International Journal of Molecular Sciences
January 15, 2021
Nakul Ravi Raval, Annette Johansen, Lene Lundgaard Donovan et al.
191 citations
A single psychedelic dose of psilocybin increases synaptic density and temporarily reduces serotonin 2A receptor density in the pig brain. One day after injection, hippocampal synaptic vesicle protein 2A (SV2A) density was 4.42% higher, while hippocampal and prefrontal cortex 5-HT2AR density dropped by 15.21% to 50.19%. Seven days later, SV2A density remained significantly higher in the hippocampus (+9.24%) and prefrontal cortex (+6.10%), but 5-HT2AR density had returned to baseline. These persistent synaptic changes and acute receptor down-regulation may underlie psilocybin’s antidepressant effects.
International Journal of Molecular Sciences
September 23, 2018
Domenico de Berardis, Michele Fornaro, Alessandro Valchera et al.
171 citations
Suicide remains difficult to predict despite advances in neuroscience. The World Health Organization reports one million suicide deaths annually, with one every 40 seconds. Recent genomic studies suggest genetics influence suicide risk. Combining genomic and clinical assessments has identified biomarkers for suicidal ideation involved in neural connectivity, mood, and immune response, including the mammalian target of rapamycin (mTOR) signaling pathway. This provides a neurobiological basis for drugs like ketamine, an NMDA antagonist, which has shown rapid antidepressant and anti-suicidal effects. This review examines preclinical and clinical evidence for ketamine's efficacy in treating suicidal ideation in mood disorders, addressing the neurobiological processes of suicide and potential therapeutics.
International Journal of Molecular Sciences
November 23, 2016
Danilo de Gregorio, Stefano Comai, Luca Posa et al.
125 citations
LSD produces hallucinogenic and psychotic-like effects through a complex mechanism involving multiple neurotransmitter systems. The primary action occurs in the Dorsal Raphe via the serotonergic system, where LSD acts as a partial agonist at 5-HT2A receptors and an agonist at 5-HT1A receptors. At higher doses, it also stimulates dopamine D2 receptors, Trace Amine Associated Receptor 1 (TAAR1), and 5-HT2A in the Ventral Tegmental Area. This pleiotropic mechanism, engaging serotonergic, dopaminergic, and glutamatergic pathways, makes LSD-induced psychosis a useful preclinical model for testing novel antipsychotic drugs, especially those targeting dual serotonergic and dopaminergic systems or TAAR1 receptors. More human studies are needed to clarify these mechanisms.
International Journal of Molecular Sciences
June 16, 2022
Adam Wojtas, Agnieszka Bysiek, Agnieszka Wawrzczak-Bargieła et al.
110 citations
Ketamine and psilocybin, both fast-acting antidepressants in clinical studies, increase extracellular levels of dopamine, serotonin, glutamate, and GABA in the rat frontal cortex. Psilocybin also raises GABA in the reticular nucleus of the thalamus. However, both drugs cause oxidative DNA damage—psilocybin in the frontal cortex and both drugs in the hippocampus. Psilocybin at 10 mg/kg increases NR2A glutamate receptor subunit levels. Behavioral tests 24 hours after administration show no antidepressant or anxiolytic effects; only ketamine reduces locomotor activity. The observed neurotransmitter changes may lead to genotoxicity and altered receptor levels without markedly affecting behavior.
International Journal of Molecular Sciences
March 3, 2021
František Baluška, William B. Miller, Arthur S. Reber
96 citations
Consciousness and sentience are not exclusive to animals with nervous systems but are grounded in the fundamental biology of all cells. The cellular basis of consciousness (CBC) model proposes that the excitable plasma membrane, which defines a cell's internal and external domains, is the foundation for biological awareness. This article examines the biomolecular structures and processes that enable and sustain this cellular consciousness from an evolutionary perspective, arguing that unicellular organisms like protists and algae, as well as the cells of multicellular fungi, plants, and animals, all possess a primitive form of sentience rooted in general cell biology.
