ACS Medicinal Chemistry Letters - The Consciousness Library

Psilocybin Therapeutic Research: The Present and Future Paradigm

ACS Medicinal Chemistry Letters March 2, 2020 Robert B. Kargbo 48 citations

Psilocybin, the active component in magic mushrooms, may offer therapeutic benefits for conditions like major depressive disorder and addiction without the addictiveness or overdose risk of drugs such as cocaine, heroin, alcohol, and methamphetamine. The need for new treatments is urgent due to rising rates of addiction, overdose, and suicide in the United States and worldwide. Anecdotal and contemporary pharmacological reports suggest psilocybin's potential for treating mental health disorders. This Viewpoint summarizes current psilocybin therapeutic research and offers insights into future directions for scientific focus.

DOI: 10.1021/acsmedchemlett.0c00048 Full text Psilocybin Computer science Data science Medicine

Microbiome–Gut–Brain Axis Modulation: New Approaches in Treatment of Neuropsychological and Gastrointestinal Functional Disorders

ACS Medicinal Chemistry Letters May 11, 2023 Robert B. Kargbo 15 citations

The gut-brain axis (GBA) is a bidirectional communication system linking the digestive system and the central nervous system through neuro-immune and hormonal pathways. The gut microbiome plays a key role in this communication, influencing mental health. This Patent Highlight describes methods to promote colonization of spore-forming bacteria in the gastrointestinal tract by administering serotonin receptor agonists, including psychedelic compounds such as psilocybin, psilocin, N,N-dimethyltryptamine, bufotenine, 5-methoxy-N,N-dimethyltryptamine, lysergic acid diethylamide, ergine, mescaline, 3,4-methylenedioxyamphetamine, and 2,5-dimethoxy-4-methylamphetamine.

DOI: 10.1021/acsmedchemlett.3c00168 Full text Gut–brain axis Neuroscience Gut microbiome Lysergic acid +3

5-MeO-DMT: Potential Use of Psychedelic-Induced Experiences in the Treatment of Psychological Disorders

ACS Medicinal Chemistry Letters October 21, 2021 Robert B. Kargbo 15 citations

5-MeO-DMT, a potent psychedelic, may be useful in treating psychological disorders by inducing profound experiences that facilitate therapeutic breakthroughs. The article discusses how psychedelic-induced experiences could help patients with conditions such as depression, anxiety, and addiction by promoting neuroplasticity and emotional processing. It highlights the potential of 5-MeO-DMT to produce rapid and sustained improvements in mental health, though further research is needed to understand its mechanisms and optimize therapeutic protocols. The work emphasizes the importance of set and setting in maximizing therapeutic outcomes and minimizing risks.

DOI: 10.1021/acsmedchemlett.1c00546 Full text Psychotherapist Medicine Clinical psychology Psychiatry

Tryptamines and Mental Health: Activating the 5-HT Receptor for Therapeutic Potential

ACS Medicinal Chemistry Letters September 15, 2023 Robert B. Kargbo 11 citations

Tryptamines, which activate serotonin receptors, are being investigated as potential treatments for mental health disorders. The FDA has designated psilocybin and MDMA as breakthrough therapies for conditions like treatment-resistant depression, major depressive disorder, and PTSD. Clinical trials show significant improvements in patient-reported outcomes through reductions in experiential avoidance, indicating a promising future for these compounds in mental health therapy.

DOI: 10.1021/acsmedchemlett.3c00390 Full text Tryptamines 5-HT Receptor Pharmacology Medicine +2

Novel 3-Pyrrolidineindole Derivatives as Serotonergic Psychedelic Agents for Treating Psychosis and Mental Illnesses Such as Depression and Post-Traumatic Stress Disorder.

ACS Medicinal Chemistry Letters January 9, 2025 Ram W. Sabnis 7 citations

No Summary

DOI: 10.1021/acsmedchemlett.4c00581 Full text

Evaluation of the Indazole Analogs of 5-MeO-DMT and Related Tryptamines as Serotonin Receptor 2 Agonists.

