There is currently a resurgence in exploring the utility of classical psychedelics to treat depression, addiction, anxiety disorders, cluster headaches, and many other neuropsychiatric disorders. A biological target of these compounds, and a hypothesized target for their therapeutic actions, is the 5-HT2A serotonin receptor. Here, we present 7 cryo-EM structures covering all major compound classes of psychedelic and non-psychedelic agonists, including a β-arrestin-biased compound RS130-180. Identifying the molecular interactions between various psychedelics and the 5-HT2A receptor reveals both common and distinct motifs among the examined psychedelic chemotypes. These findings lead to a broader mechanistic understanding of 5-HT2A activation, which can catalyze the development of novel chemotypes with potential therapeutic utility and fewer side effects. The authors present 7 cryo-EM structures of hallucinogenic and non-hallucinogenic compounds across multiple chemotypes bound to the 5-HT2A receptor, shedding light onto ligand specificity and signaling bias.

The dopamine D1 receptor (D1R) couples to Gαs and Gαolf and is crucial in regulating neurological and neuropsychiatric functions. In the brain, Gαolf is predominantly found in the striatum whereas Gαs is expressed elsewhere. Our in vitro assays revealed that the tetracyclic catechol agonists dihydrexidine, methyl-dihydrexidine, doxanthrine, and the non-catechol compounds PF-8294, PF-6142 exerted full agonism for Gαs coupling but only partial agonism for Gαolf coupling. In contrast, the non-catechol agonist tavapadon acted as a full agonist at Gαolf and a partial agonist at Gαs. The effects of these ligands on the thalamocortical and striatonigral electrophysiological events, as well as on the locomotor activity and cognitive function of mice agreed with their selectivity profiles in vitro. These findings suggest the possibility of achieving region-specific pharmacology and open new directions for developing D1R drugs to treat relevant neurological and neuropsychiatric disorders.

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. With a focus on the 5-HT2A receptor subtype, a G-protein coupled receptor known to be the primary target of psychedelics, we refer to several X-ray and cryoEM structures, with a variety of ligands bound, to illustrate the underlying atomistic basis for some of the known pharmacological observations of psychedelic drug actions. LINKED ARTICLES: This article is part of a themed issue Emerging Therapeutic Opportunities for Psychedelic and Related Drugs. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v183.14/issuetoc.

Abstract ID 95565Poster Board 354G protein heterotrimers (Galpha, Gbeta, and Ggamma) are important signal transducers upon activation of G protein coupled receptors (GPCRs). Opioid receptors belong to the class A GPCRs and play major roles in pain, mood, reward, and motivation. Opioids are used for pain management despite the side effects that contribute to the opioid crisis. The pursuit of non-addictive opioid analgesics remains unattained due to the unresolved intricacies of opioid actions, receptor signaling cascades, and neuronal plasticity. Opioid receptor activation couples to up to seven Ga subtypes (Gai1, Gai2, Gai3, GaoA, GaoB, Gaz, and/or Gustducin). The molecular basis for the G protein subtype selectivity are largely unclear; the functional consequence of individual G protein signaling remains unknown. We thus determined the active-state structures of kappa opioid receptor (KOR) in a complex with multiple G-protein heterotrimers using cryo-electron microscopy. Comparisons of these structures reveal molecular determinants critical for KOR–G-protein interactions as well as key elements governing Gi/o-family subtype selectivity. Furthermore, the G-protein subtypes display an intrinsically different allosteric activity on agonist activity at KOR. These results provide insights into the actions of opioids and G-protein-coupling specificity at KOR and establish a foundation to examine the therapeutic potential of pathway-selective agonists of KOR.The work is supported by NIH grants R35GM143061 (to T.C.)

