Table 1 Effects of rapid-acting antidepressant on DNA methylation, histone post-translational modifications, and ncRNAs.

The extent of decreases of the lncRNA FEDORA predicts the decrease in depression symptoms severity following a single ketamine administration in female (but not male) individuals with major depressive disorder (MDD)

The lncRNA FEDORA could be used as a marker of therapeutic response to ketamine in individuals who identify as female

[167]

An infusion of ketamine in individuals with treatment-resistant depression 24 hours after the first administration does not affect whole blood miRNA levels

Ketamine does not affect blood miRNA 24 hours after administration in individuals with treatment-resistant depression. The discrepancy from clinical findings might be due to the relatively small sample size, the fact that the samples were collected 24 hours after the first infusion, or the fact that whole blood was analyzed. Rapid-acting antidepressants might elicit cell type-specific miRNome fingerprints not detectable in whole blood

[162]

Deceased individuals that tested positive for ketamine have an acceleration in the mitochondrial epigenetic age of the nucleus accumbens and PFC

Ketamine abuse might accelerate the mitochondrial DNA epigenetic age

[216]

In clinical studies in individuals with neuropathic pain, ketamine differentially modulated miRNAs expression in responders and non-responders. The responder status could be predicted based on the lower pretreatment level of miR-548d-5p, which targets the UGT1A1 (UDP Glucuronosyltransferase Family 1 Member A1) gene

Ketamine elicits miRNA changes in individuals with neuropathic pain. Specific miRNAs could predict the therapeutic response to rapid-acting antidepressants

[160]

Poor responders to ketamine have considerable downregulation of circulating miR-605. Downregulating miR-605 leads to increased CXCL5 (C-X-C Motif Chemokine Ligand 5), and increased inflammation

miR-605-mediated regulation of CXCL5 predicted the treatment response to ketamine in complex pain regional syndrome

[161]

Ketamine enhances fear extinction via decreasing the stress-induced hypermethylation of Bdnf (Brain-Derived Neurotrophic Factor) exon IV (involved with traumatic memory extinction). This effect is accompanied by increased exon IV and IX transcription in the medial prefrontal cortex (PFC) and hippocampus

The therapeutic effects of ketamine in post-traumatic stress disorder (PTSD), depression, and suicidality might be mediated at least partially by decreased BDNF promoter methylation leading to increased expression in the PFC and hippocampus

[49]

Ketamine elicits antidepressant-like effects via activating cAMP Responsive Element Binding Protein 5 (CREB)-mediated BDNF exon VI transcription, putatively in the PFC microglia. Ketamine decreases the levels of methyl-CpG binding protein 2 (MeCP2), a transcriptional repressor of BDNF

The synaptogenic and antidepressant effects of ketamine might be mediated at least partially via the epigenetic regulation of CREB-BDNF exon IV transcription in the PFC microglia

[62]

Ketamine reverses the increase in chronic pain-induced hippocampal mRNA and protein levels of the DNA methyltransferase (DNMT) 1, 3a, and 3b. Ketamine restores the chronic pain-induced decrease in total BDNF and BDNF exon I transcription and protein level. Ketamine normalizes the pain-induced increase in pro-BDNF mRNA and protein levels

The therapeutic effects of ketamine in chronic pain-induced depressive states might be mediated by a DNMT-mediated restoration of BDNF expression

[52]

Ketamine normalizes the stress-induced enhancement of adult nucleus accumbens histone deacetylase (HDAC) activity in a model of early-life stress, similarly to imipramine. Ketamine has no effect on PFC, hippocampal, and amygdalar HDAC activity

The therapeutic effects of ketamine on the pathophysiological sequelae of early-life stress might be partially mediated by a reduction of the stress-induced enhanced accumbal HDAC activity

[7]