ACS Medicinal Chemistry Letters February 8, 2024 Navoda Jayakodiarachchi, Mallory A Maurer, Daniel C Schultz et al. 6 citations

A new set of indazole-based compounds was synthesized and tested as potent agonists of the serotonin 5-HT2 receptor subtypes. The direct indazole analogs of 5-MeO-DMT showed strong activity, but many, including the optimized compound VU6067416 (19d), also acted as potent 5-HT2B agonists, which prevented further development due to safety concerns. Computational docking studies suggest that the high potency of 19d may arise from a halogen-bonding interaction with Phe2345.38 in the 5-HT2A binding pocket. The work underscores the importance of rigorous subtype selectivity profiling for these serotonergic compounds.

DOI: 10.1021/acsmedchemlett.3c00566 Full text Drug development Neuroscience Serotonin receptors Medicinal chemistry +1

Discovery and In Vitro Characterization of SPL028: Deuterated N,N-Dimethyltryptamine.

ACS Medicinal Chemistry Letters September 14, 2023 Marie Layzell, Peter Rands, Meghan Good et al. 6 citations

A deuterated analogue of DMT, called D2-DMT, has a longer half-life and slower clearance in liver cell fractions than standard DMT while maintaining a similar receptor binding profile, making it a promising candidate for extended treatment of major depressive disorder.

DOI: 10.1021/acsmedchemlett.3c00143 Full text Psychedelics Neuroscience Drug development Mental health treatment +1

Novel Indole Derivatives as Serotonergic Psychedelic Agents for Treating Psychosis, Mental Illness, and CNS Disorders.

ACS Medicinal Chemistry Letters June 12, 2025 Ram W. Sabnis 4 citations

A new class of indole derivatives has been developed as serotonergic psychedelic agents. These compounds, along with pharmaceutical compositions containing them, are intended for use in treating psychosis, mental illness, and other central nervous system disorders. The work also describes processes for preparing these novel compounds.

DOI: 10.1021/acsmedchemlett.5c00309 Full text Brain conditions Neurological Psychiatric Psychosis +6

Orally Active Forms of DMT, 5-MeO-DMT, and Long-Acting MDMA for the Treatment of Neuropsychiatric Disorders.

ACS Medicinal Chemistry Letters April 13, 2023 Robert B. Kargbo 4 citations

This patent describes prodrugs—compounds that are metabolically converted into active forms—of DMT, 5-MeO-DMT, and MDMA. When given to a subject, these prodrugs could potentially be used to treat neurological diseases. The disclosure outlines methods for potentially treating conditions including major depressive disorder, post-traumatic stress disorder, Alzheimer's disease, Parkinson's disease, schizophrenia, frontotemporal dementia, Parkinson's dementia, dementia, Lewy body dementia, multiple system atrophy, or substance abuse.

DOI: 10.1021/acsmedchemlett.3c00077 Full text Psychedelics Mental health treatment Drug development Neuroscience +1

Innovative Psychedelic Therapies: Harnessing 5-MeO-DMT and DMT for Mental Health Treatment.

ACS Medicinal Chemistry Letters November 14, 2024 Robert B. Kargbo 3 citations

Recent patents show new ways to use the psychedelic compounds 5-MeO-DMT and DMT to treat mental health disorders like depression, anxiety, and trauma-related conditions. Innovations include combining 5-MeO-DMT with mood preparation agents to improve safety and effectiveness, creating DMT prodrugs for better drug absorption and processing in the body, and designing tailored therapies for specific groups such as breastfeeding mothers. These developments offer potential new options for patients with treatment-resistant mental disorders, reflecting the growing role of psychedelics in mental health care.

DOI: 10.1021/acsmedchemlett.4c00490 Full text Psychedelic therapy Alternative medicine Depression treatment Therapeutic compounds +1

Psychoplastogens: A Novel Therapeutic Approach for Neurological Diseases and Disorders.

