Mechanisms of ketamine and its metabolites as antidepressants

In the paper

“Further, NMDAR activation is inversely correlated with GluA1 S845 phosphorylation, with NMDA dose-dependently reducing expression in hippocampal slices, which is consistent with the effects of ketamine antagonism”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites Ai et al., 2011
• Disputed

  The Discussion (page not provided) suggests that activation of NR2A-containing NMDARs enhances S-845 phosphorylation, contrary to the claimed inverse relationship. It describes only a modest, nonsignificant decrease when a smaller extrasynaptic receptor population was activated. The cited passages do not report a dose-dependent NMDA effect in hippocampal slices or a ketamine experiment. (LLM, conf=0.88)

  Checked by a reasoning model — may be wrong.

  cites Spaethling et al., 2012 sourceExperimental — accuracy not yet measured
• Supported

  In “NMDAR activation regulates the phosphorylation state of GluR1 at S845” (Fig. 2; page not specified in the supplied passage), the paper reports that NMDA dephosphorylates GluR1 S845 in hippocampal slices, with a concentration-response relationship. The reference to ketamine antagonism is the citing authors’ interpretation, not a ketamine result attributed to this source. (LLM, conf=0.90)

  cites Vanhoose et al., 2006 source

In the paper

“ketamine did not alter immobility or swimming during the forced swim test 30 minutes, 24 hours, or one-week post-treatment in PVCreGluN1 mice relative to GluN1f/f mice which suggests that the antidepressant-like effects of ketamine require GluN1 in PV interneurons.”

What the sources say

• Disputed

  The Results section reports no significant difference in immobility or swimming between the mutant and control mice at the stated time points. But the claim reverses the paper’s conclusion: the Introduction says the acute antidepressant-like effects of NMDAR antagonists are not dependent on NMDAR transmission in PV neurons, and the Discussion says PV-neuron NMDAR activity is not their primary target. No page numbers are provided in our copy. (LLM, conf=0.90)

  Checked by a reasoning model — may be wrong.

  cites Pozzi et al., 2014 sourceExperimental — accuracy not yet measured

In the paper

“saline treated PVCreGluN1 and GluN1f/f mice appear to have a 2- to 3-fold higher immobility and lower swimming time relative to C57BL/6N WT which suggests that the GluN1f/f mutation was alone sufficient to impact the FST.”

What the sources say

• Disputed

  The Results (Figures 1 and 2) report saline-treated wild-type immobility of 161–208 seconds and floxed and PV-Cre mutant immobility of 174–214 seconds across the test days—not a two- to threefold difference. The paper does not establish that the floxed mutation alone affects forced-swim behavior; it reports similar immobility for the mutant and floxed littermates. (LLM, conf=0.91)

  Checked by a reasoning model — may be wrong.

  cites Pozzi et al., 2014 sourceExperimental — accuracy not yet measured

In the paper

“In the population of patients that are resistant to monoamine system targeting therapies, ketamine has been shown to facilitate remission, hence the current indication by the FDA (Lapidus et al., 2014).”

What the sources say

• Disputed

  The Results > Efficacy report a rapid antidepressant response in patients who had failed prior treatment, but do not report that ketamine produced remission. More decisively, the Discussion describes treatment of refractory depression as a potential use “should it gain approval for this indication,” contrary to the claim that it already had an FDA indication. Page numbers were not available in our copy. (LLM, conf=0.86)

  Checked by a reasoning model — may be wrong.

  cites Lapidus et al., 2014 sourceExperimental — accuracy not yet measured

In the paper

“which led to the (S)-ketamine nasal spray (under the brand name Spravato®) receiving FDA approval in March of 2019 as an adjunct treatment for adults with treatment-resistant depression, or major depression with suicidal thoughts or actions”

What the sources say

• Partly supported

  The paper states that the FDA approved esketamine for treatment-resistant depression in March 2019. It does not state that the approval covered major depression with suicidal thoughts or actions, or specify the nasal-spray formulation or adjunct use. Its mention of suicidal ideation and behaviors concerns adverse effects, not an approved indication. (LLM, conf=0.88)

  cites Cristea & Naudet, 2019 sourceExperimental — accuracy not yet measured

In the paper

“Plasma levels of ketamine, norketamine, DHNK, and (2R,6R)-HNK were still detectable (>4 ng/mL) one-day post-ketamine infusion (0.5 mg/kg i.v. over 40 minutes) in patients”

What the sources say

• Partly supported

  The Results (Plasma Concentrations of Ketamine and Metabolites; page unavailable) report day-1 concentrations of at least 4 ng/mL for ketamine, NK, DHNK, and HNK4a in patients with bipolar depression. The corresponding MDD passage instead prints day-1 concentrations as <4 ng/mL. The paper reports HNK4a as the (2S,6S;2R,6R) pair, so it does not establish that the specific (2R,6R) enantiomer alone exceeded 4 ng/mL. (LLM, conf=0.86)

  cites Zarate et al., 2012 sourceExperimental — accuracy not yet measured

In the paper

“Unfortunately, current therapeutic tools have failed to reduce the prevalence of depression, with many patients not responding to, and most having significant side effects from, first-line treatments such as selective serotonin reuptake inhibitors (SSRIs)”

What the sources say

• Partly supported

  The Introduction identifies SSRIs as first-line pharmaceutical treatments for the pediatric disorders studied. The Discussion reports a small, disorder-dependent benefit, and Results > Side Effect Analysis finds more adverse events with antidepressants than placebo. Neither passage establishes that many patients fail to respond to SSRIs or that most experience significant side effects; the study also concerns children and adolescents, not patients generally. No page numbers were provided in our copy. (LLM, conf=0.86)

  cites Locher et al., 2017 sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites Trivedi et al., 2006 source

In the paper

“Norketamine, DHNK, and (2R,6R;2S,6S)-HNK in particular are detected in human plasma as early as 40 minutes following an antidepressant dose of ketamine (0.5 mg/kg i.v. over 40 minutes) with the most abundant HNKs being (2R,6R;2S,6S)-HNK and (2S,6R;2R,6S)-HNK”

What the sources say

• Partly supported

  Results §3.4.1 reports norketamine, DHNK, and both named HNK pairs in plasma, with those HNK pairs the most abundant. But Results §3.4 and Experimental §2.7 describe sampling on day 3 of a five-day infusion for complex regional pain syndrome, not detection at 40 minutes after a 0.5 mg/kg antidepressant dose. Page numbers are unavailable in our copy. (LLM, conf=0.91)

  cites Moaddel et al., 2010 sourceExperimental — accuracy not yet measured
• Supported

  The Methods and Materials sections (page unavailable) describe a 0.5 mg/kg intravenous ketamine infusion over 40 minutes and plasma sampling at its end. The Results section (page unavailable) reports NK, DHNK, HNK4a, and HNK4b in plasma during the sampled period, treating HNK4a and HNK4b as the prominent HNK metabolites; the paper identifies them as the two stereoisomer pairs named in the claim. (LLM, conf=0.86)

  cites Zarate et al., 2012 source
• Partly supported

  The Abstract (page not provided) reports plasma sampling beginning at 40 minutes after the start of a 0.5 mg/kg, 40-minute ketamine infusion and detects norketamine, DHNK, and (2S,6S;2R,6R)-HNK. The Discussion (page not provided) identifies the two named HNKs as predominant in earlier CRPS-patient data, not in this study’s bipolar-depression patients; among the other HNKs measured in this study, it names (2S,5R;2R,5S)-HNK as most predominant. (LLM, conf=0.88)

  cites Zhao et al., 2012 sourceExperimental — accuracy not yet measured

In the paper

“A follow-up report observed that prolonged treatment (weekly or biweekly treatment) with (S)-ketamine nasal spray (56-84 mg; 16 weeks), in conjunction with an oral antidepressant (SSRI or a selective norepinephrine reuptake inhibitor [SNRI]), was well-tolerated with significant remission of symptoms.”

