Main receptor interactions and downstream effects of psychedelic compounds on pathways involved in synaptic and neuronal plasticity, neuroimmunomodulation, and modulation of neurotransmitter systems of relevance to psychiatry
For each compound (column 1), the receptors involved in signal transduction are reported with decreasing Ki (column 2). The transcription factors, enzymes, hormones, and cytokines up/downregulated by each compound are reported in terms of acute and chronic responses (where data are available, column 3). The main outcomes on modulation of neurotransmitter systems are reported in column 4. Systemic and psychological effects elicited are reported for each compound (column 5). Referenced articles are reported in column 6.
| Compound | Receptors (>Ki) | Transcription Factors/Enzymes/Hormones/Cytokines | Neurotransmitter Effects | Central Effects/Systemic Effects/Psychological Effects | References |
|---|---|---|---|---|---|
| LSD | 5-HT1B, 5-HT7, 5-HT6, 5-HT1A, 5-HT1D, 5-HT5A, 5-HT2A, D3, 5-HT2B, 5-HT2C, adrenoreceptor (ADRA) 2, 5-HT1E, D2, D4, D1, D5, ADRA1A, histamine receptor (H1), ADRB1, ADRB2, ADRA1B | Acute: ↑mTOR, ↑cFOS, ↑Egr-1, ↑Egr-2, ↑Cebpb, ↑IKB, ↑SGK, ↑Nor1, ↑ANIA3, ↑MKP1, ↑DHEA, ↑CORT, ↓IL2, ↓IL4, ↓IL6, Chronic: ↑GABRB1, ↑GABRB2, ↑GABRG3, ↑NR2A, ↑NR2B, ↑BDNF, ↑KROX20, ↓D1, ↓D2, ↓5-HT2C, ↓SLC6A13 (GABA transporter) | ↑(Prolonged) glutamate release in layer V pyramidal neurons, ↓5-HT firing in DRN via 5-HT2A (low doses), ↓DA firing via 5-HT1A (high doses), ↓DA neurotransmission in VTA (high doses) | ↑Neurogenesis, ↑axon, branching, ↑synaptic scaling, ↓inflammation, ↓depression, ↓anxiety | House et al., 1994; Watts et al., 1995; Egan et al., 1998; González-Maeso et al., 2003, 2007; Nichols and Sanders-Bush, 2004; Lambe and Aghajanian, 2006; Ray, 2010; Marona-Lewicka et al., 2011; Barrot, 2012; Martin et al., 2014; De Gregorio et al., 2016a,b; Ly et al., 2018; Rickli et al., 2015; Strajhar et al., 2016; |
| Psilocybin | 5-HT2B, 5-HT1D, D1, 5-HT1E, 5-HT1A, 5-HT5A, 5-HT7, 5-HT6, D3, 5-HT2C, 5-HT1B, 5-HT2A, I1, SERT, ADRA2B, ADRA2A, ADRA2C | ↑ACTH, ↑CORT, ↑TSH | ↑Striatal DA release (caudate/putamen) | ↑Neurogenesis, ↑axon branching, ↑synaptic scaling, ↓inflammation, ↓depression, ↓anxiety | McKenna et al., 1990; Vollenweider et al., 1999b; Ray, 2010; Hasler et al., 2004; Carhart-Harris et al., 2016a |
| Ayahuasca | 5-HT1A, 5-HT1B, 5-HT1D, 5-HT2A, 5-HT2B, 5-HT2C, 5-HT5A, 5-HT6, 5-HT7R, TAAR1, S1R | ↑5-HT2A, ↑SERT, ↑CORT (acute only), ↓CORT (awakening response), ↑GH | ↑Hippocampal GABA (dose-independently); ↑amygdalar GABA (low doses); ↓amygdalar GABA (higher doses); ↑amygdalar 5-HT, DA, and noradrenaline; ↑hippocampal 5-HT (highest doses); ↑5-HT, DA, and noradrenaline turnover | ↑Neurogenesis, ↑neuronal differentiation, ↓inflammation, ↓depression, ↓anxiety | Callaway et al., 1999; de Castro-Neto et al., 2013; Morales-Garcia et al., 2017; Galvao et al., 2018; Palhano-Fontes et al., 2019 |
| DMT | 5-HT7, 5-HT1D, 5-HT2B, ADRA2B, ADRA2C, D1, 5-HT2C, 5-HT1E, 5-HT6, 5-HT5A, I1, ADRA1B, ADRA2A, ADRA1A, 5-HT2A, SERT, S1R | ↑IL10, ↓IDO, ↓IL1β, ↓IL6, ↓IL8, ↓TNF-α | N/A | ↑Neurogenesis, ↑dendritic spines formation, ↓inflammation | Fontanilla et al., 2009; Keiser et al., 2009; Ray, 2010; Tourino et al., 2013; Szabo et al., 2014; |