Ketamine enhances HDAC5 phosphorylation at the sites S259 and S498 in a Ca²⁺ /Calmodulin-Dependent Protein Kinase II (CaMKII)- and Polycystic Kidney Disease (PKD)-dependent fashion in hippocampal neurons, leading to the cytoplasmic export of HDAC5, histones H3 and H4 acetylation, Myocyte Enhancer Factor 2 (MEF2)-mediated transcription, and Eukaryotic Translation Initiation Factor 4E Binding Protein (eIF4EBP) and CREB activation. Ketamine elicits a sustained ( > 24 h) increase of HDAC5 phosphorylation in the hippocampus, and a sustained transcriptional modulation of MEF2-target genes (Activity Regulated Cytoskeleton Associated Protein -Arc-, Nuclear Receptor Subfamily 4 Group A Member 1 -Nurr77-, KLF Transcription Factor 6 -Klf6-, and Early Growth response 1 (Egr1). Blocking HDAC5 phosphorylation nullifies the antidepressant-like effects of ketamine

Ketamine-induced, AMPA-mediated enhanced hippocampal HDAC5 phosphorylation upregulates the cytoplasmic export of HDAC5 and this step is required to elicit antidepressant-like effects in rodents

[97]

Ketamine downregulates the increased HDAC1 and HDAC5 protein expressions in the hippocampus of rats elicited by Diisopropyl Fluorophosphate, and increases BDNF levels and dendritic spine density. Ketamine restores the decreased H3K9 acetylation of the BDNF promoter IV elicited by Diisopropyl Fluorophosphate

Ketamine elicits pro-histone acetylating effects and restores neuroplasticity in a mouse model of Gulf War Illness

[95]

High-dose ketamine has a prophylactic effect on the stress-induced increase in hippocampal histone H3 lysine 9 (H3K9) methylation

Ketamine and potentially other rapid-acting antidepressants might have prophylactic effects against stress-induced epigenetic changes

[96]

Ketamine increases miR-98-5p, but not miR-23a-5p and miR-3968 in the PFC and hippocampus of chronically stressed mice. miR-98-5p inhibition nullifies the antidepressant-like effects of ketamine

miR-98-5p upregulation is required for the antidepressant-like effects of ketamine

[143]

Ketamine modulates several hippocampal miRNAs, eliciting a decrease in miR-206 and miR-181a-5p (involved in apoptosis), and an increase in miR-132-3p and miR-29a-3p (involved in N-Methyl-D-Aspartate -NMDA- mediated neuronal survival and neurite remodeling).

These effects are accompanied by a dose-dependent increase of BDNF levels in vivo and in vitro, and decreased apoptosis and electrical currents in hippocampal neuronal cultures

Ketamine-induced miRNA modulation decreases neuronal apoptosis and modulates the electrophysiological properties of hippocampal pyramidal neurons. The modulation of miR-206 by ketamine might be involved in its antidepressant effects

[147]

Ketamine and stress modulate hippocampal miRNAs (such as miR-598-5p, miR-451, miR-217, miR-203, miR-211, miR-152, miR-1, and miR-204) linked to pathways such as cAMP responsive element binding protein 5 (CREB5), GABAA, and muscarinic cholinergic receptor 5. Antidepressant effects of ketamine and electroconvulsive therapy converge on common molecular pathways (such as hippocampal miR-598-5p upregulation and miR-451 downregulation)

Ketamine and other antidepressant strategies modulate hippocampal miRNA pathways such as miR-451 which could be exploited in antidepressants drug-discovery

[124]

Ketamine administered to mice 6 hours prior to lypopolysaccharide (LPS) elicits prophylactic effects, putatively through normalizing the LPS-perturbed PFC expression of miR-149 (increased by LPS), and miR-7688-5p (decreased by LPS), and their target gene nuclear factor Nfatc4 (activated T cells 4, decreased by LPS). The expression level of miR-149 in the PFC negatively correlated to the relative abundance of the gut microbial genus Alloprevotella, while miR-7668-5p was positively correlated to the relative abundance of the latter, and negatively correlated to the relative abundance of Lactobacilllus

Ketamine elicits prophylactic effects in the PFC in response to a systemic inflammatory challenge.