What the sources say

• Partly supported

  The Maintenance Phase section (page unavailable) describes 56–84 mg esketamine with an oral antidepressant over 16 weeks, followed by weekly or biweekly maintenance dosing. The Discussion and Safety Results (pages unavailable) report no new safety concerns and mostly mild-to-moderate maintenance-phase adverse events. However, the Efficacy Results report a significant delay in relapse among patients who had already achieved remission or response—not a significant rate of remission produced by prolonged treatment. (LLM, conf=0.88)

  cites Daly et al., 2019 sourceExperimental — accuracy not yet measured

In the paper

“NMDARs are heterotetrameric ligand-gated ionotropic receptors”

What the sources say

• Supported

  The Introduction identifies NMDA receptors as ionotropic glutamate receptors and defines that class as ligand-gated ion channels. Section II.A describes NMDA receptors as tetramers assembled from different GluN subunits, supporting “heterotetrameric.” Page numbers are unavailable in our copy. (LLM, conf=0.94)

  cites Hansen et al., 2021 source
• Supported

  The Synaptic and Extrasynaptic N-Methyl-D-aspartate Receptors section describes NMDA receptors as heterotetramers. The N-Methyl-D-aspartate Receptor Agonists section says that binding glycine and glutamate is required for activation, and the Nature of the Ion Permeation Pathway section describes their ion channel. Page numbers are not available in the supplied passages. (LLM, conf=0.93)

  cites Traynelis et al., 2010 source

In the paper

“The NMDAR has two ligand binding sites, with GluN2 binding to the primary agonist glutamate whereas GluN1 and GluN3 bind glycine or D-serine, in which binding is obligatory for activation by glutamate”

What the sources say

• Supported

  The paper’s discussion of agonist-binding domains (page unavailable) states that NMDAR activation requires simultaneous binding of glutamate and glycine or D-serine, and that NR2 binds glutamate while NR1 and NR3 bind glycine. Figure 1 also identifies glycine or D-serine as a co-agonist at NR1. (LLM, conf=0.91)

  cites Paoletti & Neyton, 2007 source
• ?Not checked — no full text of the sourcecites Pérez-Otaño et al., 2016 source

In the paper

“Given that the evidence of PCP, MK-801, and memantine exerting antidepressant-like effects in rodents is mixed, with clinical studies either failing or lacking”

What the sources say

• Partly supported

  The passage labeled Abstract (page not provided) reports antidepressant-like effects of MK-801 in mice at 30 minutes and 3 hours, but not at 24 hours. It does not address rodent evidence for PCP or memantine, or whether clinical studies of those drugs failed or were lacking. Its discussion of successful clinical studies concerns ketamine instead. (LLM, conf=0.82)

  cites Autry et al., 2011 sourceExperimental — accuracy not yet measured
• Partly supported

  The Pharmacology section says NMDAR channel blockers such as MK-801 typically have not shown ketamine’s sustained antidepressant effects in preclinical models, and the Clinical Studies section reports that memantine failed in multiple placebo-controlled MDD trials. The copy does not establish mixed rodent findings for all three named drugs or state that clinical studies of PCP and MK-801 are lacking; its reference to phencyclidine concerns NMDAR activity, not antidepressant effects. Page numbers were not provided. (LLM, conf=0.86)

  cites Gould et al., 2019 sourceExperimental — accuracy not yet measured
• Partly supported

  The Introduction and Discussion (pages unavailable) describe mixed rodent findings: PCP showed a partial antidepressant-like effect in this study but no effect in an earlier forced-swim test; MK-801 lacked an antidepressant-like profile in the DRL procedure, while memantine showed antidepressant-like effects in forced-swim tests. The Introduction calls the clinical literature on PCP limited, and the Discussion says PCP is unlikely to be tested clinically. The paper does not establish that clinical studies of all three drugs failed or are lacking. (LLM, conf=0.85)

  cites Hillhouse & Porter, 2014 sourceExperimental — accuracy not yet measured

In the paper

“This study observed a similar rapid reduction (within two hours) in depression symptoms as measured by the Montgomery-Åsberg Depression Rating Scale (MADRS) following an intranasal (S)-ketamine treatment (28 or 84 mg), which separated from placebo even at one week following a single administration.”

What the sources say

• Partly supported

  The Efficacy Assessments section records MADRS measurements two hours after dosing, and the Efficacy section reports rapid improvement and greater MADRS reductions than placebo after one week for the esketamine doses. But the Design section specifies twice-weekly dosing on days 1 and 4; the one-week result was not measured after a single administration. Page numbers are unavailable in our copy. (LLM, conf=0.90)

  cites Daly et al., 2018 sourceExperimental — accuracy not yet measured

In the paper

“DHNK is not detected in brain tissue samples in mice following ketamine administration, and presumably not in humans either”

What the sources say

• Partly supported

  The Results report that DHNK was detected in mouse brain tissue after ketamine administration, but its level was below quantification—not that it was absent. The paper reports no human brain measurements, so it does not establish the proposed extension to humans. (LLM, conf=0.88)

  cites Can et al., 2016 sourceExperimental — accuracy not yet measured

In the paper

“pyramidal neurons in the cingulate and secondary motor cortex were found to respond to ketamine (10 mg/kg) through an increase in Ca2+ event rate, particularly in dendritic spines, indicative of a hyperactive state which was facilitated by a reduction in Ca2+ events in SST interneurons (Ali et al., 2020).”

