Neuron
October 5, 2022
Can Cao, Ximena Barros-Álvarez, Shicheng Zhang et al.
158 citations
Lysergic acid diethylamide (LSD) acts through serotonin 5-HT2-family receptors, primarily 5-HT2A, but the closely related 5-HT2B receptor serves as a model due to its high expression. Cryo-electron microscopy structures of LSD-bound 5-HT2B in three states—transducer-free, coupled with Gq protein, and coupled with β-arrestin-1—reveal distinct signaling snapshots from a partially active to fully active states. These findings provide comprehensive molecular insights into LSD's signaling mechanisms and may accelerate the discovery of novel psychedelic drugs.
Journal of medicinal chemistry
September 21, 2006
Thomas H Mclean, Jason C Parrish, Michael R Braden et al.
115 citations
A series of rigid analogues of the hallucinogenic phenethylamine 2C-B was synthesized to determine the active shape these molecules adopt when binding to the 5-HT(2A) receptor. Computer docking predicted that one benzocyclobutene analogue, (R)-2, would be the most potent. Chemical resolution and X-ray crystallography confirmed this: (R)-2 was equipotent to LSD in rats trained to discriminate LSD from saline, making it one of the most potent and selective compounds yet tested in this assay. The compound also acted as a functionally selective agonist at the 5-HT(2A) receptor, showing 65-fold greater potency in stimulating phosphoinositide turnover than in producing arachidonic acid release. If hallucinogenic effects are linked to arachidonic acid production, such selective agonists might lack the intoxicating properties of LSD.
Forensic science international
March 1, 2018
David E Nichols, Charles S Grob
86 citations
LSD is physiologically non-toxic and medically safe at standard doses (50-200 μg). Five sudden deaths previously attributed to LSD toxicity were actually caused by other factors: two from massive overdoses, two from fatal cardiovascular collapse after agitated individuals were placed in maximal physical restraint positions (hog-tying) by police, and one from extreme hyperthermia likely due to a substituted drug (e.g., 25i-NBOMe) that affects central nervous system temperature regulation. Accurate understanding of these fatalities is important given renewed therapeutic interest in LSD and other psychedelics.
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 and a parallel series of N-benzylated 2C-I analogues were synthesized and tested. Most compounds showed highest affinity for 5-HT2 family receptors. Para substitution on the benzyl group reduced affinity, while ortho or meta substitution enhanced it. Large lipophilic groups improved affinity but often reduced functional activity. Functional testing at human and rat 5-HT2A, 5-HT2B, and 5-HT2C receptors revealed no general correlation between affinity and function. Several tryptamine congeners were potent functional agonists (EC50 values from 7.6 to 63 nM) but mostly partial agonists. In the mouse head twitch assay, many compounds induced head twitches, and this behavior correlated significantly with functional potency at the rat 5-HT2A receptor.
Journal of Psychopharmacology
January 1, 2018
David E Nichols
68 citations
The pineal gland has been mythologized across cultures as the seat of the soul or third eye, with modern claims that it secretes the psychedelic compound N,N-dimethyltryptamine (DMT) during birth, dreaming, and near death to cause out-of-body experiences. Scientific evidence contradicts these ideas. The adult pineal gland weighs less than 0.2 g and primarily produces about 30 µg per day of melatonin, a hormone regulating circadian rhythm. Minute concentrations of DMT have been detected in the brain, but they are insufficient for psychoactive effects. Alternative explanations are offered for how stress and near-death states produce altered consciousness without DMT.
Pharmacological reviews
April 23, 2025
Benjamin R Cummins, Gerald B Billac, David E Nichols et al.
62 citations
Serotonin 5-HT2A receptors are found throughout the body and are most dense in brain cortical layer V. They are involved in normal physiology and neuropsychiatric diseases like schizophrenia. Atypical antipsychotics block these receptors, while psychedelic drugs such as psilocybin, dimethyltryptamine, and lysergic acid diethylamide activate them to produce lasting therapeutic effects in clinical trials for major depression and substance use disorders. The three main agonist scaffolds—tryptamines, ergolines, and phenylalkylamines—engage different amino acid residues in the receptor binding pocket, leading to functionally selective outcomes. Understanding these ligand-receptor interactions guides future drug discovery for optimized therapeutics.
