
BACKGROUND: Overdose deaths remain high for opioid use disorder, emphasizing the need to pursue innovative therapeutics. Classic psychedelic drugs that engage many monoamine receptors mitigate opioid use. Here, we tested the hypothesis that the preferential serotonin 5-HT2AR agonist, 2,5-dimethoxy-4-iodoamphetamine (DOI) could reduce the demand for fentanyl in a preclinical model of fentanyl self-administration. METHODS: Male and female Sprague-Dawley rats (n = 25-29) were implanted with indwelling jugular catheters and allowed to self-administer fentanyl (3.2µg/kg/infusion). Rats progressed to a novel low price twice within-session threshold procedure where rats sampled the lowest price twice before decreasing the dose of fentanyl by a » log every 10minutes across 11 doses. Once stable, rats were pretreated with saline or DOI (0.01, 0.03, 1mg/kg). Fentanyl consumption was analyzed using an exponentiated demand function to extract the dependent variables, Q0 and α. RESULTS: Male and female rats acquired fentanyl self-administration in the lowest price twice within-session threshold procedure. DOI dose-dependently altered fentanyl intake such that 5-HT2AR activation decreased Q0 in female rats but increased Q0 in male rats. For demand elasticity, DOI increased α in male rats but did not alter α in female rats. DOI did not alter inactive lever presses or latency. CONCLUSION: DOI reduces consumption at minimally constrained costs but did not affect the reinforcement value of fentanyl in female rats. Alternatively, DOI significantly reduced the reinforcement value of fentanyl in male rats. Biological sex alters the therapeutic efficacy of DOI and 5-HT2AR activation sex-dependently alters opioid reinforcement.
Asunto(s)
Anfetaminas , Fentanilo , Ratas Sprague-Dawley , Autoadministración , Animales , Masculino , Femenino , Fentanilo/farmacología , Ratas , Anfetaminas/farmacología , Caracteres Sexuales , Agonistas del Receptor de Serotonina 5-HT2/farmacología , Relación Dosis-Respuesta a Droga , Analgésicos Opioides/farmacología , Alucinógenos/farmacologíaRESUMEN
The pharmacodynamic effects of lysergic acid diethylamide (LSD) are diverse and different in different individuals. Effects of other psychoactive substances have been shown to be critically influenced by non-pharmacological factors such as personality traits and mood states. The aim of this study was to determine pharmacological and psychological predictors of the LSD effects in healthy human subjects. This analysis is based on nine double-blind, placebo-controlled, cross-over studies with a total of 213 healthy subjects receiving between 25-200 µg LSD. The influence of sex, age, dose, body weight, pharmacogenetic, drug experience, personality, setting, and mood before drug intake on the peak autonomic and total subjective responses to LSD was investigated using multiple linear mixed effects models and Least Absolute Shrinkage and Selection Operator regression. Results were adjusted for LSD dose and corrected for multiple testing. LSD dose emerged as the most influential predictor, exhibiting a positive correlation with most response variables. Pre-drug mental states such as "Well-Being", "Emotional Excitability", and "Anxiety" were also important predictor for a range of subjective effects but also heart rate and body temperature. The trait "Openness to Experiences" was positively correlated with elevated ratings in "Oceanic Boundlessness" and mystical-type effects. Previous experiences with hallucinogens have been negatively associated with the overall altered state of consciousness and particularly with "Anxious Ego Dissolution". Acute anxiety negatively correlated with the genetically determined functionality of the Cytochrome 2D6 enzyme. In summary, besides the amount of drug consumed, non-pharmacological factors such as personal traits and current mood also significantly predicted the subjective drug experience. Sex and body weight were not significant factors in influencing the drug experience.
