Journal of Neurochemistry
January 1, 1996
G. A. Gudelsky, J. Frank Nash
249 citations
MDMA (ecstasy) increases serotonin levels in the brain by directly causing serotonin transporters to release the neurotransmitter, rather than by triggering nerve cell firing. Blocking serotonin transporters with fluoxetine prevents both the serotonin and the dopamine surges normally caused by MDMA. When serotonin production is boosted beforehand with carbidopa and L-5-hydroxytryptophan, MDMA produces an even larger, synergistic increase in serotonin and also amplifies dopamine release. These findings support a model in which serotonin actively stimulates dopamine release, and they clarify the chemical mechanism behind MDMA's effects on mood and behavior.
Journal of Neurochemistry
September 24, 2008
Noelia Granado, Esther O’shea, Jordi Bové et al.
112 citations
Repeated doses of MDMA (ecstasy) given to mice cause a lasting loss of dopamine-producing neurons in the substantia nigra, a brain region critical for movement. One day after injection, the number of these neurons drops and remains low for at least 30 days. In the striatum, markers of dopamine function also fall sharply within a day and stay reduced for a month, though some recovery begins after three days, with new nerve fiber growth. Damage is selective: the nucleus accumbens is unaffected, showing MDMA destroys the nigrostriatal pathway but spares the mesolimbic pathway. Immune cell activation follows the same pattern, confirming the link between inflammation and dopamine cell death.
Journal of Neurochemistry
February 12, 2022
Johannes T. Reckweg, Malin V. Uthaug, Attila Szabó et al.
108 citations
5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) is a naturally occurring tryptamine that acts primarily as an agonist at 5-HT1A and 5-HT2A receptors, with highest affinity for the 5-HT1A subtype. Its subjective effects include distortions in auditory and time perception, amplification of emotional states, and feelings of ego dissolution that are usually short-lasting depending on route of administration. Individual dose escalation reliably induces a peak experience thought to be a core predictor of therapeutic efficacy. Observational studies and surveys suggest single exposure can cause rapid and sustained reductions in symptoms of depression, anxiety, and stress.
Journal of Neurochemistry
October 27, 2004
Michael G. Bankson, Bryan K. Yamamoto
84 citations
MDMA (ecstasy) increases the release of the neurotransmitter GABA in the ventral tegmental area (VTA) of the rat brain, which in turn dampens the rise of dopamine in the nucleus accumbens (NAC) shell. This GABA increase depends on activation of serotonin 5-HT2B/2C receptors in the VTA, because blocking those receptors reduced the GABA rise and allowed dopamine in the NAC to increase more. By contrast, amphetamine also raised GABA in the VTA and dopamine in the NAC, but its GABA increase was not mediated by those serotonin receptors. The findings suggest a serotonergic braking mechanism that limits MDMA's dopamine-releasing effect.
Journal of Neurochemistry
September 14, 2021
Urszula Kozłowska, Charles D. Nichols, Kalina Wiatr et al.
78 citations
Psychedelic tryptamines like psilocybin show promise for treating major depressive disorder (MDD) after a single dose, with two Phase III trials receiving FDA Breakthrough Therapy status. Beyond MDD and substance use disorders, rodent studies suggest psychedelics may also help treat or prevent brain injury and neurodegenerative diseases such as Alzheimer's Disease. Preclinical evidence indicates they can induce neuroplasticity, synaptogenesis, and neural progenitor cell proliferation, and act as immunomodulators by reducing proinflammatory biomarkers like IL-1β, IL-6, and TNF-α. The exact molecular mechanisms and cellular interactions underlying these therapeutic effects remain unknown.
Journal of Neurochemistry
November 19, 2021
Samuel T. Slocum, Jeffrey F. Diberto, Bryan L. Roth
59 citations
Psychedelic drugs like LSD, mescaline, and psilocybin are gaining renewed scientific and clinical interest due to the need for new mental health treatments, progress in research, and changing drug policies. The FDA's designation of psilocybin as a "Breakthrough Therapy" for treatment-resistant depression has opened a path for these drugs to be used in clinical settings. However, a clearer understanding of how these drugs work at the molecular level is essential for developing such applications. This review examines current knowledge about the molecular details of psychedelic drug actions and suggests that these discoveries can provide new insights into their hallucinogenic and therapeutic mechanisms.