Psychopharmacology
June 1, 2012
Adam L Halberstadt, David E Nichols, Mark A Geyer
55 citations
A combination of the hallucinogenic tryptamine 5-MeO-DMT and a monoamine oxidase inhibitor (MAOI) produces a biphasic effect on rat locomotor activity: an initial reduction followed by an increase. This study tested whether the delayed hyperactivity results from slowed metabolism of 5-MeO-DMT. A deuterated form of 5-MeO-DMT that resists MAO metabolism, when given alone at a higher dose (3.0 mg/kg), produced the same biphasic pattern as the 5-MeO-DMT/MAOI combination, while lower doses caused only hypoactivity. Receptor binding showed deuterium substitution did not alter 5-MeO-DMT's affinity for neurotransmitter sites. The findings indicate that MAO inhibition prolongs 5-MeO-DMT's occupation of central serotonin receptors, causing hyperactivity.
Neuron
July 15, 2025
Manish K Jain, Ryan H Gumpper, Samuel T Slocum et al.
42 citations
Classical psychedelics like LSD, psilocybin, and mescaline produce their mind-altering effects by activating the 5-HT2A serotonin receptor. Recent clinical studies indicate they may also help treat depression, anxiety, migraines, cluster headaches, drug abuse, and PTSD. This work examined 41 psychedelics from three chemical classes, testing them against 318 human G-protein-coupled receptors and, for LSD, over 450 human kinases. The compounds potently activated nearly every serotonin, dopamine, and adrenergic receptor. They also stimulated multiple signaling pathways through the 5-HT2A receptor, each linked to psychedelic-like effects in animals. The findings suggest that many molecular targets contribute to the overall actions of psychedelics.
British journal of pharmacology
October 2, 2024
Ryan H Gumpper, David E Nichols
9 citations
Classic serotonergic psychedelics come in three main chemical families: phenethylamines, ergolines, and tryptamines. Each family has distinct structural features that determine its psychedelic activity in humans. The 5-HT2A receptor, a G-protein coupled receptor, is the primary target for these compounds. Recent X-ray and cryoEM structures showing various ligands bound to the receptor reveal the atomic-level details of how different psychedelic molecules interact with this receptor. These structural insights help explain known pharmacological observations about how psychedelic drugs work and may guide future drug development.
International review of neurobiology
January 1, 2025
David E Nichols, Charles D Nichols
3 citations
Classic psychedelics have been used for millennia for healing and religious purposes. Modern psychedelic science began in 1898 when Dr. Arthur Heffter identified mescaline as the active alkaloid in peyote. Western society's relationship with psychedelics has been contentious: initially valued as medicines and scientific tools, they were later criminalized during the 1960s counterculture, halting research for nearly 20 years. As the political climate shifted, clinical trials resumed, with high-profile studies demonstrating efficacy for psychiatric disorders. This review covers 125 years of psychedelic science, highlighting key events and findings that advanced understanding of their pharmacology, chemistry, and therapeutic potential.
Pharmacology & therapeutics
February 1, 2004
David E Nichols
1 citation
Hallucinogens (psychedelics) powerfully alter perception, mood, and cognition, are physiologically safe, and do not cause dependence. Their use predates written history in ritual contexts. Early research linked LSD to serotonin (5-HT), and it is now known that hallucinogens stimulate 5-HT(2A) receptors on neocortical pyramidal cells, increasing cortical glutamate. These effects are compared to acute psychosis, with thalamocortical interactions key to altered states of consciousness. Brain imaging shows increased prefrontal cortical metabolism. The 5-HT(2A) receptor is essential for cognitive processing, and its ligands may aid cognitive neuroscience. Hallucinogens may also have therapeutic utility for alcoholism, substance abuse, and psychiatric disorders.