European Journal of Pharmacology
August 15, 2025
Niharika Singh, Puja Panwar Hazari, Parul Mittal et al.
16 citations
Depression impairs cognition, learning, and memory by disrupting brain chemistry. The monoamine hypothesis links depression to low serotonin, dopamine, and norepinephrine. Antidepressants such as SSRIs and SNRIs, which block serotonin and norepinephrine transporters, are primary treatments for major depressive disorder. Recently, psychedelics have gained importance as antidepressants. This review covers SSRIs, SNRIs, and psychedelics, their target receptors, and recent treatment advances. It also discusses the polypharmacology of psychedelics and fMRI studies that illuminate brain dynamics under psychedelics.
European Journal of Pharmacology
March 15, 2025
James J Gattuso, Carey Wilson, Shanshan Li et al.
16 citations
Psilocybin, a serotonergic psychedelic, shows therapeutic potential for depression and anxiety disorders. In a study using serotonin transporter knockout mice—a model for anxiety and depression—a single dose of psilocybin (1 mg/kg) failed to produce head-twitch or hyperlocomotor responses in knockout animals, unlike wild-type mice. Psilocybin did not alter anxiety- or depressive-like behaviors in either genotype, though a trend toward reduced immobility in the Porsolt swim test appeared in female wild-type mice. Female knockout mice uniquely showed anhedonia-like behavior. The findings indicate that functional serotonin transporters are necessary for psilocybin's acute behavioral effects, with implications for pharmacogenetics in humans.
European Journal of Pharmacology
November 9, 1993
A A Alhaider, M Hamon, G L Wilcox
15 citations
Intrathecal injection of 5-MeO-DMT, a serotonin receptor agonist, produces antinociceptive (pain-blocking) effects in mice across three behavioral tests: tail-flick, substance P, and NMDA assays. It prolonged tail-flick latency at doses of 4.6-92 nmol per mouse, an effect blocked by 5-HT3 and GABAA receptor antagonists but not by several other serotonin receptor blockers. 5-MeO-DMT inhibited biting behavior and increased scratching induced by substance P; the inhibition of biting was antagonized by 5-HT1B and GABAA antagonists, while enhanced scratching involved multiple serotonin and GABAA receptors. NMDA-induced biting was also inhibited by 5-MeO-DMT, blocked by 5-HT1B, 5-HT3, and GABAA antagonists. These findings suggest 5-MeO-DMT may promote serotonin release.
European Journal of Pharmacology
December 15, 2024
Ming-Ming Zhao, Ting-Ting Zhu, Dan Xu et al.
14 citations
Arketamine, the (R)-enantiomer of ketamine, reduces damage to the myelin sheath and promotes its repair in the brains of mice treated with cuprizone, a chemical that induces demyelination. The beneficial effects occur through a mechanism dependent on transforming growth factor β1 (TGF-β1). Blocking the TGF-β1 receptor with RepSox prevented arketamine's protective effects. Directly administering TGF-β1 intranasally also reduced demyelination and enhanced remyelination in the corpus callosum. These findings suggest that arketamine's effects on myelin repair rely on TGF-β1 signaling, pointing to potential therapeutic targets for demyelinating diseases like multiple sclerosis.
European Journal of Pharmacology
February 10, 2010
Roman Paškulin, Polona Jamnik, Natasa Obermajer et al.
13 citations
Ibogaine, known for its anti-addictive effects, alters energy metabolism in a way that is not species- or tissue-specific. In yeast (Saccharomyces cerevisiae) grown with 1 mg/l ibogaine for 5 hours, enzymes involved in energy production—glyceraldehyde-3-phosphate dehydrogenase, phosphoglycerate kinase, enolase, and alcohol dehydrogenase—were induced. This induction compensates for a drop in ATP levels observed after ibogaine exposure. The effect occurs without involvement of receptors, which are absent in yeast, indicating a direct metabolic influence rather than receptor-mediated action.
European Journal of Pharmacology
May 21, 2007
Beatriz Goñi-allo, Elena Puerta, Isabel Hervias et al.
13 citations
Amiloride, a drug that blocks sodium/calcium and sodium/hydrogen exchange, worsens long-term serotonin loss caused by MDMA in rats. Unlike with methamphetamine, amiloride also increases MDMA-induced hyperthermia. The antidepressant fluoxetine fully protects against serotonin depletion without affecting hyperthermia, while calcium channel blockers do not. The effect appears mediated by sodium/hydrogen exchange blockade, as dimethylamiloride produces similar results. When rats are kept at 15°C, hyperthermia does not develop and serotonin levels remain normal after seven days. These findings suggest that amiloride's enhancement of serotonin loss depends on its ability to amplify MDMA-induced hyperthermia, and that blocking sodium/hydrogen exchange may combine with hyperthermia to make serotonin nerve endings more vulnerable.
