Chemistry/structural biology of psychedelic drugs and their receptor(s).

This brief review highlights some of the structure-activity relationships of classic serotonergic psychedelics. In particular, we discuss structural features of three chemotypes: phenethylamines, ergolines and certain tryptamines, which possess psychedelic activity in humans. Where they are known, we point out the underlying molecular mechanisms utilized by each of the three chemotypes of psychedelic molecules.

Ligand and G-protein selectivity in the κ-opioid receptor.

The κ-opioid receptor (KOR) represents a highly desirable therapeutic target for treating not only pain but also addiction and affective disorders. However, the development of KOR analgesics has been hindered by the associated hallucinogenic side effects. The initiation of KOR signalling requires the G-family proteins including the conventional (G, G, G, G and G) and nonconventional (G and G) subtypes.

Signaling snapshots of a serotonin receptor activated by the prototypical psychedelic LSD.

Serotonin (5-hydroxytryptamine [5-HT]) 5-HT2-family receptors represent essential targets for lysergic acid diethylamide (LSD) and all other psychedelic drugs. Although the primary psychedelic drug effects are mediated by the 5-HT serotonin receptor (HTR2A), the 5-HT serotonin receptor (HTR2B) has been used as a model receptor to study the activation mechanisms of psychedelic drugs due to its high expression and similarity to HTR2A. In this study, we determined the cryo-EM structures of LSD-bound HTR2B in the transducer-free, Gq-protein-coupled, and β-arrestin-1-coupled states.

Preface to the special issue "Psychedelics and Neurochemistry".

Psychedelics are a relatively recent field of research that had not gained much support half a century ago, yet it developed into a much acknowledged, highly relevant field that extends to many people's lives. Psychedelics have demonstrated profound and durable therapeutic potential for the treatment of several psychiatric disorders including depression, anxiety, and substance use disorders, among others. In this special issue, basic science of psychedelics is reviewed with respect to fundamental cellular, molecular, and genetic mechanisms, all the way up to the human systems level with clinical reviews.

Entactogens: How the Name for a Novel Class of Psychoactive Agents Originated.

At first glance, it appears there is little difference between the molecular structures of methylenedioxymethamphetamine (MDMA), which has an -methyl attached to its amino group, and methylenedioxyamphetamine (MDA), a primary amine that is recognized to have hallucinogenic activity. It is known from studies with other hallucinogenic amphetamines that -methylation of hallucinogenic amphetamines attenuates or abolishes hallucinogenic activity. Nevertheless, MDMA is biologically active and has a potency only slightly less than its MDA parent.

The History of Psychedelics in Psychiatry.

Initial interest in the value of psychedelic drugs ("psychotomimetics") in psychiatry began in the early 20 century, with explorations of the possibility that mescaline or peyote could produce psychosis-like effects. Over time, interest was focused on whether the effects of psychedelics could inform as to the underlying basis for psychiatric disorders. As research continued, and especially after the discovery of LSD in 1943, increasing interest in a role for psychedelics as adjuncts to psychotherapy began to evolve and became the major focus of work with psychedelics up to the present day.

Structure of a Hallucinogen-Activated Gq-Coupled 5-HT Serotonin Receptor.

Hallucinogens like lysergic acid diethylamide (LSD), psilocybin, and substituted N-benzyl phenylalkylamines are widely used recreationally with psilocybin being considered as a therapeutic for many neuropsychiatric disorders including depression, anxiety, and substance abuse. How psychedelics mediate their actions-both therapeutic and hallucinogenic-are not understood, although activation of the 5-HT serotonin receptor (HTR2A) is key. To gain molecular insights into psychedelic actions, we determined the active-state structure of HTR2A bound to 25-CN-NBOH-a prototypical hallucinogen-in complex with an engineered Gαq heterotrimer by cryoelectron microscopy (cryo-EM).

Psilocybin: from ancient magic to modern medicine.

Psilocybin (4-phosphoryloxy-N,N-dimethyltryptamine) is an indole-based secondary metabolite produced by numerous species of mushrooms. South American Aztec Indians referred to them as teonanacatl, meaning "god's flesh," and they were used in religious and healing rituals. Spanish missionaries in the 1500s attempted to destroy all records and evidence of the use of these mushrooms.

Microdosing psychedelics: More questions than answers? An overview and suggestions for future research.

Background: In the past few years, the issue of 'microdosing' psychedelics has been openly discussed in the public arena where claims have been made about their positive effect on mood state and cognitive processes such as concentration. However, there are very few scientific studies that have specifically addressed this issue, and there is no agreed scientific consensus on what microdosing is.

Aim: This critique paper is designed to address questions that need to be answered by future scientific studies and to offer guidelines for these studies.

Correction to: Pharmacological characterization of the LSD analog N-ethyl-N-cyclopropyl lysergamide (ECPLA).

The author of this article wanted to change the Acknowledgments section to: These studies were supported by an award from NIDA (R01 DA041336), as well as by the Veteran's Administration VISN 22 Mental Illness Research, Education, and Clinical Center. Receptor binding and functional data were generously.

Pharmacological characterization of the LSD analog N-ethyl-N-cyclopropyl lysergamide (ECPLA).

Rationale: The lysergamide lysergic acid diethylamide (LSD) is a prototypical classical hallucinogen with remarkably high potency. LSD remains a popular recreational drug but is also becoming an important research tool for medical and neuroscience studies. Recently, several lysergamides that are close structural analogs of LSD have been sold as recreational drugs, which suggests that further studies are needed to explore the pharmacological properties of these compounds.

Understanding Central Nervous System Effects of Deliriant Hallucinogenic Drugs through Experimental Animal Models.

