ACS Pharmacology & Translational Science - The Consciousness Library

The Emergence of Isotryptamine Analogs as Novel Serotonergic Agents with Psychotherapeutic Potential

ACS Pharmacology & Translational Science August 18, 2026 Richard A. Glennon, Maƚgorzata Dukat

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...

DOI: 10.1021/acsptsci.6c00288

Overcoming Pharmacokinetic and Peripheral Safety Challenges in Psychedelic Therapies: The Promise of Advanced Drug Delivery Systems.

ACS Pharmacology & Translational Science June 12, 2026 Tianshu Zhang, Cong Lin, Xiaohui Wang

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,...

DOI: 10.1021/acsptsci.6c00146 Full text Drug delivery systems Intranasal administration Microneedle arrays Pharmacokinetics +2

Development of Bioisosteres of Iboga Alkaloids: A Step-Economical Synthesis to Enhance the Antinociceptive and Anxiolytic Activity with Neuroprotective Effects

ACS Pharmacology & Translational Science April 14, 2026 Abhishek Gupta, Tuhin Bhattacharya, Subhamoy Pratihar et al.

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...

DOI: 10.1021/acsptsci.5c00301 Full text Neuroprotection Anxiolytic Nociception Analgesic +3

Differential Effects of Acute and Chronic Fluoxetine on Psychedelic-Induced Behavior in Mice: Implications for Clinical Trials.

ACS Pharmacology & Translational Science March 13, 2026 Bo Jarrett Wood, M Frances Vest, Catharine Carfagno et al.

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...

DOI: 10.1021/acsptsci.5c00484 Full text Serotonin Ssris Head twitch response Psychedelics +1

The Research Deficit and Expert Disagreement Regarding Music Selection for Psychedelic Assisted Therapy.

ACS Pharmacology & Translational Science October 10, 2025 Milo Moskovitz 2 citations

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....

DOI: 10.1021/acsptsci.5c00583 Full text Psilocybin Music

Hypoxia, Psychedelics, and Terminal Lucidity: A Perspective on Neuroplasticity and Neuropsychiatric Disorders.

ACS Pharmacology & Translational Science September 12, 2025 Junjie Zhang, Xiubo Du, Xinying Li et al.

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...

DOI: 10.1021/acsptsci.5c00440 Full text Neuroplasticity Acute intermittent hypoxia Hypoxia therapy Neuropsychiatric disorders +2

Psilocybin Enhances Cued Fear Extinction and Extinction Recall in Stress-Naïve, Acutely Stressed, and Chronically Stressed Mice

ACS Pharmacology & Translational Science September 11, 2025 Noelle Cataldo, John A. Razidlo, Cody J. Wenthur 2 citations

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...

DOI: 10.1021/acsptsci.5c00462

Assessing the Potential Cardiovascular Risk of Microdosing the Psychedelic LSD in Mice

ACS Pharmacology & Translational Science August 22, 2025 Devin P. Effinger, Serena S. Schalk, Jillian L. King et al. 3 citations

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...

DOI: 10.1021/acsptsci.5c00202 Full text Pharmacology

Applying the EU Regulatory Framework to Determine the Benefit-Risk Profile of Psychedelics.

ACS Pharmacology & Translational Science August 8, 2025 Kate Browne, Ewa Bałkowiec-iskra, André Elferink et al. 1 citation

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...

DOI: 10.1021/acsptsci.5c00456 Full text Challenges Clinical trials Marketing authorization Mental-health disorders +2

The Causal Role of Consciousness in Psychedelic Therapy for Treatment-Resistant Depression: Hypothesis and Proposal

ACS Pharmacology & Translational Science July 16, 2025 Tobías Fernández-Borkel, Lucas F Borkel, Jaime Rojas-Hernández et al. 3 citations

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...

DOI: 10.1021/acsptsci.5c00445 Consciousness Depression economics Psychotherapist Clinical psychology +2

Females in Psychedelic Research: A Perspective for Advancing Research and Practice.

ACS Pharmacology & Translational Science July 11, 2025 Zahira Ziva Cohen, Grace Blest‐hopley 9 citations

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...

DOI: 10.1021/acsptsci.5c00255 Full text Psilocybin Estrogen Menstrual cycle Progesterone +18

Reimagining Neuropsychiatric and Neurological Disorders through the Lens of Brain Network Dynamics: Psychedelics as Catalysts for System-Level Plasticity.

ACS Pharmacology & Translational Science July 11, 2025 Cong Zhang, Yibo Wang, Xiaohui Wang 2 citations

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...

DOI: 10.1021/acsptsci.5c00379 Full text Neuroplasticity Brain entropy Brain networks Circuit remodeling +2

The Medial Prefrontal Cortex Modulates Psychedelic-like Effects of Psilocin

ACS Pharmacology & Translational Science July 8, 2025 Miyuan Zhang, Haiyan Zhai, Liu Yang et al. 1 citation

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,...

