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David E. Nichols

University of North Carolina at Chapel Hill, University of Nottingham

58 papers in the library · 3,287 citations · publishing 1975-2025

Papers

Proposed Consensus Statement on Defining Psychedelic Drugs.

Psychedelic Med (New Rochelle) March 13, 2023 David E. Nichols, Charles D. Nichols, Peter S. Hendricks 39 citations

A proposed consensus statement defines psychedelic drugs as substances that reliably produce profound alterations in consciousness, perception, and mood through agonist activity at the serotonin 2A receptor. The definition emphasizes pharmacological mechanism over subjective effects, distinguishing psychedelics from other psychoactive compounds. The authors argue that a standardized definition is essential for advancing medical research, drug development, and clinical applications by providing a clear framework for classification and nomenclature. This consensus aims to reduce ambiguity in scientific and therapeutic contexts, supporting more precise communication and regulatory clarity in psychedelic research.

DOI: 10.1089/psymed.2022.0008 Full text Psychedelic drugs Psychedelics Hallucinogens Entheogens +25

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

ACS Chemical Neuroscience September 25, 2018 Andrey D. Volgin, Oleg A. Yakovlev, Konstantin A. Demin et al. 38 citations

Deliriant hallucinogens, such as atropine and scopolamine, are a distinct class of drugs that induce hyperactivity and dream-like hallucinations by blocking muscarinic acetylcholine receptors. Despite their long history of use and being well-studied in cholinergic physiology, they are the least-studied class of hallucinogens regarding their behavioral and neurological effects. This review comprehensively evaluates the preclinical effects of these drugs in various animal models, detailing their mechanisms of action and potential interactions with other signaling pathways. It parallels experimental and clinical findings to outline future directions for translational research, emphasizing the need for novel approaches and new model organisms to investigate their central nervous system effects.

DOI: 10.1021/acschemneuro.8b00433 Hallucinogen Neuroscience Cholinergic Pharmacology +7

Synthesis and evaluation of 2,3-dihydrobenzofuran analogs of the hallucinogen 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane: drug discrimination studies in rats

Journal of Medicinal Chemistry February 1, 1986 David E. Nichols, Andrew J. Hoffman, Robert Oberlender et al. 34 citations

Two new chemical analogues of the hallucinogen DOM were created and tested in rats trained to distinguish LSD from saline. Both analogues produced LSD-like effects, but only at doses more than ten times higher than DOM. The authors suggest this weakened activity may be due to the orientation of oxygen atoms in the analogues, which may not fit a specific binding site on the brain receptor.

DOI: 10.1021/jm00152a022 Citation Icon Altmetrics Social media +3

A demand for clarity regarding a case report on the ingestion of 5-methoxy-N, N-dimethyltryptamine (5-MeO-DMT) in an Ayahuasca preparation.

J Anal Toxicol July 1, 2006 J.C. Callaway, Charles S. Grob, Dennis J. Mckenna et al. 33 citations

A published case report about someone ingesting 5-MeO-DMT in an ayahuasca preparation contained unclear or ambiguous details, prompting a call for greater clarity and precision in such scientific accounts. The authors argue that accurate reporting is essential for understanding risks, ensuring public safety, and supporting harm reduction in the context of psychoactive substances.

DOI: 10.1093/jat/30.6.406 5-MEO-DMT Ayahuasca Psychoactive substances Psychedelics +32

The structural diversity of psychedelic drug actions revealed.

Nat Commun March 19, 2025 Ryan H. Gumpper, Manish K. Jain, Kuglae Kim et al. 31 citations

Classical psychedelics are being studied for treating depression, addiction, anxiety, and cluster headaches. Their therapeutic effects are thought to involve the 5-HT2A serotonin receptor. Seven cryo-EM structures were determined, covering major classes of psychedelic and non-psychedelic agonists, including a β-arrestin-biased compound. These structures reveal both common and distinct molecular interactions between different psychedelics and the receptor. The findings provide a mechanistic understanding of 5-HT2A activation that could aid development of new drugs with fewer side effects.

