David E. Nichols

Neural correlates of the LSD experience revealed by multimodal neuroimaging

Significance Lysergic acid diethylamide (LSD), the prototypical “psychedelic,” may be unique among psychoactive substances. In the decades that followed its discovery, the magnitude of its effect on science, the arts, and society was unprecedented. LSD produces profound, sometimes life-changing experiences in microgram doses, making it a particularly powerful scientific tool. Here we sought to examine its effects on brain activity, using cutting-edge and complementary neuroimaging techniques in the first modern neuroimaging study of LSD. Results revealed marked changes in brain blood flow, electrical activity, and network communication patterns that correlated strongly with the drug’s hallucinatory and other consciousness-altering properties. These results have implications for the neurobiology of consciousness and for potential applications of LSD in psychological research. Lysergic acid diethylamide (LSD) is the prototypical psychedelic drug, but its effects on the human brain have never been studied before with modern neuroimaging. Here, three complementary neuroimaging techniques: arterial spin labeling (ASL), blood oxygen level-dependent (BOLD) measures, and magnetoencephalography (MEG), implemented during resting state conditions, revealed marked changes in brain activity after LSD that correlated strongly with its characteristic psychological effects. Increased visual cortex cerebral blood flow (CBF), decreased visual cortex alpha power, and a greatly expanded primary visual cortex (V1) functional connectivity profile correlated strongly with ratings of visual hallucinations, implying that intrinsic brain activity exerts greater influence on visual processing in the psychedelic state, thereby defining its hallucinatory quality. LSD’s marked effects on the visual cortex did not significantly correlate with the drug’s other characteristic effects on consciousness, however. Rather, decreased connectivity between the parahippocampus and retrosplenial cortex (RSC) correlated strongly with ratings of “ego-dissolution” and “altered meaning,” implying the importance of this particular circuit for the maintenance of “self” or “ego” and its processing of “meaning.” Strong relationships were also found between the different imaging metrics, enabling firmer inferences to be made about their functional significance. This uniquely comprehensive examination of the LSD state represents an important advance in scientific research with psychedelic drugs at a time of growing interest in their scientific and therapeutic value. The present results contribute important new insights into the characteristic hallucinatory and consciousness-altering properties of psychedelics that inform on how they can model certain pathological states and potentially treat others.

The G Protein–Biased κ -Opioid Receptor Agonist RB-64 Is Analgesic with a Unique Spectrum of Activities In Vivo

The hypothesis that functionally selective G protein–coupled receptor (GPCR) agonists may have enhanced therapeutic benefits has revitalized interest for many GPCR targets. In particular, although κ-opioid receptor (KOR) agonists are analgesic with a low risk of dependence and abuse, their use is limited by a propensity to induce sedation, motor incoordination, hallucinations, and dysphoria-like states. Several laboratories have produced a body of work suggesting that G protein–biased KOR agonists might be analgesic with fewer side effects. Although that has been an intriguing hypothesis, suitable KOR-selective and G protein–biased agonists have not been available to test this idea. Here we provide data using a G protein–biased agonist, RB-64 (22-thiocyanatosalvinorin A), which suggests that KOR-mediated G protein signaling induces analgesia and aversion, whereas β-arrestin-2 signaling may be associated with motor incoordination. Additionally, unlike unbiased KOR agonists, the G protein–biased ligand RB-64 does not induce sedation and does not have anhedonia-like actions, suggesting that a mechanism other than G protein signaling mediates these effects. Our findings provide the first evidence for a highly selective and G protein–biased tool compound for which many, but not all, of the negative side effects of KOR agonists can be minimized by creating G protein–biased KOR agonists.

Striatal dopamine D1 receptor suppression impairs reward-associative learning.

ABSTRACT 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. Separating the striatal D1R contribution to learning vs. motivation, however, has been challenging. We suppressed striatal D1R expression in mice using a D1R‐targeting short hairpin RNA (shRNA), delivered locally to the striatum via an adeno‐associated virus (AAV). We then assessed reward‐ and punishment‐associative learning using a probabilistic learning task and motivation using a progressive‐ratio breakpoint procedure. We confirmed suppression of striatal D1Rs immunohistochemically and by testing locomotor activity after the administration of (+)‐doxanthrine, a full D1R agonist, in control mice and those treated with the D1RshRNA. D1RshRNA‐treated mice exhibited impaired reward‐associative learning, while punishment‐associative learning was spared. This deficit was unrelated to general learning impairments or amotivation, because the D1shRNA‐treated mice exhibited normal Barnes maze learning and normal motivation in the progressive‐ratio breakpoint procedure. Suppression of striatal D1Rs selectively impaired reward‐associative learning whereas punishment‐associative learning, aversion‐motivated learning, and appetitive motivation were spared. Because patients with schizophrenia exhibit similar reward‐associative learning deficits, D1R‐targeted treatments should be investigated to improve reward learning in these patients.

