Table 1.
Preclinical studies investigating psychedelics' effects on molecular and (sub)cellular neuroplasticity.
| References | Aim | Tissue | Comparison/conditions | Psychedelic | Post-administration measurement | Methods and measurements | Findings |
|---|---|---|---|---|---|---|---|
| Ly et al. (53) | Effects of psychedelics on neural plasticity in cortical neurons, In vitro, in vivo, ex vivo | In vitro: cortical embryonic rat neurons n = 39–4. In vivo: cortical pyramidal neurons, n = 11–38 | Vehicle, DOI | Single dose, In vitro: 90 μM DMT, 10 μM LSD, DOI for 24 h. In vivo: 10 mg/kg DMT i.p. | In vitro: Directly. In vivo: 24 h | Sholl analysis, ICC, whole-cell voltage-clamp recordings, Golgi-Cox staining | Dendritic complexity+; Spinogenesis+; synapse density+; EPSC frequency+, amplitude+; Dendritic spine density+; |
| Dakic et al. (43) | In vitro effects of 5-MeO-DMT on cellular and molecular systems | Human cortical organoids; 45 days old. n = 4–5 | Vehicle, medium only | Single dose, 13 μM DMT for 24 h | Directly | Shotgun mass spectrometry, ICC, protein expression | NMDAR+, CaMK2+, CREB+, PLC–, CaM–, AC1/8–, IP3R–, EPAC1–, PKA–, mGluR5–. |
| Szabo et al. (42) | Examine the neuroprotective role of DMT after hypoxic stress, In vitro | Human iPSCs differentiated into cortical neurons n = 3 | BD1063 dihydrochloride, normoxia | Single dose, 1, 10, 50, 200 μM DMT, 1–100 μM BD1063 | Measured over 6 h. Unknown when DMT was added. | Hypoxia, FACS, Western blot, cellular viability assays, siRNA knockdown, flow cytometry. | Survival+ (hypoxia, DMT), survival—(hypoxia, DMT, S1R KO) |
| Morales-Garcia et al. (41) | In vitro and in vivo short- and long effect of DMT on neurogenesis and behavior | In vitro: NSCs from SGZ, HC in vivo: Male adult mice. 6 (In vitro); 5 (short-term); 5 (long-term); 12 (behavior) | Vehicle, clorgyline | In vitro: Daily, 7 days 1 μM DMT. in vivo: 2 mg/kg DMT, i.p, 4 or 21 days (every other day), Behavior: 21 days | 24 h (short-term), 24 h (long-term), behavior: for 10 days post-treatment | In vitro: ICC. In vivo: BrdU+ (and DCX+) cells in DC. Behavior: MWM, OR. | In vitro: Proliferation+; differentiation into neurons+, astrocytes+, oligodendrocytes+; S1R mediated. in vivo short term: proliferation+; migration+; S1R mediated. in vivo long-term: Neurogenesis+; S1R mediated. Behavior: escape latency–; exploration+, learning+, memory+ |
| Katchborian-Neto et al. (44) | Evaluate the neuroprotective potential of ayahuasca on the viability In vitro | Neuroblastoma cells, SH-SY5Y, n = 3 | Vehicle, 6-OHDA | Every 24 h, 1, 1.5, 2.5, 10.5 μg/mL ayahuasca* | 48, 72 h | IHC, MTT assay. | Aya –> proliferation+ (dose 1, 1.5, 2.5 μg/mL at 48 h), Aya and 6-ODHA –> cell viability + (dose 1, 1.5, 2.5 μg/mL at 48 h) |
| Lima da Cruz et al. (54) | In vivo effects of 5-MeO-DMT on neurogenesis | HC of adult mice, M, F, n = 5 | Saline | Single dose, 100 μg 5-MeO-DMT, i.c.v | 12–13 h | IHC, patch clamp. | Proliferation+; survival+, maturation+; dendritic complexity+; AP threshold – |
| Jefsen et al. (55) | Effects of acute psilocybin administration on gene expression in the rat brain in vivo | Cortex and HC of male adult rats, n = 10 | Vehicle | Single dose, 0.5, 1.0, 2.0, 4.0, 8.0, 14.0 or 20.0 mg/kg Psi, i.p. | 90 min | PCR, Western blot, gene expression | PFC: C/EBP-β+, c-Fos+, Dups1+, Fosb+, Junb+, Iκβ-α+, Nr4a1+, P11+, Psd95+, Sgk1+, Clk1-HC: Arrdc2+, Dusp1+, Iκβ-α+, Sgk1+ (dose- dependently), Arc –, Clk1–, Egr2 –, Ptgs2– |