International Journal of Molecular Sciences
November 16, 2022
Orr Shahar, Alexander Botvinnik, Noam Esh-Zuntz et al.
60 citations
Psilocybin and the serotonin precursor 5-HTP produce a characteristic head twitch response in mice, which is linked to the human psychedelic experience. This response depends primarily on the 5-HT2A receptor, as blocking it with M100907 reduced twitching. Activating the 5-HT1A receptor with 8-OH-DPAT also suppressed the response, while blocking the 5-HT2C receptor with RS-102221 had a bimodal effect—enhancing twitching at lower doses but reducing it at higher doses. Blocking the trace amine-associated receptor 1 (TAAR1) with EPPTB reduced 5-HTP-induced twitching but not psilocybin-induced twitching. These findings highlight multiple receptor systems that could modulate psychedelic effects and may inform therapeutic applications.
International Journal of Molecular Sciences
December 21, 2021
Agata Zięba, Piotr Stępnicki, Dariusz Matosiuk et al.
55 citations
Depression affects millions globally and current treatments are not fully curative. Recent insights into the structure and function of the serotonin 2A (5-HT2A) receptor have enabled the design of new antidepressant compounds. This review summarizes the role of 5-HT2A receptor signaling modulators in depression treatment, describes the receptor's structural and physiological features, and overviews recent virtual screening campaigns that identified novel 5-HT2A receptor ligands, along with data on newly synthesized ligands acting through this protein.
International Journal of Molecular Sciences
November 15, 2022
Klára Gotvaldová, Jan Borovička, Kateřina Hájková et al.
50 citations
Wild mushrooms that contain psilocybin also carry several other tryptamine alkaloids in highly variable concentrations, making their effects unpredictable compared to pure psilocybin. Using ultra-high performance liquid chromatography with tandem mass spectrometry, researchers measured psilocybin, psilocin, baeocystin, norbaeocystin, and aeruginascin in 226 fruiting bodies from 82 collections across seven genera. Psilocybe species had the highest psilocybin and psilocin levels, but no tryptamines were detected in Psilocybe fuscofulva or Psilocybe fimetaria. For many species, concentrations of baeocystin, norbaeocystin, and aeruginascin were reported for the first time. The extreme variability in tryptamine content poses a risk of overdose for consumers and complicates interpretation of medicinal effects compared to chemically pure psilocybin.
International Journal of Molecular Sciences
December 4, 2020
Sara Malaca, Alfredo Fabrizio Lo Faro, Alice Tamborra et al.
48 citations
Tryptamines are 5-HT2A receptor agonists that alter perceptions of reality. Their prevalence in drug overdoses is low but increasing, yet they are not part of typical toxicology testing, so their contribution may be underestimated. From 2015 to 2020, 22 new analytical methods, primarily liquid chromatography tandem mass spectrometry, were developed to identify tryptamines and metabolites in biological samples. The most prevalent tryptamines are 5-MeO-DiPT, 5-MeO-DALT, and DMT. Morbidity from tryptamine intake is considerable, and clinicians and laboratorians need updated data on this public health threat.
International Journal of Molecular Sciences
January 10, 2023
Andrea Mastinu, Margrate Anyanwu, Marinella Carone et al.
45 citations
Psychedelic compounds such as psilocybin and LSD are being reexamined as potential treatments for psychiatric disorders like depression, obsessive-compulsive disorder, and post-traumatic stress disorder, though clinical results remain unclear and definitive. The mechanisms of action of these molecules are not fully understood. This review summarizes the ethnobotanical uses of well-known psychedelic plants and the pharmacological mechanisms of their active ingredients. It provides an overview of structural and computational studies on the binding of ibogaine, mescaline, DMT, psilocin, and LSD to biological receptors. Recent clinical studies evaluating psychedelics in psychiatric disorders are compared with existing therapies.
International Journal of Molecular Sciences
February 23, 2021
Jiří Patočka, Ran Wu, Eugenie Nepovimová et al.
