The FASEB Journal
February 1, 1997
Rabi Simantov, M Tauber
89 citations
MDMA (ecstasy), an amphetamine analog that causes hallucination and psychostimulation, can trigger programmed cell death (apoptosis) in human serotonergic JAR cells. The drug altered the cell cycle, increased G2/M phase arrest, and caused DNA fragmentation, effects that were blocked by cycloheximide. This apoptosis did not occur in nonserotonergic human NMB cells. The process depended on nitric oxide and dopamine and was stereospecific for amphetamines. The findings suggest a mechanism for long-term neuropsychiatric effects in users, though direct evidence in human neurons remains unclear.
The FASEB Journal
December 1, 2002
Bruce Ladenheim, Michael Mccoy, Jean Lud Cadet et al.
34 citations
MDMA (ecstasy) triggers changes in gene activity in the rat cortex within hours of a single injection. The genes affected are involved in signaling, transcription regulation, and xenobiotic metabolism, suggesting that the cortex responds acutely by altering transcription of genes that could lead to long-term brain changes. MDMA is known to cause hyperthermia, reactive oxygen species, and long-term serotonin depletion, with the cortex especially sensitive. These molecular changes may underlie the drug's lasting effects on the brain.
The FASEB Journal
April 1, 2020
Meghan Hibicke, Charles D. Nichols
9 citations
A single dose of psilocybin given in late adolescence mitigates cognitive and behavioral deficits in female rats exposed to chronic restraint stress during adolescence. Stressed rats that received psilocybin performed as well as non-stressed rats on an object pattern separation task, a test of dentate gyrus and CA3 hippocampal function, while stressed rats given saline could not discriminate between moved and stationary objects. Psilocybin also normalized immobility in the forced swim test, a measure of behavioral despair. Performance on the object pattern separation task inversely correlated with immobility, supporting its validity as a cognitive outcome measure for depression.
The FASEB Journal
August 26, 2025
Joshua C. Flowers, Paige E. Vetter, McKennon J. Wiles et al.
7 citations
Low-dose ketamine rapidly induces the expression of calcium-permeable AMPA receptors (CP-AMPARs) in the hippocampus, which enhances glutamatergic synaptic strength. In mice subjected to chronic restraint stress, low-dose ketamine reverses social dysfunction, loss of hippocampus-dependent fear learning and memory, and depression-like behavior in both females and males. These antistress effects depend on CP-AMPAR expression. The findings suggest that subanesthetic low-dose ketamine triggers CP-AMPAR expression in the hippocampus, producing antidepressant and antistress effects.
The FASEB Journal
April 1, 2019
Meghan Hibicke, Alexus N. Landry, Zoe K. Talman et al.
7 citations
A single dose of psilocybin produces long-lasting antidepressant-like and anxiolytic effects in male Wistar-Kyoto rats, a model of treatment-resistant depression. LSD also produces a long-lasting antidepressant-like effect, while ketamine does not. These findings indicate that at least a substantial portion of the therapeutic effects of psychedelics has a biological basis and can be studied in animal models, rather than relying solely on psychological integration of the human experience.
The FASEB Journal
April 1, 2017
Thomas W. Flanagan, Melaine N. Sebastian, Charles D. Nichols
2 citations
Activating the 5-HT2A receptor with the agonist (R)-DOI before allergen exposure reduces airway hyperresponsiveness in a chronic mouse model of allergic asthma, suggesting a potential new treatment for inflammatory airway diseases. The authors previously showed that (R)-DOI prevents asthma symptoms in an acute ovalbumin-induced model, and here they extend those findings to a persistent asthma model. They also report testing psilocybin and other tryptamines for effects on airway hyperresponsiveness in rodents. The overall goal is to develop 5-HT2A receptor agonism as a therapy for asthma and related inflammatory disorders.
The FASEB Journal
April 1, 2008
Krzysztof Jozwiak, Ruin Moaddel, Irving W. Wainer et al.
2 citations
Ibogaine analogs, especially 18-methoxycoronaridine (18-MC), bind to a specific site within the ion channel of the nicotinic acetylcholine receptor (AChR) when the receptor is in a desensitized state. The affinity of 18-MC for this site is about 0.17 μM in the desensitized state, much higher than in the resting state (12 μM). The binding site overlaps with the TCP locus, located between valine and leucine rings in the channel. These compounds enhance binding of the agonist cytisine only when the receptor is in a resting but activable state, not when desensitized. The findings suggest that ibogaine analogs inhibit the AChR by promoting receptor desensitization.