The PFC levels of selected miRNA affected by ketamine correlate to the abundance of specific gut microbiome taxa

[152]

Ketamine increases the hippocampal (but not PFC) transcription of a cluster of miRNAs (764-5p, 1912-3p, 1264-3p, 1298-5p, and 448-3p) hosted in the 5-HT_2C gene locus through Glycogen Synthase Kinase 3 (GSK-3). These effects on miRNA expression are not detected following acute or repeated treatment with the selective serotonin (5-HT) reuptake inhibitor (SSRI) fluoxetine. Blocking miR-448-3- decreases the antidepressant-like effect of ketamine

Hippocampal GSK-3-miR-448-3p signaling is required for the antidepressant-like effects of ketamine. Ketamine elicits a rapid and sustained modulation of hippocampal miRNA which is not shared with acute or repeated fluoxetine treatment and may contribute to its capacity to elicit antidepressant effects in individuals that do not respond to classical treatment

[150]

Ketamine increases miR-29b-3p expression and restores its expression in stressed mice selectively in the PFC, but not the hippocampus or the hypothalamus. While the miR-29b-3p target gene Glutamate Metabotropic Receptor 4 (GRM4) gradually declines following ketamine administration, the levels of miR-29b-3p increase. miR-29b-3p overexpression increases the high-voltage-activated current type in primary neuron cells, and promotes cell survival and cytodendritic growth

The brain area-specific effects of ketamine on miRNAs and their target genes (such as miR-29b-3p and GRM4) might be involved in its antidepressant effects.The synaptic-potentiating and neurotrophic properties of ketamine might be mediated by specific miRNAs in specific brain areas

[142]

Ketamine prophylactic treatment in chronically stressed mice affects the level of 32 miRNAs in the PFC; the miRNA with the most significant change (decrease) following ketamine is miR-132-5p, which targets the BDNF and Transforming Growth Factor Beta 1 (TGF-β1) genes, which are involved in the antidepressant effects of ketamine. Ketamine rescues the stress-induced decrease of BDNF and TGF-β1. Ketamine decreases the expression of Methyl-CpG Binding Protein 2 (MeCP2) in the PFC

Ketamine-induced miR-132-5p in the PFC and its resulting effects on gene expression plays an important role in the prophylactic antidepressant effects of ketamine, potentially through its regulatory effects on the expression of BDNF, TGF-β1, and MeCP2 in the PFC

[144]

Acute ketamine administration increases the PFC levels of miR-219a-5p, miR-7a-5p, miR-181b-5p and miR-148a-3p and decreases the levels of miR-128-3p. These miRNAs target genes involved with transcription, protein ubiquitination, and protein phosphorylation

Ketamine affects PFC miRNAs involved with transcription, and protein ubiquitination and phosphorylation in the PFC

[151]

Repeated ketamine increases the hippocampal expression of the circRNAs 003460, 014900, 006565, 013109, and decreases circRNA-005442. The predicted downstream effects converge on calcium signaling, G protein signaling, protein phosphorylation, Mammalian Target of Rapamycin (mTOR) signaling, transcription, alternative splicing, and neuroplasticity

Ketamine modulates hippocampal circRNAs, and these effects might be involved in its antidepressant and neurotrophic effects

[164]

Ketamine decreases miR-214-3p and Glutathione Peroxidase 4 (GPX4) levels. miR-214-3p inhibition relieves the decreased GPX4 expression. Ectopic expression of long non-coding Pvt1 Oncogene (lncPVT1) reverses the suppressed GPX4 levels caused by ketamine. Ketamine elicits ferropoptosis

Ketamine might have hepatic antineoplastic effects at least partially through lncRNA PVT1/miR-214-3p/GPX4 signaling and ferropoptosis

[263]

Repeated ketamine during early gestation decreases the cardiac histone H3K9 acetylation level at the Modulator Of VRAC Current 1 (Mlc2) promoter by increasing histone deacetylase activity, cardiac HDAC3 level, and the binding of HDAC3 at the Mlc2 promoter. This leads to cardiac enlargement, ventricular chamber enlargement, ventricular wall thinning, vacuolar degeneration of cardiomyocytes, reduced systolic function, and decreased expression level of several cardiomyogenesis-related genes

Repeated ketamine during early pregnancy elicits deleterious effects in the cardiac physiology of the offspring through its modulation of histone acetylation activity