Psychedelic MedicineVol. 1, No. 1 Consensus StatementProposed Consensus Statement on Defining Psychedelic DrugsDavid E. Nichols, Charles D. Nichols, and Peter S. HendricksDavid E. Nichols*Address correspondence to: David E. Nichols, Department of Chemical Biology and Medicinal Chemistry, University of North Carolina, Chapel Hill, North Carolina, USA, E-mail Address: [email protected]Department of Chemical Biology and Medicinal Chemistry, University of North Carolina, Chapel Hill, North Carolina, USA.Search for more papers by this author, Charles D. NicholsDepartment of Pharmacology, Louisiana State University Health Sciences Center, New Orleans, Louisiana, USA.Search for more papers by this author, and Peter S. HendricksDepartment of Health Behavior, The University of Alabama at Birmingham School of Public Health, Birmingham, Alabama, USA.Search for more papers by this authorPublished Online:13 Mar 2023https://doi.org/10.1089/psymed.2022.0008AboutSectionsView articleView Full TextPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail View article"Proposed Consensus Statement on Defining Psychedelic Drugs." Psychedelic Medicine, 1(1), pp. 12–13FiguresReferencesRelatedDetailsCited byLetter to the Editor: What Is in a Name? The Many Meanings of “Psychedelic” Kelley C. O'Donnell, Daniel E. Roberts, Terence H.W. Ching, Gianni Glick, Noam Goldway, Natalie Gukasyan, Jamila Hokansen, Benjamin Kelmendi, Stephen Ross, Mary E. Yaden, and Christopher Pittenger21 July 2023 | Psychedelic Medicine, Vol. 0, No. 0 Volume 1Issue 1Mar 2023 InformationCopyright 2023, Mary Ann Liebert, Inc., publishersTo cite this article:David E. Nichols, Charles D. Nichols, and Peter S. Hendricks.Proposed Consensus Statement on Defining Psychedelic Drugs.Psychedelic Medicine.Mar 2023.12-13.http://doi.org/10.1089/psymed.2022.0008Published in Volume: 1 Issue 1: March 13, 2023Online Ahead of Print:October 28, 2022PDF download

Regulation of clinical research on schedule 1 drugs with therapeutic potential should be reviewed, argue Leslie King, David Nutt and David Nichols

The κ-opioid receptor (KOR) represents a highly desirable therapeutic target for treating not only pain but also addiction and affective disorders 1 . However, the development of KOR analgesics has been hindered by the associated hallucinogenic side effects 2 . The initiation of KOR signalling requires the G i/o -family proteins including the conventional (G i1 , G i2 , G i3 , G oA and G oB ) and nonconventional (G z and G g ) subtypes. How hallucinogens exert their actions through KOR and how KOR determines G-protein subtype selectivity are not well understood. Here we determined the active-state structures of KOR in a complex with multiple G-protein heterotrimers—G i1 , G oA , G z and G g —using cryo-electron microscopy. The KOR–G-protein complexes are bound to hallucinogenic salvinorins or highly selective KOR agonists. Comparisons of these structures reveal molecular determinants critical for KOR–G-protein interactions as well as key elements governing G i/o -family subtype selectivity and KOR ligand selectivity. Furthermore, the four G-protein subtypes display an intrinsically different binding affinity and allosteric activity on agonist binding at KOR. These results provide insights into the actions of opioids and G-protein-coupling specificity at KOR and establish a foundation to examine the therapeutic potential of pathway-selective agonists of KOR.

Psychedelic MedicineVol. 1, No. 4 Editor's RebuttalIf Everything Is Psychedelic, Then Nothing Is: A Response to O'Donnell et al. and Lepow et al.David E. Nichols, Peter S. Hendricks, and Charles D. NicholsDavid E. NicholsDepartment of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, Chapel Hill, North Carolina, USA.Search for more papers by this author, Peter S. HendricksDepartment of Psychiatry and Behavioral Neurobiology, School of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.Search for more papers by this author, and Charles D. Nichols*Address correspondence to: Charles D. Nichols, PhD, Department of Pharmacology and Experimental Therapeutics, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA, E-mail Address: [email protected]Department of Pharmacology and Experimental Therapeutics, Louisiana State University Health Sciences Center, New Orleans, Louisiana, USA.Search for more papers by this authorPublished Online:13 Dec 2023https://doi.org/10.1089/psymed.2023.29003.cdnAboutSectionsView articleView Full TextPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookXLinked InRedditEmail View articleFiguresReferencesRelatedDetails Volume 1Issue 4Dec 2023 InformationCopyright 2023, Mary Ann Liebert, Inc., publishersTo cite this article:David E. Nichols, Peter S. Hendricks, and Charles D. Nichols.If Everything Is Psychedelic, Then Nothing Is: A Response to O'Donnell et al. and Lepow et al..Psychedelic Medicine.Dec 2023.195-197.http://doi.org/10.1089/psymed.2023.29003.cdnPublished in Volume: 1 Issue 4: December 13, 2023Online Ahead of Print:December 5, 2023PDF download