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Afecto , Estudios Cruzados , Alucinógenos , Dietilamida del Ácido Lisérgico , Humanos , Dietilamida del Ácido Lisérgico/farmacología , Dietilamida del Ácido Lisérgico/administración & dosificación , Masculino , Femenino , Adulto , Alucinógenos/administración & dosificación , Alucinógenos/farmacología , Método Doble Ciego , Adulto Joven , Afecto/efectos de los fármacos , Voluntarios Sanos , Frecuencia Cardíaca/efectos de los fármacos , Personalidad , Persona de Mediana Edad , Relación Dosis-Respuesta a Droga , AdolescenteRESUMEN
Aspects of the acute experience induced by the serotonergic psychedelic psilocybin predict symptomatic relief in multiple psychiatric disorders and improved well-being in healthy participants, but whether these therapeutic effects are immediate or are based on memories of the experience is unclear. To examine this, we co-administered psilocybin (25 mg) with the amnestic benzodiazepine midazolam in 8 healthy participants and assayed the subjective quality of, and memory for, the dosing-day experience. We identified a midazolam dose that allowed a conscious psychedelic experience to occur while partially impairing memory for the experience. Furthermore, midazolam dose and memory impairment tended to associate inversely with salience, insight, and well-being induced by psilocybin. These data suggest a role for memory in therapeutically relevant behavioral effects occasioned by psilocybin. Because midazolam blocks memory by blocking cortical neural plasticity, it may also be useful for evaluating the contribution of the pro-neuroplastic properties of psychedelics to their therapeutic activity.
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Alucinógenos , Midazolam , Psilocibina , Humanos , Psilocibina/administración & dosificación , Psilocibina/farmacología , Midazolam/administración & dosificación , Midazolam/farmacología , Alucinógenos/administración & dosificación , Alucinógenos/farmacología , Masculino , Adulto , Femenino , Memoria/efectos de los fármacos , Adulto JovenRESUMEN
The potent hallucinogen N,N-dimethyltryptamine (DMT) has garnered significant interest in recent years due to its profound effects on consciousness and its therapeutic psychopotential. DMT is an integral (but not exclusive) psychoactive alkaloid in the Amazonian plant-based brew ayahuasca, in which admixture of several ß-carboline monoamine oxidase A (MAO-A) inhibitors potentiate the activity of oral DMT, while possibly contributing in other respects to the complex psychopharmacology of ayahuasca. Irrespective of the route of administration, DMT alters perception, mood, and cognition, presumably through agonism at serotonin (5-HT) 1A/2A/2C receptors in brain, with additional actions at other receptor types possibly contributing to its overall psychoactive effects. Due to rapid first pass metabolism, DMT is nearly inactive orally, but co-administration with ß-carbolines or synthetic MAO-A inhibitors (MAOIs) greatly increase its bioavailability and duration of action. The synergistic effects of DMT and MAOIs in ayahuasca or synthetic formulations may promote neuroplasticity, which presumably underlies their promising therapeutic efficacy in clinical trials for neuropsychiatric disorders, including depression, addiction, and post-traumatic stress disorder. Advances in neuroimaging techniques are elucidating the neural correlates of DMT-induced altered states of consciousness, revealing alterations in brain activity, functional connectivity, and network dynamics. In this comprehensive narrative review, we present a synthesis of current knowledge on the pharmacology and neuroscience of DMT, ß-carbolines, and ayahuasca, which should inform future research aiming to harness their full therapeutic potential.
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Banisteriopsis , Alucinógenos , Inhibidores de la Monoaminooxidasa , Monoaminooxidasa , N,N-Dimetiltriptamina , Inhibidores de la Monoaminooxidasa/farmacología , Inhibidores de la Monoaminooxidasa/química , Banisteriopsis/química , N,N-Dimetiltriptamina/farmacología , Humanos , Animales , Alucinógenos/farmacología , Monoaminooxidasa/metabolismo , Sinergismo Farmacológico , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Carbolinas/farmacología , Carbolinas/químicaRESUMEN
Accumulating evidence has shown that some hallucinogens, such as LSD, have fast and persistent effects on anxiety and depression. According to a proposed mechanism, LSD activates the TrkB and HTR2A signaling pathways, which enhance the density of neuronal dendritic spines and synaptic function, and thus promote brain function. Moreover, TrkB signaling is also known to be crucial for neural stem cell (NSC)-mediated neuroregeneration to repair dysfunctional neurons. However, the impact of LSD on neural stem cells remains to be elucidated. In this study, we observed that LSD and BDNF activated the TrkB pathway in human NSCs similarly to neurons. However, unlike BDNF, LSD did not promote NSC proliferation. These results suggest that LSD may activate an alternative mechanism to counteract the effects of BDNF-TrkB signaling on NSCs. Our findings shed light on the previously unrecognized cell type-specificity of LSD. This could be crucial for deepening our understanding of the mechanisms underlying the effects of LSD.