[218]

Ketamine abuse induces Ten-Eleven-Translocation (TET) methylcytosine dioxygenase-mediated hypomethylation of NF-κB CpG promoter sites in cyclooxygenase 2 (COX2) promoters, upregulating COX-2. Ketamine upregulates (permissive) H3K4m3, and downregulates (repressive) H3K27me3 and H3K36me3 at NF-κB responsive COX-2 promoter sites, leading to ulcerative colitis

Epigenetic-mediated inflammatory dysfunction is involved in ketamine abuse-induced ulcerative cystitis. Low-dose ketamine might have a modulatory role over the epigenetic-mediated inflammatory control

[208]

Repeated high-dose ketamine leads to an upregulation of the circRNA circ-SFMBT2 which sponges and downregulates miR-224-5p, leading to increased Metadherin (MTDH) expression

circ-SFMBT2/miR-224-5p/MTDH signaling might be involved in the inflammatory dysfunction underlying ketamine-induced cystitis

[212]

In rats with ketamine-induced conditioned place preference (CPP), thirty-four hippocampal miRNAs were differentially expressed, including a strong downregulation of miR-331-5p, which targets the NR4A2 (Nuclear Receptor Subfamily 4 Group A Member 2) gene, and an increased expression of NR4A2, p-CREB, and BDNF

Hippocampal miRNAs might be involved in the rewarding and drug-seeking effects elicited by repeated ketamine exposure

[225]

Successful ketamine-induced CPP downregulates 122 miRNAs in the rat serum exosomes involved in processes such as nervous system development, neuron generation and differentiation, apoptotic processes, and pathways such as SNARE interaction, Protein Kinase CGMP-Dependent (PKG) signaling, and dopaminergic and GABAergic synapse. The downregulated miRNAs include miR-128-3p, 133a-3p, 152-3p, 181a-5p, 192-3p, 194-5p, 218b, 22-5p, 362-3p, 674-3p

Repeated ketamine exposure and CPP is accompanied by changes in serum exosomes miRNAs in rats

[231]

Repeated high-dose ketamine decreases miR-15a-3p, miR-15b-3p, and miR-16-1-3p expression in the PFC. Repeated high-dose ketamine decreases miR-16-1 in the hippocampus and Dopamine Receptor D1 (DRD1) levels in the PFC and hippocampus. These neurobiological changes are associated with schizophrenia-like behavior

Ketamine abuse may elicit maladaptive miRNAs expression in the PFC leading to schizophrenia-like behavior

[242]

Repeated high dose ketamine decreases miR-199a-5p expression and increases that of its target gene Hypoxia Inducible Factor 1 Subunit Alpha (HIF-1α). The regimen induces learning and memory impairment in neonatal rats through the regulation of the miR-199a-5p - HIF-1α pathways. Exposure to ketamine in neonatal rats induces learning and memory impairments. Exposure to ketamine impairs spatial learning memory ability by up-regulating HIF-1α expression

Repeated ketamine administration to neonates elicits cognitive and memory impairments through the miR-199a5p - HIF-1α pathway

[239]

miR-34c is upregulated in the hippocampus following repeated high-dose ketamine in neonatal rats. miR-34c knockdown increases the levels of BCL2 Apoptosis Regulator (Bcl-2), phospho-Protein Kinase C (PKC), and phospho-Mitogen-Activated Protein Kinase 1 (ERK). miR-34c knockdown ameliorates the ketamine-induced hippocampal toxicity Repeated high-dose ketamine elicits neurotoxicity in the CA1 region of the hippocampus

Repeated ketamine administration in the neonatal period elicits hippocampal neurotoxicity at least partially through miR-34c upregulation

[236]

miR-34a overexpression reverses the neurological and cognitive deficits, histopathological brain changes, and exacerbation of circulating proinflammatory cytokines elicited by repeated high-dose ketamine in rats

Repeated high-dose ketamine elicits neurotoxic and proinflammatory changes which can be counteracted by miR-34a overexpression

[213]

