Table 1.
Hypothesized mechanisms underlying the antidepressant actions of ketamine and psychedelics.
| Mechanism | Area of Effect | Ketamine | Psychedelics |
|---|---|---|---|
| Serotonergic Signaling | Expression | Ketamine increased extracellular levels of 5-HT in the PFC (Ago et al., 2019; López-Gil et al., 2019) | |
| 5-HT depletion blocked the effects of (S)-ketamine (du Jardin et al., 2018) | |||
| 5-HT depletion did not block the effects of (R)-ketamine (Zhang et al., 2018) | |||
| 5-HT Receptors | Ketamine increased 5-HT1B receptor binding (Spies et al., 2018; Tiger et al., 2020; Yamanaka et al., 2014) | Non-hallucinogenic analogues of psychedelics (Cao et al., 2022) and novel monoamine transporter ligands (Rudin et al., 2022) exerted antidepressant effects via 5-HT receptors | |
| Antidepressant and antidepressant-like effects were reportedly primarily mediated through 5-HT2A receptor activation (Cao et al., 2022; López-Giménez and González-Maeso, 2018; Ly et al., 2018; Pędzich et al., 2022; Rolland et al., 2014) | |||
| Behavioral response to psilocybin was not blocked by ketanserin (a 5-HT2A/2C receptor antagonist) | |||
| DOI (a selective 5-HT2A receptor antagonist) did not have antidepressant-like effects | |||
| SERT binding | Ketamine increased SERT binding ((Spies et al., 2018; Tiger et al., 2020; Yamanaka et al., 2014) | Increased occupancy with LSD and 5-MeO-DMT administration (Kyzar and Kalueff, 2016; Rickli et al., 2015), but no interactions with LSD (Blough et al., 2014; Rickli et al., 2015) | |
| Dopaminergic Signaling | Expression | Chemogenetic inhibition of dopamine signaling blocked ketamine’s antidepressant-like effects (Wu et al., 2021a; Wu et al., 2021b) | DMT, psilocybin, and mescaline may convert to dopamine after ingestion (Fitzgerald, 2021) |
| Dopaminergic Receptors | Drd1 activation mediated the antidepressant-like behavioral effects of ketamine and increased cortical spinogenesis (Hare et al., 2019; Wu et al., 2021a). Drd1 expression also increased after ketamine administration (Li et al., 2022a) | ||
| (R)-ketamine had Drd1-activation independent effects (Chang et al., 2020) | |||
| Firing activity | Ketamine increased the firing activity of dopaminergic neurons (Iro et al., 2021) | In high doses, LSD increased dopaminergic firing activity (De Gregorio et al., 2016) | |
| Glutamatergic Signaling | Glutamate surge | Glutamate “surge” (reviewed in (Kadriu et al., 2021)) | Glutamate “surge” (reviewed in (Kadriu et al., 2021)) |
| NMDAR-related effects | An extensive literature describes the role of NMDAR antagonism in ketamine’s antidepressant effects, particularly on GABA-ergic interneurons (reviewed in (Miller et al., 2016; Zanos and Gould, 2018)) | Psilocybin increased AMPAR/NMDAR ratios in hippocampal slices (Hesselgrave et al., 2021) | |
| (R)-ketamine and (2R,6R)-HNK appeared to have NMDAR-independent effects (Dravid et al., 2007; Lumsden et al., 2019; Zhao et al., 2012) | Ibogaine may antagonize NMDARs (Underwood et al., 2021) | ||
| Psilocybin increased NR2A expression but was not associated with an antidepressant response (Wotjas et al., 2022) | |||
| AMPAR-related effects | Ketamine upregulated mTORC1 signaling via increased AMPAR activation (Aguilar-Valles et al., 2021; Li et al., 2010; Rafało-Ulińska and Pałucha-Poniewiera, 2022; Zanos et al., 2016; Zhou et al., 2014) | Psychedelics upregulated mTORC1 signaling via increased AMPAR activation (Ly et al., 2020; Madrid-Gambin et al., 2022; Ornelas et al., 2022; Vollenweider and Preller, 2020; Vollenweider and Smallridge, 2022) | |
| (2R,6R)-HNK had mGluR2-dependent antidepressant-like effects (Zanos et al., 2019) | |||
| (R)-ketamine increased ERK signaling, particularly on microglia, which mediated its antidepressant-like effects (Yang et al., 2018b; Yao et al., 2022) | |||
| mGluR-related effects | Co-administration of ketamine and an mGluR2/3 antagonist sustained antidepressant-like response (Pałucha-Poniewiera et al., 2021; Rafało-Ulińska et al., 2022) | mGluR2/3 agonists inhibited the effects of DOI in mice (Benvenga et al., 2018) | |