The FASEB Journal
May 1, 2022
Grant C. Glatfelter, David R. Manke, Andrew R. Chadayne et al.
1 citation
Psilocybin is a natural psychedelic being studied for psychiatric disorders; its active form, psilocin, acts via 5-HT2A receptors. Several psilocybin analogs, like psilacetin, have emerged as new psychoactive substances. This study examined in vitro receptor affinities for a series of psilocybin analogs with different N-alkyl or 4-position substitutions, and in vivo head twitch responses (HTRs) in male C57BL/6J mice after psilocybin, psilacetin, or psilocin administration. All analogs showed low to mid nM affinities for 5-HT1A, 5-HT2A, 5-HT2B, and 5-HT2C receptors; non-serotonergic affinities were weaker. In mice, the potency order for HTRs was psilocin > psilacetin > psilocybin. HTRs from all three compounds (0.6 mg/kg) were blocked by the 5-HT2A antagonist M100907 (0.01 mg/kg), indicating 5-HT2A involvement. Psilacetin may be an alternative prodrug for psilocin with possible independent psychedelic activity.
The FASEB Journal
April 1, 2019
Gerald Billac, Charles D. Nichols
1 citation
Classical serotonergic psychedelics are being re-examined as treatments for various diseases. While most research focuses on their central nervous system effects, previous work suggests that serotonin 2A receptor (5-HT2AR) agonists can modulate TNF-alpha-mediated inflammatory responses in the periphery. This study characterizes signaling pathway activation for a panel of 5-HT2AR ligands from three chemical classes: tryptamines, ergolines, and phenethylamines. Initial results examining the canonical Gαq pathway and β-arrestin2 recruitment showed no significant correlation between potency or efficacy and anti-inflammatory activity in vivo. Ongoing studies are examining additional GPCR-mediated signaling via cAMP accumulation to understand the structural basis for biased signaling and inform drug design.
The FASEB Journal
April 1, 2016
David Martin, Connie Porretta, Charles D. Nichols
1 citation
The classic psychedelic (R)-DOI, a selective 5-HT2 receptor agonist, activates a diverse set of brain cells beyond just neurons. In the medial prefrontal and somatosensory cortex of mice, (R)-DOI induced immediate early genes like cfos in parvalbumin- and somatostatin-expressing interneurons, HTR2A-expressing neurons, and astrocytes. A new flow cytometry method that preserves intact cytoplasm and extracellular membranes allowed isolation of pure populations of somatostatin and parvalbumin interneurons from whole cortex. Further sorting by cFos activation revealed that different immediate early genes, such as egr2, are not uniformly induced across all activated cells. The technique is broadly applicable for studying cell-type-specific transcriptional and translational effects of any manipulation in the brain.
The FASEB Journal
April 1, 2015
David Martin, Connie Porretta, Charles D. Nichols
1 citation
Serotonin hallucinogens such as LSD and DOI primarily act through the 5-HT2A receptor, but their effects on brain function at the cellular and network levels remain incompletely understood. In adult rats treated with LSD, DOI, or saline, the somatosensory and medial prefrontal cortices were collected and dissociated into single cells. Using fluorescence-activated flow cytometry to separate neurons from glia and activated from non-activated neurons, qPCR analysis revealed an enrichment of immediate early genes (including c-fos, fosb, arc, krox-20/egr-2) in a small population of activated cortical neurons. Differences in gene abundance (htr2a, slc17a7, gad67) between activated and non-activated cells indicate which specific cell types are directly activated. Further research is needed to determine how this transcriptional program contributes to long-term psychological changes.
The FASEB Journal
April 1, 2015
Émeline L. Maillet, Nicolas Milon, James A. Fishback et al.
1 citation
Noribogaine, the primary metabolite of the anti-addictive substance ibogaine, modulates opioid receptors in ways that may explain its therapeutic effects. At mu-opioid receptors, noribogaine acts as a moderately potent antagonist of both G-protein and β-arrestin signaling pathways. At kappa-opioid receptors, it is a partial agonist of the G-protein pathway, activating at 75% the maximal efficacy of Dynorphin A with a potency of 9 µM, while poorly activating the β-arrestin pathway. Noribogaine functionally inhibits Dynorphin A-induced β-arrestin recruitment at physiologically relevant concentrations, with an IC50 of 1.45 µM. Computational simulations suggest noribogaine binds to the orthosteric morphinan binding site.
The FASEB Journal
April 1, 2012
Evan J. Kyzar, Christopher Collins, Jeremy Green et al.