What the sources say

• Supported

  Split into 2 atoms — 2 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites Ali et al., 2020 source

In the paper

“another study showed that the IC50 values of ketamine at GluN2A/B/C/D-containing NMDARs expressed in Xenopus laevis oocytes in the presence of 50 μM glutamate, 30 μM glycine, and in the absence of Mg2+ at a pH of 7.6, are 3.3, 0.9, 1.7, and 2.4 μM, respectively, which suggests that GluN2B is most vulnerable to ketamine antagonism”

What the sources say

• Supported

  Results Table 2 gives the pH 7.6 IC50 values for racemic ketamine at NR1/NR2A, B, C and D as 3.31, 0.927, 1.65 and 2.42 μM, respectively; NR2B has the lowest value. The Table 2 note specifies 50 μM glutamate and 30 μM glycine, while the Methods describe recordings in Xenopus oocytes using a bath solution without Mg2+. Page numbers are unavailable in our copy. (LLM, conf=0.94)

  cites Dravid et al., 2007 source

In the paper

“A study found that ketamine (20 μM bath application) enhances phosphorylation of GluA1 S845 at the SC-CA1 synapse of mice up to two hours post-treatment and its rapid (30 minutes) and long-term (7 days) antidepressant-like effects in the forced swim test (10 mg/kg i.p.) are blocked in mice with S845 mutated to an alanine residue that cannot be phosphorylated”

What the sources say

• Partly supported

  The Results sections on GluA1 phosphorylation and S845A mice report that bath-applied ketamine increased Ser845 phosphorylation in hippocampal CA1 tissue and that ketamine reduced forced-swim immobility in wild-type mice but not S845A mice (page unavailable). The phosphorylation experiments described there used rat slices, not mouse slices; our copy reports an effect as early as 15 minutes but does not establish the claimed 20 μM dose or persistence for two hours. The S845A results do not establish forced-swim effects at both 30 minutes and seven days, or the specified 10 mg/kg dose. (LLM, conf=0.89)

  cites Zhang et al., 2016 sourceExperimental — accuracy not yet measured

In the paper

“Conversely, Ro25-6981 (1 μM, 20-minute bath application) does not significantly impact action potential probability and increases inhibitory currents.”

What the sources say

• Supported

  The Results report that 1 μM Ro 25-6981 significantly increased both the frequency and amplitude of spontaneous inhibitory postsynaptic currents, while synaptically driven action-potential probability did not increase significantly (P = 0.25). The Methods describe comparing a 10-minute baseline with the last five minutes of drug application, consistent with the 20-minute application described in the claim. Page numbers are unavailable in our copy. (LLM, conf=0.92)

  cites Widman & McMahon, 2018 source

In the paper

“These authors suggest that ketamine may have some selectivity for GluN2C/D-containing NMDARs in the presence of physiological Mg2+”

What the sources say

• Supported

  The Discussion states that 1 mM extracellular Mg2+ enhances ketamine’s selectivity for NR1/2C and NR1/2D receptors. It also describes ketamine’s preferential inhibition as weaker than memantine’s, consistent with the citing sentence’s cautious wording. No page number is supplied in our copy. (LLM, conf=0.94)

  cites Kotermanski & Johnson, 2009 source

In the paper

“Likewise, (2R,6R)-HNK (10 μM, 60-minute bath application) was observed to increase AMPAR-mediated synaptic strength in the CA1 of rats, however it appears that this effect is likely presynaptic due to an increase in glutamate release probability”

What the sources say

• Supported

  The Results report that 10 µM (2R,6R)-HNK potentiated Schaffer collateral–CA1 fEPSPs and reduced paired-pulse ratio, consistent with increased glutamate release probability. The Fig. 1 caption identifies these as AMPAR-mediated responses in rat hippocampal slices; the Fig. 2 caption shows measurements after 60 minutes of superfusion. No page numbers are available in our copy. (LLM, conf=0.90)

  cites Riggs et al., 2020 source

In the paper

“This behavioral effect corresponded to a disinhibition of layer 5 mPFC pyramidal neurons whereby inhibition of GABA signaling strengthened pyramidal neuron activity.”

What the sources say

• Partly supported

  The Discussion reports that GluN2B knockdown or deletion in Sst interneurons increased excitatory currents in layer V mPFC pyramidal neurons and was associated with antidepressant-like behavior in male mice. It identifies this as disinhibition, but says the electrophysiological association was not observed in females; the claim omits that limitation. The indexed passages provide a section label but no page number. (LLM, conf=0.86)

  cites Gerhard et al., 2020 sourceExperimental — accuracy not yet measured

In the paper

“Notably, 50 μM and 1 mM glutamate roughly estimate extrasynaptic and active synaptic glutamate levels, respectively”

What the sources say

• Partly supported

  The Abstract (p. 5265) says glutamate in the synaptic cleft is thought to rapidly rise above 1 mM, supporting 1 mM as a rough synaptic value. But it estimates the extrasynaptic peak at 160–190 μM, not 50 μM. (LLM, conf=0.90)

  cites Dzubay & Jahr, 1999 sourceExperimental — accuracy not yet measured
• Partly supported

  The Abstract says glutamate in the synaptic cleft exceeds 1 mM briefly after action-potential-mediated release, supporting the active-synaptic estimate. But it gives 0.02–30 μM for extracellular glutamate outside the cleft, while the section on in vivo measurements identifies a tonic pool of 1–5 μM; neither supports 50 μM as a rough extrasynaptic level. Page numbers are unavailable in our copy. (LLM, conf=0.91)

  cites Moussawi et al., 2011 sourceExperimental — accuracy not yet measured

In the paper

“Intriguingly, the lack of an effect on action potential probability may be due to differential effects of Ro-256981 on individual cells, given that only a subset of cells showed an increase or showed a decrease following treatment.”

What the sources say

• Partly supported

  The Results report no statistically significant effect of Ro 25-6981 on synaptically driven action-potential probability across 10 recorded cells (Fig. 3E–F), and no effect on population excitability (Fig. 6D). The passages do not report that some individual cells increased while others decreased, or propose that such differences explain the nonsignificant result. (LLM, conf=0.83)

  cites Widman & McMahon, 2018 sourceExperimental — accuracy not yet measured

In the paper

“ketamine (3 mg/kg) reduced immobility and increased swimming behavior in wild-type (WT) mice 30 minutes and 24 hours post-treatment.”

What the sources say

• Supported

  The Results section ('Acute and sustained antidepressant effects of ketamine and MK801 in C57 mice,' Fig. 4A–B) reports that 3 mg/kg ketamine significantly reduced immobility and increased swimming in C57BL/6N mice at both 30 minutes and 24 hours compared with saline. These mice were the non-mutant mice used for the time-course experiment; the copy does not give a page number. (LLM, conf=0.95)

  cites Pozzi et al., 2014 source

In the paper

“peak levels of (2R,6R)-HNK in the mouse hippocampus were 7.57 ± 2.13 μM 10 minutes following systemic administration of a dose (10 mg/kg i.p.) that results in antidepressant-like effects in several behavioral tests and returned to near baseline levels by two hours post-administration.”

What the sources say

• Supported

  The Results report that hippocampal extracellular (2R,6R)-HNK peaked at 7.57 ± 2.13 μM 10 minutes after a 10 mg/kg i.p. dose in mice. By two hours, it had fallen to 0.054 ± 0.015 μM, or 0.7% of the maximum; the paper describes this dose as producing antidepressant-relevant effects. (LLM, conf=0.95)

  cites Lumsden et al., 2019 source

In the paper

“(2R,6R)-HNK has a binding affinity (Ki) and IC50 greater than 100 μM with 24% inhibition at 100 μM, and fails to impact NMDA-evoked currents in CA1 interneurons (Moaddel et al., 2013; Morris et al., 2017; Zanos et al., 2016).”