ACS Medicinal Chemistry Letters September 14, 2023 Robert B. Kargbo 3 citations

Psychoplastogens—substances that stimulate neuronal growth and enhance neural structures—may help counteract changes in synaptic connectivity and plasticity common in neurological diseases. These compounds activate key targets such as AMPA receptors, TrkB, and mTOR. Examples include ketamine, scopolamine, N,N-dimethyltryptamine, and rapastinel. Clinical trials show psychedelic psychoplastogens have antidepressant, anxiolytic, and anti-addictive effects. The patent highlights potential novel therapies for neurological disorders by modulating synaptic connections and plasticity.

DOI: 10.1021/acsmedchemlett.3c00309 Full text Brain plasticity Neuroscience Mental health Psychopharmacology +1

Advancements in Psychoactive Alkaloid Delivery, Neuroenhancement, and Psychedelic Therapies: Exploring the Frontiers of Modern Pharmacology

ACS Medicinal Chemistry Letters May 8, 2024 Robert B. Kargbo 2 citations

Advancements in pharmacology are being made through novel delivery and application of psychoactive substances. Innovations include transdermal formulations for psychoactive alkaloids, neuroenhancement techniques to augment emotional responses, and intravenous infusion of psilocybin or psilocin for therapeutic purposes. The characterization and potential uses of crystalline forms of tryptamine derivatives are also explored. These developments represent progress in drug delivery systems, neurostimulation methods, and the therapeutic use of psychedelic compounds, potentially revolutionizing treatment for psychological and neurological disorders.

DOI: 10.1021/acsmedchemlett.4c00181 Psilocybin Transdermal Pharmacology Neurostimulation +3

Subhallucinogenic Concentrations of Substituted Phenethylamines as a Novel Therapeutic Approach for Inflammatory and Neurological Disorders.

ACS Medicinal Chemistry Letters July 13, 2023 Robert B. Kargbo 2 citations

A patent describes a method for treating inflammatory or neurological disorders by administering a composition containing a subhallucinogenic dose of a substituted phenethylamine, such as those from the 2C-X family (e.g., 2C-H, 2C-I, 2C-B, or 2C-E). The dose depends on the severity of chronic inflammation: 25 mg for mild, 50 mg for moderate, and 100 mg for severe cases. The method is intended for subjects in need of treatment.

DOI: 10.1021/acsmedchemlett.3c00220 Full text Novel therapeutics Sub-hallucinogenic dosing Phenethylamine compounds Chronic disease treatment

Optimized Parenteral and Intranasal Formulations of Tryptamine Psychedelics for Rapid-Acting Antidepressant Therapy.

ACS Medicinal Chemistry Letters June 12, 2025 Robert B. Kargbo 1 citation

New formulations of the psychedelic compounds DMT and 5-MeO-DMT allow injection or nasal spray delivery, bypassing the body's rapid breakdown of these drugs. These delivery methods produce fast-acting, short-lived therapeutic effects, making them suitable for controlled psychiatric treatments like depression that does not respond to standard therapies. The formulations aim to improve tolerability, ease of use, and clinical practicality.

DOI: 10.1021/acsmedchemlett.5c00265 Full text 5-MEO-DMT Treatment-resistant depression Entheogenic treatment Hallucinogen-assisted therapy +9

Reducing Cardiovascular Side Effects of DMT Using Beta-Blockers.

ACS Medicinal Chemistry Letters May 8, 2025 Robert B. Kargbo 1 citation

DMT produces fast-acting antidepressant effects, but its use is limited by acute side effects like high blood pressure and rapid heart rate. This work describes coformulations of DMT with short-acting beta-blockers or nitrates that are matched to DMT's pharmacokinetics. These combinations reduce peripheral cardiovascular risks without interfering with the central therapeutic effects, potentially enabling safer psychedelic therapy for vulnerable populations.