| Gonzales-Maeso et al. (56) | Investigate 5-HT2AR-dependent responses elicited by different agonists in vivo | SSCx of adult male mice, n = 12 (LSD/wt), n = 6 (2AR KO) | LSD, DOI, LHM, vehicle, 5-HT2AR KO mice | Single dose, 0.24 mg/kg LSD; 2 mg/kg DOI; 0.5 mg/kg LHM, i.p. | Behavior:20 min. Gene-expression: 60 min | in situ hybridization, gene expression | Egr1+; Egr2+; Period-1+; Ikba+, c-fos+, N-10+ |
| Nichols and Sanders-Bush (57) | In vivo effect of acute LSD on gene expression | Cortex, HC of male rats, n = 4 | Saline | Single dose, 1.0 mg/kg LSD, i.p. | 90 min | DNA microarray, RNAse protection analysis | PFC: + C-fos+, Arc+, Sgk+, Ikb+, Nor-1+, Ania3+, Krox20+ HC:C-fos+, Arc+, Sgk+, Ikβ+, Krox20+ |
| Nichols et al. (58) | In vivo expression patterns of previously identified genes in the LSD mechanisms of action. | Cortex of male rats, n = 4 | MDL100907; WAY100635. | Single dose, 0.20, 1.0, 0.5 mg/kg LSD; 1 or 0.5 mg/ kg MDL100907; 10 mg/kg WAY100635; 1.0 mg/kg LSD timing exp., i.p. | 45, 90, 180, or 300 min (timing-experiment); 90 min (other experiments) | RNA protection analysis, mRNA. | Low dose: Krox20+, Ikβ+; High dose: Ania3+; Arc+, C-fos+, Nor-1+, Sgk+. Peak at t = 90, baseline by 5 h, except for Nor-1. |
| Nichols and Sanders-Bush (59) | In vivo effects of acute LSD on expression patterns of three genes | Cortex, HC and MB* of male rats, n = 4 | LSD, MDL100907, WAY100635. | Single dose, 1.0 mg/kg LSD, i.p. Dose-response study: 0.20, 0.5 and 1.0 mg/kg LSD | 90 min; except for timing study | DNA microarray, RNAse protection analysis, PCR, mRNA. | In PFC at 90 min: 0.5 mg/kg dose: C/EBP-β+; Ilad-1+; 1.0 mg/kg dose: MKP1+. 5-HT2AR mediated |
| Jha et al. (60) | In vivo effects of acute or chronic LSD on 5-HT2A/2C receptors on proliferation | HC of adult male rats, n = 3–5 | DOI, ketanserin, vehicle | 0.5 mg/kg LSD, 5.0 mg/kg ketanserin, i.p. Daily, 7 consecutive days (chronic) | 2.5 h (acute); 26 h (chronic) | IHC: Proliferation | Acute: Proliferation = Chronic: Proliferation = |
| Martin et al. (61) | In vivo effects of chronic LSD on cortical gene expression | Cortex of adult male rats, n = 10 | Saline | 0.16 mg/kg LSD, i.p. Every other day, 90 days | 4 weeks | RNA sequencing, mRNA. | + for genes involved in neurotransmission and synaptic plasticity processes, including Krox20, Bdnf, Npy, Nor-1, Drd1, Drd2 |
| Catlow et al. (62) | Effects of psilocybin on neurogenesis and fear conditioning in vivo | HC of male mice, n = 9–10 | Ketanserin, 25I-NBMeO, vehicle | Single dose, 0.1, 0.5, 1.0 mg/kg Psi (IHC), 0.1, 0.5, 1.0, 1.5 mg/kg Psi (behavior) | 48 h, behavior after 14 days | IHC, fear behavior (FC) | 1.0 mg/kg: Proliferation–; 0.1 and 0.5 mg/kg: Extinction + (FC) |
| Colaço et al. (63) | In vivo effect of chronic ayahuasca on serotonin, dopamine, norepinephrine and metabolites and BDNF levels | HC of 5-week-old rats, M, F, n = 7–10 | H2O and fluoxetine | 0.5X; 1X; 2X** ayahuasca, p.o (gavage) Daily, 28 days | 3 h | Hematological analysis: ELISA Behavior: OF (locomotion), EPM; | Fluoxetine group; female high dose group: BDNF protein. All: +Locomotion =; EPM =, no toxicity |
| Nardai et al. (46) | In vivo neuroprotective effects of DMT | Cortex of male mice, n = 10 | Vehicle, BD-106 | Single dose 1 mg/kg DMT, i.v. with maintenance of 2 mg/kg/h over 24 h | 25 h after MCAO (protein levels); Behavior: daily for 2 weeks, then on every 4th day till the 30th day after MCAO | MCAO, MRI, behavior, ELISA (mRNA). Lesion volume, protein levels, motor function and functional recovery with stair-case method | bdnf+, serum BDNF+; IL-6 –, Ischemic lesion volume–; Motor function+ |
Sample size is given per group.