What the sources say

• Partly supported

  Results §3.3 reports an NMDA-receptor binding Ki >100 μM for (2R,6R)-HNK. The Abstract reports IC50 >100 μM for inhibition of α3β4 nicotinic-receptor currents, not NMDA-evoked currents. Our copy does not report 24% inhibition at 100 μM or measurements of NMDA-evoked currents in CA1 interneurons; its NMDA binding assay used rat brain membranes (Methods §2.6; page numbers unavailable). (LLM, conf=0.88)

  cites Moaddel et al., 2013 sourceExperimental — accuracy not yet measured
• Partly supported

  The NMDA-receptor assay discussion (section labeled Abstract; page unavailable) reports that (2R,6R)-HNK produced 24% inhibition at 100 μM. Our copy does not state the claimed Ki and IC50 values for this compound or report an experiment on NMDA-evoked currents in CA1 interneurons. (LLM, conf=0.85)

  cites Morris et al., 2017 sourceExperimental — accuracy not yet measured
• Partly supported

  The '(2R,6R)-HNK effects on glutamate receptors' section says (2R,6R)-HNK does not displace NMDAR [3H]-MK-801 binding or functionally inhibit NMDARs on hippocampal stratum radiatum interneurons, supporting the claim about NMDA-evoked currents. Our copy does not report a Ki or IC50 greater than 100 μM or 24% inhibition at 100 μM, so it does not support those numerical details. (LLM, conf=0.87)

  cites Zanos et al., 2016 sourceExperimental — accuracy not yet measured

In the paper

“The mGluR2/3 receptor is inhibitory through its coupling to Gαi and consequent reduction in adenylate cyclase activity and cAMP production. It is most frequently localized to the presynaptic terminal and acts as an autoreceptor for glutamate that when activated inhibits the opening of voltage gated Ca2+ channels thus reducing vesicular release of neurotransmitter (Chavis et al., 1994; Shigemoto et”

What the sources say

• Partly supported

  Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites Chavis et al., 1994 sourceExperimental — accuracy not yet measured
• Partly supported

  Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites Shigemoto et al., 1997 sourceExperimental — accuracy not yet measured

In the paper

“The ketamine metabolite (2R,6R)-HNK has received significant attention due to its efficacy in rodent models of depression, while lacking psychotomimetic side effects and abuse potential (Zanos et al., 2016).”

What the sources say

• Supported

  The “Antidepressant actions of HNK” section reports antidepressant-like effects of (2R,6R)-HNK in several mouse behavioural tests. The “(2R,6R)-HNK lacks ketamine’s side effects” section reports no ketamine-like sensory-gating or drug-discrimination effects, and no self-administration at pharmacologically relevant doses under the tested conditions. These rodent findings support the citing sentence; they do not establish an absence of abuse potential in humans. (LLM, conf=0.90)

  cites Zanos et al., 2016 source

In the paper

“heterozygous and homozygous Val/Met and Met/Met mice had significantly reduced dendrite length, distal spine density, reduced spine diameter, and increased spine length (spine length not impacted in heterozygotes) in layer 5 mPFC pyramidal neurons relative to Val/Val WT controls (Liu et al., 2012).”

What the sources say

• Partly supported

  Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites Liu et al., 2012 sourceExperimental — accuracy not yet measured

In the paper

“Using a chronic (21 day) corticosterone (CORT) exposure model of depression in mice, this study demonstrated that CORT induces dendritic spine elimination in the mPFC which is rescued 24 hours following a single ketamine treatment (10 mg/kg i.p.).”

What the sources say

• Partly supported

  The Results sections report spine loss after chronic CORT exposure, including a 21-day assessment, and imaging 24 hours after a single 10 mg/kg intraperitoneal ketamine dose (page numbers unavailable). Ketamine reversed the effect on spine density, but “rescued” overstates recovery of the eliminated spines: 51.7% of lost spines were not restored, and ketamine did not significantly change spine elimination rates. (LLM, conf=0.88)

  cites Moda-Sava et al., 2019 sourceExperimental — accuracy not yet measured

In the paper

“BDNF can be stored in presynaptic terminals or dendrites and released in an activity-dependent manner. Once released, BDNF binds to its primary receptor Tropomyosin receptor kinase B (TrkB) (De Vincenti et al., 2019).”

What the sources say

• Supported

  The “Pre vs. Postsynaptic Release of BDNF and Its Impact on LTP” section (page unavailable) describes presynaptic BDNF release and activity-evoked release from a stimulated dendritic spine, followed by TrkB activation. The “Subcellular Compartmentalization” section (page unavailable) also describes BDNF localization in dendrites. Together, these passages support the claim’s account of where BDNF is present, how it is released, and its TrkB signaling. (LLM, conf=0.88)

  cites De Vincenti et al., 2019 source

In the paper

“Brain derived neurotrophic factor (BDNF) is a peptide consisting of 118 highly conserved amino acids among vertebrate species that regulates cellular and molecular mechanisms of neuronal survival and synaptic plasticity in the adult brain and has therefore been implicated in several neuropsychiatric disorders (Autry & Monteggia, 2012; Duman et al., 2016; Götz et al., 1992; Radziejewski et al., 199”

What the sources say

• Partly supported

  The Introduction and “Brain-Derived Neurotrophic Factor Functions in Neurons” describe BDNF’s role in synaptic plasticity in the mature brain, neuronal survival, and neuropsychiatric disorders. The passages on BDNF’s structure and functions do not state that it consists of 118 amino acids or that its sequence is highly conserved among vertebrates; no page numbers are available in our copy. (LLM, conf=0.88)

  cites Autry & Monteggia, 2012 sourceExperimental — accuracy not yet measured
• Partly supported

  The “Reduced neurotrophic factor expression in stress and depression” section (page not provided) links BDNF to synaptic connections, neuronal survival pathways, and depression; “Antidepressants and synaptic plasticity” (page not provided) describes BDNF-dependent plasticity in adult animals. Our copy does not state that BDNF has 118 amino acids conserved among vertebrates or implicate it in several neuropsychiatric disorders beyond depression. (LLM, conf=0.88)

  cites Duman et al., 2016 sourceExperimental — accuracy not yet measured
• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites Götz et al., 1992

In the paper

“It appears that (2R,6R)-HNK produces antidepressant-like effects and an enhancement in AMPAR signaling independent of NMDAR antagonism which suggests that NMDARs do not fully explain the mechanism of action of ketamine (Riggs et al., 2020; Zanos et al., 2016).”

