David E Nichols - The Consciousness Library

The polypharmacology of psychedelics reveals multiple targets for potential therapeutics.

Neuron July 15, 2025 Manish K. Jain, Ryan H. Gumpper, Samuel T. Slocum et al. 42 citations

The classical psychedelics (+)-lysergic acid diethylamide (LSD), psilocybin, and mescaline exert their psychedelic effects via activation of the 5-HT2A serotonin receptor (5-HT2AR). Recent clinical studies have suggested that classical psychedelics may additionally have therapeutic potential for many neuropsychiatric conditions including depression, anxiety, migraine and cluster headaches, drug...

DOI: 10.1016/j.neuron.2025.06.012 Full text G-protein-coupled receptors Dopamine receptors Hallucinogen Psychedelics +3

5-HT2A receptors: Pharmacology and functional selectivity.

Pharmacological Reviews April 23, 2025 Benjamin R. Cummins, Gerald Billac, David E Nichols et al. 62 citations

Serotonin 5-HT2A receptors were one of the first serotonin receptors to be pharmacologically characterized. In mammals, they are expressed throughout the body in nearly every cell and tissue type, with the highest density in cortical layer V of the brain. They are involved in several aspects of normal physiological processes and behaviors and have been implicated in the etiology of...

DOI: 10.1016/j.pharmr.2025.100059 Full text Serotonin Psychedelics Mental health Brain chemistry

History of psychedelic drug science and molecular pharmacology.

International review of neurobiology 2025 David E Nichols, Charles D. Nichols 3 citations

Classic psychedelics have been used by various cultures for millennia for healing and religious purposes. The modern era of psychedelic science began with the first empirical experiments by Dr. Arthur Heffter in 1898 to determine just what they are when he discovered the active alkaloid in the peyote cactus responsible for its intoxicating effects and named it mescaline. As with many aspects of...

DOI: 10.1016/bs.irn.2025.02.001 Full text Psychedelic therapy 5-ht2a receptors Classical psychedelics Psychedelic history +12

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

British Journal of Pharmacology October 2, 2024 Ryan H. Gumpper, David E Nichols 9 citations

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...

DOI: 10.1111/bph.17361 Full text LSD Psilocybin Psychedelic research Drug development +13

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

Nature May 1, 2023 Jianming Han, Jingying Zhang, Antonina L. Nazarova et al. 79 citations

The κ-opioid receptor (KOR) represents a highly desirable therapeutic target for treating not only pain but also addiction and affective disorders1. However, the development of KOR analgesics has been hindered by the associated hallucinogenic side effects2. The initiation of KOR signalling requires the Gi/o-family proteins including the conventional (Gi1, Gi2, Gi3, GoA and GoB) and...

DOI: 10.1038/s41586-023-06030-7 Full text Κ-opioid receptor Kor Kappa opioid receptor Receptor structure +19

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

Neuron October 5, 2022 Can Cao, Ximena Barros-Álvarez, Shicheng Zhang et al. 158 citations

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...

DOI: 10.1016/j.neuron.2022.08.006 Full text LSD Gq protein Htr2b Functional selectivity +10

Is LSD toxic?

Forensic Science International March 1, 2018 David E Nichols, Charles S. Grob 86 citations

LSD (lysergic acid diethylamide) was discovered almost 75 years ago, and has been the object of episodic controversy since then. While initially explored as an adjunctive psychiatric treatment, its recreational use by the general public has persisted and on occasion has been associated with adverse outcomes, particularly when the drug is taken under suboptimal conditions. LSD's potential to...

DOI: 10.1016/j.forsciint.2018.01.006 Full text Maximal restraint Positional asphyxiation LSD Safety Physiologically non-toxic +10

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

Journal of Psychopharmacology 2018 David E Nichols 68 citations

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...

DOI: 10.1177/0269881117736919

N-Benzyl-5-methoxytryptamines as Potent Serotonin 5-HT2 Receptor Family Agonists and Comparison with a Series of Phenethylamine Analogues.

ACS Chemical Neuroscience July 15, 2015 David E Nichols, M Flori Sassano, Adam L. Halberstadt et al. 81 citations

A series of N-benzylated-5-methoxytryptamine analogues was prepared and investigated, with special emphasis on substituents in the meta position of the benzyl group. A parallel series of several N-benzylated analogues of 2,5-dimethoxy-4-iodophenethylamine (2C-I) also was included for comparison of the two major templates (i.e., tryptamine and phenethylamine). A broad affinity screen at...

DOI: 10.1021/cn500292d Full text Serotonin 5-ht2 receptors 5-ht2a 5-methoxytryptamine +4

Extensive rigid analogue design maps the binding conformation of potent N-benzylphenethylamine 5-HT2A serotonin receptor agonist ligands.

ACS Chemical Neuroscience January 16, 2013 Jose I Juncosa, Martin Hansen, Lisa A Bonner et al.

