Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors

Science, Год журнала: 2023, Номер 379(6633), С. 700 - 706

Опубликована: Фев. 16, 2023

Decreased dendritic spine density in the cortex is a hallmark of several neuropsychiatric diseases, and ability to promote cortical neuron growth has been hypothesized underlie rapid sustained therapeutic effects psychedelics. Activation 5-hydroxytryptamine (serotonin) 2A receptors (5-HT2ARs) essential for psychedelic-induced plasticity, but it currently unclear why some 5-HT2AR agonists neuroplasticity, whereas others do not. We used molecular genetic tools demonstrate that intracellular 5-HT2ARs mediate plasticity-promoting properties psychedelics; these results explain serotonin does not engage similar plasticity mechanisms. This work emphasizes role location bias signaling, identifies as target, raises intriguing possibility might be endogenous ligand cortex.

Язык: Английский

---

5-HT2ARs Mediate Therapeutic Behavioral Effects of Psychedelic Tryptamines

ACS Chemical Neuroscience, Год журнала: 2023, Номер 14(3), С. 351 - 358

Опубликована: Янв. 11, 2023

Psychedelic compounds have displayed antidepressant potential in both humans and rodents. Despite their promise, psychedelics can induce undesired effects that pose safety concerns limit clinical scalability. The rational development of optimized psychedelic-related medicines will require a full mechanistic understanding how these molecules produce therapeutic effects. While the hallucinogenic properties are generally attributed to activation serotonin 2A receptors (5-HT2ARs), it is currently unclear if also mediate as several nonhallucinogenic analogues with antidepressant-like been developed. Moreover, many exhibit promiscuous pharmacology, making challenging identify primary target(s). Here, we use combination pharmacological genetic tools demonstrate 5-HT2A essential for tryptamine-based Our results suggest psychedelic tryptamines through same receptor.

Язык: Английский

---

A complex systems perspective on psychedelic brain action

Trends in Cognitive Sciences, Год журнала: 2023, Номер 27(5), С. 433 - 445

Опубликована: Фев. 3, 2023

Язык: Английский

---

The Potential of Flavonoids and Flavonoid Metabolites in the Treatment of Neurodegenerative Pathology in Disorders of Cognitive Decline

Antioxidants, Год журнала: 2023, Номер 12(3), С. 663 - 663

Опубликована: Март 7, 2023

Flavonoids are a biodiverse family of dietary compounds that have antioxidant, anti-inflammatory, antiviral, and antibacterial cell protective profiles. They received considerable attention as potential therapeutic agents in biomedicine been widely used traditional complimentary medicine for generations. Such medical herbal formulations extremely complex mixtures many pharmacologically active provide outcome through network pharmacological effects complexity. Methods emerging to determine the components their targets decipher complexities how pharmacology provides such effects. The gut microbiome has important roles play generation bioactive flavonoid metabolites retaining or exceeding antioxidative anti-inflammatory properties intact and, some cases, new antitumor antineurodegenerative bioactivities. Certain food items identified with high prebiotic profiles suggesting neutraceutical supplementation may be beneficially employed preserve healthy population bacterial symbiont species minimize establishment harmful pathogenic organisms. Gut health is an consideration effecting overall wellbeing linked organ systems. Bioconversion generates can also transported by vagus nerve systemic circulation brain populations exert beneficial effect. This particularly number neurological disorders (autism, bipolar disorder, AD, PD) characterized on moods, resulting depression anxiety, impaired motor function, long-term cognitive decline. Native flavonoids alleviation inflammation tissues, however, concerns raised levels not achieved, thus allowing them display optimal Dietary manipulation vagal stimulation both yielded responses treatment autism spectrum disorders, depression, establishing route communication gut-brain axis established disease intervention. While native known penetrate blood–brain barrier, microbiome-generated (e.g., protocatechuic acid, urolithins, γ-valerolactones), which retain antioxidant potency addition promote mitochondrial cerebrovascular microcapillary should considered biotherapeutic agents. Studies warranted experimentally examine efficacy directly, they emerge novel options.

Язык: Английский

---

Psilocybin-assisted therapy for depression: A systematic review and dose-response meta-analysis of human studies

European Neuropsychopharmacology, Год журнала: 2023, Номер 76, С. 61 - 76

Опубликована: Авг. 7, 2023

Psilocybin is increasingly studied for its antidepressant effect, but optimal dosage depression remains unclear. We conducted a systematic review and dose-response meta-analysis to find the of psilocybin reduce scores. Following our protocol (CRD 42022220190) multiple electronic databases were searched from their inception until February 2023, identify double-blind randomized placebo-controlled (RCTs) fixed-dose trials evaluating use adult patients with primary or secondary depression. A one-stage restricted cubic splines was used. Cochrane risk bias used assess bias. Our analysis included seven studies total 489 participants. Among these, four focused on (N = 366), including one study suffering treatment-resistant The remaining three examined 123). determined 95% effective doses per day (ED95) 8.92, 24.68, 36.08 mg/70 kg depression, both subgroups, respectively. observed significant associations all curves, each plateauing at different levels, except bell-shaped curve in case Additionally, we found various side effects, physical discomfort, blood pressure increase, nausea/vomiting, headache/migraine, prolonged psychosis. In conclusion, discovered specific ED95 values populations, indicating higher groups. Further RCTs are necessary population determine dosage, allowing maximum efficacy while minimizing effects.