DOI: 10.1021/acsmedchemlett.5c00180 Full text Psychedelic therapy Cardiovascular medicine Mental health treatment Drug safety +1

Expanding the Therapeutic Horizons of Psilocybin in Mental Health

ACS Medicinal Chemistry Letters October 15, 2024 Robert B. Kargbo 1 citation

Psilocybin, a naturally occurring psychedelic compound, shows promise as a therapeutic agent for mental health. Innovations include clinical trials targeting severe psychiatric conditions, incorporating low-dose psilocybin into dietary products for general mental well-being, and personalizing dosing for optimal treatment of depression and anxiety. These developments highlight psilocybin's versatility and potential to transform conventional mental health treatment through personalized medicine and accessible wellness applications.

DOI: 10.1021/acsmedchemlett.4c00488 Psilocybin New horizons Hallucinogen Mental health +5

Innovative Ketamine Formulations: Enhancing Therapeutic Efficacy and Safety.

ACS Medicinal Chemistry Letters August 8, 2024 Robert B. Kargbo 1 citation

Ketamine, originally an anesthetic, is now used for depression and chronic pain but causes side effects like hallucinations and dizziness from rapid blood concentration spikes. Recent patents describe new delivery methods: subcutaneous injections, ketamine conjugates with other molecules, and dual-release formulations combined with aspirin. These innovations aim to improve how the drug is absorbed and processed in the body, potentially enhancing therapeutic outcomes and safety.

DOI: 10.1021/acsmedchemlett.4c00330 Full text Ketamine-therapy Drug-delivery-systems Pharmaceutical-innovation Depression-treatment

Perceptual Modifying Compounds and Their Potential Therapeutic Applications in Neuropsychiatric Disorders.

ACS Medicinal Chemistry Letters January 11, 2024 Robert B. Kargbo 1 citation

Psychedelic compounds such as ketamine and LSD promote neuronal growth by activating AMPA receptors, TrkB, and mTOR, acting as psychoplastogens. The prefrontal cortex exerts top-down control over brain regions involved in motivation, fear, and reward, contributing to therapeutic effects. These compounds enhance synaptic plasticity and neurogenesis, producing antidepressant effects, and modulate fear circuits to provide anxiolytic properties. They also disrupt addictive patterns and promote neuroplasticity, showing promise as anti-addictive agents. This exploration reveals new opportunities for treating major depressive disorder, anxiety, and addiction.

DOI: 10.1021/acsmedchemlett.3c00535 Full text Neuroscience Psychedelics Mental-health Brain-plasticity +1

Advancing Next-Generation Psychedelic Therapeutics through Selective 5-HT2A Activation, Precision Aerosol Delivery, and Optimized 5-MeO-DMT Treatment Paradigms

ACS Medicinal Chemistry Letters July 10, 2026 Anna C. Renner, Robert B. Kargbo

The psychedelic therapeutics field is moving beyond classical hallucinogens to integrated treatment platforms that combine optimized pharmacology, drug delivery, and clinical implementation. Recent patent applications describe selective 5-HT2A receptor activators, precision aerosol delivery technologies for psychedelic compounds, and structured 5-MeO-DMT treatment regimens for depression. These innovations represent a convergence toward scalable, safer, and clinically practical neuropsychiatric therapies that may reshape the future of serotonergic medicine.

DOI: 10.1021/acsmedchemlett.6c00364 Aerosol Precision medicine Computer science Nanotechnology

Novel 6,5-Bicyclic Compounds as 5-HT2A Receptor Agonists for Treating Depression, Anxiety, Substance Abuse, and Headaches

ACS Medicinal Chemistry Letters July 3, 2026 Ram W. Sabnis, Anika R. Sabnis

The document describes novel 6,5-bicyclic compounds that act as agonists of the 5-HT2A receptor. It covers pharmaceutical compositions containing these compounds, their potential use in treating depression, anxiety, substance abuse, and headaches, and processes for synthesizing them. This is a patent or chemical disclosure focused on drug discovery and pharmacology, not an empirical study with results.

