Abstract Contemporary models of psychedelic action hold that clinical outcomes arise from an interaction between a pharmacologically induced brain state and the lived experience that unfolds within it. Research effort is distributed very unevenly across those two domains: pharmacological variables receive dose-finding trials, power calculations, and effect-size estimates, while the variables...
Abstract Isotryptamines, or 2-(1-indolyl)ethylamines, are positional or geometric isomers of tryptamines where the aminoethyl substituent has been relocated from the indole 3-position to the N1-position. Early studies with these types of agents relied on peripheral tissue assays for examination of their serotonin (5-hydroxytryptamine; 5-HT) receptor affinities to investigate structure–affinity...
Classic serotonergic psychedelics-such as lysergic acid diethylamide (LSD), psilocybin, and N,N-dimethyltryptamine (DMT)-hold remarkable promise for treating neuropsychiatric disorders, yet their clinical translation is severely constrained by first-pass metabolism, erratic pharmacokinetics, unsuitable action profiles, and off-target peripheral serotonin effects. To overcome these barriers,...
The clinical importance of iboga alkaloids lies in their efficacy in reversing drug addiction and modulating drug tolerance. However, due to safety concerns, their use is restricted to appropriate medical supervision. These alkaloids often cause severe psychedelic effects due to differential binding to various brain receptors and cardiotoxicity by blocking the human ether-a-go-go-related gene...
Selective serotonin reuptake inhibitors (SSRIs) are widely prescribed for mood and anxiety disorders, the same conditions under which psychedelic-assisted therapies are gaining renewed interest. However, it remains unclear how SSRI treatment may influence sensitivity to psychedelics, particularly through the shared engagement of serotonergic pathways. Here, we used the head-twitch response...
Prior research has determined that music plays a central role in psychedelic assisted therapy (PAT). While there is a general consensus of the importance of music during PAT, there are only three empirical studies published to date that directly investigate which type of music might best support PAT. Importantly, no review to date has critically analyzed these studies and identified the gaps....
Hypoxia and psychedelics, despite their distinct origins, both induce altered states of consciousness and promote neuroplasticity, suggesting a shared underlying mechanism relevant to neuropsychiatric treatment and neurological recovery. Terminal lucidity, the transient resurgence of cognitive function in late-stage dementia, highlights the brain's latent capacity for rapid reorganization, a...
Serotonergic psychedelics have shown promise in clinical trials for treating an array of mental health disorders, including depression, anxiety, and post-traumatic stress disorder. Despite these findings, our understanding of how these drugs mechanistically exert their therapeutic effects remains incomplete. While researchers have regularly employed rodent preclinical models to assess such...
High Resolution Image Download MS PowerPoint Slide Microdosing, the prolonged ingestion of psychedelics at subhallucinogenic doses, has gained popularity for its perceived cognitive and emotional benefits. Psychedelics have high affinity for 5-HT 2B receptors, a receptor known to cause human heart disease with strong chronic activation. We investigated the effects of microdosed psychedelics on...
Marketing authorization applications for psychedelics must align with the regulatory requirements and evidentiary standards required for the approval of all medicinal products in the European Union. While medicine regulators recognize the therapeutic potential of psychedelics, their characteristics present methodological challenges that complicate the design and interpretation of pivotal trials...
The therapeutic potential of psychedelic substances, particularly psilocybin, for treatment-resistant depression (TRD) has garnered considerable attention. However, the necessity of subjective psychedelic experiences for therapeutic efficacy remains unclear, creating a critical gap in the field. To determine whether subjective psychedelic experiences induced by psilocybin are required for its...
The influence of ovarian hormone fluctuations on neurochemistry, cognition, and psychological responses remains insufficiently examined in current psychedelic research and clinical protocols. Traditional practices and case studies underscore the importance of accounting for these factors in investigations of psychedelic effects. This opinion paper explores the critical intersections between...
Neuropsychiatric disorders reflect disruptions in brain network dynamics along an "order-complexity-chaos" continuum. Psychedelics may therapeutically increase neural entropy, disrupt maladaptive patterns, and promote network reorganization. This system-level framework emphasizes dynamic connectome remodeling over static molecular correction, offering a novel strategy for treating psychiatric...