Язык: Английский

---

Efficacy and safety of psychedelics for the treatment of mental disorders: A systematic review and meta-analysis

Psychiatry Research, Год журнала: 2024, Номер 335, С. 115886 - 115886

Опубликована: Март 28, 2024

Язык: Английский

---

Serotonergic Psychedelics: A Comparative Review of Efficacy, Safety, Pharmacokinetics, and Binding Profile

Biological Psychiatry Cognitive Neuroscience and Neuroimaging, Год журнала: 2024, Номер 9(5), С. 472 - 489

Опубликована: Фев. 1, 2024

Psychedelic compounds, including psilocybin, LSD, DMT, and 5-MeO-DMT all of which are serotonin (5-HT) 2A receptor agonists being investigated as potential treatments. This review aims to summarize the current clinical research on these four compounds mescaline guide future research. Their mechanism/s action, pharmacokinetics, pharmacodynamics, efficacy, safety were reviewed. While evidence for therapeutic indications, with exception psilocybin depression, is still relatively scarce, we noted no differences in psychedelic effects beyond effect duration. It remains therefore unclear whether different profiles contribute compounds. More needed differentiate order inform might be best uses.

Язык: Английский

---

Glutamate-Mediated Excitotoxicity in the Pathogenesis and Treatment of Neurodevelopmental and Adult Mental Disorders

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(12), С. 6521 - 6521

Опубликована: Июнь 13, 2024

Glutamate is the main excitatory neurotransmitter in brain wherein it controls cognitive functional domains and mood. Indeed, areas involved memory formation consolidation as well fear emotional processing, such hippocampus, prefrontal cortex, amygdala, are predominantly glutamatergic. To ensure physiological activity of brain, glutamatergic transmission finely tuned at synaptic sites. Disruption mechanisms responsible for glutamate homeostasis may result accumulation excessive levels, which turn leads to increased calcium mitochondrial abnormalities, oxidative stress, eventually cell atrophy death. This condition known glutamate-induced excitotoxicity considered a pathogenic mechanism several diseases central nervous system, including neurodevelopmental, substance abuse, psychiatric disorders. On other hand, these disorders share neuroplasticity impairments areas, accompanied by structural remodeling neurons. In current narrative review, we will summarize role both pathophysiology therapeutic interventions neurodevelopmental adult mental with focus on autism spectrum disorders, drugs under preclinical clinical development treatment different that dysfunctions. Although evidence still limited more studies required, regulation attracting attention potential crucial target control diseases.

Язык: Английский

---

Multidimensional Personality Changes Following Psilocybin-Assisted Therapy in Patients With Alcohol Use Disorder: Results From a Double-Blind, Placebo-Controlled Clinical Trial

American Journal of Psychiatry, Год журнала: 2025, Номер 182(1), С. 114 - 125

Опубликована: Янв. 1, 2025

Evidence suggests that psilocybin-assisted therapy (PAT) leads to durable shifts in personality structure. However, such changes have yet be characterized disorders of addiction. In this secondary analysis from a randomized controlled trial, the authors examined effect PAT on dimensions patients with alcohol use disorder (AUD), hypothesizing would attenuate abnormalities AUD and reductions trait impulsiveness associated lower drinking.

Язык: Английский

---

More than meets the eye: The role of sensory dimensions in psychedelic brain dynamics, experience, and therapeutics

Neuropharmacology, Год журнала: 2022, Номер 223, С. 109300 - 109300

Опубликована: Ноя. 10, 2022

Psychedelics are undergoing a major resurgence of scientific and clinical interest. While multiple theories frameworks have been proposed, there is yet no universal agreement on the mechanisms underlying complex effects psychedelics subjective experience brain dynamics, nor their therapeutic benefits. Despite being prominent in psychedelic phenomenology distinct from those elicited by other classes hallucinogens, low-level sensory - particularly visual dimensions experience, corresponding often disregarded contemporary research as ‘epiphenomenal byproducts’. Here, we review available evidence neuroimaging, pharmacology, questionnaires, studies; propose extensions to existing models, provide testable hypotheses for potential roles psychedelic-induced hallucinations, simulations phenomena relying cortical dynamics. In sum, show that alterations 1) unlikely be entirely causally reconducible high-level alterations, but rather co-occur with them dialogical interplay, 2) likely play relevant role determining outcomes. We conclude reevaluating currently underappreciated states will highly valuable neuroscience practice, integrating domain-specific aspects into nonspecific models necessary step further understand how these substances effect both acute long-term change human brain.

Язык: Английский

---