Journal of Psychoactive Drugs
October 1, 1986
David E. Nichols
568 citations
MDMA, MBDB, and classic hallucinogens have distinct mechanisms of action. MDMA and MBDB produce a unique psychological profile characterized by enhanced empathy and emotional openness, differing from both stimulants and hallucinogens. This profile defines a new therapeutic class called entactogens. The paper argues that entactogens, by their specific neurochemical effects, offer potential for psychotherapy distinct from that of classic hallucinogens or amphetamines.
The Journal of Antibiotics
May 12, 2020
David E. Nichols
184 citations
Psilocybin, the active compound in certain mushrooms used by Aztec Indians in religious and healing rituals, was identified and synthesized in the mid-20th century after a search sparked by a 16th-century Spanish friar's writings. Recent FDA-approved clinical studies suggest potential value for psilocybin-assisted psychotherapy in treating depression, anxiety, and certain addictions, though larger studies are needed to validate these early findings.
Journal of Medicinal Chemistry
May 1, 1982
David E. Nichols, David Harley Lloyd, Andrew J. Hoffman et al.
178 citations
The enantiomers of MDA, PMA, and MDMA, along with their alpha,alpha-dimethylated derivatives, were tested for their ability to release serotonin from rat whole brain synaptosomes. At bath concentrations of 1 and 10 micrometers, the amphetamine isomers potently induced serotonin release, but were inactive at 0.1 micrometers. At 1 micrometer, the (+) isomer of MDMA was more effective than the (-) isomer, and because the (+) isomer is the clinically active form, this suggests that transmitter release may contribute to MDMA's biological activity. The alpha,alpha-dimethyl compounds did not release serotonin even at the highest concentration.
Trends in Pharmacological Sciences
September 22, 2017
Evan J. Kyzar, Charles D. Nichols, Raul R. Gainetdinov et al.
155 citations
Psychedelic drugs like LSD, mescaline, and psilocybin produce strong effects on the brain and behavior. After decades of research difficulties, they are being tested again as possible treatments for hard-to-treat medical conditions. Preclinical research, human brain imaging, and early clinical trials suggest these compounds may help with addiction, depression, anxiety, and other disorders. However, many questions about how they work, their safety, and their effectiveness remain. This review summarizes recent preclinical and clinical data, discusses their pharmacological mechanisms, and outlines key areas for future research to maximize the potential benefits of psychedelic medicine for patients.
Journal of Medicinal Chemistry
October 19, 2000
Joseph B. Blair, Deborah Kurrasch‐orbaugh, Danuta Marona‐lewicka et al.
132 citations
Fluorination of hallucinogenic tryptamines generally preserves their affinity and intrinsic activity at 5-HT2A/2C serotonin receptors but reduces affinity at the 5-HT1A receptor, except for one compound. 4-Fluoro-5-methoxy-DMT (compound 6) showed markedly enhanced 5-HT1A receptor affinity (Ki = 0.23 nM) and functional potency, greater than the standard 5-HT1A agonist 8-OH-DPAT, with an ED50 of 0.17 µmol/kg in a drug discrimination assay. Hallucinogen-like activity was attenuated or abolished for all fluorinated analogues. The findings suggest that while 5-HT2A activation is key for hallucinogenic effects, the 5-HT1A receptor may also play a role with tryptamines.
Pharmacopsychiatry
December 7, 2020
David E. Nichols, Hannes Walter
131 citations
Interest in psychedelic drugs in psychiatry began in the early 20th century, initially exploring whether mescaline or peyote could produce psychosis-like effects. Over time, researchers focused on whether these effects could illuminate the underlying basis of psychiatric disorders. After LSD's discovery in 1943, interest shifted toward using psychedelics as adjuncts to psychotherapy, which became the primary focus of research through to the present day.
Journal of Medicinal Chemistry
September 1, 2002
David E. Nichols, Stewart Frescas, Danuta Marona‐lewicka et al.
89 citations
Lysergic acid amides containing a rigid dimethylazetidine ring—a constrained version of diethylamine—were synthesized and tested for hallucinogenic activity. The (S,S)-(+)-2,4-dimethylazetidine lysergamide showed slightly greater LSD-like behavioral effects in rats than LSD itself and had the highest affinity and functional potency at the serotonin 5-HT(2A) receptor, the presumed target for hallucinogens. Its receptor profile across a panel of screens most closely matched that of LSD. In contrast, the cis- and (R,R)-trans-dimethylazetidine lysergamides were less potent. These results suggest that the N,N-diethyl groups of LSD bind optimally in a conformation different from that seen in the solid state. Incorporating isomeric dialkylazetidines into other molecules may help model active conformations of dialkylamines and dialkylamides.