| 5-MeO-DMT | 5-HT1A, 5-HT7, 5-HT1D, 5-HT6, 5-HT1B, D1, 5-HT5A, 5-HT1E, D3, ADRA2C, 5-HT2C, ADRA2A, 5-HT2A, SERT, I1, ADRA2B, NET1, D4, D2, 5-HT2B | ↑NMDAR, ↑ERK 1/2, ↑CREB, ↑CAMK2, ↓NF-ĸB, ↓NFAT, ↓TLR, ↓mGluR5, ↓PKC, ↓PLC, ↓IP3R, ↓EPAC1, ↓PKA, ↓IL1β, ↓IL6, ↓IL8, ↓TNF-α, ↑IL10 | N/A | ↑Neurogenesis, ↑dendritic spines formation, ↑long-term potentiation, ↓neurodegeneration, ↑cytoskeletal reorganization, ↓inflammation, ↑T lymphocytes differentiation, ↓cell death, ↓depression, ↓anxiety | Ray, 2010; Szabo et al., 2014; Dakic et al., 2017; Lima da Cruz et al., 2018; Ly et al., 2018; Davis et al., 2019; Szabo et al., 2014 |
| DOI | 5-HT2C, ADRA2A, ADRB2, 5-HT2A, ADRA2B, 5-HT2BR, 5-HT1D, CHRM4, ADRB1, ADRA2C, SERT, 5-HT1E, CHRM3, H1, CHRM2, 5-HT6, CHRM5, 5-HT1A, CHRM1, 5-HT7, S1R, S2R, D1 | ↑Egr-1, ↑Egr-2, ↑cFOS, ↑IKBA, ↓Egr-3, ↓TNF-α, ↓ILB, ↓IL6, ↓iNOS, ↓ICAM1, ↓VCAM1, ↓MCP1, ↓CX3CL1 | N/A | ↓Inflammation | González-Maeso et al., 2003; Yu et al., 2008; Ray, 2010; Nau et al., 2013; Lima da Cruz et al., 2018 |
| Ketamine | NMDAR, D1, D2, 5-HT2A, 5-HT3, S1R, S2R, OPRM1, OPRK1, OPRD1 | Acute: ↑mTOR, ↑BDNF, ↑IL1β, ↑IL6, ↑TNF-α, ↓EEAT2, Chronic: ↓TNF-α | ↑DA activity via DR1 in the NA, ↑DA neurotransmission in VTA after amphetamine withdrawal | ↑Neurogenesis, ↑dendritic spines growth, ↑synapse formation, ↑dopaminergic activity, ↓depression, ↓anxiety | Li et al., 2010, 2017; Murrough et al., 2013b; Belujon and Grace, 2014; Belujon et al., 2016; Choi et al., 2017; Lisek et al., 2017; |
| MDMA | TAAR1, NMDAR, VMAT2, 5-HT1A, SERT, I1, 5-HT2B, CACNA1A, ADRA2C, ADRA2B, CHRM3, ALPHA2A, CHRM5, CHRM4 | ↑Cortisol, ↑prolactin, ↑oxytocin, ↑IL10, ↓IL1β, ↓IL6, ↓IL12, ↓IL15, ↓TNF-α, ↓CXCL10, ↓CCL5 | ↑5-HT, DA, and NE neurotransmission; ↓5-HT and DA reuptake; oxytocin-dependent reopening of long-term depression in the NA | ↓PTSD symptoms, ↑long-term depression in the NA, ↓inflammation | Gouzoulis-Mayfrank et al., 1999; Ray, 2010; Boyle and Connor, 2010; Yuan et al., 2016; Mithoefer et al., 2018; Nardou et al., 2019 |
ADRA, alpha adrenergic receptor; ADRB, beta adrenergic receptor; ALPHA2A, alpha 2 adrenergic receptor; ANIA3, activity and neurotransmitter-induced early gene 3; CACNA1A, voltage-dependent P/Q-type calcium channel subunit alpha-1A; CAMK2, calcium/calmodulin-dependent protein kinase 2; CCL5, C-C motif chemokine 5; CHRM, muscarinic acetylcholine receptor M2; Cebpb, CCAAT/enhancer-binding protein beta; CORT, cortisol; CX3CL1, fractalkine; CXCL10, C-X-C motif chemokine 10; EEAT2, excitatory amino acid transporter 2; EPAC1, rap guanine nucleotide exchange factor 3; GABR, gamma-aminobutyric acid type B receptor; GH, growth hormone; I1, imidazoline receptor 1; ICAM, intercellular adhesion molecule; IP3R, inositol trisphosphate receptor; KROX20, early growth response protein 2; MAPK1, mitogen-activated protein kinase 1; N/A, not available; NET1, norepinephrine transporter 1; NFAT, nuclear factor o activated T-cells; NMDAR, N-methyl-D-aspartic acid receptor; Nor1, neuron-derived orphan receptor-1; OPRM1, mu-type opioid receptor; OPRK1, kappa-type opioid receptor; OPRD1, delta-type opioid receptor; IKB, inhibitor of kB kinases; PLC, pospholipase C; PKA, protein kinase A; PKC, protein kinase C; SGK, serine/threonine-protein kinase Sgk1; SLC6A13, sodium- and chloride-dependent GABA transporter 2; TLR, toll-like receptor; TSH, thyroid stimulating hormone; VCAM, vascular cell adhesion protein.