DOI: 10.1038/s41467-025-57956-7 Full text Psychedelics Neuroscience Mental health Pharmacology +1

Synthesis and Pharmacological Characterization of a Series of Geometrically Constrained 5-HT2A/2C Receptor Ligands

Journal of Medicinal Chemistry July 1, 2003 James J. Chambers, Jason C. Parrish, Niels Jensen et al. 27 citations

Conformationally constrained tetrahydronaphthofurans were designed to study the optimal shape of the 2-aminoethyl moiety in phenethylamine-type serotonin 5-HT(2A) receptor agonists. In vitro assays showed that benzofuran-containing analogues (6a and 6b) had significantly higher affinity for 5-HT(1A), 5-HT(2A), and 5-HT(2C) receptors than benzodihydrofuran-containing compounds. The most potent compound, 6b, had K(i) values of 2.6 nM at 5-HT(2A) and 1.1 nM at 5-HT(2C) cloned rat receptors. Despite high affinity, these naphthofuran compounds lacked high intrinsic activity at the 5-HT(2A) receptor in the phosphoinositide hydrolysis assay. Compound 6b failed to substitute for LSD in a rat drug discrimination assay, typical for low intrinsic activity compounds. Conformational constraint produced high-affinity partial agonists, but full receptor activation requirements remain unidentified.

DOI: 10.1021/jm030064v Serotonin Stereochemistry Phenethylamine Intrinsic activity +6

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

Psychopharmacology February 14, 2019 Adam L. Halberstadt, Landon M. Klein, Muhammad Chatha et al. 25 citations

The lysergamide ECPLA, a close structural analog of LSD, binds with high affinity to serotonin, adrenergic, and dopamine receptors, and acts as a potent agonist at the 5-HT₂A receptor, which mediates psychedelic effects. In mice, ECPLA induced head twitches with an ED₅₀ of 317.2 nmol/kg, about 40% as potent as LSD. Two other analogs, LAMPA (ED₅₀ = 358.3 nmol/kg) and MIPLA (ED₅₀ = 421.7 nmol/kg), showed similar or slightly lower potency. These findings indicate that ECPLA, MIPLA, and LAMPA share pharmacological properties with LSD and other lysergamide hallucinogens.

DOI: 10.1007/s00213-018-5055-9 Full text LSD 5-HT Receptor Lysergamide Psychedelics +1

Synthesis and Pharmacological Evaluation of Ring-Methylated Derivatives of 3,4-(Methylenedioxy)amphetamine (MDA)

Journal of Medicinal Chemistry February 24, 1998 Matthew Parker, Danuta Marona‐lewicka, Deborah M. Kurrasch et al. 25 citations

Adding a methyl group to the 2 or 5 position of the ring of MDA produces compounds that are more potent and more selective than MDA itself at releasing serotonin in rat brain tissue. The 2-methyl and 5-methyl derivatives were tested in rats trained to distinguish serotonin-releasing drugs from saline, confirming their activity in living animals. These compounds are among the most potent serotonin-releasing agents known and may serve as leads for developing antidepressants that work by releasing serotonin rather than blocking its reuptake.

DOI: 10.1021/jm9705925 Serotonin Methylenedioxy Pharmacology Hallucinogen +13

Stereoselective LSD-like Activity in a Series of d-Lysergic Acid Amides of (R)- and (S)-2-Aminoalkanes

Journal of Medicinal Chemistry March 1, 1995 Aaron Monte, Danuta Marona‐lewicka, Arthi Kanthasamy et al. 25 citations

Amides of d-lysergic acid with 3-pentyl, (R)- and (S)-2-pentyl, 2-hexyl, and 2-heptyl substituents were synthesized and tested for LSD-like activity. (R)-lysergamides bound more strongly than (S)-amides to 5-HT2A and 5-HT1A receptors in rat brain tissue. As the amide alkyl chain lengthened from pentyl to heptyl, (R)-isomer affinity for 5-HT2A sites decreased, while affinity for 5-HT1A peaked with (R)-2-hexyllysergamide. In rats trained to discriminate LSD from saline, (R)-alkylamides produced stronger LSD-like effects than (S)-isomers, but longer chains reduced activity, with (R)-hexylamide only partially substituting for LSD. Both isomers acted as potent 5-HT2A agonists, but (R)-pentyllysergamide stimulated phosphoinositide hydrolysis about 20 times more than the (S)-form.