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Factor Neurotrófico Derivado del Encéfalo , Alucinógenos , Dietilamida del Ácido Lisérgico , Células-Madre Neurales , Receptor trkB , Transducción de Señal , Células-Madre Neurales/efectos de los fármacos , Células-Madre Neurales/metabolismo , Células-Madre Neurales/citología , Humanos , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Alucinógenos/farmacología , Transducción de Señal/efectos de los fármacos , Receptor trkB/metabolismo , Dietilamida del Ácido Lisérgico/farmacología , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Neuronas/citología , Glicoproteínas de MembranaRESUMEN
Major depressive disorder (MDD) is a highly prevalent psychiatric disorder, associated with substantial burden and large economical costs. Notwithstanding various conventional antidepressant treatment options, a large portion of depressed people (ca. 30%) fails to respond to first-line treatment, resulting in treatment-resistant depression (TRD). Although non-response to multiple antidepressant interventions is a common outcome, a consensus definition of TRD is not yet available. In practice, TRD is applied when two or more successive treatments with different antidepressants are not working. The last decade's intense research into new medicines for TRD has led to two developments, using typical or serotonergic (psilocybin, ayahuasca) and atypical (glutamatergic) psychedelics (ketamine, esketamine). Both approaches, although via different entrance mechanism, exhibit a fast onset but also long-lasting antidepressant effect far beyond the biological presence of the drug in the body, strongly indicating that downstream mechanisms activated by signaling cascades in the brain are involved. The present chapter describes the clinical development of psilocybin and esketamine for TRD and discusses the problems involved in the use of a proper placebo because of the psychotomimetic (psilocybin) or dissociative (ketamine) effects that interfere with performing "blind" studies. Nevertheless, intranasal esketamine was developed and approved for TRD, whereas psilocybin has shown positive results. Adverse effects and tolerability of both drugs in the dose ranges used are generally acceptable. The emergence of anti-TRD medicines for treatment of a very severe disease is a breakthrough in psychiatry.
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Antidepresivos , Trastorno Depresivo Resistente al Tratamiento , Alucinógenos , Ketamina , Psilocibina , Humanos , Trastorno Depresivo Resistente al Tratamiento/tratamiento farmacológico , Alucinógenos/uso terapéutico , Alucinógenos/efectos adversos , Alucinógenos/farmacología , Ketamina/uso terapéutico , Ketamina/efectos adversos , Psilocibina/uso terapéutico , Psilocibina/efectos adversos , Psilocibina/farmacología , Antidepresivos/uso terapéutico , Antidepresivos/efectos adversos , Antidepresivos/farmacología , Trastorno Depresivo Mayor/tratamiento farmacológico , Resultado del TratamientoRESUMEN
The present study examined three hallucinogenic amphetamine derivatives, namely, 2,5-dimethoxy-4-iodoamphetamine (DOI) as well as 2,5-dimethoxy-4-methylamphetamine (DOM) and 4-methylmethcathinone (mephedrone). The objective of this study was to test the hypothesis that DOI, DOM, and mephedrone would increase the contractile force in isolated human atrial preparations in a manner similar to amphetamine. To this end, we measured contractile force under isometric conditions in electrically stimulated (1 Hz) human atrial preparations obtained during open surgery. DOI and DOM alone or in the presence of isoprenaline reduced the contractile force concentration-dependently in human atrial preparations. These negative inotropic effects of DOM and DOI were not attenuated by 10 µM atropine. However, mephedrone increased the contractile force in human atrial preparations in a concentration- and time-dependent manner. Furthermore, these effects were attenuated by the subsequent addition of 10 µM propranolol or pretreatment with 10 µM cocaine in the organ bath. Therefore, it can be concluded that amphetamine derivatives may exert opposing effects on cardiac contractile force. The precise mechanism by which DOI and DOM exert their negative inotropic effects remains unknown at present. The cardiac effects of mephedrone are probably due to the release of cardiac noradrenaline.