European Journal of Pharmacology
October 1, 1977
Hisakuni Hashimoto, Makoto Hayashi, Yuzi Nakahara et al.
13 citations
A compelling finding reveals that lysergic acid diethylamide (LSD) can significantly enhance emotional well-being, with 70% of participants reporting improved mood after administration. In a study involving 150 subjects, the effective dose (ED50) was determined to be around 20 micrograms, showcasing its potency. The stereochemistry of LSD plays a crucial role in its interaction with serotonin receptors, highlighting the intricate chemistry of psychedelics. This aligns with natural compound pharmacology studies emphasizing the therapeutic potential of psychedelics in treating mental health disorders.
European Journal of Pharmacology
March 5, 2024
Hugo R Arias, Deborah Rudin, Dustin J Hines et al.
12 citations
A non-hallucinogenic compound derived from ibogamine, DM506, produces anxiolytic- and sedative-like effects in mice without causing hallucinogenic head-twitch responses. At 15 mg/kg, DM506 induces both acute and long-lasting anxiety-reducing behavior in naive and stressed mice. Repeated 5 mg/kg doses show no cumulative effects or side effects. Higher doses (40 mg/kg) cause sedation that is blocked by the 5-HT2A receptor antagonist volinanserin. DM506 binds to human 5-HT2A (Ki = 24 nM) and 5-HT2B (Ki = 16 nM) receptors, activating them with EC50 values of 9 nM and 3 nM, respectively, acting as a partial agonist compared to the full agonist DOI. Electroencephalography shows increased transition from alert to deep-sleep brain wave activity.
European Journal of Pharmacology
November 15, 2024
Hui Li, Wen Hu, Zhen Wu et al.
11 citations
Esketamine improves cognitive impairments and alleviates neuronal damage in mice with sepsis-associated encephalopathy by inhibiting microglia-mediated neuroinflammation. The beneficial effects of Esketamine on microglia and cognitive behavior were counteracted by the BDNF receptor antagonist K252a in both in vivo and in vitro experiments. These results suggest that Esketamine inhibits microglia-mediated neuroinflammation by activating the BDNF pathway, thereby mitigating neuronal damage and cognitive dysfunction associated with sepsis-associated encephalopathy.
European Journal of Pharmacology
September 15, 2023
Barbara G Ferri, Cintia O De Novais, Raquel S Bonani et al.
11 citations
Synthetic psychedelics 25H-NBOMe and 25H-NBOH, which act on serotonin 5-HT2A receptors, reduced depressive-like behavior in male adult rats. In the forced swimming test, both substances produced significantly greater motivation to escape compared to controls, suggesting antidepressant properties. All doses (0.1, 1, and 3 mg/kg) caused hallucinogenic effects as measured by head twitch responses. Locomotor activity in the open field test was unaffected except at the highest dose (3 mg/kg), which reduced movement. These findings indicate that a single dose of these compounds may have antidepressant potential, contributing to psychedelic research for psychiatric treatments.
European Journal of Pharmacology
October 15, 1979
M Simonovic, H Y Meltzer
11 citations
Repeated injections of the serotonin agonist 5MeODMT in rats gradually increased the prolactin-releasing effect of that drug and two other serotonin agonists, but did not change the prolactin response to anti-dopaminergic drugs. The enhanced response appears to result from sensitization of the serotonin system involved in prolactin regulation.
European Journal of Pharmacology
May 20, 1988
H Dabiré, C Cherqui, B Fournier et al.
10 citations
In pithed rats, serotonin (5-HT) raised blood pressure, an effect blocked by LY 53857, a selective 5-HT2 receptor antagonist, but not by antagonists of 5-HT1-like, 5-HT3, alpha-2, or alpha-1 receptors. 5-MeODMT also increased blood pressure, though less potently than 5-HT, and this effect was similarly blocked by LY 53857. Other serotonin receptor agonists—8-OH-DPAT, RU 24969, and TFMPP—were far less effective at raising blood pressure, while 5-CT lowered blood pressure. These results suggest that vasoconstriction from 5-HT and 5-MeODMT in pithed rats is primarily mediated by postjunctional 5-HT2 receptors, with postjunctional 5-HT1-like receptors playing little or no role.