DOI: 10.1021/jm00006a015 Lysergic acid diethylamide Stereochemistry Stereoselectivity Carboxamide +3

The Heffter Research Institute: Past and Hopeful Future

Journal of Psychoactive Drugs January 1, 2014 David E. Nichols 24 citations

The Heffter Research Institute, founded in 1993, is the only scientific organization dedicated to studying the medical value of psychedelics, focusing on psilocybin. Its first clinical trial examined psilocybin for obsessive-compulsive disorder. Subsequent studies include a UCLA trial for end-of-life distress in cancer patients, a Johns Hopkins study for anxiety and depression from cancer diagnosis, and a New York University trial nearing completion. A pilot study for alcoholism at the University of New Mexico is also finishing, with a larger two-site trial planned. Other ongoing work includes psilocybin for smoking cessation and effects on long-term meditators. The institute is planning a Phase 3 trial for distress in end-stage cancer patients.

DOI: 10.1080/02791072.2014.873688 Psilocybin Anxiety Distress Psychiatry +5

C-(4,5,6-Trimethoxyindan-1-yl)methanamine: A Mescaline Analogue Designed Using a Homology Model of the 5-HT2AReceptor

Journal of Medicinal Chemistry June 21, 2006 Thomas H. Mclean, James J. Chambers, Jason C. Parrish et al. 24 citations

A new molecule, C-(4,5,6-trimethoxyindan-1-yl)-methanamine, was designed based on a computer model of the 5-HT(2A) receptor. This compound showed three times higher affinity and potency than mescaline at the receptor, with equal efficacy. In drug discrimination tests, it fully substituted for LSD and was five times more potent than mescaline. Separating the molecule into its mirror-image forms confirmed the computer predictions: the R-(+) isomer had higher affinity and potency than the S-(-) isomer, with efficacy similar to mescaline at the 5-HT(2A) receptor.

DOI: 10.1021/jm060272y Mescaline Potency Stereochemistry Homology modeling +8

Lipophilicity and serotonin agonist activity in a series of 4-substituted mescaline analogs

Journal of Medicinal Chemistry February 1, 1977 David E. Nichols, Donald C. Dyer 23 citations

Replacing the 4-methoxy group of mescaline with larger alkyl groups or bromine increases activity at serotonin receptors in a sheep umbilical artery preparation. This increase correlates with lipophilicity, measured by 1-octanol-water partition coefficients, but activity declines when the 4-substituent reaches about five atoms in length. The findings suggest that a 3,4,5-trisubstituted pattern may be more effective than a 2,4,5-substitution pattern for receptor activity.

DOI: 10.1021/jm00212a022 Mescaline Lipophilicity Stereochemistry Serotonin agonist +2

Substituted Naphthofurans as Hallucinogenic Phenethylamine−Ergoline Hybrid Molecules with Unexpected Muscarinic Antagonist Activity

Journal of Medicinal Chemistry May 1, 1998 Aaron Monte, Danuta Marona‐lewicka, Mechelle M. Lewis et al. 20 citations

A series of racemic naphthofurans were synthesized as hybrid molecules of phenethylamine and tryptamine/ergoline hallucinogens. Although the compounds were expected to have high affinity for serotonin 5-HT2A/2C receptors, they instead showed low affinity for those receptors and unexpected affinity for muscarinic receptors. One compound, 4d, had affinities of 12-33 nM at all muscarinic M1-M5 sites and fully antagonized carbachol at M1 and M2 receptors. The naphthofurans lacked LSD-like activity in a drug discrimination paradigm in rats, indicating that the tricyclic naphthofuran nucleus is not bioisosteric with LSD and that hallucinogenic phenethylamines cannot be directly superimposed on LSD in a common binding orientation, contrary to previous hypotheses.

DOI: 10.1021/jm980076u Serotonin Phenethylamines Muscarinic acetylcholine receptor Stereochemistry +7

trans-2-(2,5-Dimethoxy-4-iodophenyl)cyclopropylamine and trans-2-(2,5-dimethoxy-4-bromophenyl)cyclopropylamine as potent agonists for the 5-HT2 receptor family

Beilstein Journal of Organic Chemistry October 8, 2012 Adam Pigott, Stewart Frescas, John D. Mccorvy et al. 19 citations

Replacing the ethylamine side chain of two psychedelic amphetamine derivatives, DOI and DOB, with a cyclopropylamine moiety produced compounds with high affinity for the 5-HT(2) family of serotonin receptors. The more potent stereoisomer of these cyclopropane analogues had the expected (-)-(1R,2S)-configuration. However, the cyclopropane congeners also showed increased affinity at several other serotonin receptor subtypes beyond 5-HT(2A) and 5-HT(2B). While at appropriate doses the compounds may serve as tools to probe 5-HT(2) receptor function, their selectivity for 5-HT(2A) receptors is somewhat less than that of DOI itself.