Journal of Medicinal Chemistry
September 1, 1997
Aaron Monte, Steve R. Waldman, Danuta Marona‐lewicka et al.
89 citations
Conformationally restricted bioisosteres of mescaline's methoxy groups—dihydrobenzofuran (8) and tetrahydrobenzodifuran (9)—were synthesized and tested against mescaline (1) in drug discrimination assays in rats trained to discriminate LSD from saline. Neither 8 nor 9 substituted for LSD: only 50% of rats given 8 and 29% given 9 selected the drug lever, whereas mescaline fully substituted (ED50 = 33.5 mumol/kg). All compounds showed micromolar affinity for 5-HT1A and 5-HT2A receptors in rat brain homogenate, but rank order of affinities at 5-HT2A sites reversed their behavioral potency. At 5-HT2A receptors, 8 and 9 were less efficacious (61% and 45% of maximal response), while all compounds matched serotonin's efficacy at 5-HT2C receptors.
ACS Chemical Neuroscience
February 20, 2018
David E. Nichols
87 citations
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 its accidental discovery in 1943, Sandoz Laboratories supplied it as an experimental drug for psychotherapy and psychiatric insight. The discovery of serotonin in the mammalian brain in 1953 and its structural resemblance to LSD sparked research into serotonin's role in mental disorders. LSD proved physiologically safe and nonaddictive with a low incidence of adverse events in controlled experiments.
Journal of Medicinal Chemistry
February 1, 1990
David E. Nichols, William K. Brewster, Michael P. Johnson et al.
83 citations
Four cyclic analogues of the psychoactive compound MDA were tested in rats trained to discriminate either LSD or MDMA from saline. None of the methylenedioxy compounds caused LSD-like effects, but two of them (3a and 3b) fully substituted for MDMA, indicating similar acute behavioral effects. However, unlike MDA, neither 3a nor 3b reduced serotonin or its metabolite levels in the cortex or hippocampus, nor did they decrease serotonin transporter binding sites after a single 40 mg/kg dose. These results suggest that 3a and 3b share MDMA-like acute behavioral properties but lack the serotonin neurotoxicity associated with MDA.
Synthesis
June 1, 1999
David E. Nichols
68 citations
An improved chemical procedure for synthesizing psilocybin, the psychoactive compound in magic mushrooms, is reported. The method uses the O-lithium salt of psilocin reacting with tetra-O-benzylpyrophosphate, followed by catalytic hydrogenation to remove benzyl groups. Because psilocybin preparation is difficult, the authors suggest 4-acetoxy-N,N-dimethyltryptamine as a useful alternative for pharmacological studies. This alternative is obtained by catalytic O-debenzylation of 4-benzyloxy-N,N-dimethyltryptamine in the presence of acetic anhydride and sodium acetate.
Frontiers in Psychiatry
March 25, 2022
David E. Nichols
65 citations
MDMA (ecstasy) is structurally very similar to the hallucinogenic amphetamine MDA, yet its effects are fundamentally different. N-methylation normally reduces hallucinogenic activity, but MDMA retains potency. A key clue is stereochemistry: the dextro isomer of MDMA is more active, whereas the levo isomer is more active for hallucinogens. Also, extending the alpha-methyl to an alpha-ethyl group abolishes hallucinogenic activity but not MDMA-like effects, as shown with the analog MBDB. These three structural differences led to MDMA being classified as an "entactogen" in 1986, a drug that promotes social bonding, reduces anxiety, and induces introspection rather than hallucination. Its mechanism involves serotonin transporter-mediated release of stored serotonin.
Journal of Medicinal Chemistry
September 1, 1985
Andrew J. Hoffman, David E. Nichols
44 citations
A series of N(6)-alkyl norlysergic acid N,N-diethylamide derivatives was synthesized and tested in rats trained to discriminate LSD from saline. The N(6)-ethyl and -allyl derivatives were 2–3 times more potent than LSD itself, the N(6)-propyl was equally potent, the isopropyl derivative was half as active, and the n-butyl compound was 10 times less potent. No substitution occurred for norlysergic acid N,N-diethylamide or the N(6)-2-phenethyl derivative. These structure-activity relationships resemble those of certain serotonin and dopamine agonists.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Elsevier eBooks
January 1, 2009
Mark A. Geyer, David E. Nichols, Franz X. Vollenweider
12 citations
No Summary
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.
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.