45 citations
Mushroom poisoning remains a global health concern, with numerous annual reports of poisonous mushroom ingestion. This review focuses on the genus Inocybe, which contains toxic substances such as muscarine, psilocybin, psilocin, aeruginascin, lectins, and baeocystin. The article summarizes the chemistry, toxic effects, and mechanisms of these major toxins, particularly muscarine, psilocybin, and psilocin, drawing on previously published toxicity data from different species and administration routes. It also discusses treatment options and potential medical applications of these bioactive compounds, aiming to improve understanding of Inocybe toxicology and support future clinical benefits.
International Journal of Molecular Sciences
December 5, 2024
Simone Pardossi, Andrea Fagiolini, Alessandro Cuomo
43 citations
Brain-derived neurotrophic factor (BDNF) supports neuroplasticity and neuronal survival, and its expression is reduced in depression-related brain regions. This narrative review summarizes human studies of BDNF changes in patients treated with ketamine or esketamine. Traditional antidepressants can increase BDNF levels, and ketamine and esketamine produce rapid antidepressant effects partly through glutamate pathways and neurotrophic mechanisms involving BDNF. Clinical findings are mixed; most studies report increased plasma BDNF after intravenous ketamine, but some contradict this. Few studies examine BDNF and esketamine. More research with larger samples and intranasal esketamine, approved for treatment-resistant depression, is needed.
International Journal of Molecular Sciences
September 28, 2022
Dominika Psiuk, Emilia Magdalena Nowak, Natalia Dycha et al.
36 citations
A systematic review of 12 studies examined two psychoactive compounds, psilocybin and esketamine, for treating depression. Esketamine, a laboratory-made substance, showed significant reduction in depressive symptoms and suicidal ideation shortly after intake and after one month, compared to baseline and standard antidepressants. Psilocybin, a naturally occurring psychedelic, produced antidepressant effects one day after intake and after 6–7 weeks, with benefits lasting up to 6 or 8 months. One study suggested psilocybin's effects are comparable to and may be superior to escitalopram. Both compounds demonstrated rapid and sustained effects, indicating potential as novel antidepressant agents after addressing limitations.
International Journal of Molecular Sciences
July 31, 2021
Karolina E. Kolaczynska, Jan Thomann, Marius C. Hoener et al.
35 citations
Pyrovalerone cathinones, a class of potent psychoactive substances, were tested for their effects on monoamine transporters and receptors. All tested compounds strongly inhibited the dopamine and norepinephrine transporters, with IC50 values in the low micromolar range, but showed no activity at the serotonin transporter at concentrations below 10 µM. None of the substances triggered monoamine efflux. Two compounds, 4F-PBP and NEH, were particularly selective for the dopamine transporter, suggesting they likely produce strong psychostimulant effects and have high abuse potential. Extending the alkyl chain increased inhibition potency at dopamine and norepinephrine transporters, while a 3,4-methylenedioxy group enhanced serotonin transporter inhibition.
International Journal of Molecular Sciences
December 17, 2020
Veronica Cocchi, Sofia Gasperini, Patrizia Hrelia et al.
32 citations
Several psychedelic and stimulating phenethylamines, including 2C-H, 2C-I, 2C-B, and 25B-NBOMe, but not MDMA, damaged DNA in a human cell line (TK6 cells). The genetic damage was detected as an increase in micronucleus frequency. All genotoxic substances also elevated reactive oxygen species (ROS) levels, suggesting ROS production as a likely mechanism. Even at doses that do not cause immediate severe harm, exposure to these substances may still pose long-term risks through genotoxicity.
International Journal of Molecular Sciences
February 24, 2022
Emőke Borbély, Viktória É Varga, Titanilla Szögi et al.