What the sources say

• Supported

  The Introduction reports antidepressant-like actions of (2R,6R)-HNK and says AMPAR activation is required for them, while HNK has low potency for inhibiting NMDARs. The Discussion reports that HNK potentiated hippocampal glutamatergic transmission despite NMDAR blockade; the Introduction also notes that other NMDAR antagonists have not reproduced ketamine’s full antidepressant effects. Page numbers were not provided in our copy. (LLM, conf=0.88)

  cites Riggs et al., 2020 source
• Supported

  The “Antidepressant actions of HNK” section reports antidepressant-like effects of (2R,6R)-HNK in mouse behavioral tests. The “(2R,6R)-HNK effects on glutamate receptors” section reports increased AMPA receptor-mediated signaling without detectable NMDAR inhibition, and the Discussion implicates an NMDAR inhibition-independent mechanism in ketamine’s antidepressant effects. Page numbers were not provided in our copy. (LLM, conf=0.93)

  cites Zanos et al., 2016 source

In the paper

“Estimates suggest that 51.4% of the opioid prescriptions in the United States are received by the 16% of Americans who have a mood or anxiety disorder”

What the sources say

• Supported

  The Abstract defines the studied mental health disorders as mood and anxiety disorders and states that the 16% of Americans with these disorders receive 51.4% of opioid prescriptions. The Results give the same prescription estimate for U.S. adults. (LLM, conf=0.94)

  cites Davis et al., 2017 source

In the paper

“This study also used G-protein recruitment assays to conclude that (2R,6R)-HNK acts as an inverse agonist, with IC50 values of 0.56 nM and 2.1 x 10−5 nM for the μ and κ-opioid receptor, respectively.”

What the sources say

• Supported

  The Results and Discussion section, “Inverse Agonism of HNK in MOR and KOR,” reports that HNK was an inverse agonist in [35S]GTPγS assays and gives IC50 values of 0.56 nM for MOR and 2.1 × 10−5 nM for KOR. It notes that the KOR estimate was too low for a precise confidence interval. (LLM, conf=0.95)

  cites Joseph et al., 2021 source

In the paper

“Ketamine and (2R,6R)-HNK could displace binding of fluoxetine to TrkB which suggests that they are also capable of binding TrkB.”

What the sources say

• Supported

  In Results, under “Antidepressants bind to TRKB transmembrane domain,” the paper reports that ketamine (KET) and R,R-HNK displaced biotinylated fluoxetine binding to TRKB. The same section explicitly interprets their competition with fluoxetine as evidence that these compounds bind TRKB. (LLM, conf=0.95)

  cites Casarotto et al., 2021 source

In the paper

“cholesterol is an essential component in the function of TrkB, and is necessary for TrkB to engage downstream PLC activity.”

What the sources say

• Partly supported

  In Results, “Cholesterol sensing by TRKB” (page not provided), cholesterol enhances BDNF-induced TRKB phosphorylation, while cholesterol sequestration or synthesis inhibition blocks the BDNF-induced increase in TRKB–PLC-γ1 interaction. These experiments support a role for cholesterol in that coupling, but measure interaction rather than PLC activity and do not establish that cholesterol is universally essential for all TRKB function. (LLM, conf=0.84)

  cites Casarotto et al., 2021 sourceExperimental — accuracy not yet measured

In the paper

“Another study reported similar observations that ketamine interactions are stereoselective for recombinant human opioid receptors expressed in Chinese hamster ovary cells (Hirota et al., 1999).”

What the sources say

• Partly supported

  The Results (p. 5) report greater binding potency for S(+)- than R(−)-ketamine at μ, κ, and δ receptors in CHO cells. But the Discussion (pp. 6–7) limits the δ finding to a small effect at supraclinical concentrations, rather than the stereoselectivity observed at μ and κ. Our copy identifies the μ, κ, and δ receptors as recombinant, but does not establish that those receptors were human. (LLM, conf=0.86)

  cites Hirota et al., 1999 sourceExperimental — accuracy not yet measured

In the paper

“fluoxetine, ketamine, and (2R,6R)-HNK facilitated PLC activity in cortical neurons through TrkB which was prevented by cholesterol sequestration.”

What the sources say

• Partly supported

  The Results section on antidepressant binding (Figure 2A; page unavailable) reports that fluoxetine and ketamine increased phosphorylated TRKB associated with PLC-γ1 in cortical neurons, but it does not establish increased PLC activity or report that result for (2R,6R)-HNK. The cholesterol-sensing Results (Figure 1C,F; page unavailable) show that cholesterol sequestration blocked BDNF-induced TRKB–PLC-γ1 interaction and fluoxetine-induced TRKB surface exposure, not the claimed drug-induced PLC activity. (LLM, conf=0.88)

  cites Casarotto et al., 2021 sourceExperimental — accuracy not yet measured

In the paper

“this study showed that (S)-ketamine acted as a partial G protein signaling agonist at μ opioid receptors (EC50 = 9 μM, Emax = 48%) and as a full agonist at κ opioid receptors (EC50 = 16 μM, Emax = 84 %)”

What the sources say

• Supported

  The Results section reports that, in the cAMP assay, (S)-ketamine was a partial agonist at MOR and a full agonist at KOR. It gives the same EC50 and Emax values as the citing sentence, rounded without their uncertainty ranges. (LLM, conf=0.95)

  cites Bonaventura et al., 2021 source

In the paper

“ketamine counters the hyper-excitatory state present in ascending pain circuitry through NMDAR inhibition while also enhancing the activity of brain regions involved in top-down inhibition of pain centers such as the PFC and brainstem (Niesters et al., 2012).”

What the sources say

• Partly supported

  The PAIN MEDICINE section identifies ketamine as an NMDA receptor antagonist and links pain relief to increased connectivity in the orbitofrontal cortex and brainstem, regions involved in descending pain inhibition. The RSN Connectivity on Pain Processing section attributes that connectivity change to variation in pain scores, not simply to a drug-induced increase in activity. The paper does not establish that ketamine counters a hyper-excitatory state in ascending pain circuitry through NMDA receptor inhibition. (LLM, conf=0.86)

  cites Niesters et al., 2012 sourceExperimental — accuracy not yet measured

In the paper

“Whereas naltrexone blocked the antidepressant-like effects of ketamine in the forced swim test, it had no impact on immobility on its own.”

What the sources say

• Supported

  In “Antidepressant Effect of Ketamine Is Blocked by Naltrexone,” the authors report that naltrexone pretreatment abolished ketamine’s reduction of immobility in cLH rats in the modified forced swim test. They also report that naltrexone alone had no significant effect on immobility (Fig. 2A). (LLM, conf=0.94)

  cites Klein et al., 2020 source

In the paper

“However, this study’s main findings rely on computational analysis and the predicted affinity and G protein recruitment values it reports are not consistent with several prior publications (Bonaventura et al., 2021; Hirota et al., 1999; Nemeth et al., 2010).”