Hallucinogenic drugs potently alter human behavior and have a millennia-long history of use for medicinal and religious purposes. Interest is rapidly growing in their potential as CNS modulators and therapeutic agents for brain conditions. Antimuscarinic cholinergic drugs, such as atropine and scopolamine, induce characteristic hyperactivity and dream-like hallucinations and form a separate group of hallucinogens known as "deliriants".

Dark Classics in Chemical Neuroscience: Lysergic Acid Diethylamide (LSD).

Lysergic acid diethylamide (LSD) is one of the most potent psychoactive agents known, producing dramatic alterations of consciousness after submilligram (≥20 μg) oral doses. Following the accidental discovery of its potent psychoactive effects in 1943, it was supplied by Sandoz Laboratories as an experimental drug that might be useful as an adjunct for psychotherapy, or to give psychiatrists insight into the mental processes in their patients. The finding of serotonin in the mammalian brain in 1953, and its structural resemblance to LSD, quickly led to ideas that serotonin in the brain might be involved in mental disorders, initiating rapid research interest in the neurochemistry of serotonin.

N,N-dimethyltryptamine and the pineal gland: Separating fact from myth.

The pineal gland has a romantic history, from pharaonic Egypt, where it was equated with the eye of Horus, through various religious traditions, where it was considered the seat of the soul, the third eye, etc. Recent incarnations of these notions have suggested that N,N-dimethyltryptamine is secreted by the pineal gland at birth, during dreaming, and at near death to produce out of body experiences. Scientific evidence, however, is not consistent with these ideas.

Psychedelic Drugs in Biomedicine.

Psychedelic drugs, such as lysergic acid diethylamide (LSD), mescaline, and psilocybin, exert profound effects on brain and behavior. After decades of difficulties in studying these compounds, psychedelics are again being tested as potential treatments for intractable biomedical disorders. Preclinical research of psychedelics complements human neuroimaging studies and pilot clinical trials, suggesting these compounds as promising treatments for addiction, depression, anxiety, and other conditions.

Return of the lysergamides. Part IV: Analytical and pharmacological characterization of lysergic acid morpholide (LSM-775).

Lysergic acid diethylamide (LSD) is perhaps one of the best-known psychoactive substances and many structural modifications of this prototypical lysergamide have been investigated. Several lysergamides were recently encountered as 'research chemicals' or new psychoactive substances (NPS). Although lysergic acid morpholide (LSM-775) appeared on the NPS market in 2013, there is disagreement in the literature regarding the potency and psychoactive properties of LSM-775 in humans.

Experimental evaluation of the generalized vibrational theory of G protein-coupled receptor activation.

Recently, an alternative theory concerning the method by which olfactory proteins are activated has garnered attention. This theory proposes that the activation of olfactory G protein-coupled receptors occurs by an inelastic electron tunneling mechanism that is mediated through the presence of an agonist with an appropriate vibrational state to accept the inelastic portion of the tunneling electron's energy. In a recent series of papers, some suggestive theoretical evidence has been offered that this theory may be applied to nonolfactory G protein-coupled receptors (GPCRs), including those associated with the central nervous system (CNS).

Chemistry and Structure-Activity Relationships of Psychedelics.

This chapter will summarize structure-activity relationships (SAR) that are known for the classic serotonergic hallucinogens (aka psychedelics), focusing on the three chemical types: tryptamines, ergolines, and phenethylamines. In the brain, the serotonin 5-HT receptor plays a key role in regulation of cortical function and cognition, and also appears to be the principal target for hallucinogenic/psychedelic drugs such as LSD. It is one of the most extensively studied of the 14 known types of serotonin receptors.

Return of the lysergamides. Part III: Analytical characterization of N -ethyl-6-norlysergic acid diethylamide (ETH-LAD) and 1-propionyl ETH-LAD (1P-ETH-LAD).

The psychoactive properties of lysergic acid diethylamide (LSD) have fascinated scientists across disciplines and the exploration of other analogues and derivatives has been motivated by deepening the understanding of ligand-receptor interactions at the molecular level as well as by the search for new therapeutics. Several LSD congeners have appeared on the new psychoactive substances (NPS) market in the form of blotters or powders. Examples include 1-propionyl-LSD (1P-LSD), AL-LAD, and LSZ.

Striatal dopamine D1 receptor suppression impairs reward-associative learning.

Dopamine (DA) is required for reinforcement learning. Hence, disruptions in DA signaling may contribute to the learning deficits associated with psychiatric disorders. The DA D1 receptor (D1R) has been linked to learning and is a target for cognitive/motivational enhancement in patients with schizophrenia.

Crystal Structure of an LSD-Bound Human Serotonin Receptor.

The prototypical hallucinogen LSD acts via serotonin receptors, and here we describe the crystal structure of LSD in complex with the human serotonin receptor 5-HT. The complex reveals conformational rearrangements to accommodate LSD, providing a structural explanation for the conformational selectivity of LSD's key diethylamide moiety. LSD dissociates exceptionally slow from both 5-HTR and 5-HTR-a major target for its psychoactivity.

Return of the lysergamides. Part II: Analytical and behavioural characterization of N -allyl-6-norlysergic acid diethylamide (AL-LAD) and (2'S,4'S)-lysergic acid 2,4-dimethylazetidide (LSZ).

Lysergic acid N,N-diethylamide (LSD) is perhaps one of the most intriguing psychoactive substances known and numerous analogs have been explored to varying extents in previous decades. In 2013, N -allyl-6-norlysergic acid diethylamide (AL-LAD) and (2'S,4'S)-lysergic acid 2,4-dimethylazetidide (LSZ) appeared on the 'research chemicals'/new psychoactive substances (NPS) market in both powdered and blotter form. This study reports the analytical characterization of powdered AL-LAD and LSZ tartrate samples and their semi-quantitative determination on blotter paper.