31 citations
Alzheimer's disease (AD), the most common form of dementia, involves cognitive decline. Two sigma-1 receptor (S1R) agonists, dimethyltryptamine (DMT) and PRE084, were tested in a mouse model of AD induced by amyloid-beta (Aβ). DMT, which also binds strongly to serotonin receptors, reduced neurogenesis, likely due to its mixed receptor activity. In contrast, the highly selective S1R agonist PRE084 increased hippocampal cell proliferation and differentiation. Both DMT and PRE084 significantly reduced astrogliosis (a marker of neuroinflammation) caused by Aβ, but neither affected microglial activation. The findings suggest that selective S1R agonists like PRE084 may be promising therapeutic agents for AD, though further research is needed.
International Journal of Molecular Sciences
October 26, 2020
Motohiro Okada, Yasuhiro Kawano, Kouji Fukuyama et al.
31 citations
Ketamine, an NMDAR antagonist, has been approved for treatment-resistant depression despite its schizophrenia-like side effects. It improves anhedonia, suicidal ideation, and bipolar depression where conventional antidepressants fail. The antidepressant dose is comparable to that producing psychotic symptoms, and psychotropic effects precede antidepressant effects. Repeated administration is often needed but carries risks of abuse and memory deficits. The article reviews clinical evidence for NMDAR antagonists and the temporal mechanisms underlying ketamine's schizophrenia-like and antidepressant-like effects, also discussing rodent pharmacological studies.
International Journal of Molecular Sciences
October 2, 2021
Paul J. Fitzgerald
30 citations
Many drugs of abuse, including stimulants, opioids, psychedelics, and alcohol, may be directly converted in the body into catecholamines—dopamine, norepinephrine, and epinephrine—rather than merely modulating these neurotransmitter systems through receptor binding. This hypothesized transformation could explain both the intoxicating effects and the physiological side effects (elevated heart rate, blood pressure, rapid breathing, increased temperature, sweating, and dilated pupils) typically associated with these substances. If correct, this would revise understanding of catecholamine biosynthesis and the neural basis of substance abuse, dependence, and stress-induced relapse. The hypothesis can be tested by administering stable isotope-labeled drugs to rodents or humans and detecting labeled catecholamines in brain, blood, or urine using liquid chromatography-mass spectrometry.
International Journal of Molecular Sciences
June 20, 2024
Hana Shafique, Julie C Demers, Julia Biesiada et al.
29 citations
NMDA receptor antagonists show promise for neurological and psychiatric conditions such as neurodegenerative diseases, epilepsy, traumatic brain injury, substance use disorder, and major depressive disorder. (S)-ketamine was the first rapid-acting antidepressant approved for medical use. Its stereoisomer, (R)-ketamine (arketamine), is under development for treatment-resistant depression and has shown efficacy in multiple animal models. Two clinical studies reported efficacy in treatment-resistant depression and bipolar depression, though a sponsor study failed to meet primary endpoints; post hoc analysis indicated efficacy. (R)-ketamine is less sedating, produces fewer psychotomimetic or dissociative effects, and has lower abuse potential than (S)-ketamine. Its antidepressant mechanisms may involve NMDA receptor antagonism and non-NMDA receptor pathways. Further clinical research may lead to improved treatments for underserved neurological and psychiatric disorders.
International Journal of Molecular Sciences
April 18, 2020
Xun Zhou, Jamal Bouitbir, Matthias E. Liechti et al.
29 citations
Halogenating amphetamines and methcathinones at the para position increases their neurotoxic properties. In lab-grown SH-SY5Y cells, 4-fluoroamphetamine (4-FA), 4-chloroamphetamine (PCA), and 4-chloromethcathinone (4-CMC) reduced cellular energy (ATP) and damaged plasma membranes, with differentiated cells less sensitive than undifferentiated ones. The order of toxicity was chloride > fluoride > hydrogen for both drug families. These compounds also lowered mitochondrial membrane potential, disrupted the electron transport chain, raised reactive oxygen species, and triggered apoptosis via the intrinsic pathway. Although the toxic concentrations exceeded those needed for psychoactive effects, the findings raise concerns about uncontrolled recreational use of these designer drugs.
International Journal of Molecular Sciences
February 15, 2023
Martina di Bartolomeo, Tibor Stark, Serena di Martino et al.