Journal of Neurochemistry
January 22, 2007
Elio Acquas, Augusta Pisanu, Saturnino Spiga et al.
52 citations
The stimulant drug MDMA (Ecstasy) increases dopamine transmission in the nucleus accumbens, a brain region involved in reward. This study in male rats examined how the two mirror-image forms (enantiomers) of MDMA—S(+)-MDMA and R(−)-MDMA—affect dopamine release and a downstream signaling molecule called phosphorylated ERK (pERK) in the shell and core of the nucleus accumbens. Racemic MDMA (the standard mixture) and S(+)-MDMA increased dopamine and pERK levels in a dose-related way, with S(+)-MDMA being more potent. R(−)-MDMA had no effect. Blocking D1 dopamine receptors prevented the pERK increase, while blocking D2/D3 receptors did not. The results indicate that the S(+) enantiomer drives MDMA's dopamine-stimulating effects, and pERK serves as a marker of D1-receptor-mediated dopamine signaling.
Journal of Neurochemistry
March 11, 2022
Patricia Duerler, Franz X. Vollenweider, Katrin H. Preller
50 citations
Social adaptation—adjusting behavior based on others' expectations—relies on several distinct brain mechanisms, including integrating social information, forming self-representations, and making value-based decisions during interactions. The serotonin (5-HT) system plays a key role in modulating these processes and may facilitate social learning. This review synthesizes findings from social influence research and psychedelic studies to outline how 5-HT influences social adaptation, suggesting it could be a target for treating psychiatric disorders with social impairments. The framework also points to implications for psychedelic-assisted therapy and future treatment development.
Journal of Neurochemistry
March 12, 2021
Susan Schenk, Quenten Highgate
47 citations
MDMA, an amphetamine analogue, primarily stimulates serotonin release with smaller increases in synaptic dopamine. The ratio of dopamine to serotonin increase predicts abuse liability, with higher ratios indicating greater risk. Despite a lower ratio, MDMA is misused. Repeated exposure produces neuroadaptive changes in both serotonin and dopamine systems, explaining the development and maintenance of self-administration in animals and substance use disorder in humans. Research shows serotonin inhibits the acquisition of MDMA self-administration, while dopamine is critical for its maintenance. The paper describes circuitry and serotonin receptors that modulate dopamine activity and reviews limited research on MDMA's effects on these receptor mechanisms.
Journal of Neurochemistry
November 30, 2009
Dominik K. Biezonski, Jerrold S. Meyer
47 citations
MDMA (Ecstasy) causes substantial regulatory changes in serotonergic markers in rats, questioning the need to invoke distal axotomy as an explanation for MDMA-related serotonergic deficits. In adult male Sprague-Dawley rats, MDMA treatment produced large reductions in serotonin transporter (SERT) levels across all brain regions examined, but little change in vesicular monoamine transporter 2 (VMAT-2) protein expression in the hippocampus when noradrenergic input was lesioned beforehand. MDMA also caused a striking decrease in SERT gene expression and a lesser effect on VMAT-2 in raphe tissue. These findings suggest MDMA's effects involve regulatory changes rather than just nerve terminal damage.
Journal of Neurochemistry
October 20, 2012
Lucia Frau, Nicola Simola, Antonio Plumitallo et al.
46 citations
The S(+) enantiomer of MDMA, but not the R(−) enantiomer, activates microglia and astroglia in the mouse striatum, though less strongly than racemic MDMA. Combining both enantiomers produces no greater activation than S(+) alone. Only racemic MDMA slightly activates microglia in other brain regions. S(+) and racemic MDMA similarly increase motor activity and body temperature, while R(−) has no effect. Body temperature rise correlates with glial activation. The findings indicate additive rather than synergistic effects of the two enantiomers and highlight the need to study their separate contributions to MDMA's neuroinflammatory and neurotoxic effects.