Psychedelic MedicineVol. 1, No. 1 Roundtable DiscussionPast, Present, and Future of Psychedelics: A Psychedelic Medicine Roundtable DiscussionModerators: Peter S. Hendricks, Charles D. Nichols, Participants: Kathryn A. Cunningham, Mark A. Geyer, Roland Griffiths, and David NicholsModerators: Peter S. HendricksDepartment of Health Behavior, School of Public Health, University of Alabama at Birmingham, Birmingham, USA.Search for more papers by this author, Charles D. NicholsDepartment of Pharmacology and Experimental Therapeutics, LSU Health Sciences Center, New Orleans, Louisiana, USA.Search for more papers by this author, Participants: Kathryn A. CunninghamCenter of Addiction Research and Department of Pharmacology and Pharmacology, Department of Psychiatry, John Sealy School of Medicine, University of Texas Medical Branch, Galveston, Texas, USA.Search for more papers by this author, Mark A. GeyerDepartment of Psychiatry, University of California San Diego, La Jolla, USA.Search for more papers by this author, Roland GriffithsDepartment of Psychiatry and Behavioral Sciences, Department of Neuroscience, and Center for Psychedelic and Consciousness Research, The Johns Hopkins University, Baltimore, Maryland, USA.Search for more papers by this author, and David NicholsUniversity of North Carolina Chapel Hill, Chapel Hill, North Carolina, USA.Search for more papers by this authorPublished Online:13 Mar 2023https://doi.org/10.1089/psymed.2022.0003AboutSectionsView articleView Full TextPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail View articleFiguresReferencesRelatedDetails Volume 1Issue 1Mar 2023 InformationCopyright 2023, Mary Ann Liebert, Inc., publishersTo cite this article:Moderators: Peter S. Hendricks, Charles D. Nichols, Participants: Kathryn A. Cunningham, Mark A. Geyer, Roland Griffiths, and David Nichols.Past, Present, and Future of Psychedelics: A Psychedelic Medicine Roundtable Discussion.Psychedelic Medicine.Mar 2023.2-11.http://doi.org/10.1089/psymed.2022.0003Published in Volume: 1 Issue 1: March 13, 2023Online Ahead of Print:October 28, 2022PDF download

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-HT2A serotonin receptor (HTR2A), the 5-HT2B 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. These structures provide distinct signaling snapshots of LSD’s action, ranging from the transducer-free, partially active state to the transducer-coupled, fully active states. Insights from this study will both provide comprehensive molecular insights into the signaling mechanisms of the prototypical psychedelic LSD and accelerate the discovery of novel psychedelic drugs.

At first glance, it appears there is little difference between the molecular structures of methylenedioxymethamphetamine (MDMA), which has an N-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 N-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. Importantly, it is the Ievo-isomer of hallucinogenic phenethylamines that is more biologically active, whereas it is the dextro isomer of MDMA that is more active. This reversal of stereochemistry for the activity of two very closely related molecules is a very powerful clue that their mechanisms of action differ. Finally, extension of the alpha-methyl of hallucinogenic amphetamines to an alpha-ethyl moiety completely abolishes their hallucinogenic activity. Ultimately, we extended the alpha-methyl group of MDMA to an alpha-ethyl to afford a molecule we named (N-Methyl-1-(1,3-benzodioxol-5-yl)-2-butanamine (MBDB) that retained significant MDMA-like psychoactivity. Hence, there are three structural features that distinguish MDMA from the hallucinogenic amphetamines: (1) the N-methyl on the basic nitrogen, (2) the reversal of stereochemistry and, (3) tolerance of an alpha-ethyl moiety as contrasted with the alpha-methyl of hallucinogenic phenethylamines. Clearly, MDMA is distinct from classical hallucinogenic phenethylamines in its structure, and its psychopharmacology is also unique. Thus, in 1986 I proposed the name "Entactogen" for the pharmacological class of drugs that includes 3,4-methylenedioxymethamphetamine (MDMA) and other substances with a similar psychopharmacological effect. The name is derived from roots that indicate that entactogens produce a "touching within." Rather than having significant psychostimulant, or hallucinogenic effects, MDMA powerfully promotes affiliative social behavior, has acute anxiolytic effects, and can lead to profound states of introspection and personal reflection. Its mechanism of action is now established as involving transport of MDMA by the neuronal serotonin reuptake carrier followed by carrier-mediated release of stored neuronal serotonin.