Based on the structure of the superpotent 5-HT(2A) agonist 2-(4-bromo-2,5-dimethoxyphenyl)-N-[(2-methoxyphenyl)methyl]ethanamine, which consists of a ring-substituted phenethylamine skeleton modified with an N-benzyl group, we designed and synthesized a small library of constrained analogues to identify the optimal arrangement of the pharmacophoric elements of the ligand. Structures consisted...

DOI: 10.1021/cn3000668 Full text

Behavioral effects of α,α,β,β-tetradeutero-5-MeO-DMT in rats: comparison with 5-MeO-DMT administered in combination with a monoamine oxidase inhibitor.

Psychopharmacology June 1, 2012 Adam L. Halberstadt, David E Nichols, Mark A. Geyer 55 citations

Ayahuasca is a psychoactive tea prepared from a combination of plants that contain a hallucinogenic tryptamine and monoamine oxidase inhibitors (MAOIs). Behavioral pattern monitor (BPM) experiments demonstrated that the combination of 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) and a behaviorally inactive dose of an MAO(A) inhibitor such as harmaline or clorgyline induces biphasic effects on...

DOI: 10.1007/s00213-011-2616-6 Full text Neuropharmacology Drug metabolism Behavioral effects Pharmacological research

Dopamine D4 receptor involvement in the discriminative stimulus effects in rats of LSD, but not the phenethylamine hallucinogen DOI.

Psychopharmacology April 2009 Danuta Marona‐lewicka, Benjamin R Chemel, David E Nichols

Lysergic acid diethylamide (LSD) differs from other types of hallucinogens in that it possesses direct dopaminergic effects. The exact nature of this component has not been elucidated. The present study sought to characterize the effects of several dopamine D(4) agonists and antagonists on the discriminative stimulus effect of LSD at two pretreatment times and 2,5-dimethoxy-4-iodoamphetamine...

DOI: 10.1007/s00213-008-1238-0 Full text

Ambient temperature effects on 3,4-methylenedioxymethamphetamine-induced thermodysregulation and pharmacokinetics in male monkeys.

Drug metabolism and disposition: the biological fate of chemicals October 2007 Matthew L Banks, Jon E. Sprague, David F Kisor et al.

Changes in ambient temperature are known to alter both the hyperthermic and the serotonergic consequences of 3,4-methylenedioxymethamphetamine (MDMA). Metabolism of MDMA has been suggested to be a requisite for these neurotoxic effects, whereas the hyperthermic response is an important contributing variable. The aim of the present study was to investigate the interaction between ambient...

DOI: 10.1124/dmd.107.016261 Full text

Further evidence that the delayed temporal dopaminergic effects of LSD are mediated by a mechanism different than the first temporal phase of action.

Pharmacology, biochemistry, and behavior October 2007 Danuta Marona‐lewicka, David E Nichols

Activation of 5-HT(2A) receptors is thought to mediate the hallucinogenic effects of LSD. Nevertheless, in a previous report we provided evidence that a delayed temporal phase of the behavioral pharmacology of LSD is mediated by D(2)-like dopamine receptor stimulation. In this study rats were trained to discriminate LSD with either a 30 min preinjection time (LSD-30, N=12) or a 90 min...

DOI: 10.1016/j.pbb.2007.06.001 Full text

1-Aminomethylbenzocycloalkanes: conformationally restricted hallucinogenic phenethylamine analogues as functionally selective 5-HT2A receptor agonists.

Journal of Medicinal Chemistry September 21, 2006 Thomas H. Mclean, Jason C. Parrish, Michael R Braden et al. 115 citations

A series of conformationally restricted analogues of the hallucinogenic phenethylamine 1 (2,5-dimethoxy-4-bromophenethylamine, 2C-B) was synthesized to test several hypotheses concerning the bioactive conformation of phenethylamine ligands upon binding to the 5-HT(2A) receptor. These benzocycloalkane analogues were assayed for their receptor binding affinity and ability to activate downstream...

DOI: 10.1021/jm060656o Full text LSD Psychopharmacology: neuropharmacology Drug action Brain chemistry +15

Distinct temporal phases in the behavioral pharmacology of LSD: dopamine D2 receptor-mediated effects in the rat and implications for psychosis.

Psychopharmacology July 2005 Danuta Marona‐lewicka, Ronald A Thisted, David E Nichols

The effect of LSD in humans has been described as occurring in two temporal phases. The behavioral effects in rats also occur in two temporal phases: an initial suppression of exploration followed by increased locomotor activity. We decided to investigate this phenomenon from the perspective that the pharmacology might have relevance to the neurochemical mechanisms underlying psychosis....

DOI: 10.1007/s00213-005-2183-9 Full text

Hallucinogens.

Pharmacology & Therapeutics February 1, 2004 David E Nichols 1 citation

Hallucinogens (psychedelics) are psychoactive substances that powerfully alter perception, mood, and a host of cognitive processes. They are considered physiologically safe and do not produce dependence or addiction. Their origin predates written history, and they were employed by early cultures in a variety of sociocultural and ritual contexts. In the 1950s, after the virtually contemporaneous...

DOI: 10.1016/j.pharmthera.2003.11.002 Full text

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