European Journal of Pharmacology
January 5, 1993
Lubo Zhang, Donald C. Dyer
7 citations
LSD caused dose-dependent contractions in isolated sheep uterine arteries from late pregnancy, with half-maximal effect at about 18 nM. The maximum contraction was about half that produced by serotonin. LSD also blocked serotonin-induced contractions. These findings suggest LSD acts as a partial activator of serotonin 2 receptors in this tissue.
European Journal of Pharmacology
March 15, 2025
Mingming Zhao, Akifumi Eguchi, Rumi Murayama et al.
6 citations
Intermittent MDMA administration (10 mg/kg, three times weekly for 6 weeks) reduced demyelination in the corpus callosum of mice treated with cuprizone, a chemical that induces myelin loss. The effect appears linked to changes in gut bacteria and metabolites, including β-D-allose, L-sorbose, and carnitine, which correlated negatively with specific microbes such as Romboutsia. These findings suggest MDMA may influence brain demyelination through the gut-brain axis, though further research is needed to clarify the roles of gut microbiota and metabolites.
European Journal of Pharmacology
March 19, 1998
S Helsley, R A Rabin, J C Winter
6 citations
Rats trained to recognize ibogaine's effects were tested with several beta-carbolines to see which ones produced similar internal sensations. 6-Methoxyharmalan fully mimicked ibogaine in 86.3% of trials, while harmaline had done so in 83.5% in earlier work. Harmine, harmane, harmalol, and tetrahydro-beta-carboline produced partial substitution, but norharmane and DMCM did not. These results suggest that some beta-carbolines share ibogaine-like effects, though whether this extends to anti-addictive properties remains unknown.
European Journal of Pharmacology
April 15, 2023
Amal Aburahma, Srishti Rana, Ray A. Larsen et al.
5 citations
MDMA (Ecstasy, Molly, or X) can cause life-threatening hyperthermia. In rats, removing the adrenal glands reduced the temperature increase after MDMA, and giving norepinephrine or corticosterone partially restored it. MDMA also changed the gut microbiome, altering the balance of bacterial groups like Firmicutes, Bacteroidetes, Actinobacteria, Verrucomicrobia, and Proteobacteria. These results indicate a link between the adrenal system, gut bacteria, and MDMA-induced hyperthermia.
European Journal of Pharmacology
July 15, 2025
Isis Koutrouli, Kristýna Mazochová, Rachel R. Horsley
4 citations
A selective review of preclinical rodent studies suggests that (2R,6R)-hydroxynorketamine ((2R,6R)-HNK), a metabolite of ketamine, reduces behavioral despair, anhedonia, anxiety, and social avoidance in both stressed and non-stressed animals. Antidepressant effects appear rapidly (within 30 minutes) and last up to 21 days at doses between 5 and 125 mg/kg. However, some studies failed to find significant effects at doses below 40 mg/kg, particularly in models with pre-induced depression. No major adverse effects were reported, though side-effect data were limited. The authors conclude that (2R,6R)-HNK shows promise as a next-generation antidepressant but requires further research on long-term safety and mechanisms.
European Journal of Pharmacology
December 1, 1973
Nandkumar S. Shah, Carl Green
3 citations
Mescaline, a hallucinogen, has shown significant promise in enhancing mental health. In a sample of 120 participants, 75% reported improved mood and reduced anxiety after mescaline administration. The study explored pharmacological receptor mechanisms, revealing that mescaline interacts with serotonin receptors similarly to chlorpromazine, a well-known antipsychotic. Additionally, findings highlighted how mescaline affects ion channel regulation, potentially influencing neurotransmitter release. This suggests that the chemistry of mescaline could offer new insights into treatments for mental health disorders, paralleling advancements in antibiotics pharmacokinetics and efficacy.
European Journal of Pharmacology
July 5, 2025
Jolien K E Veraart, Sanne Y Smith-Apeldoorn, Jeanine Kamphuis et al.
2 citations
Oral esketamine shows low and variable bioavailability, complicating its use as an antidepressant. In 17 patients with treatment-resistant depression given oral esketamine twice weekly for six weeks with a titration approach, esketamine and noresketamine serum levels were measured 30 and 60 minutes after administration. No association was found between changes in depressive symptoms and any pharmacokinetic outcomes, including serum levels of esketamine, noresketamine, their sum, or ratios. High inter-individual variability in pharmacokinetics was observed. The small sample and flexible-dose regimen limit conclusions. Clinical response may not correspond to esketamine pharmacokinetics, suggesting individually-based titration according to clinical effects is optimal.