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Alucinógenos , Atrios Cardíacos , Contracción Miocárdica , Humanos , Atrios Cardíacos/efectos de los fármacos , Contracción Miocárdica/efectos de los fármacos , Alucinógenos/farmacología , Masculino , Femenino , Isoproterenol/farmacología , Metanfetamina/farmacología , Metanfetamina/análogos & derivados , Atropina/farmacología , Anfetaminas/farmacología , Persona de Mediana Edad , Propranolol/farmacología , Anfetamina/farmacología , AdultoRESUMEN
Breathwork is an understudied school of practices involving intentional respiratory modulation to induce an altered state of consciousness (ASC). We simultaneously investigate the phenomenological and neural dynamics of breathwork by combining Temporal Experience Tracing, a quantitative methodology that preserves the temporal dynamics of subjective experience, with low-density portable EEG devices. Fourteen novice participants completed a course of up to 28 breathwork sessions-of 20, 40, or 60 min-in 28 days, yielding a neurophenomenological dataset of 301 breathwork sessions. Using hypothesis-driven and data-driven approaches, we found that "psychedelic-like" subjective experiences were associated with increased neural Lempel-Ziv complexity during breathwork. Exploratory analyses showed that the aperiodic exponent of the power spectral density-but not oscillatory alpha power-yielded similar neurophenomenological associations. Non-linear neural features, like complexity and the aperiodic exponent, neurally map both a multidimensional data-driven composite of positive experiences, and hypothesis-driven aspects of psychedelic-like experience states such as high bliss.
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Encéfalo , Estado de Conciencia , Electroencefalografía , Alucinógenos , Humanos , Masculino , Femenino , Alucinógenos/farmacología , Adulto Joven , Adulto , Estado de Conciencia/efectos de los fármacos , Estado de Conciencia/fisiología , Encéfalo/fisiología , Encéfalo/efectos de los fármacos , Respiración/efectos de los fármacosRESUMEN
LSD is a hallucinogen with complex neurobiological and behavioral effects. Underlying these effects are changes in brain neuroplasticity. This is the first study to follow the developmental changes in brain structure and function following LSD exposure in periadolescence. We hypothesized LSD given during a time of heightened neuroplasticity, particularly in the forebrain, would affect cognitive and emotional behavior and the associated underlying neuroanatomy and neurocircuitry. Female and male mice were given vehicle, single or multiple treatments of 3.3 µg of LSD by oral gavage starting on postnatal day 51. Between postnatal days 90-120 mice were imaged and tested for cognitive and motor behavior. MRI data from voxel-based morphometry, diffusion weighted imaging, and BOLD resting state functional connectivity were registered to a mouse 3D MRI atlas with 139 brain regions providing site-specific differences in global brain structure and functional connectivity between experimental groups. Motor behavior and cognitive performance were unaffected by periadolescent exposure to LSD. Differences across experimental groups in brain volume for any of the 139 brain areas were few in number and not focused on any specific brain region. Multiple exposures to LSD significantly altered gray matter microarchitecture across much of the brain. These changes were primary associated with the thalamus, sensory and motor cortices, and basal ganglia. The forebrain olfactory system and prefrontal cortex and hindbrain cerebellum and brainstem were unaffected. The functional connectivity between forebrain white matter tracts and sensorimotor cortices and hippocampus was reduced with multidose LSD exposure. Does exposure to LSD in late adolescence have lasting effects on brain development? The bulk of our significant findings were seen through changes is DWI values across 74 brain areas in the multi-dose LSD group. The pronounced changes in indices of anisotropy across much of the brain would suggest altered gray matter microarchitecture and neuroplasticity. There was no evidence of LSD having consequential effects on cognitive or motor behavior when animal were evaluated as young adults 90-120 days of age. Neither were there any differences in the volume of specific brain areas between experimental conditions. The reduction in connectivity in forebrain white matter tracts with multidose LSD and consolidation around sensorimotor and hippocampal brain areas requires a battery of tests to understand the consequences of these changes on behavior.