1 citation
Mescaline and phencyclidine (PCP) alter zebrafish behavior in distinct ways, while psilocybin shows no behavioral effects at the doses tested. Mescaline (10–20 mg/L) reduces anxiety-like behavior in the novel tank test, increases shoaling, and changes movement in the open field. PCP (1–3 mg/L) decreases freezing and causes erratic swimming. Both mescaline and PCP disrupt normal exploratory behavior. Psilocybin (0.5–3 mg/L) is inactive in all behavioral tests. Psilocybin and PCP raise whole-body cortisol levels without affecting brain c-fos expression; mescaline does not alter either measure. Zebrafish models are sensitive to hallucinogenic compounds with complex behavioral and physiological effects.
The FASEB Journal
May 1, 2022
Deborah Rudin, Dino Luethi, Marius C. Hoener et al.
4-Halogenated derivatives of 2,5-dimethoxyamphetamine (DOX) show increasing selectivity for the 5-HT2A receptor as the halogen size increases, with DOI exhibiting nearly 1000-fold higher selectivity than DOF. All tested derivatives acted as partial to full agonists at the 5-HT2A receptor. Their 5-HT2 receptor interaction potency resembled that of their 2C analogues, but with greater 5-HT2A versus 5-HT1A selectivity. None showed nanomolar affinity for TAAR1, adrenergic, dopaminergic, or monoamine transporters. This enhanced selectivity may explain the higher clinical potency of DOX derivatives but could also increase seizure risk, suggesting 2C derivatives may be safer for clinical applications.
The FASEB Journal
May 1, 2022
Dino Luethi, Deborah Rudin, Marius C. Hoener et al.
The pharmacological properties of 4-alkylated 2,5-dimethoxyamphetamines were examined in vitro, focusing on how the length of the 4-alkyl chain affects interactions with monoaminergic targets. The 4-alkylated derivatives (DOM, DOET, DOBU, DOAM) showed potent nanomolar affinity at serotonin 5-HT2A and 5-HT2C receptors, unlike the parent compound 2,5-DMA. Increasing alkyl chain length enhanced selectivity for 5-HT2A over 5-HT1A and 5-HT2C receptors. DOM and DOET activated the 5-HT2B receptor as partial agonists (EC50: 68–128 nM, Emax: 73–85%), while DOBU and DOAM did not (EC50 > 10,000 nM). The derivatives showed weak or no interaction with other monoaminergic targets. The findings suggest that 5-HT2A and 5-HT2C receptor affinity alone does not sufficiently predict clinical or psychedelic potency.
The FASEB Journal
April 1, 2019
Madeline M. Pantoni, Stephan Anagnostaras
Low to moderate doses of MDMA (less than 3 mg/kg), typical of recreational or therapeutic use, may not impair learning and memory as severely as high doses. In mice trained with a Pavlovian fear conditioning paradigm, doses from 0.1 to 8 mg/kg were tested. Immediate memory and long-term contextual and cued memory were assessed one week later. The findings help determine whether low doses are therapeutically viable without adverse cognitive effects.
The FASEB Journal
April 1, 2018
Matthias E. Liechti, Dino Luethi
For amphetamine-type novel psychoactive substances (NPS), the potency of inhibiting the norepinephrine transporter (NET) in cells correlated significantly with the doses people typically use to get psychoactive effects, while inhibition of dopamine or serotonin transporters did not. For hallucinogenic NPS and classic hallucinogens (tryptamines, phenethylamines), binding affinity at the serotonin 5-HT2A receptor strongly predicted human psychoactive dose; binding at 5-HT2C did so less strongly, and 5-HT1A showed no relationship. In vitro pharmacological profiling of NET inhibition and 5-HT2 receptor binding may help estimate psychoactive doses of new substances, though factors like metabolism and brain penetration also matter.
The FASEB Journal
April 1, 2017
C. Nichols, Melaine N. Sebastian, Thomas W. Flanagan
Activating the serotonin 5-HT2A receptor with the psychedelic (R)-DOI reduces inflammation in a mouse model of atherosclerosis. In ApoE-deficient mice fed a high-fat diet, (R)-DOI treatment slowed atherosclerotic plaque development. The anti-inflammatory effect was specific to certain inflammatory pathways in innate and Th2 cells, not a generalized immune suppression. These findings suggest that 5-HT2A receptor activation may offer a novel therapeutic strategy for atherosclerosis, though the work was conducted only in mice.
