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.
Journal of Medicinal Chemistry
October 1, 1986
David E. Nichols, Andrew J. Hoffman, Robert Oberlender et al.
189 citations
A new phenethylamine derivative, 1-(1,3-benzodioxol-5-yl)-2-butanamine, was synthesized in both racemic and enantiomerically pure forms, along with the related compound MDA. In rats trained to discriminate LSD from saline, only the racemate and R-(-) enantiomer of the alpha-methyl homologue, and the S-(+) enantiomer of the alpha-ethyl primary amine, produced stimulus generalization; other enantiomers and N-methyl derivatives did not. Human studies indicated the N-methyl derivative was nonhallucinogenic but had a novel psychoactive effect. The authors propose this compound as the prototype of a new pharmacological class, termed entactogens, potentially useful in facilitating psychotherapy.
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
January 1, 1996
Aaron Monte, Danuta Marona‐lewicka, Matthew Parker et al.
106 citations
A series of eight new phenylalkylamine derivatives with conformationally restricted dihydrofuran rings were synthesized and tested in rats. One compound, 7b, substituted for LSD in a drug discrimination assay with an ED50 of 61 nmol/kg and bound to 5-HT2 receptors with nanomolar to subnanomolar affinity, making it among the most potent hallucinogen-like phenylalkylamines reported. All compounds with a hydrophobic substituent para to the alkylamine side chain matched or exceeded the activity of flexible parent compounds. The results suggest the dihydrofuran rings model the active binding conformations of methoxy groups and provide information about agonist binding topography in serotonin 5-HT2 receptors.
Journal of Medicinal Chemistry
January 26, 2001
James J. Chambers, Deborah Kurrasch‐orbaugh, Matthew Parker et al.
98 citations
Modifying the 2,5-oxygen substituents typical of hallucinogenic amphetamines such as DOB enhanced ligand affinity for 5-HT(2A) and 5-HT(2C) agonist binding sites. Restricting flexible 2,5-dimethoxy groups into fused dihydrofuran rings generally increased potency. Pure enantiomers were synthesized via enantiospecific acylation, ketone reduction, and N-deprotection. R-enantiomers bound with slightly higher affinity than S-enantiomers at both receptors and generally showed greater potency in functional studies. Aromatization of dihydrofuran rings further increased affinity and potency. Most compounds were partial agonists with intrinsic activities of 60-80%. Compounds with a fully aromatic linear tricyclic nucleus are among the highest-affinity 5-HT(2A) receptor ligands reported.
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.
Wiley Interdisciplinary Reviews Membrane Transport and Signalling
February 28, 2012
David E. Nichols
80 citations
Of the 14 known serotonin receptor types, the 5-HT2A receptor is one of the most studied. In the brain, it regulates cortical function and cognition, is the main target for hallucinogenic drugs like LSD, and is also a target for newer atypical antipsychotic drugs that act as antagonists or inverse agonists. Three chemical classes of agonists exist: tryptamines, ergolines, and phenethylamines. Key structural features for agonist activity are identified, and some agonists share common features. Much of the structure-activity relationship knowledge comes from human studies conducted before modern pharmacological techniques.
Journal of Medicinal Chemistry
December 1, 1998
Matthew Parker, Danuta Marona‐lewicka, Virginia L. Lucaites et al.
69 citations
A novel (benzodifuranyl)aminoalkane compound was synthesized and evaluated for activity at the 5-HT2A receptor. The compound exhibited extremely potent activity, with a Ki value of 0.4 nM at the human 5-HT2A receptor, making it one of the most potent 5-HT2A receptor agonists reported. It also showed high selectivity over other serotonin receptor subtypes. In rodent behavioral assays, the compound produced effects consistent with 5-HT2A receptor activation, including the head-twitch response in mice. These findings suggest the compound is a valuable tool for studying 5-HT2A receptor function and may have implications for developing new therapeutic agents.
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
March 1, 1999
Joseph B. Blair, Danuta Marona‐lewicka, Arthi Kanthasamy et al.
63 citations
Two thienopyrrole compounds, designed as structural replacements for the indole ring in N,N-dimethyltryptamine (DMT), were synthesized and tested. Neither compound produced LSD-like effects in rats trained to discriminate LSD or DOI, even at high doses. However, both fully substituted for a 5-HT1A receptor agonist and caused behaviors consistent with 5-HT1A activation, such as serotonin syndrome and salivation. At the 5-HT2A receptor, one compound had twice the affinity of the other, while at 5-HT2B and 5-HT2C receptors the pattern reversed. The thienopyrrole replacement thus failed to mimic DMT's activity at 5-HT2 receptors but enhanced activity at the 5-HT1A receptor, indicating that serotonin receptor subtypes respond differently to subtle electronic changes in the aromatic ring system.