23 citations
Rats exposed to the toxin methylazoxymethanol acetate (MAM) before birth or to THC shortly after birth showed adult behaviors resembling schizophrenia, such as social withdrawal and memory problems, along with increased expression of cannabinoid and dopamine receptor genes in the prefrontal cortex linked to DNA methylation changes. Giving THC during adolescence impaired social behavior in otherwise healthy rats but did not worsen the schizophrenia-like traits in rats already exposed to THC after birth. In rats exposed to MAM before birth, adolescent THC paradoxically reversed their memory deficit by altering dopamine receptor gene expression. The effects of adolescent THC exposure appear to depend on individual differences in dopamine signaling.
International Journal of Molecular Sciences
August 31, 2024
Beldisa Taflaj, Nunzia La Maida, Roberta Tittarelli et al.
22 citations
New psychoactive substances (NPSs) are diverse drugs sold as legal substitutes for controlled drugs, and their psychiatric consequences are not well understood. A review of 109 NPS-related intoxication cases published between 2013 and 2024 found that synthetic cannabinoids were the most common cause of acute or chronic psychiatric symptoms, followed by synthetic cathinones, hallucinogens, natural NPSs, and stimulants. The most frequent acute symptoms included hallucinations, aggressiveness, and psychotic or bizarre behavior, linked to neurotransmitter imbalances in the central nervous system. The absence of clear diagnostic criteria and toxicological analyses complicates psychiatric diagnosis; implementing toxicological screening in emergency rooms and follow-up care is recommended.
International Journal of Molecular Sciences
November 23, 2022
Lourdes Poyatos, Alfredo Fabrizio Lo Faro, Diletta Berardinelli et al.
22 citations
After controlled oral doses of 50–200 mg methylone given to 12 male volunteers, plasma concentrations increased in proportion to dose. Maximum concentrations ranged from 153 ng/mL at the lowest dose to 604 ng/mL at the highest dose. The drug was absorbed rapidly, reaching peak levels in 1.5–2 hours, and had a half-life of about 6 hours. Its metabolite HMMC reached peak concentrations 10–14 times lower than methylone. Unlike MDMA, methylone showed linear pharmacokinetics across the dose range. A validated LC-MS/MS method was used to measure methylone, MDMA, and their metabolites in plasma.
International Journal of Molecular Sciences
March 12, 2019
Stefania Schiavone, Margherita Neri, Angela Bruna Maffione et al.
22 citations
MDMA (ecstasy) neurotoxicity may involve nitrosative stress driven by the enzyme iNOS rather than by NOX enzymes that produce reactive oxygen species. In rats given MDMA, iNOS expression increased, and cells positive for 3-nitrotyrosine (a marker of nitrosative damage) rose in the frontal cortex. No changes occurred in NOX2, NOX1, or NOX4 immunoreactivity or in the oxidative stress marker 8OHdG. MDMA and nitrosative markers colocalized with dopamine-transporter-positive cells, which were neurons, not microglia or astrocytes. The findings indicate that iNOS-derived nitrosative stress, not NOX enzymes, likely contributes to MDMA-induced neurotoxicity.
International Journal of Molecular Sciences
March 27, 2025
Blerida Banushi, Jemma Collova, Helen Milroy
19 citations
Trauma can affect individuals within a single generation and also pass to future generations through a mix of biological and environmental factors. This review describes epigenetic mechanisms linked to trauma's transmission, such as DNA methylation, histone modifications, and non-coding RNAs, which regulate stress-related genes like NR3C1 and FKBP5. While animal studies suggest possible epigenetic pathways for intergenerational effects, applying these to humans is difficult due to confounding variables, methodological limits, and ethical concerns. Emerging therapies, including psychedelic-assisted treatments and mind-body interventions, may address both psychological and epigenetic aspects of trauma. Enriched environments, cultural reconnection, and psychosocial interventions also show promise. The review emphasizes interdisciplinary approaches to break cycles of trauma and foster resilience.