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-HT2A 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. Important structural features will be identified for activity and, where possible, those that the psychedelics have in common will be discussed. Because activation of the 5-HT2A receptor is the principal mechanism of action for psychedelics, compounds with 5-HT2A agonist activity generally are quickly discarded by the pharmaceutical industry. Thus, most of the research on psychedelics can be related to activation of 5-HT2A receptors. Therefore, much of the discussion will include not only clinical or anecdotal studies, but also will consider data from animal models as well as a certain amount of molecular pharmacology where it is known.

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. However, many questions regarding the mechanisms of action, safety, and efficacy of psychedelics remain. Here, we summarize recent preclinical and clinical data in this field, discuss their pharmacological mechanisms of action, and outline critical areas for future studies of psychedelic drugs, with the goal of maximizing the potential benefits of translational psychedelic biomedicine to patients.

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

Significance Herein, we test the present iteration of the vibrational theory of protein activation by comparing predictions obtained from Turin’s vibrational theory for the activation of olfactory receptors measuring affinity and activation at a nonolfactory receptor family of G protein-coupled receptors. This was done at the CNS serotonin receptor family h5-HT2 and with both the 2,5-dimethoxy-4-iodoamphetamine and N,N-dimethyllysergamide agonists. Invalidation was performed through a comparative analysis of agonist behavior between isotopologues. 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). [Chee HK, June OS (2013) Genomics Inform 11(4):282–288; Chee HK, et al. (2015) FEBS Lett 589(4):548–552; Oh SJ (2012) Genomics Inform 10(2):128–132]. Herein, we test the viability of this idea, both by receptor affinity and receptor activation measured by calcium flux. This test was performed using a pair of well-characterized agonists for members of the 5-HT2 class of serotonin receptors, 2,5-dimethoxy-4-iodoamphetamine (DOI) and N,N-dimethyllysergamide (DAM-57), and their respective deuterated isotopologues. No evidence was found that selective deuteration affected either the binding affinity or the activation by the selected ligands for the examined members of the 5-HT2 receptor class.

Emerging Designer Drugs

Abstract Recently, a plethora of new and formerly obscure compounds have appeared on the illicit drug market, and many have become quite popular. These new drugs of abuse often prove to be established research chemicals that have diffused out of laboratories and scientific journals and onto the streets. Their rapid appearance and largely unknown character put them into a legal gray area, where they are often referred to by sellers and users as “legal highs,” until emergency scheduling can be invoked. A factor that has contributed to this explosion of new street drugs is the ready access to information about their effects as well as sources of the drugs that has been provided by the Internet. This chapter will survey the types of new designer drugs that are emerging, and provide some basic information about each class. At the end, we provide a commentary about legal issues involved in control of new designer drugs.

A Chemogenetic Platform for Spatio-temporal Control of β-arrestin Translocation and Signaling at G protein-Coupled Receptors

Although ligand-activated GPCRs induce both G-protein and β-arrestin dependent signaling, gaining precise spatio-temporal control of β-arrestin signaling has proven elusive. Here we describe a platform for specifically activating β-arrestin-dependent signaling in situ. The platform, which we have dubbed “GA-PAIR” (GPCR/β-Arrestin –Plant protein and Abscisic acid Induced Recruitment), can be controlled by the inert phytochemical S-(+)-abscisic acid (ABA). ABA induces interaction between ABI1 (ABA Insensitive 1) and PYL1 (Pyrabactin Resistance (PYR) 1-Like), two plant proteins with no mammalian counterparts. We fused ABI to the engineered human muscarinic M3 G protein-coupled receptor (hM3Dq) and PYL1 to β-arrestin2. Addition of ABA induced rapid and nearly complete translocation of the PYL-β-arrestin fusion protein and, importantly, induced both ERK and Akt signaling. Photo-uncaging a new photo-caged ABA analogue allowed us to gain relatively precise spatio-temporal control over β-arrestin translocation. Because GA-PAIR facilitates the exclusive activation of endogenous β-arrestin signaling pathways in the absence of a GPCR ligand or G protein, the GA-PAIR system will facilitate deconvoluting GPCR signaling in situ.

Status of the Vibrational Theory of Olfaction

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 the 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.