What the sources say

• Partly supported

  The Results section reports measured ketamine binding affinities and opioid-receptor signaling, including G-protein-sensitive [35S]GTPγS recruitment. Bonaventura et al. do not discuss Joseph et al.’s predictions or computational methods, so this source alone cannot establish that Joseph et al.’s values conflict with these measurements or that their conclusions depend on computational analysis. No page numbers were provided in our copy. (LLM, conf=0.78)

  cites Bonaventura et al., 2021 sourceExperimental — accuracy not yet measured
• Partly supported

  Table 2 (Discussion, p. 5) reports measured ketamine affinities at μ, κ, and δ opioid receptors, providing earlier values against which predictions could be compared. The Discussion (p. 8) reports effects on cAMP signaling, but the paper does not measure G protein recruitment or compare its results with Joseph et al.’s predictions. It therefore cannot establish the claimed inconsistency in recruitment values. (LLM, conf=0.82)

  cites Hirota et al., 1999 sourceExperimental — accuracy not yet measured
• Partly supported

  The Methods and Results sections (“In vitro binding studies”; page unavailable) report measured KOR binding affinity and G-protein activity for ketamine and salvinorin A, so Nemeth et al. provides earlier experimental findings relevant to the comparison. This paper does not address Joseph et al.’s computational analysis or report its predicted values, so our copy cannot establish the claimed inconsistency. (LLM, conf=0.82)

  cites Nemeth et al., 2010 sourceExperimental — accuracy not yet measured

In the paper

“at sufficient doses (R)-ketamine does induce a conditioned place preference, as well as locomotor stimulation, in mice (Yang et al., 2020; Zanos, Highland, Liu, et al., 2019).”

What the sources say

• ?Not checked — no full text of the sourcecites Yang et al., 2020 source
• Supported

  The Results section (3.3) reports that (R)-ketamine induced hyperlocomotion at 40 and 80 mg·kg−1 and robust conditioned place preference at 40 mg·kg−1 in mice. The Discussion likewise states that 40 mg·kg−1 was sufficient for both effects. (LLM, conf=0.94)

  cites Zanos, Highland, Liu, et al., 2019 source

In the paper

“(S)-ketamine induces conditioned place preference in mice and conditioned operant lever responding for an infusion in rats whereas (R)-ketamine largely does not”

What the sources say

• Supported

  The Results section reports conditioned place preference in male mice given (S)-ketamine but not (R)-ketamine, and reliable intravenous self-administration of (S)-ketamine but not (R)-ketamine in rats. The Methods section specifies that rats pressed an active lever to receive infusions. Page numbers were not available in our copy. (LLM, conf=0.94)

  cites Bonaventura et al., 2021 source

In the paper

“compounds that target the monoamine systems such as SSRIs, SNRIs, and tricyclic antidepressants which collectively impair the clearance of monoamines from the extracellular space by blocking the serotonin transporter (SERT) and norepinephrine transporter (NET) (Ferguson, 2001).”

What the sources say

• Supported

  In “SSRI Antidepressant Medications: Adverse Effects and Tolerability” (page not specified), the paper says SSRIs inhibit serotonin reuptake, lists serotonin–norepinephrine reuptake inhibitors as inhibiting both, and says tricyclics inhibit reuptake of serotonin and norepinephrine, among other transmitters. It does not use the names SERT and NET, but blocking those transporters is a reasonable paraphrase of the reuptake mechanism described; the claim does not require every drug to block both. (LLM, conf=0.88)

  cites Ferguson, 2001 source

In the paper

“These behavioral effects corresponded to a reduction in serotonin clearance in the CA3 region of the hippocampus in WT mice but not SERT or PMAT knockout mice.”

What the sources say

• Supported

  Results §2.3 reports that ketamine prolonged serotonin clearance in hippocampal CA3 of wild-type mice, but not SERT or PMAT knockouts. Results §2.4 reports the matching pattern of antidepressant-like effects in the forced swim test. Page numbers are not available in our copy. (LLM, conf=0.94)

  cites Bowman et al., 2020 source

In the paper

“(2R,6R)-HNK (20 mg/kg) increased serotonin at 40- and 60-minutes post-treatment with a peak effect at ~140% of baseline whereas (2S,6S)-HNK and (R) and (S)-norketamine (20 mg/kg) were ineffective.”

What the sources say

• Partly supported

  The Results section reports that (2R,6R)-HNK at 20 mg/kg slightly but significantly increased prefrontal serotonin release, while (2S,6S)-HNK and both norketamine enantiomers at 20 mg/kg did not. Our text copy, including the Figure 1 caption, does not specify an increase at 40 and 60 minutes or a peak around 140% of baseline; those details remain unsupported. (LLM, conf=0.88)

  cites Ago et al., 2019 sourceExperimental — accuracy not yet measured

In the paper

“These behavioral effects corresponded to an increase in activity of serotonin neurons in the DRN as measured by c-Fos immunoreactivity which was blocked by NBQX.”

What the sources say

• Supported

  The Results report that LY341495 and ketamine increased c-Fos immunoreactivity in DRN serotonin neurons, and that NBQX microinjected into the mPFC blocked both increases. A separate Results passage reports that the same NBQX treatment blocked their behavioral effects in the forced swimming test. Page numbers were not provided in the supplied copy. (LLM, conf=0.94)

  cites Fukumoto et al., 2016 source

In the paper

“Conversely, (S)-ketamine (20 mg/kg) produced a large increase (~240% of baseline) 40 minutes post-treatment with a significant increase maintained following 120 minutes.”

What the sources say

• Partly supported

  The Results section reports that (S)-ketamine at 20 mg/kg significantly increased prefrontal dopamine release in mice. It does not give a value of approximately 240% of baseline at 40 minutes or establish that the increase remained significant at 120 minutes; the Figure 1 caption also provides no plotted values. Page numbers are unavailable in our copy. (LLM, conf=0.85)

  cites Ago et al., 2019 sourceExperimental — accuracy not yet measured

In the paper

“Intriguingly, (R) and (S)-ketamine appear to have agonist properties at μ and κ opioid receptors, with (S)-ketamine having a higher affinity”

What the sources say

• Supported

  The Results section on in vitro target engagement reports that both enantiomers activated μ and κ opioid receptors in a cAMP assay, with (R)-ketamine showing weaker partial agonism. The same section reports higher binding affinity for (S)-ketamine at both receptors. (LLM, conf=0.94)

  cites Bonaventura et al., 2021 source

In the paper

“with five dopamine receptors (D1-5), three norepinephrine receptors each with three subtypes (α1a,b,d, α2a,b,c and β1,2,3) and seven serotonin receptor families (5-HT1-7) comprised of 14 total receptors all of which are G-protein coupled, except for 5-HT3”

What the sources say

• ?Not checked — no full text of the sourcecites Beaulieu & Gainetdinov, 2011 source
• ?Not checked — no full text of the sourcecites Nichols & Nichols, 2008 source
• Partly supported

  The Abstract and “Nine subtypes” section identify three adrenergic receptor types, each with three subtypes, and describe adrenergic receptors as G-protein coupled. The paper does not establish the claimed counts for dopamine or serotonin receptors, or the 5-HT3 exception. Its α1 subtype list also uses α1C rather than the claim’s α1d; page numbers are unavailable in our copy. (LLM, conf=0.88)

  cites Strosberg, 1993 sourceExperimental — accuracy not yet measured

In the paper

“The endogenous source for the majority of monoamines in the forebrain come from the midbrain, with serotonin, norepinephrine, and dopamine arising from the dorsal raphe (DR), locus coeruleus (LC), and ventral tegmental area (VTA) or substantia nigra pars compacta, respectively”

What the sources say

• Partly supported

  The Introduction (page not provided) identifies the VTA and substantia nigra pars compacta as major sources of dopamine in the cerebral cortex and most subcortical areas. Our copy does not establish the claimed dorsal-raphe source of forebrain serotonin, locus-coeruleus source of forebrain norepinephrine, or the broader statement about most forebrain monoamines. (LLM, conf=0.88)

  cites Bromberg-Martin et al., 2010 sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites Itoi & Sugimoto, 2010 source
• ?Not checked — no full text of the sourcecites Michelsen et al., 2008 source

In the paper

“5-HT1B receptor binding was found to be significantly increased in the nucleus accumbens, ventral globus pallidus, and the midline nucleus reuniens of the thalamus which was blocked by AMPAR antagonism.”