Repeated high-dose ketamine decreases miR-214 and increases Phosphatase And Tensin Homolog (PTEN) expression in the hippocampus. Repeated high-dose ketamine elicits cognitive deficits in rats

Repeated high-dose ketamine elicits cognitive deficits in rats which might be due to decreased miR-214 and increased PTEN hippocampal expression

[240]

Repeated high-dose ketamine in the neonatal period downregulates hippocampal miR-137, leading to apoptosis in hippocampal CA1 neurons and significant long-term memory dysfunction. miR-137 overexpression protects against hippocampal neurodegeneration and memory loss

miR-137 is involved in the neonatal, repeated high dose ketamine-induced hippocampal neurodegeneration and memory loss

[238]

Chronic ketamine administration induces bladder fibrosis and bladder upregulation of 14 and downregulation of 9 miRNAs. Moreover, chronic ketamine administration leads to the upregulation of 37 and downregulation of 34 lncRNAs in the bladder. Additionally, the treatment leads to 14 downregulated and 54 upregulated circRNAs

The ketamine abuse-induced bladder fibrosis is accompanied by changes in ncRNAs in the bladder

[211]

Repeated ketamine administration increases histone deacetylase and DNA methyltransferase activity in the PFC and striatum, but not the hippocampus, eliciting hyperlocomotion and altered exploratory activity. Repeated ketamine administration decreases Nerve Growth Factor (NGF) and Glial Cell Derived Neurotrophic Factor (GDNF) in the striatum

Repeated ketamine administration elicits histone deacetylation and DNA methylation, effects opposite to those elicited by clinically relevant doses

[235]

Ketamine dose-dependently inhibits the expression of HDAC6 and its nuclear import. Ketamine decreases dendritic growth, dendrite branches, and dendritic spine density in medium spiny neurons in a time- and concentration-dependent manner

Ketamine elicits neurotoxic effects in in vitro GABAergic neurons through HDAC6 inhibition

[248]

In PC12 neuronal cells, ketamine dose-dependently decreases the expression of the neuroprotective miR-429. This effect is accompanied by an increase in caspase 3 and reactive oxygen species (ROS) activity, and a dose-dependent increase in the miR-429 target BAG Cochaperone 5 (BAG5), expression. miR-429 overexpression is sufficient to attenuate the neurotoxic action

Ketamine elicits a dose-dependent neurotoxic effect in the PC12 neuronal cell line, mediated by its inhibitory effects on miR-429. Specific miRNAs are responsible for the in vitro neurotoxic effects of ketamine

[210]

Ketamine downregulates miR-22 in PC12 cells and upregulates BAG Cochaperone 5 (BAG5) in a dose-dependent manner. Lipoxin A4 methyl ester decreases these effects, attenuating neurotoxicity

Ketamine elicits a dose-dependent neurotoxic effect in PC12 cells, mediated by its effects on the miR-22/BAG5

[249]

Ketamine at higher doses increases miR-375 expression and decreases cell viability, neurite outgrowth, and BDNF levels, while increasing ROS production in human embryonic stem cell-derived neurons. miR-375 inhibition ameliorates these effects

Ketamine elicits dose-dependent neurotoxic effects in human embryonic stem cell-derived neurons, mediated partly by its inhibitory effects on miR-375. Specific miRNAs are involved in the in vitro neurotoxic effects of ketamine at higher doses

[215]

Ketamine exposure in CA1 hippocampal cell cultures increases miR-124 expression. miR-124 inhibition partially decreases the ketamine-induced neurotoxicity and upregulates the expression of AMPA, phospho-Glutamate Ionotropic Receptor AMPA Type Subunit 1 (GluR1), p-PKC, and p-ERK. Repeated high-dose ketamine in young mice leads to memory impairments during adulthood, and these effects are partially normalized by miR-124 antagonism

The neurotoxic effects elicited by higher dose ketamine in hippocampal cell culture and young mice might be mediated by miR-124 upregulation, which results in decreased AMPA, p-GluR1, p-PKC, and p-ERK hippocampal levels

[237]