Serotonin (5-hydroxytryptamine; 5-HT) 5-HT2-family receptors represent essential targets for the prototypical psychedelic LSD and all other psychedelic drugs. Although the canonical signaling pathway for 5-HT2 receptors is mediated by Gq protein activation, signaling pathways mediated by β-arrestin recruitment appear essential for actions of LSD in vitro and in vivo. To gain comprehensive molecular insights into the signaling mechanisms of LSD, we determined the cryoEM structures of LSD-bound 5-HT2BR in the transducer-free, Gq protein-coupled and β-arrestin-1-coupled states. These structures provide distinct signaling snapshots of LSD’s action ranging from the transducer-free partially active state to the transducer-coupled fully active states. Insights from this study will both accelerate the discovery of novel psychedelic drugs and provide approaches for the structural studies of other GPCR-arrestin signaling complexes.

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. Nevertheless, a 16th century Spanish Franciscan friar and historian mentioned teonanacatl in his extensive writings, intriguing 20th century ethnopharmacologists and leading to a decades-long search for the identity of teonanacatl . Their search ultimately led to a 1957 photo-essay in a popular magazine, describing for the Western world the use of these mushrooms. Specimens were ultimately obtained, and their active principle identified and chemically synthesized. In the past 10–15 years several FDA-approved clinical studies have indicated potential medical value for psilocybin-assisted psychotherapy in treating depression, anxiety, and certain addictions. At present, assuming that the early clinical studies can be validated by larger studies, psilocybin is poised to make a significant impact on treatments available to psychiatric medicine.

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-HT2A 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). We also obtained the X-ray crystal structures of HTR2A complexed with the arrestin-biased ligand LSD or the inverse agonist methiothepin. Comparisons of these structures reveal determinants responsible for HTR2A-Gαq protein interactions as well as the conformational rearrangements involved in active-state transitions. Given the potential therapeutic actions of hallucinogens, these findings could accelerate the discovery of more selective drugs for the treatment of a variety of neuropsychiatric disorders.

Initial interest in the value of psychedelic drugs ("psychotomimetics") in psychiatry began in the early 20 (th) 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.

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 22Mental Illness Research, Education, and Clinical Center. Receptor binding and functional data were generously

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. Approach: Owing to its proximity for a possible approval in clinical use and short-lasting pharmacokinetics, our focus is predominantly on psilocybin. Psilocybin is allegedly, next to lysergic acid diethylamide (LSD), one of the two most frequently used psychedelics to microdose. Where relevant and available, data for other psychedelic drugs are also mentioned. Conclusion: It is concluded that while most anecdotal reports focus on the positive experiences with microdosing, future research should also focus on potential risks of (multiple) administrations of a psychedelic in low doses. To that end, (pre)clinical studies including biological (e.g. heart rate, receptor turnover and occupancy) as well as cognitive (e.g. memory, attention) parameters have to be conducted and will shed light on the potential negative consequences microdosing could have.

The vibrational theory of olfaction is an attempt to describe a possible mechanism for olfaction which is explanatory and provides researchers with a set of principles which permit predictions allowing for structure-odor relations. Similar theories have occurred several times throughout olfactory science; this theory has again recently come to prominence by Luca Turin, who suggested that inelastic electron tunneling is the method by which vibrations are detected by the olfactory receptors within the hose. This work is intended to convey to the reader an up-to-date account of the vibrational theory of olfaction, both the historical iterations as well as the present iteration. This text is designed to give a chronological account of both theoretical and experimental studies on the topic, while providing context, comments, and background where they were found to be needed.

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. LSD proved to be physiologically very safe and nonaddictive, with a very low incidence of adverse events when used in controlled experiments. Widely hailed by psychiatry as a breakthrough in the 1950s and early 1960s, clinical research with LSD ended by about 1970, when it was formally placed into Schedule 1 of the Controlled Substances Act of 1970 following its growing popularity as a recreational drug. Within the past 5 years, clinical research with LSD has begun in Europe, but there has been none in the United States. LSD is proving to be a powerful tool to help understand brain dynamics when combined with modern brain imaging methods. It remains to be seen whether therapeutic value for LSD can be confirmed in controlled clinical trials, but promising results have been obtained in small pilot trials of depression, anxiety, and addictions using psilocybin, a related psychedelic molecule.