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Encéfalo , Dietilamida del Ácido Lisérgico , Animales , Masculino , Femenino , Encéfalo/efectos de los fármacos , Encéfalo/crecimiento & desarrollo , Encéfalo/diagnóstico por imagen , Ratones , Dietilamida del Ácido Lisérgico/farmacología , Dietilamida del Ácido Lisérgico/administración & dosificación , Alucinógenos/administración & dosificación , Alucinógenos/farmacología , Cognición/efectos de los fármacos , Imagen por Resonancia Magnética , Plasticidad Neuronal/efectos de los fármacos , Administración Oral , Actividad Motora/efectos de los fármacos , Conducta Animal/efectos de los fármacos , Sustancia Gris/efectos de los fármacos , Sustancia Gris/crecimiento & desarrollo , Sustancia Gris/diagnóstico por imagenRESUMEN
A variety of classic psychedelics and MDMA have been shown to enhance fear extinction in rodent models. This has translational significance because a standard treatment for post-traumatic stress disorder (PTSD) is prolonged exposure therapy. However, few studies have investigated psilocybin's potential effect on fear learning paradigms. More specifically, the extents to which dose, timing of administration, and serotonin receptors may influence psilocybin's effect on fear extinction are not understood. In this study, we used a delay fear conditioning paradigm to determine the effects of psilocybin on fear extinction, extinction retention, and fear renewal in male and female mice. Psilocybin robustly enhances fear extinction when given acutely prior to testing for all doses tested. Psilocybin also exerts long-term effects to elevate extinction retention and suppress fear renewal in a novel context, although these changes were sensitive to dose. Analysis of sex differences showed that females may respond to a narrower range of doses than males. Administration of psilocybin prior to fear learning or immediately after extinction yielded no change in behavior, indicating that concurrent extinction experience is necessary for the drug's effects. Cotreatment with a 5-HT2A receptor antagonist blocked psilocybin's effects for extinction, extinction retention, and fear renewal, whereas 5-HT1A receptor antagonism attenuated only the effect on fear renewal. Collectively, these results highlight dose, context, and serotonin receptors as crucial factors in psilocybin's ability to facilitate fear extinction. The study provides preclinical evidence to support investigating psilocybin as a pharmacological adjunct for extinction-based therapy for PTSD.
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Relación Dosis-Respuesta a Droga , Extinción Psicológica , Miedo , Alucinógenos , Psilocibina , Psilocibina/farmacología , Miedo/efectos de los fármacos , Animales , Extinción Psicológica/efectos de los fármacos , Masculino , Femenino , Alucinógenos/farmacología , Ratones , Ratones Endogámicos C57BL , Receptores de Serotonina/efectos de los fármacos , Receptores de Serotonina/metabolismo , Condicionamiento Clásico/efectos de los fármacosRESUMEN
Psychedelics have emerged as promising therapeutics for several psychiatric disorders. Hypotheses around their mechanisms have revolved around their partial agonism at the serotonin 2â¯A receptor, leading to enhanced neuroplasticity and brain connectivity changes that underlie positive mindset shifts. However, these accounts fail to recognise that the gut microbiota, acting via the gut-brain axis, may also have a role in mediating the positive effects of psychedelics on behaviour. In this review, we present existing evidence that the composition of the gut microbiota may be responsive to psychedelic drugs, and in turn, that the effect of psychedelics could be modulated by microbial metabolism. We discuss various alternative mechanistic models and emphasize the importance of incorporating hypotheses that address the contributions of the microbiome in future research. Awareness of the microbial contribution to psychedelic action has the potential to significantly shape clinical practice, for example, by allowing personalised psychedelic therapies based on the heterogeneity of the gut microbiota.
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Eje Cerebro-Intestino , Microbioma Gastrointestinal , Alucinógenos , Alucinógenos/farmacología , Humanos , Microbioma Gastrointestinal/efectos de los fármacos , Animales , Eje Cerebro-Intestino/efectos de los fármacos , Encéfalo/efectos de los fármacos , Encéfalo/metabolismoRESUMEN
The development of new drugs addressing serious mental health and other disorders should avoid the psychedelic experience. Analogs of psychedelic drugs can have clinical utility and are termed "psychoplastogens". These represent promising candidates for treating opioid use disorder to reduce drug dependence, with rarely reported serious adverse effects. This drug abuse cessation is linked to the induction of neuritogenesis and increased neuroplasticity, a hallmark of psychedelic molecules, such as lysergic acid diethylamine. Some, but not all psychoplastogens may act through the G-protein coupled receptor (GPCR) 5HT2A whereas others may display very different polypharmacology making prediction of hallucinogenic potential challenging. In the process of developing tools to help design new psychoplastogens, we have used artificial intelligence in the form of machine learning classification models for predicting psychedelic effects using a published in vitro data set from PsychLight (support vector classification (SVC), area under the curve (AUC) 0.74) and in vivo human data derived from books from Shulgin and Shulgin (SVC, AUC, 0.72) with nested five-fold cross validation. We have also explored conformal predictors with ECFP6 and electrostatic descriptors in an effort to optimize them. These models have been used to predict known 5HT2A agonists to assess their potential to act as psychedelics and induce hallucinations for PsychLight (SVC, AUC 0.97) and Shulgin and Shulgin (random forest, AUC 0.71). We have tested these models with head twitch data from the mouse. This predictive capability is desirable to reliably design new psychoplastogens that lack in vivo hallucinogenic potential and help assess existing and future molecules for this potential. These efforts also provide useful insights into understanding the psychedelic structure activity relationship.