DOI: 10.1021/acsptsci.5c00324 Full text Prefrontal cortex Consumer neuroscience

The Selective Serotonin 5-HT2A Receptor Agonist (S)-3-(2,5-Dimethoxy-4-(trifluoromethyl)phenyl)piperidine (LPH-5) Induces Persistent and Robust Antidepressant-Like Effects in Rodents

ACS Pharmacology & Translational Science May 29, 2025 Meghan Hibicke, Erik Kaadt, Emil Märcher-Rørsted et al. 3 citations

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...

DOI: 10.1021/acsptsci.5c00208 Serotonin Antidepressant Piperidine Agonist +3

The Intersection of Psychedelics and Sleep: Exploring the Impacts on Sleep Architecture, Dream States, and Therapeutic Implications

ACS Pharmacology & Translational Science May 15, 2025 Haojiang Zhai, Hongshuang Wang, Haohong Li et al. 3 citations

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.

DOI: 10.1021/acsptsci.5c00234 Psilocybin Insomnia Psychedelics Profoundly impact +7

Exploring End-of-Life Experiences and Consciousness through the Lens of Psychedelics.

ACS Pharmacology & Translational Science March 14, 2025 Hongyuan Li, Xiaohui Wang 5 citations

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.

DOI: 10.1021/acsptsci.5c00118 Full text

Psychedelics and Eating Disorders: Exploring the Therapeutic Potential for Anorexia Nervosa and Beyond

ACS Pharmacology & Translational Science March 7, 2025 Shuai Hu, Cong Lin, Hongshuang Wang et al. 8 citations

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...

DOI: 10.1021/acsptsci.5c00094 Eating disorders Anorexia nervosa Psychotherapist Bulimia nervosa +1

Psychedelics and the Autonomic Nervous System: A Perspective on Their Interplay and Therapeutic Potential.

ACS Pharmacology & Translational Science February 18, 2025 Hong-Yuan Li, Hongshuang Wang, Xiao-Hui Wang

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...

DOI: 10.1021/acsptsci.5c00005

Psychedelics and Pro-Social Behaviors: A Perspective on Autism Spectrum Disorders

ACS Pharmacology & Translational Science February 10, 2025 Xue Wang, Cong Lin, Xiaohui Wang 5 citations

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...

DOI: 10.1021/acsptsci.5c00034 Mental health treatment Psychedelics Autism spectrum disorders Social cognition

Nitric Oxide Donor Sodium Nitroprusside Reduces Racemic Ketamine-But Not Esketamine-Induced Pain Relief.

ACS Pharmacology & Translational Science July 12, 2024 Albert Dahan, Simone C Jansen, Rutger van der Schrier et al. 8 citations

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...

DOI: 10.1021/acsptsci.4c00133 Full text Ketamine research Pain medication Blood pressure drugs Pharmacology +1

1-(2,5-Dimethoxy-4-iodophenyl)-2-aminopropane (DOI): From an Obscure to Pivotal Member of the DOX Family of Serotonergic Psychedelic Agents - A Review.

ACS Pharmacology & Translational Science June 14, 2024 Richard A Glennon, Małgorzata Dukat 21 citations

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)...

DOI: 10.1021/acsptsci.4c00157 Full text

Comparative Pharmacological Effects of Lisuride and Lysergic Acid Diethylamide Revisited.

ACS Pharmacology & Translational Science March 8, 2024 Grant C. Glatfelter, Eline Pottie, John S. Partilla et al. 28 citations

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...

DOI: 10.1021/acsptsci.3c00192 Full text Brain chemistry Psychedelics Pharmacology Drug interactions

Serotonin-2 Receptor Agonists Produce Anti-inflammatory Effects through Functionally Selective Mechanisms That Involve the Suppression of Disease-Induced Arginase 1 Expression

ACS Pharmacology & Translational Science January 25, 2024 Thomas W. Flanagan, Timothy P. Foster, Thomas E. Galbato et al. 18 citations

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,...

DOI: 10.1021/acsptsci.3c00297 Full text Serotonin Functional selectivity Agonist 5-HT Receptor +8

α-Ethyltryptamine: A Ratiocinatory Review of a Forgotten Antidepressant.

ACS Pharmacology & Translational Science December 8, 2023 Richard A Glennon, Mal Gorzata Dukat 3 citations

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....

DOI: 10.1021/acsptsci.3c00139 Full text

The Psychedelic N,N-Dipropyltryptamine Prevents Seizures in a Mouse Model of Fragile X Syndrome via a Mechanism that Appears Independent of Serotonin and Sigma1 Receptors

ACS Pharmacology & Translational Science September 18, 2023 Richa Tyagi, Tanishka S. Saraf, Clinton E. Canal 5 citations

The serotonergic psychedelic psilocybin shows efficacy in treating neuropsychiatric disorders, though the mechanism(s) underlying its therapeutic effects remain unclear. We show that a similar psychedelic tryptamine, N,N-dipropyltryptamine (DPT), completely prevents audiogenic seizures (AGS) in an Fmr1 knockout mouse model of fragile X syndrome at a 10 mg/kg dose but not at lower doses (3 or...

DOI: 10.1021/acsptsci.3c00137 Serotonin Serotonergic Knockout mouse Pharmacology +5

Papers