Specific composition of ayahuasca was not reported,
ayahuasca (composition: 0.26 mg/kg DMT, 2.58 mg/kg harmine, 0.171 mg/kg harmaline and 0.33 mg/kg tetrahydroharmine).
5-HT, Serotonin; 5-HT2AR, Serotonergic 2A receptor; 5-HT2CR, Serotonergic 2C receptor; 5-MeO-DMT, 5-methoxy-N,N-dimethyltryptamine; 6-OHDA, 6-hydroxydopamine; AC1/8–, Ca2+-stimulated type 1 and type 8 adenylyl cyclases; Akt, Protein kinase B; AMPAR, α-amino-3-hydroxy-5-methyl-4-isozalopropionic acid receptor; AP, Action potential; Arc–, Activity-regulated cytoskeleton-associated protein; Aya, Ayahuasca; BD-1063, 1-[2-(3,4-dichlorophenyl)ethyl]-4-methylpiperazine; BDNF, Brain-derived neurotropic factor; BrdU, Bromodeoxyuridine; C/EBP-β, CCAAT enhancer binding protein; CaM, calmodulin; CAMK2, Ca2+/calmodulin-dependent protein kinase; Clk1, CDC2-like kinase isoforms 1; Arrdc2, Arrestin domain containing 2 (or induced by lysergic acid diethylamide 1, ilad1); DCX, Doublecortin; DG, Dentate gyrus; DMT, N,N-dimethyltryptamine; DOI, 2,5-Dimethoxy-4-iodoamphetamine; Drd, Dopamine receptor D1; Drd2, Dopamine receptor D2; Dups1, dual specificity phosphatases; Egr1, Early growth response protein 1; Egr2, Early Growth Response Protein 2; ELISA, Enzyme-linked immunosorbent assay; EPAC1, exchange factor directly activated by cAMP 1; EPM, Elevated Plus Maze; EPSCs, excitatory postsynaptic currents; ERG2 or Krox20, Early Growth Response Protein 2; ERK 1/2, extracellular regulated kinase 1/2; F, Female; FACS, Fluorescence-activated cell sorting; HC, Hippocampus; i.c.v., intracerebroventricular; i.p., Intraperitoneal; i.v., Intravenous; ICC, Immunocytochemistry; IEGs, Immediate Early Genes; IHC, Immuohistochemistry; Iκβ-α, nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor alpha; IL-6, Interleukin 6; Ilad-1, Induced by lysergic acid diethylamide 1 also named Arrestin domain containing 2 (arrdc2); IP3, Inositol triphosphate; iPSCs, induced pluripotent stem cells; KO, knocked out; LSD, Lysergic acid diethylamide; LTD, Long-term depression; LTP, Long-term potentiation; M, male; MCAO, Middle cerebral occlusion; mGluR5, Metabotropic glutamate receptor 5; MKP1, Map Kinase Protein 1; mPFC, Medial prefrontal cortex; MRI, Magnetic Resonance Imaging; mRNA, messenger ribonucleic acid; mTOR, Mammalian target of rapamycin; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide; MWM, Morris Water Maze; NMDAR, N-methyl-D-asparate receptor; Nor1, Neuron-derived orphan receptor 1; Npy, Neuropeptide Y; Nr4a1, Nuclear receptor 4A1; NSCs, Neural stem cells; NSCs, Neuronal stem cells; OR, Object recognition task; p.o., Oral administration; P11, S100 calcium-binding protein A10; PCR, Polymerase chain reaction; PFC, Prefrontal cortex; PI3K, Phosphatidylinositol-4,5-bisphosphate 3-kinase; PKA, Protein Kinase A; PLA2, Phospholipase A2; PLC, Phospholipase C; Psd95, Postsynaptic density 95; Psi, Psilocybin; Ptgs2, prostaglandin-endoperoxide synthase 2; RNA, Ribonucleic acid; Nor-1, Neuron-derived orphan receptor 1; S1R, Sigma-1-receptor; Sgk1, Serum glucocorticoid kinase1; SGZ, Subgranular zone; siRNA, small interfering RNA; SSRIs, Selective-serotonin reuptake inhibitors; TRD, Treatment-resistant depression; TrkB, Tropomyosin receptor kinase B.