Journal of Neurochemistry
August 15, 2006
Jason C. Parrish, David E. Nichols
61 citations
Activation of the serotonin 5-HT(2A) receptor stimulates the production and release of the endocannabinoid 2-arachidonoylglycerol. In cells expressing the rat 5-HT(2A) receptor, stimulation with 10 μM serotonin led to formation and release of 2-arachidonoylglycerol, partially dependent on phosphatidylinositol-specific phospholipase C activation. Diacylglycerol from phospholipase D or phosphatidylcholine-specific phospholipase C did not contribute. The findings support a model where neurotransmitters like serotonin regulate endocannabinoid tone at excitatory synapses via phospholipase C-coupled G-protein coupled receptors.
Drug Testing and Analysis
June 5, 2017
Simon D. Brandt, Pierce V. Kavanagh, Brendan Twamley et al.
56 citations
Lysergic acid morpholide (LSM-775), a structural relative of LSD, appeared on the market for new psychoactive substances in 2013, but its potency and psychoactive effects in humans have been disputed. This investigation characterized a powdered sample using multiple analytical techniques and tested its receptor activity. LSM-775 acted as a nonselective agonist at 5-HT1A and 5-HT2A receptors. In head twitch studies with C57BL/6J mice, LSM-775 did not induce the head twitch response unless 5-HT1A receptors were blocked by the antagonist WAY-100,635 (1 mg/kg, subcutaneous). The findings suggest that activation of 5-HT1A receptors by LSM-775 masks its hallucinogen-like effects, consistent with reports that it produces only weak LSD-like effects in humans.
Journal of Medicinal Chemistry
May 1, 1991
Michael P. Johnson, Stewart Frescas, Robert Oberlender et al.
53 citations
Two experimental compounds—racemic and enantiomeric forms of 1-(3-methoxy-4-methylphenyl)-2-aminopropane (6) and racemic 5-methoxy-6-methyl-2-aminoindan (11)—produced effects in rats similar to those of MDMA and related drugs, substituting with high potency in drug-discrimination tests for MDMA and its analog. However, unlike MDMA, these compounds did not cause serotonin neurotoxicity: rat brain monoamine levels remained unchanged one week after a single high dose or two weeks after repeated dosing, and serotonin transporter binding was unaffected. The compounds also potently inhibited serotonin uptake in vitro, with the S enantiomer of 6 being most active.
Journal of Medicinal Chemistry
January 1, 1991
David E. Nichols, Scott E. Snyder, Robert Oberlender et al.
45 citations
Two new compounds related to hallucinogenic amphetamines were synthesized and tested in rats trained to discriminate LSD from saline, and for their ability to bind to serotonin 5-HT2 receptors in rat brain tissue. The compounds, which contain a rigid dihydrofuran ring, showed activity similar to their more flexible counterparts. Adding a bromine atom to the compounds contributed 2.4–3.2 kcal/mol of binding energy, 2–3 times more than expected from hydrophobic binding alone, suggesting that the bromine's effect cannot be explained solely by its hydrophobicity and that an unknown receptor interaction is involved.
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.
Journal of Medicinal Chemistry
February 1, 1975
Charles F. Barfknecht, David E. Nichols, William J. Dunn
42 citations
The hallucinogenic potency of certain amphetamines and phenethylamines in humans may be related to their lipophilicity, as measured by the 1-octanol-water partition coefficient. For 11 amphetamines, these coefficients were measured directly, and for 17 additional amines they were estimated using published Hansch pi constants. The analysis suggests that an ideal log P value for psychotomimetic activity in humans may fall between 2.89 and 3.72.
Journal of Neurochemistry
November 8, 2005
Jason C. Parrish, M. Braden, Emily Gundy et al.
40 citations
Phenylisopropylamine hallucinogens (such as DOI) produce a stronger activation of the serotonin 5-HT2A receptor than their phenethylamine counterparts (such as mescaline), as measured by the receptor's ability to trigger phosphatidyl inositol hydrolysis in cells. Among phenylisopropylamines, those with the (R) configuration at the alpha carbon are more potent than those with the (S) configuration. Computer simulations of how these molecules dock into the receptor reveal different orientations of key binding site residues. The findings support the idea that phenylisopropylamines' greater hallucinogenic potency stems from higher intrinsic activity at the 5-HT2A receptor, though the three-dimensional structure of receptor microdomains also matters.