What the sources say

• Supported

  The Discussion reports that, in conscious rhesus monkeys, ketamine significantly increased 5-HT1B receptor binding in the nucleus accumbens (Acb), ventral globus pallidus (ventral GP), and thalamic nucleus reuniens (Tha-Re). It also reports that pretreatment with the AMPA-receptor antagonist NBQX blocked those increases. (LLM, conf=0.94)

  cites Yamanaka et al., 2014 source

In the paper

“(2R,6R)-HNK but not (2S,6S)-HNK produced a transient peak effect (~160% of baseline) at 20 minutes which disappeared following 60 minutes.”

What the sources say

• Partly supported

  The Results section reports that (2R,6R)-HNK caused a slight but significant increase in prefrontal serotonin release, whereas (2S,6S)-HNK did not. Our text does not give a peak of approximately 160% of baseline at 20 minutes or say that the effect disappeared by 60 minutes; the Figure 1 caption identifies the experiment but does not provide those values. (LLM, conf=0.86)

  cites Ago et al., 2019 sourceExperimental — accuracy not yet measured

In the paper

“(S)-norketamine (20 mg/kg) produced a peak effect size (~150% of baseline) 40 minutes post-treatment whereas (R)-norketamine was ineffective.”

What the sources say

• Partly supported

  The Results section on prefrontal monoamine levels in normal mice reports that (S)-norketamine at 20 mg/kg increased noradrenaline release, whereas (R)-norketamine at the same dose did not. Figure 1’s caption identifies the treatments, but the text in our copy does not establish a peak of approximately 150% of baseline at 40 minutes; that numerical and timing detail remains unsupported. (LLM, conf=0.87)

  cites Ago et al., 2019 sourceExperimental — accuracy not yet measured

In the paper

“whereas (2R,6R)-HNK may be an inverse agonist at μ and κ-opioid receptors within antidepressant relevant concentrations, though these findings require replication.”

What the sources say

• Supported

  The Results and Discussion report that (2R,6R)-HNK was an inverse agonist at both μ and κ opioid receptors in G-protein recruitment assays. The Conclusions describe its low-nanomolar IC50 values as consistent with ketamine doses used for depression and call for further study. The claim’s cautious wording reflects that the paper does not establish an antidepressant mechanism in humans. (LLM, conf=0.93)

  cites Joseph et al., 2021 source

In the paper

“(S)-ketamine (20 mg/kg) produced an increase at 20,40, and 60 minutes with a peak effect size at ~175% of baseline with the 10 mg/kg dose lacking an effect at 60 minutes.”

What the sources say

• Partly supported

  The Results section on normal mice reports that (S)-ketamine at 20 mg/kg increased prefrontal serotonin release, and the Figure 1 caption says measurements were compared at individual time points (page not supplied). Our text copy does not give the claimed 20-, 40-, and 60-minute effects, the approximately 175% peak, or whether 10 mg/kg lacked an effect specifically at 60 minutes. It reports a significant overall increase at 10 mg/kg, which does not settle that time-specific claim. (LLM, conf=0.85)

  cites Ago et al., 2019 sourceExperimental — accuracy not yet measured

In the paper

“On the other hand, (S) and (R)-ketamine have agonist properties at μ and κ opioid receptors, an interaction which may be necessary for their antidepressant effects (Bonaventura et al., 2021).”

What the sources say

• Partly supported

  The Results section on in vitro target engagement reports that both enantiomers activate μ and κ opioid receptors, though (R)-ketamine is a weaker partial agonist. The Discussion links opioid receptors to ketamine’s antidepressant effects but notes conflicting human evidence and does not establish that this activity is necessary for the antidepressant effects of both enantiomers. Page numbers are unavailable in our copy. (LLM, conf=0.84)

  cites Bonaventura et al., 2021 sourceExperimental — accuracy not yet measured

In the paper

“dopamine, norepinephrine, and serotonin signaling have all been associated with strengthening AMPAR signaling through phosphorylation and membrane insertion which likely contribute to the antidepressant effects of ketamine (Cai et al., 2013; Diering & Huganir, 2018; Hu et al., 2007; Sun et al., 2005).”

What the sources say

• Partly supported

  The Results section (‘Molecular basis of 5-HT-mediated potentiation’; page not supplied) reports that serotonin strengthens AMPA receptor responses through CaMK-dependent GluA1 phosphorylation. It does not establish membrane insertion or the same AMPAR mechanism for dopamine or norepinephrine. The Discussion mentions ketamine’s potentiation of excitatory synapses, but does not link the serotonin mechanism to ketamine’s antidepressant effects. (LLM, conf=0.88)

  cites Cai et al., 2013 sourceExperimental — accuracy not yet measured
• Partly supported

  In “The AMPAR code and LTP” (page unavailable), the review links dopamine and adrenergic signaling to GluA1 phosphorylation and surface targeting, and serotonin to phosphorylation and synaptic potentiation. It separately says ketamine’s effect requires GluA1 S845 phosphorylation. It does not establish that the three neuromodulators’ effects on AMPAR phosphorylation and membrane insertion collectively contribute to ketamine’s antidepressant effect. (LLM, conf=0.87)

  cites Diering & Huganir, 2018 sourceExperimental — accuracy not yet measured
• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites Hu et al., 2007

In the paper

“(2R,6R)-HNK, was predicted to bind and was reported to act as an inverse agonist with IC50 values of 0.56 nM and 2.1 x 10−5 nM for the μ and κ-opioid receptor, respectively (Joseph et al., 2021).”

What the sources say

• Supported

  The Results and Discussion section, “Inverse Agonism of HNK in MOR and KOR,” reports that HNK was an inverse agonist in both receptors and gives the stated IC50 values. The paper also reports computationally predicted binding affinities. It cautions that the extremely low KOR IC50 could not be assigned a precise confidence interval with the ligand dilutions used. (LLM, conf=0.94)

  cites Joseph et al., 2021 source

In the paper

“(2R,6R)-HNK only produces transient increases in norepinephrine and serotonin in the PFC whereas dopamine was unchanged.”