| GABAergic signaling | Expression | Ketamine increased hippocampal GABA turnover (Silberbauer et al., 2020) and GABA release (Pham et al., 2020) | Psychedelics increased GABA expression in the mPFC (Carhart-Harris and Nutt, 2017; Mason et al., 2020) |
| Receptors | GABAA receptor activity was upregulated by ketamine (Wang et al., 2017) | LSD did not affect EEG response in GABAA receptor delta subunit knockout mice (Grotell et al., 2021) | |
| Benzodiazepines (which also increase GABAA receptor activity) decreased ketamine’s antidepressant effects (Andrashko et al., 2020; Fuchikami et al., 2015) | |||
| Signaling | Ketamine rescued deficits in synaptic GABA-ergic markers and the frequency of inhibitory post-synaptic currents in the mPFC (Ghosal et al., 2020) | Stress-induced alterations in GABA-ergic circuitry were reversed by 5-HT2aR agonists in the VTA (Kimmey et al., 2019) | |
| Opioid system | Receptors | Ketamine had a strong affinity for the mu-opioid receptor and weak affinity for the kappa opioid receptor (Bonaventura et al., 2021) | Psychedelic binding to mu- and kappa-opioid receptors correlated with “therapeutic component scores” (Zamberlan et al., 2018) |
| Opioid receptor antagonists abolished ketamine’s (and its metabolites’) rapid-acting antidepressant effects in clinical and preclinical models (Klein et al., 2020; Williams et al., 2019; Williams et al., 2018; Wulf et al., 2022; Zhang et al., 2021a) | Mu-opioid receptor binding after psychedelic administration correlated with self-report dependence measures (Zamberlan et al., 2018) | ||
| Inflammation | Cytokines | (R)-, but not (S)-ketamine reduced blood IL-6 levels in a model of ulcerative colitis (Fujita et al., 2021) | Psilocybin, LSD, and DOI reduced levels of cytokines and TNF-α (Kozłowska et al., 2021; Nardai et al., 2020; Nkadimeng et al., 2021; Smedfors et al., 2022; Yu et al., 2008) |
| (R)-ketamine reduced central and peripheral levels of pro-inflammatory cytokines in mice administered LPS (Zhang et al., 2021b) | |||
| Ketamine decreased levels of pro-inflammatory cytokines in a sex-dependent manner after maternal deprivation (Abelaira et al., 2022) | |||
| Baseline IL-8 levels predicted treatment response to ketamine in females but not males (Kruse et al., 2021) | |||
| Ketamine had prophylactic effects against upregulation of inflammatory markers after stress exposure (Brachman et al., 2016; Camargo et al., 2021; Costi et al., 2022) | DOI had prophylactic effects against TNF-alpha administration, preventing the upregulation of pro-inflammatory cytokines (Nau et al., 2013) | ||
| HPA-axis signaling | Ketamine restored glucocorticoid receptor expression in the hippocampus (Wang et al., 2019) | Short-term increases in cortisol and ACTH were observed during the peak hallucinogenic effects of psilocybin (Hasler et al., 2004) | |
| Corticosterone and ACTH levels were reduced by ketamine after LPS injection (Besnier et al., 2017) | |||
| Kynurenic signaling | Ketamine restored the KYN:tryptophan ratio (Moaddel et al., 2018; Wang et al., 2015) | ||
| Increased kynurenic acid post-ketamine correlated with treatment response (Zhou et al., 2018) |
5-HT: 5-hydroxytryptamine; 5-Meo-DMT: 5-methoxy-N,N-dimethyltryptamine; ACTH: adrenocorticotropic hormone; AMPAR: α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; DOI: 2,5-Dimethoxy-4-iodoamphetamine; Drd1: dopamine receptor D1; ERK: extracellular signal-related kinase; GABA: gamma aminobutyric acid; HNK: hydroxynorketamine; IL: interleukin; KYN: kynurenine; LPS: lipopolysaccharide; LSD: lysergic acid diethylamide; mGluR: metabotropic glutamate receptor; mPFC: medial prefrontal cortex; mTORC1: mechanistic target of rapamycin complex 1; NMDAR: N-methyl-D-aspartate receptor; PFC: prefrontal cortex; SERT: serotonin transporter; TNF-α: tumor necrosis factor alpha; VTA: ventral tegmental area