Recent advancements in the study of psilocybin and its active metabolite psilocin have highlighted their unique psychedelic properties and potential therapeutic applications, particularly in the rapid and sustained treatment of depression. However, the potent acute psychedelic effects of psilocybin necessitate a deeper understanding of the neural mechanisms underlying its action. In this study,...
Psychedelics have emerged as a promising treatment for mental health disease, and the therapeutic potential of psilocybin and lysergic acid diethylamide (LSD) is presently being pursued in numerous clinical trials. This has prompted a search for novel agents with more specific pharmacological activities than the rather promiscuous classical psychedelics. Here we present the detailed...
The interplay between psychedelics, such as psilocybin, lysergic acid diethylamide (LSD) and dimethyltryptamine (DMT), and sleep is an emerging area, but their impact on sleep remains relatively underexplored. This viewpoint provides a perspective on how psychedelics may alter sleep phases, dreaming, and their potential therapeutic applications for sleep disorders.
Exploring dying through the lens of psychedelic experiences offers transformative perspectives on the end-of-life process, potentially alleviating existential distress and enriching the quality of life for those nearing death. Their potential in palliative care, therapy, and spiritual exploration is increasingly recognized, promising to revolutionize end-of-life understanding and care.
Anorexia nervosa (AN) is a severe psychiatric disorder characterized by extreme food restriction, an intense fear of weight gain, and a distorted body image, leading to significant morbidity and mortality. Conventional treatments such as cognitive-behavioral therapy (CBT) and pharmacotherapy often prove inadequate, especially in severe cases, highlighting the need for novel therapeutic...
Psychedelics, known for their therapeutic potential in psychiatric disorders, interact with the autonomic nervous system in ways that are not well understood. This viewpoint examines the complex relationships between psychedelics and autonomic functions, focusing on sympathetic and parasympathetic modulation. We propose a research framework to elucidate how these interactions influence...
Autism Spectrum Disorders (ASD) are complex neurodevelopmental conditions characterized by deficits in social interaction, communication, and repetitive behaviors. This viewpoint explores the potential mechanisms through which psychedelics such as lysergic acid diethylamide (LSD), psilocybin, and 3,4-methylenedioxymethamphetamine (MDMA) may positively influence pro-social behaviors, focusing on...
The anesthetic, analgesic and antidepressant drug ketamine produces dissociation with symptoms of psychosis and anxiety, an effect attributed to neuronal nitric oxide depletion following N-methyl-d-aspartate blockade. There is evidence that dissociation induced by racemic ketamine, containing both ketamine enantiomers (S- and R-ketamine) but not esketamine (the S-isomer) is inhibited by nitric...
1-(2,5-Dimethoxy-4-iodophenyl)-2-aminopropane (DOI, or DOX where X = -I) was first synthesized in 1973 in a structure-activity study to explore the effect of various aryl substituents on the then newly identified, and subsequently controlled, hallucinogenic agent 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM, or DOX where X = -CH3). Over time, DOI was found to be a serotonin (5-HT)...
Lisuride is a non-psychedelic serotonin (5-HT) 2A receptor (5-HT2A) agonist and analogue of the psychedelic lysergic acid diethylamide (LSD). Lisuride also acts as an agonist at the serotonin 1A receptor (5-HT1A), a property known to counter psychedelic effects. Here, we tested whether lisuride lacks psychedelic activity due to a dual mechanism: (1) partial agonism at 5-HT2A and (2) potent...
Functional selectivity in the context of serotonin 2A (5-HT 2A ) receptor agonists is often described as differences psychedelic compounds have in the activation of Gq vs β-arrestin signaling in the brain and how that may relate to inducing psychoactive and hallucinatory properties with respect to each other. However, the presence of 5-HT 2A receptors throughout the body in several cell types,...
α-Ethyltryptamine (AET) is quite an interesting, but perhaps long-forgotten, centrally acting agent. Known for more than 75 years, AET was once clinically available as an antidepressant but was withdrawn shortly after its introduction. AET was subsequently controlled as a U.S. Schedule I substance due to its perceived abuse liability and/or toxicity but remains an agent of interest....