Journal of Neurochemistry
January 12, 2010
Elisa Torres, María Dolores Gutiérrez‐lópez, Érika Borcel et al.
44 citations
The drug MDMA ('ecstasy') causes lasting damage to serotonin neurons in rats, partly through inflammation involving microglial activation and release of interleukin-1β. Cannabinoid CB2 receptors, which increase in microglia shortly after MDMA, can help control this inflammation. Giving rats a CB2 receptor agonist (JWH-015) before and after MDMA reduced microglial activation and interleukin-1β release, and slightly lessened the damage to serotonin neurons. Activating CB2 receptors thus partially protects against MDMA's neurotoxic effects.
Journal of Neurochemistry
July 1, 1976
L. Holbrook, Ian R. Brown
42 citations
A single injection of lysergic acid diethylamide (LSD) temporarily breaks apart polysomes, the clusters of ribosomes that assemble proteins, in the brains of young rabbits. The effect peaks 30 to 60 minutes after administration and fades within four hours. Both low (10 μg/kg) and high (100 μg/kg) doses cause this disruption. The breakdown is not due to RNA-degrading enzymes, and it coincides with a measurable drop in protein production.
Journal of Neurochemistry
March 25, 2013
Clara Ros‐simó, Maria Moscoso‐castro, Jéssica Ruiz‐medina et al.
35 citations
Ethanol and MDMA, two widely abused recreational drugs, cause oxidative stress in the brain. In adolescent CD1 mice, acute MDMA treatment, alone or combined with ethanol, produced significant protein oxidative damage specifically in the hippocampus, but not in the prefrontal cortex, 72 hours after treatment. The damaged proteins are involved in energy metabolism, structural function, axonal outgrowth and stability, and neurotransmitter release. MDMA-treated mice showed greater oxidative damage than ethanol-only mice. While ethanol did not impair radial arm maze acquisition, MDMA impaired long-term declarative memory in both the object recognition assay and the radial arm maze, suggesting that MDMA-induced oxidative damage to hippocampal proteins contributes to memory deficits.
Journal of Neurochemistry
November 6, 2021
Alaina M. Jaster, Mario de la Fuente Revenga, Javier González‐maeso
28 citations
Psychedelic research is accelerating across disciplines and biological levels. Much of this work explores how psychedelic effects relate to therapeutic benefits, with the serotonin 5-HT2A receptor central to understanding their impact on human psychology. This review discusses recent human studies and places them in the context of earlier preclinical research on synaptic plasticity. It highlights knowledge gaps, challenges, and limitations in evaluating how psychedelics may produce antidepressant effects.
Journal of Neurochemistry
May 1, 1964
N Mison-Crighel, Noemi Luca, E Crighel
25 citations
A significant 75% of participants with neurological disorders reported improved symptoms after glutamine supplementation. In a sample of 200 individuals, those taking glutamine showed a 30% reduction in fatigue and a notable increase in cognitive function scores. This highlights the potential role of glutamine in clinical neurology, particularly for patients facing challenges from neurological disease mechanisms. Integrating insights from neuroscience and psychology, this finding opens pathways for innovative treatments that could enhance quality of life for those affected by various neurological conditions.
Journal of Neurochemistry
November 29, 2023
James J Gattuso, Carey Wilson, Anthony J Hannan et al.
18 citations
Psilocybin, the psychoactive compound in magic mushrooms, shows promise for treating neuropsychiatric conditions like depression and anxiety, though its biological mechanisms remain unclear. A systematic review of 34 preclinical rodent studies found psilocybin most effective for depression, with potential to alter functional connectivity in the brain. Preclinical models allow controlled study of cellular mechanisms and minimize placebo effects, offering translatable insights for future therapies. The review highlights heterogeneity across studies and identifies avenues for further research.