Ketamine elicits a dose-dependent miR-107 (an upstream regulator of BDNF). Ketamine induces apoptosis and neurite degeneration in embryonic stem cells-derived neurons. miR-107 downregulation attenuates these effects

Ketamine elicits neurotoxic effects in embryonic stem cells-derived neurons at least partially through miR-107 signaling

[247]

Ketamine decreases the expression of the lncRNA Long Intergenic Non-Protein Coding RNA 641 (LINC00641), leading to increased neuronal apoptosis. Downregulation of LINC00641 results in an increase in its target miR-497-5p and a decrease in BDNF expression, which is repressed by miR-497-5p inhibition. LINC00641 improves ketamine-induced neuronal injury by activating the TRKB/Phosphoinositide 3-kinases (PI3K)/Protein Kinase B (Akt) signaling pathway

The neurotoxic effects of high-dose ketamine in vitro might be mediated by LINC00641/miR-497-5p/BDNF signaling

[214]

Ketamine elicits lncRNA SPRY4 Intronic Transcript 1 (SPRY4-IT1) upregulation, dose-dependent apoptosis, and neurite degeneration in human embryonic stem cells-induced neurons. Lentivirus-mediated SPRY4-IT1 downregulation protects against ketamine neurotoxicity. Enhancer Of Zeste 2 Polycomb Repressive Complex 2 Subunit (EZH2) expression is positively correlated with SPRY4-IT1 in hESC-induced neurons. EZH2 overexpression markedly reverses the protective effects of SPRY4-IT1 knockdown on ketamine neurotoxicity

The lncRNA SPRY4-IT1 is involved in the neurotoxicity elicited by ketamine in human embryonic stem cell-derived neurons, possibly through the regulation on EZH2 gene

[250]

Repeated ketamine upregulates miR-206 expression. Repeated ketamine downregulates KCNQ1 Opposite Strand/Antisense Transcript 1 (KCNQ1OT1) and BDNF expression. Repeated ketamine induces hippocampal apoptosis in rats, and the apoptosis of PC-12 cells

The KCNQ1OT1/miR-206/BDNF axis may represent a regulatory mechanism mediating ketamine-induced neural injury

[243]

Ketamine increases the expression of the BDNF antisense RNA (BDNF-AS) and decreases that of BDNF in mouse embryonic neural stem cells-derived neurons, leading to apoptosis. BDNF-AS downregulation activates Neurotrophic Receptor Tyrosine Kinase 2 (TRKB) signaling, protects against the ketamine-induced apoptosis and promotes neurite outgrowth

The neurotoxic effects of ketamine in vitro might be mediated by a modulation of BDNF-AS

[251]

Repeated high-dose ketamine upregulates hippocampal miR-34a, which targets the Fibroblast Growth Factor Receptor 1 (FGR1) gene, and elicits apoptosis in hippocampal CA1 neurons. Inhibition of miR-34 decreases these effects

Repeated high-dose ketamine elicits hippocampal damage at least partially through miR-34a-FGR1 signaling

[241]

Ketamine downregulates the lncRNA Small Nucleolar RNA Host Gene 16 (SNHG16), and it induces apoptosis and oxidative stress in human embryonic stem cell-derived neurons. SNHG16 overexpression attenuates the ketamine-induced neurotoxicity. Neuronal Differentiation 1 (NeuroD1) gene inhibition reverses the protective effect of SNHG16 on ketamine-induced neurotoxicity

Ketamine elicits neuronal damage at least partially through downregulation of the lncRNA SNHG16

[246]

Repeated LSD modulated DNA methylation in 635 CpG sites of the mouse PFC, and the expression level of 181 proteins. Gene signaling pathways affected are involved in nervous system development, axon guidance, synaptic plasticity, quantity and cell viability of neurons, and protein translation

LSD affects the DNA methylation, and gene and protein expression related to neurotropic-, neurotrophic- and neuroplasticity signaling

[69]

Acute LSD increases histone acetylation in the midbrain and cortex, but not cerebellum of rabbits. RNA production is also increased

Acute LSD induces histone acetylation in the cortex and midbrain, which increases gene expression

[98]