DOI: 10.3762/bjoc.8.194 Full text Serotonin Ethylamine Moiety Stereochemistry +7

Stereoselective LSD-like activity in d-lysergic acid amides of R- and S-2-aminobutane

Journal of Medicinal Chemistry January 1, 1992 Robert Oberlender, Robert C. Pfaff, Michael P. Johnson et al. 17 citations

Both the (R)- and (S)-2-butylamides of d-lysergic acid fully substituted for LSD in rats trained to discriminate LSD from saline, and both showed very high affinity for 5-HT2 and 5-HT1A receptors. The R isomer was significantly more potent than the S isomer in both behavioral and binding assays. Molecular mechanics modeling indicated that the (R)-2-butylamide adopts a conformation similar to LSD, whereas the (S)-2-butylamide does not. These results suggest that the stereochemistry of the amide substituent critically influences hallucinogenic activity, possibly through stereoselective interactions with a hydrophobic receptor region or by inducing conformational changes elsewhere in the molecule.

DOI: 10.1021/jm00080a001 Lysergic acid diethylamide Stereochemistry Agonist Substituent +4

Resolution and absolute configuration of trans-2-(2,5-dimethoxy-4-methylphenyl)cyclopropylamine, a potent hallucinogen analog

Journal of Medicinal Chemistry April 1, 1979 David E. Nichols, Ronald W. Woodard, Bruce A. Hathaway et al. 16 citations

The hallucinogen analogue DMCPA was separated into its two mirror-image forms using a crystallization technique. By comparing the optical properties of these forms to a related compound of known structure, the absolute configuration of the (-) isomer was determined to be (1R,2S) and the (+) isomer (1S,2R). Earlier work showed the (-) isomer causes selective behavioral effects in cats and mice; this study found it also selectively raises body temperature in rabbits compared to the (+) isomer. This stereoselective activity supports a model linking the active binding conformation of phenethylamine hallucinogens to that of serotonin and tryptamines.

DOI: 10.1021/jm00190a021 Citation Altmetrics Computer science Icon +3

4‐Aryl‐Substituted 2,5‐Dimethoxyphenethylamines: Synthesis and Serotonin 5‐HT2AReceptor Affinities

Chemistry & Biodiversity May 1, 2009 Daniel Trachsel, David E. Nichols, Stephanie Kidd et al. 15 citations

A series of novel 2-phenylethylamine compounds with a 4'-aryl substituent was synthesized and tested for binding affinity at the serotonin 5-HT(2A) receptor. Most compounds acted as antagonists with generally low affinity, except for a few with substituents at the 4''-position. The 4''-butyl, 4''-phenyl, and 4'-naphthyl derivatives showed relatively high affinity, with K(i) values of 32, 33, and 41 nM, respectively, indicating tolerance for bulky groups at this location. The 4'-aryl moiety was introduced via a palladium-catalyzed Suzuki reaction.

DOI: 10.1002/cbdv.200800235 Serotonin Moiety Pharmacophore Aryl +9

Further Studies on Oxygenated Tryptamines with LSD-like Activity Incorporating a Chiral Pyrrolidine Moiety into the Side Chain

Journal of Medicinal Chemistry September 16, 1999 Madina R. Gerasimov, Danuta Marona‐lewicka, Deborah Kurrasch‐orbaugh et al. 15 citations

The R enantiomers of two rigid tryptamine analogues show a 10-20-fold higher affinity for the 5-HT(2A) receptor than the S enantiomers, with no distinction based on the position of the oxygen group. The R enantiomers of both compounds have nearly identical affinities at the agonist-labeled receptor, while racemic versions of related compounds have about one-tenth the affinity. In rats trained to discriminate LSD or DOI from saline, the R enantiomers are about equipotent to DOI but about 10-fold less potent than LSD. One compound produced only partial substitution even at a dose nearly 5-fold higher than for the active R enantiomer. The results suggest these compounds would possess LSD-like psychopharmacology in humans.