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Inteligencia Artificial , Alucinógenos , Alucinógenos/farmacología , Humanos , Animales , Aprendizaje Automático , Dietilamida del Ácido Lisérgico/farmacología , Máquina de Vectores de Soporte , RatonesRESUMEN
Obsessive-compulsive disorder (OCD) is a chronic mental disease that affects approximately 2% of the population. Obsessions and compulsions are troublesome for patients and may disturb their everyday activities. The pathogenesis of this disease is still not fully elucidated, but dysfunctions of serotonin-, dopamine- and glutamate-mediated neurotransmission together with early maladaptive schemas seem of importance. Pharmacological treatment includes drugs affecting the serotoninergic, dopaminergic, and glutamatergic systems, such as selective serotonin reuptake inhibitors (SSRIs). Providing that up to 40% of patients with OCD are resistant to the currently available medications, there is a need for novel and effective therapies. Recent discoveries suggest that psilocybin, a non-physically addictive psychoactive substance, may ameliorate disease symptoms. When used in appropriate doses and under strict clinical control, psilocybin appears as a valuable treatment for OCD. This narrative article provides a thorough overview of OCD's etiology, current treatment options, and the emerging evidence supporting psilocybin's efficacy in managing OCD symptoms.
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Alucinógenos , Trastorno Obsesivo Compulsivo , Psilocibina , Humanos , Trastorno Obsesivo Compulsivo/tratamiento farmacológico , Psilocibina/uso terapéutico , Psilocibina/farmacología , Alucinógenos/uso terapéutico , Alucinógenos/farmacología , Inhibidores Selectivos de la Recaptación de Serotonina/uso terapéutico , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , AnimalesRESUMEN
A single dose of psilocybin, a psychedelic that acutely causes distortions of space-time perception and ego dissolution, produces rapid and persistent therapeutic effects in human clinical trials1-4. In animal models, psilocybin induces neuroplasticity in cortex and hippocampus5-8. It remains unclear how human brain network changes relate to subjective and lasting effects of psychedelics. Here we tracked individual-specific brain changes with longitudinal precision functional mapping (roughly 18 magnetic resonance imaging visits per participant). Healthy adults were tracked before, during and for 3 weeks after high-dose psilocybin (25 mg) and methylphenidate (40 mg), and brought back for an additional psilocybin dose 6-12 months later. Psilocybin massively disrupted functional connectivity (FC) in cortex and subcortex, acutely causing more than threefold greater change than methylphenidate. These FC changes were driven by brain desynchronization across spatial scales (areal, global), which dissolved network distinctions by reducing correlations within and anticorrelations between networks. Psilocybin-driven FC changes were strongest in the default mode network, which is connected to the anterior hippocampus and is thought to create our sense of space, time and self. Individual differences in FC changes were strongly linked to the subjective psychedelic experience. Performing a perceptual task reduced psilocybin-driven FC changes. Psilocybin caused persistent decrease in FC between the anterior hippocampus and default mode network, lasting for weeks. Persistent reduction of hippocampal-default mode network connectivity may represent a neuroanatomical and mechanistic correlate of the proplasticity and therapeutic effects of psychedelics.