LSD decreases the interaction between nucleic acids and proteins

LSD might directly bind DNA or histone proteins, affecting chromatin structure

[268]

d-LSD binds to helical DNA (less so to denaturated DNA or RNA) with max 1 molecule per base moiety

LSD might directly bind chromatin, altering its structure, and affecting its functioning

[199]

LSD causes structural changes to the DNA double-helix conformation, possibly through intercalating DNA

LSD might cause the dissociation of DNA from histones through neutralizing the phosphate anions on the DNA double-helix backbone

[197]

LSD and tryptamines bind to DNA

LSD and tryptamines might directly interact with chromatin, affecting gene expression

[198]

A racemic mixture of l-LSD and d-LSD leads to LSD-DNA Binding. l-LSD but not d-LSD may bind to DNA directly

LSD might directly bind DNA

[197]

The increase in methylation level of one CpG site (cg08276280) in the corticotropin-releasing factor receptor 1 gene and one (cg01391283) within the glucocorticoid receptor gene in saliva samples correlates with symptom reduction in individuals with severe PTSD receiving MDMA-assisted psychotherapy

A modulation of DNA methylation in stress-responsive genomic regions might be involved in the therapeutic effects of MDMA-assisted psychotherapy in individuals with severe PTSD

[83]

Acute MDMA increases me3H3K4 (permissive) at the promoters of nociceptin/orphaninFQ (pN/OFQ)-NOP and dynorphin (DYN)-KOP DNA regions. Acute MDMA increases acH3K9 (permissive) and decreases me2H3K9 (repressive) at the pDYN (coupled to transcriptional upregulation). Acute and repeated MDMA decrease acH3K9 (permissive) at the pN/OFQ promoter (coupled to transcriptional downregulation)

Acute and repeated MDMA administration upregulates the DYN system and downregulates the N/OFQ system via modulating histone PTMs in promoter DNA regions in the nucleus accumbens

[232]

Chronic MDMA leads to cardiac gene promoters hypermethylation and circadian-related gene expression changes, coupled to cardiac hypertrophy and progressive damage

MDMA abuse affects cardiac DNA methylation, and this might be involved in cardiotoxicity

[217]

Repeated Ayahuasca in ceremonial settings affects the methylation level of 5 CpG sites located in the BDNF promoter (more so in individuals with greater childhood trauma) but does not affect the methylation level of one CpG site within the FKBP Prolyl Isomerase 5 (FKBP5) gene. These effects are accompanied by decreases in anxiety and depression detectable for up to 6 months

Repeated Ayahuasca administration in ceremonial settings elicits sustained antidepressant and anxiolytic effects which are accompanied by DNA methylation changes in the regulatory region of the BDNF gene

[79]

Hypothesis- Ayahuasca might contribute to fear extinction learning and memory reconsolidation via a Sigma-1 receptor-mediated epigenetic mechanism

Ayahuasca might modulate epigenetics processes, and these effects might be involved in the therapeutic effects of Ayahuasca over traumatic memories, fear extinction, and memory reconsolidation

[80]

DOI affects the acetylation level of the transcriptional enhancer histone H3K27 in neuronal cells of the mouse PFC with highly specific spatio-temporal dynamics and for up to 7 days post-administration. These changes result in transcriptomics shifts, and a structural (5-HT_2A-mediated) and functional modulation of synaptic plasticity, and decreased depressive-like behavior

A single DOI administration elicits long-lasting acetylation and transcriptional changes which are accompanied by long-lasting structural and functional modulation of synaptic plasticity

[107]

β-carbolines directly interact with DNA in vitro with affinity harmine>harmalol>harmaline>tryptoline

β-carbolines might affect chromatin compaction via direct interaction or via interacting with chromatin-remodeling complexes

[196]

Psilocybin at the dose of 10 mg/kg increases oxidative DNA damage in the PFC and hippocampus

Higher-than clinically-relevant doses of psilocybin elicit DNA damage in the PFC

[260]

Hypothesis- Psilocybin might affect genetic aging via epigenetic regulation of telomere length

Psilocybin might affect epigenetics processes involved with aging, preventing telomere degradation

[68]