DOI: 10.1021/jm990325u Enantiomer Stereochemistry Tryptamine Ligand biochemistry +7

Synthesis and evaluation of substituted 2-phenylcyclobutylamines as analogs of hallucinogenic phenethylamines: lack of LSD-like biological activity

Journal of Medicinal Chemistry September 1, 1984 David E. Nichols, K. P. Jadhav, Robert Oberlender et al. 12 citations

Three new compounds—cis- and trans-2-(2,4,5-trimethoxyphenyl)cyclobutylamine and trans-2-(2,5-dimethoxy-4-methylphenyl)cyclobutylamine—were synthesized as rigid versions of hallucinogenic phenylisopropylamines. In rats trained to distinguish LSD from saline, the cis compound did not produce LSD-like effects at doses up to 20 mg/kg. Both trans compounds partially mimicked LSD at 5 mg/kg or higher. In contrast, a related cyclopropylamine compound fully substituted for LSD. The trans cyclobutylamines were about 50 to 75 times less potent than the cyclopropylamine analogue. The lack of full generalization suggests these cyclobutylamines either produce different effects from LSD or lack discriminative effects entirely.

DOI: 10.1021/jm00375a004 Mescaline Phenethylamines Hallucinogen Biological activity +2

A new view of the structural relationship between LSD and mescaline

Brain Research Bulletin May 1, 1977 David E. Nichols, William Pfister, G.k.w. Yim et al. 10 citations

The S-(-) enantiomer of 2-amino-1,2,3,4-tetrahydronaphthalene (2-AT) produces selective central effects in mice and rabbits that resemble those of hallucinogens such as mescaline. A stereochemical analysis of these findings suggests that the structural relationship between mescaline and other phenethylamine-type hallucinogens may involve a correspondence between the aromatic ring of the phenethylamines and the pyrrole portion of the indole nucleus in LSD.

DOI: 10.1016/0361-9230(77)90034-x Mescaline Hallucinogen Phenethylamines Tryptamines +3

Isomeric cyclopropyl ring-methylated homologs of trans-2-(2,5-dimethoxy-4-methylphenyl)cyclopropylamine, an hallucinogen analog

Journal of Medicinal Chemistry May 1, 1982 James N. Jacob, David E. Nichols 6 citations

Adding a methyl group at the 3-position of the cyclopropyl ring, in either the cis or trans orientation relative to the amino group, eliminated the activity of the hallucinogen analogue trans-2-(2,5-dimethoxy-4-methylphenyl)cyclopropylamine. Neither the cis nor the trans isomer showed appreciable activity in the mouse ear-scratch assay or in producing contraction in the rat fundus preparation, compared to the nonmethylated parent compound.

DOI: 10.1021/jm00347a009 Hallucinogen Stereochemistry Ring chemistry Pharmacology +2

N -Benzyl-5-methoxytryptamines as Potent Serotonin 5-HT 2 Receptor Family Agonists and Comparison with a Series of Phenethylamine Analogues

UNC Libraries October 29, 2020 Simon D. Brandt, Maria F. Sassano, David E. Nichols et al. 4 citations

A series of N-benzylated-5-methoxytryptamine analogues and N-benzylated analogues of 2,5-dimethoxy-4-iodophenethylamine (2C-I) were synthesized and tested. Most compounds showed highest affinity for the 5-HT2 family of serotonin receptors. Substitution at the para position of the benzyl group reduced affinity, while ortho or meta substitution enhanced it. Large lipophilic groups improved affinity but often reduced functional activity. Functional potency was measured at human 5-HT2A, 5-HT2B, and 5-HT2C receptors and rat 5-HT2A and 5-HT2C receptors using intracellular calcium mobilization. Several tryptamine congeners were very potent functionally (EC50 values from 7.6 to 63 nM) but were mostly partial agonists. In mouse head twitch tests, many compounds induced the behavior, which correlated significantly with functional potency at the rat 5-HT2A receptor.

DOI: 10.17615/6efy-d986 Serotonin Phenethylamine 5-HT Receptor 5-ht2 receptor +4