DOI: 10.1021/acsmedchemlett.6c00354 Headaches Receptor Agonist Drug discovery +3

Novel 5,6-Bicyclic Compounds as 5-HT2A Receptor Agonists for Treating Depression, Anxiety, Substance Abuse, and Headaches

ACS Medicinal Chemistry Letters June 3, 2026 Ram W. Sabnis, Anika R. Sabnis

This patent describes novel 5,6-bicyclic compounds that act as agonists of the 5-HT2A receptor. These compounds are intended for use in pharmaceutical compositions to treat conditions such as depression, anxiety, substance abuse, and headaches. The document also outlines processes for synthesizing these compounds. No experimental data, results, or clinical findings are presented.

DOI: 10.1021/acsmedchemlett.6c00270 Full text Headaches Agonist Receptor Drug +4

Advances in Psychedelic Therapeutics: Multimodal Iboga Analogs, EEG-Guided Psilocybin Dosing, and Optimized Harmine–DMT Formulations

ACS Medicinal Chemistry Letters December 16, 2025 Anna C. Renner, Robert B. Kargbo

Recent inventions create a framework for safer, more reliable psychedelic medicines. Simplified iboga analogs offer tunable polypharmacology, real-time EEG biomarkers personalize psilocybin dosing, and standardized harmine-DMT ratios achieve high bioavailability. These innovations improve mechanistic precision, receptor selectivity, and pharmacokinetic control.

DOI: 10.1021/acsmedchemlett.5c00714 Full text Psilocybin Electroencephalography Hallucinogen Investigational drugs +4

Molecular Diagnostics, Circuit-Calming Modulators, and Controlled Neuroplastogens: Emerging Strategies in Precision Neuropsychiatric Therapeutics

ACS Medicinal Chemistry Letters December 16, 2025 Anna C. Renner, Robert B. Kargbo

Three new approaches in neuropsychiatric therapeutics are converging: a blood test measuring FOXG1 gene expression for objective PTSD detection; benzocyclobutenyl-methylamine compounds that reduce excessive neuronal firing; and a sublingual 5-MeO-DMT formulation that promotes neuroplasticity without hallucinations. These advances link molecular diagnostics, targeted neural circuit modulation, and scalable treatments for affective disorders.

DOI: 10.1021/acsmedchemlett.5c00716 Full text Neuroscience Computer science Scalability Computational biology +2

Novel Psilocin Derivatives as Serotonergic Psychedelic Agents for Treating CNS Disorders

ACS Medicinal Chemistry Letters October 22, 2025 Ram W. Sabnis

This work describes novel psilocin derivatives designed as serotonergic psychedelic agents. It covers pharmaceutical compositions containing these compounds, their use in treating central nervous system disorders, and processes for preparing them.

DOI: 10.1021/acsmedchemlett.5c00608 Serotonergic Serotonin Central nervous system Hallucinogen +4

Stabilizing Psilocybin Pharmacology and Tuning Safety with Atypical Antipsychotic Cotherapy

ACS Medicinal Chemistry Letters October 10, 2025 Anna C. Renner, Robert B. Kargbo

A new crystalline cocrystal combining psilocin and psilocybin increases drug exposure, boosts markers of neuroplasticity, and alters functional brain activity. Adding atypical antipsychotics to the treatment changes serotonin signaling, reducing safety risks linked to the 5-HT2B receptor, which is associated with heart valve problems. These chemical advances improve how the therapy works, its selectivity for desired effects, and the ability to measure its impact in lab models. Together, they offer a chemistry-based way to develop scalable psychedelic treatments that are safer for the heart and produce lasting neuroplastic changes, as shown in organoid and animal studies.

DOI: 10.1021/acsmedchemlett.5c00595

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