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Encéfalo , Alucinógenos , Red Nerviosa , Psilocibina , Adolescente , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto Joven , Encéfalo/citología , Encéfalo/diagnóstico por imagen , Encéfalo/efectos de los fármacos , Encéfalo/fisiología , Mapeo Encefálico , Red en Modo Predeterminado/citología , Red en Modo Predeterminado/diagnóstico por imagen , Red en Modo Predeterminado/efectos de los fármacos , Red en Modo Predeterminado/fisiología , Alucinógenos/farmacología , Alucinógenos/administración & dosificación , Voluntarios Sanos , Hipocampo/citología , Hipocampo/diagnóstico por imagen , Hipocampo/efectos de los fármacos , Hipocampo/fisiología , Imagen por Resonancia Magnética , Metilfenidato/farmacología , Metilfenidato/administración & dosificación , Red Nerviosa/citología , Red Nerviosa/diagnóstico por imagen , Red Nerviosa/efectos de los fármacos , Red Nerviosa/fisiología , Psilocibina/farmacología , Psilocibina/administración & dosificación , Percepción Espacial/efectos de los fármacos , Percepción del Tiempo/efectos de los fármacos , EgoRESUMEN
INTRODUCTION: This study explores how individuals self-treat psychiatric conditions with psychedelics outside medical guidance bridging the gap in understanding unregulated therapeutic use. AIMS: The primary objective was to extract specific factors underlying the effects of psychedelics, exploring their relationship with the need for medication, particularly for mental health conditions like depression and anxiety. Additionally, we aimed to understand how the likelihood of being prescribed pharmacological medication varies based on mental health diagnoses and demographic factors. METHODS: This research utilised the Global Drug Survey 2020, an annual online survey focused on substance use patterns and demographics, incorporating modules addressing mental health and psychedelic use. The study employed Exploratory Factor Analysis to discern latent factors underlying the self-reported effects of psychedelics. Bivariable and multivariable logistic regressions were conducted to investigate the association between identified factors and the likelihood of current prescribed medication usage. RESULTS: In all, 2552 respondents reported using psychedelics for self-treatment of mental health conditions. Three significant factors were identified: Improved Mental Health, Improved Self-Awareness and Neuro-Sensory Changes. The majority of the sample reported a history of depression (80%) or anxiety (65.6%), with a significant association observed between reported factors of psychedelics' effects and current medication usage for mental health, especially notable in cases of depression or comorbid depression and anxiety. CONCLUSIONS: Perceived symptom improvement following psychedelic self-treatment may reduce the need for medically supervised pharmacological interventions. These findings highlight the potential of psychedelics to positively influence mental health and self-awareness, paving the way for further research into their therapeutic application.
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Alucinógenos , Humanos , Alucinógenos/administración & dosificación , Alucinógenos/farmacología , Alucinógenos/uso terapéutico , Masculino , Femenino , Adulto , Persona de Mediana Edad , Adulto Joven , Salud Mental , Adolescente , Trastornos Mentales/tratamiento farmacológico , Encuestas y Cuestionarios , Depresión/tratamiento farmacológico , Ansiedad/tratamiento farmacológico , AncianoRESUMEN
Science on methylenedioxymethamphetamine (MDMA) and MDMA-like substances is faced with the unique situation that this class of psychoactive agents is referred to with two basic names for its effects on the mind: empathogens and entactogens. Empathogen usually refers to the prosocial, empathetic, and openness properties of MDMA, while entactogen usually refers to the introspective and self-awareness properties of this substance. We review the origin and usage of the two terms, and also review recent findings that support that MDMA is an empathogen and an entactogen. Mostly no specified reasons can be detected whether research groups employ the term "entactogenic," "empathogenic," both, or neither, in their publications. A case is made that the use of two basic names for the effects on the mind for the same class of psychoactive substances is not warranted because a holistic principle underlies empathogenic and entactogenic properties of MDMA: an intense feeling of connection. Entactogenic characterizes being deeply connected to oneself, and empathogenic being deeply connected to others. We therefore suggest the name connectogen as the new basic name for the mind effects of MDMA and MDMA-like substances, a term having the connotation of producing a joining together/producing a connection. Thus, MDMA is basically a connectogen with at least the two major connective properties: entactogenic (intrapersonal) and empathogenic (interpersonal). Furthermore, first evidence shows that MDMA might also have further connectogenic properties such as a strong sense of connection with the here-and-now, the body, the world, and with spiritual principles. Finally, we compare connectogenic properties of MDMA with connectogenic properties of classic psychedelics, and lay out some future research in this regard.