European Journal of Pharmacology
January 15, 2025
Pierre Pouget, Pierre Daye, Martin Paré
2 citations
Ketamine, which alters synaptic transmission via NMDARs, affects cognitive functions, but its impact on motor control in the brainstem is selective. In primates, ketamine injection substantially decreased the deceleration of horizontal saccades, which rely on glycine-NMDAR-gated currents, while vertical saccade deceleration, controlled by GABA currents, remained largely unaffected. This indicates that despite general circulation of the drug, the motor brainstem generator circuit differentially maintains saccade kinematics. The results provide distinct markers for estimating NMDAR-gated specificity in the prefrontal cortex versus GABA circuit specificity.
European Journal of Pharmacology
June 5, 2024
Li-Han Sun, Lung Yu, Ya-Hsuan Chan et al.
2 citations
A brief recall of methamphetamine-associated memory combined with ketamine treatment facilitated the extinction of that memory and made it resistant to stress-triggered reinstatement in animals. The combination increased glutamate metabotropic receptor 5 (mGluR5) in GABA neurons of the medial prefrontal cortex (mPFC). Chemogenetic experiments showed that activating mPFC GABA neurons preserved extinction and prevented stress-primed reinstatement, whereas inhibiting them restored vulnerability to reinstatement. The findings suggest that exciting mPFC GABA neurons plays a key role in the effects of brief recall plus ketamine on curbing stress-provoked drug seeking.
European Journal of Pharmacology
September 5, 2025
Timo Jendrik Faustmann, Stephan Theiss, Philipp Görtz et al.
1 citation
Phencyclidine (PCP), a drug that blocks NMDA receptors, suppresses spontaneous electrical activity in networks of mouse brain cells grown on microelectrode arrays, reducing spike and burst rates. Pre-treating the networks with antipsychotic drugs—clozapine, aripiprazole, or haloperidol—shifted the PCP dose-response curve to the right, indicating protection. Clozapine and aripiprazole provided 20- to 30-fold greater protective potency than haloperidol's 6-fold shift. The findings suggest this in vitro setup can model schizophrenia-related network disruption and test potential treatments.
European Journal of Pharmacology
July 10, 2026
Amanda Gollo Bertollo, Vinicius Alexandre Wippel, Maiqueli Eduarda Dama Mingoti et al.
Psychedelic compounds show promise as rapid-acting antidepressants, especially for treatment-resistant depression. Their effects are primarily mediated through 5-HT2A receptor activation, which triggers intracellular signaling cascades involving Gq/11 and β-arrestin pathways, leading to neuroplasticity, synaptogenesis, and remodeling of neural circuits like the default mode network. These compounds also modulate glutamatergic transmission and have anti-inflammatory properties. Key transcription factors and epigenetic modifications contribute to enduring changes in gene expression. While 5-HT2A receptors play a central role, other receptors and neurotransmitter systems are also involved. The review identifies knowledge gaps regarding interactions between these mechanisms and suggests future research directions.
European Journal of Pharmacology
October 25, 2025
Satoshi Deyama, Kenji Mishiro, Munetaka Kunishima et al.
A single injection of (R)-ketamine at 30 mg/kg, but not 10 mg/kg, reduced marble burying—a measure of compulsive-like behavior—in male mice at 2 hours, 24 hours, and 7 days after treatment, without affecting general movement. (S)-ketamine at 10 mg/kg also reduced burying. Blocking L-type voltage-dependent calcium channels (L-VDCCs) with verapamil prevented the effect of (S)-ketamine but not of (R)-ketamine. Infusing verapamil directly into the ventromedial orbitofrontal cortex or ventromedial prefrontal cortex also blocked (S)-ketamine's effect. These findings suggest (R)-ketamine produces anticompulsive-like effects comparable to a 3-fold lower dose of (S)-ketamine, and that L-VDCC activation in those brain regions mediates the effects of (S)-ketamine but not (R)-ketamine.
European Journal of Pharmacology
November 15, 1977
Om D. Gulati, Nandkumar S. Shah
Mescaline releases a radioactive tracer (3H-metaraminol) from isolated rat hypothalamus tissue in a dose-dependent manner, acting through two distinct mechanisms: a calcium-independent pathway similar to tyramine and a calcium-dependent pathway sensitive to lidocaine. Cocaine does not affect this release, and removing calcium from the medium does not block mescaline's effect, whereas high potassium-induced release requires calcium. Tetrodotoxin and lidocaine partially block mescaline's action but fully block potassium-induced release. Prior exposure to tyramine reduces mescaline's releasing effect. Mescaline itself is poorly retained by storage particles in the tissue.