The FASEB Journal
April 1, 2017
Gerald Billac, Charles D. Nichols
A panel of 5-HT2A receptor ligands, including the psychedelic drug (R)-DOI, shows superpotent anti-inflammatory effects in mouse models of asthma and atherosclerosis. The ligands exhibit differential activation of signaling pathways, with (R)-2C-BCB strongly biased toward the Gq pathway as measured by calcium mobilization. Ongoing studies examine β-arrestin signaling, receptor internalization, and other GPCR pathways. The goal is to use structure-activity relationships to develop novel therapies targeting specific effector pathways for inflammation-based diseases.
The FASEB Journal
April 1, 2016
Kelly Jean Sherman, Charles D. Nichols
Lysergic acid diethylamide (LSD), a mixed serotonin receptor agonist, alters circadian activity in Drosophila melanogaster in a dose-dependent manner, with a more robust effect in females. Five concentrations (0.01, 0.1, 1.0, 3.0, and 10.0 mM) were administered for seven days in a light/dark environment, and activity was monitored using the Drosophila Activity Monitor. LSD disrupted endogenous circadian rhythms in free run (dark/dark) conditions at doses of 1.0 and 3.0 mM in both sexes. Changes in RNA levels of circadian and P450 genes in fly heads were measured. The findings suggest LSD affects circadian activity potentially through modulating expression of circadian genes downstream of serotonin receptor activation.
The FASEB Journal
April 1, 2015
Émeline L. Maillet, Qing Chang, Nicolas Milon et al.
Noribogaine, a drug that acts on opioid receptors, nicotinic receptors, and serotonin transporters, was tested for its effects on nicotine dependence. It inhibited several types of nicotinic acetylcholine receptors, including α3β4 and α7. In a rat model of nicotine self-administration, noribogaine dose-dependently reduced nicotine intake by up to 64% compared to saline-treated rats, an effect comparable to the approved smoking cessation drug varenicline. These results suggest noribogaine may have potential for treating smoking cessation, substance abuse, and anxiety disorders.
The FASEB Journal
April 1, 2013
Jonathan M. Slezak, Melanie Mueller, George A Ricaurte et al.
MDMA's behavioral effects are primarily due to central nervous system actions, not peripheral ones. In rats trained to distinguish MDMA from saline, the drug produced dose-related increases in drug-appropriate responses. A quaternary analog of MDMA (qMDMA), which cannot cross the blood-brain barrier, did not substitute for MDMA when given peripherally, but partially substituted when infused directly into the brain. This validates qMDMA as a tool for separating central from peripheral effects of MDMA.
The FASEB Journal
April 1, 2012
David Martin, David E. Nichols, Charles D. Nichols
A novel rat model of schizophrenia was developed by treating rats with low doses of LSD for three months. This treatment caused persistent behavioral abnormalities including social deficits, hyperactivity, and anhedonia that continued after the drug was stopped. Protein analysis of the medial prefrontal cortex identified 12 differentially expressed proteins, 9 of which are also dysregulated in post-mortem brain tissue from people with schizophrenia. RNA sequencing showed that chronic LSD alters genes across all major neurotransmitter systems linked to schizophrenia, with many changes involving synaptic plasticity. The findings support chronic LSD treatment as a valid model for studying schizophrenia and may provide insights into the disease's underlying mechanisms.
The FASEB Journal
April 1, 2012
Ai‐ming Yu
Indolealkylamine drugs like 5-MeO-DMT act on serotonin neurotransmission and are often co-abused with harmaline. Concurrent use of harmaline, a monoamine oxidase inhibitor, blocks the metabolic elimination of 5-MeO-DMT, leading to increased and prolonged exposure. In mice, coadministration of harmaline and 5-MeO-DMT produced more severe hyperthermia than a higher dose of 5-MeO-DMT alone, indicating that harmaline interacts at both pharmacokinetic and pharmacodynamic levels. These results suggest that combining a monoamine oxidase inhibitor with 5-MeO-DMT heightens the risk of serotonin toxicity and intoxication.
The FASEB Journal
April 1, 2012
Ilana Emert, Katarzyna M. Targowska‐duda, Dominik Feuerbach et al.
Ibogaine inhibits calcium influx through human α3β4 nicotinic acetylcholine receptors with roughly nine times higher potency than phencyclidine (PCP). Radioligand binding shows ibogaine binds to a single site on the receptor with a dissociation constant of 0.46 μM, and it has slightly higher affinity for desensitized receptors than for resting ones. Docking studies indicate both compounds interact with a binding domain between the serine (position 6′) and valine/phenylalanine (position 13′) rings, primarily through van der Waals contacts, consistent with the measured enthalpic contribution. Entropic contributions suggest local conformational changes upon binding.