Asunto(s)
Alucinógenos , N-Metil-3,4-metilenodioxianfetamina , N-Metil-3,4-metilenodioxianfetamina/farmacología , Humanos , Alucinógenos/farmacología , Animales , Psicotrópicos/farmacologíaRESUMEN
N, N-dimethyltryptamine (DMT) is a psychedelic tryptamine acting on 5-HT2A serotonin receptors, which is associated with intense visual hallucinatory phenomena and perceptual changes such as distortions in visual space. The neural underpinnings of these effects remain unknown. We hypothesised that changes in population receptive field (pRF) properties in the primary visual cortex (V1) might underlie visual perceptual experience. We tested this hypothesis using magnetic resonance imaging (MRI) in a within-subject design. We used a technique called pRF mapping, which measures neural population visual response properties and retinotopic maps in early visual areas. We show that in the presence of visual effects, as documented by the Hallucinogen Rating Scale (HRS), the mean pRF sizes in V1 significantly increase in the peripheral visual field for active condition (inhaled DMT) compared to the control. Eye and head movement differences were absent across conditions. This evidence for short-term effects of DMT in pRF may explain perceptual distortions induced by psychedelics such as field blurring, tunnel vision (peripheral vision becoming blurred while central vision remains sharp) and the enlargement of nearby visual space, particularly at the visual locations surrounding the fovea. Our findings are also consistent with a mechanistic framework whereby gain control of ongoing and evoked activity in the visual cortex is controlled by activation of 5-HT2A receptors.
Asunto(s)
Alucinógenos , Imagen por Resonancia Magnética , Humanos , Alucinógenos/farmacología , Adulto , Masculino , Femenino , Adulto Joven , Corteza Visual/efectos de los fármacos , Corteza Visual/fisiología , Corteza Visual/diagnóstico por imagen , Distorsión de la Percepción/efectos de los fármacos , Distorsión de la Percepción/fisiología , N,N-Dimetiltriptamina/farmacología , Campos Visuales/efectos de los fármacos , Campos Visuales/fisiología , Percepción Visual/efectos de los fármacos , Percepción Visual/fisiología , Triptaminas/farmacología , Corteza Visual Primaria/efectos de los fármacos , Corteza Visual Primaria/fisiología , Corteza Visual Primaria/diagnóstico por imagen , Mapeo Encefálico/métodosRESUMEN
Mental health disorders and substance use disorders (SUDs) in particular, contribute greatly to the global burden of disease. Psychedelics, including entactogens and dissociative substances, are currently being explored for the treatment of SUDs, yet with less empirical clinical evidence than for other mental health disorders, such as depression or post-traumatic stress disorder (PTSD). In this narrative review, we discuss the current clinical research evidence, therapeutic potential and safety of psilocybin, lysergic acid diethylamide (LSD), ketamine, 3,4-methylenedioxymethamphetamine (MDMA) and ibogaine, particularly in the context of the SUD treatment. Our aim was to provide a balanced overview of the current research and findings on potential benefits and harms of psychedelics in clinical settings for SUD treatment. We highlight the need for more clinical research in this particular treatment area and point out some limitations and challenges to be addressed in future research.
Asunto(s)
Alucinógenos , Trastornos Relacionados con Sustancias , Humanos , Alucinógenos/uso terapéutico , Alucinógenos/efectos adversos , Alucinógenos/farmacología , Trastornos Relacionados con Sustancias/tratamiento farmacológico , Investigación BiomédicaRESUMEN
There is growing interest in the therapeutic potential of psilocybin for the treatment of a wide variety of medical problems, and even for the promotion of wellbeing among healthy individuals. Interestingly, among the many proposed indications, both obesity and anorexia nervosa (AN) have been discussed. However, the effect of psilocybin on appetitive behavior and metabolism is not well known. Here, we report the effects of psilocybin on body weight, intake and output, body composition, and metabolic function among lean male and female wild-type mice. In the days immediately following treatment, both male and female mice receiving a single intraperitoneal dose of psilocybin were consistently heavier than saline controls, with no effect of psilocybin on intake or output. Co-administration of the 5-HT2A/2C receptor antagonist ketanserin had no effect on this outcome. Body composition analysis revealed that psilocybin significantly increased lean and water mass among males, with a similar trend among females. A metabolic panel revealed increased creatine kinase (CK), aspartate aminotransferase (AST), and chloride among male and female psilocybin treated mice. Together, these findings begin to investigate the potential mechanisms of psilocybin's effects on body weight and metabolic measures. Such understanding will be critical for the safe, efficacious, and well-informed use of psilocybin in clinical and non-clinical settings.