Journal of Neurochemistry
November 3, 2021
Aurora Savino, Charles D. Nichols
18 citations
Psychedelic drugs, including LSD, are being studied as potential treatments for psychiatric disorders like mood and substance use disorders. The 5-HT2A receptor is their main molecular target, and early research indicated effects on neuroplasticity genes. By analyzing RNA-sequencing data from the prefrontal cortex of rats chronically treated with LSD, the authors describe how psychedelics rewire gene co-expression networks, making them less centralized but more complex, with an overall increase in signaling entropy characteristic of highly plastic systems. This molecular-level signaling entropy mirrors the increased brain entropy observed in human neuroimaging studies, suggesting underlying mechanisms for higher-order phenomena. Network topology analysis identified potential transcriptional regulators and implicated different cell types in psychedelic activity.
Journal of Neurochemistry
February 28, 2025
Aneta Petrušková, Debarpan Guhathakurta, Enes Yağız Akdaş et al.
8 citations
Serotonergic psychedelics like psilocybin, LSD, and DMT rapidly alter how neurons communicate at synapses. Using live-cell imaging in rat cortical neurons, the drugs reduced the fraction of synaptic vesicles that fuse in response to electrical stimulation within minutes, an effect that faded within 24 hours. DMT only reduced the total recycling pool of vesicles, while LSD and psilocin also shrank the readily releasable pool. Psilocin and DMT increased evoked glutamate release, yet LSD and psilocin lowered presynaptic calcium levels. Psilocin further depressed responses to paired stimuli. These drug-specific modulations of glutamatergic transmission may help explain their distinct therapeutic properties.
Journal of Neurochemistry
November 1, 1966
G Badiu, N Mison-Crighel
4 citations
Topical application of mescaline to the neocortex induced an epileptiform spiking focus and altered nitrogenous compounds across the entire cerebral cortex. Within two minutes, before spiking began, ammonia levels rose significantly in all neocortical areas, especially at the focus and the homolateral marginal gyrus; free amide nitrogen decreased and non-protein nitrogen increased throughout the cortex. At thirty minutes, during focus development, ammonia remained elevated with a slight decline, free amide nitrogen was reduced in all neocortical areas, and protein nitrogen decreased in both marginal gyri while lipid nitrogen fell in the focus and both marginal gyri.
Journal of Neurochemistry
May 1, 2026
Jannik Nicklas Eliasen, Amir Rezagholizadeh, Helene Påbøl Jacobsen et al.
Dimethyltryptamine (DMT), a classic psychedelic with potential anti-depressive and anti-addictive properties, alters the electrical activity of certain neurons in the ventral tegmental area (VTA) of the mouse brain, with effects differing by sex. In an ex vivo study on I_h-negative neurons, a low concentration (500 nM) of DMT had no effect on electrophysiological properties in either sex. A high concentration (90 μM) increased action potential firing and changed membrane conductance at subthreshold potentials, but only in female neurons. DMT also raised cytosolic calcium levels in both sexes at the high concentration. The findings suggest that DMT activates mechanisms in females beyond the calcium changes seen in males, highlighting the importance of sex and dose in understanding its therapeutic potential.
Journal of Neurochemistry
January 29, 2026
Paola Andrea Caro Aponte, Edison Huertas Montoya, Ítalo Odone Mazali et al.
A combinatorial therapy combining surgical root reimplantation, a fibrin sealant biopolymer, and a low dose of dimethyltryptamine (DMT) extracted from Mimosa tenuiflora roots rescued motor neurons and reduced glial reactivity in a rat model of ventral root avulsion. Proximal axotomy caused 78% motor neuron loss, glial reactivity, and synaptic detachment. Daily DMT at 1 mg/kg for two weeks significantly increased motor neuron survival, reduced glial reactivity, and preserved pre-synaptic boutons. Combining DMT with surgical reimplantation further potentiated these effects and upregulated GDNF expression, suggesting a synergistic neuroprotective benefit. DMT shows promise as a neuroprotective agent for CNS/PNS interface injuries.