What the sources say

• Partly supported

  The Results section reports increased prefrontal serotonin after (2R,6R)-HNK and no change in dopamine; the Discussion also says it increased norepinephrine. The claim’s “only brief” qualifier is not supported: the Discussion cites an increase in baseline prefrontal serotonin 24 hours after injection. No page numbers are available in our copy. (LLM, conf=0.85)

  cites Ago et al., 2019 sourceExperimental — accuracy not yet measured

In the paper

“These behavioral effects corresponded to a reduction in dopamine neuron activity in the VTA in helpless rats which was rescued by ketamine 20 minutes post-treatment.”

What the sources say

• Supported

  The Results section, “Ketamine restores dopaminergic population activity in the VTA of helpless rats,” reports reduced VTA dopamine-neuron population activity in helpless rats and its restoration 20 minutes after ketamine injection. The Discussion also links restored escape behavior with restored VTA dopamine activity at that time. Page numbers were not provided in our copy. (LLM, conf=0.94)

  cites Belujon & Grace, 2014 source

In the paper

“It is possible that inverse agonism of μ and κ-opioid receptors may help to restrict the potential for abuse of (2R,6R)-HNK similar to how naltrexone helps prevent relapse in opioid and alcohol use disorders, however this assertion requires further research”

What the sources say

• Partly supported

  The Results and Discussion section reports that HNK acts as an inverse agonist at μ and κ opioid receptors, and the Conclusions call for further study of its effects. The paper does not suggest that this action limits HNK’s abuse potential or discuss naltrexone preventing relapse in opioid or alcohol use disorders; its discussion of naltrexone concerns ketamine’s antidepressant effect. (LLM, conf=0.85)

  cites Joseph et al., 2021 sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites Anton et al., 2006 source
• Partly supported

  The paper’s introduction says extended-release naltrexone can protect against opioid relapse, and its Discussion reports short-term abstinence in people with opioid dependence. It does not study (2R,6R)-HNK or μ- and κ-receptor inverse agonism, and it does not establish relapse prevention in alcohol use disorder. Page numbers are unavailable in our copy. (LLM, conf=0.88)

  cites Tanum et al., 2017 sourceExperimental — accuracy not yet measured

In the paper

“Experimental conditions such as the concentration of NaCl and temperature can influence D2 receptor binding which might explain the discrepancy in these results (Can et al., 2016).”

What the sources say

• ?Could not verify

  The Discussion reports a discrepancy between earlier findings of ketamine affinity for D2-type receptors and this study’s findings, but does not attribute it to NaCl concentration or temperature. Searches for those experimental conditions found no passage in our copy linking them to D2 receptor binding. (LLM, conf=0.72)

  cites Can et al., 2016 sourceExperimental — accuracy not yet measured

In the paper

“(2R,6R)-HNK produces transient increases in extracellular serotonin and norepinephrine in the PFC of mice whereas (R) and (S)-ketamine collectively produced larger, prolonged increases in extracellular serotonin, norepinephrine, and dopamine (Ago et al., 2019).”

What the sources say

• Partly supported

  The Results section on monoamine levels in normal mouse PFC reports that (2R,6R)-HNK increased serotonin, that both ketamine enantiomers increased serotonin and norepinephrine, and that they increased dopamine at the tested doses. The Discussion also identifies an HNK-related norepinephrine increase. These passages do not establish the claimed comparison in duration—brief HNK effects versus prolonged ketamine effects—or a larger ketamine response for every transmitter. (LLM, conf=0.84)

  cites Ago et al., 2019 sourceExperimental — accuracy not yet measured

In the paper

“When administered 24 hours prior to recordings, ketamine rescued a decrease in the number of spontaneously firing dopamine neurons and rescued a reduction in their firing rate in learned helpless rats.”

What the sources say

• Supported

  The Results section, “Ketamine has sustained action on escape behavior and activity in the VTA,” reports that helpless rats had reduced dopamine-neuron population activity and firing rate, and that both were restored by ketamine injected 24 hours before recording. Population activity is measured as the number of spontaneously active dopamine neurons per electrode track. (LLM, conf=0.94)

  cites Belujon & Grace, 2014 source

In the paper

“several metabolites of ketamine have neuroactive effects of their own and may be leveraged as therapeutics”

In the paper

“Indeed, an emerging conclusion is that ketamine and its metabolites may have effects that are both dependent and independent of NMDAR antagonism, impacting several neurotransmitter systems to elicit their antidepressant effects”

In the paper

“While this finding was revolutionary and led to the FDA approval of (S)-ketamine (esketamine) for use in adults with treatment-resistant depression and suicidal ideation”

In the paper

“Given these observations, NMDAR antagonism is unlikely to be the sole mechanism of action that produces antidepressant effects.”

In the paper

“To overcome Mg2+ block, antecedent membrane depolarization is required. This often occurs through activation of the ionotropic glutamatergic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs)”

In the paper

“Additionally, SSRIs and other traditional antidepressants are problematic as they typically take weeks before therapeutic effects are observed and require daily administration”

What the sources say

• ?Not checked — no full text of the sourcecites Entsuah et al., 2001 source
• ?Not checked — no full text of the sourcecites Thase et al., 2005 source

In the paper

“There are three principal subunit types for NMDARs: GluN1, GluN2, and GluN3 with GluN1 being obligatory for cell surface expression.”

In the paper

“These properties are mimicked by other open-channel blockers such as PCP and MK-801 which are commonly used to model schizophrenia in preclinical studies”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites Jentsch & Roth, 1999

In the paper

“Regarding elimination of ketamine and its metabolites, the elimination half-life is between two to four hours, varying slightly with the route of administration”

What the sources say

• ?Not checked — no full text of the sourcecites Clements et al., 1982 source

In the paper

“Next, (R,S)-norketamine can either be converted into (R,S)-dehydronorketamine (DHNK) or into (R,S)-hydroxynorketamine (HNK).”

In the paper

“An emerging viewpoint is that the mechanism of action of ketamine may be related to the pharmacological properties of its metabolites.”

In the paper

“With Mg2+ lifted, the NMDAR is permeable to Na+, K+, and importantly, Ca2+ which serves as a critical intracellular signal that regulates a variety of second messenger systems”

In the paper

“However, this approval and the use of ketamine generally to treat depression has met some criticism concerning the adverse effects associated with (S)-ketamine treatment, especially the dissociative properties, as well as the potential for abuse that limit patients’ treatments to specialized clinics or hospital settings”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites Gastaldon et al., 2019
• ?Not checked — no full text of the sourcecites Liu et al., 2016 source
• ?Not checked — no full text of the sourcecites Turner, 2019 source

In the paper

“Agonist binding alone is insufficient for ion conductance through NMDARs, as the ion channel pore is often blocked at resting membrane potential by a Mg2+ ion.”

In the paper

“(2R,6R)-hydroxynorketamine (HNK), is readily observed in humans following ketamine treatment and has shown therapeutic potential in preclinical tests of antidepressant efficacy and synaptic potentiation while being devoid of the negative adverse effects of ketamine, including its dissociative properties and abuse potential.”

In the paper

“Collectively, these observations highlight that antidepressant doses of ketamine readily enter the brain and are rapidly metabolized.”

In the paper

“Typically, the quaternary structure of NMDARs is comprised of two GluN1 and two GluN2 subunits.”

In the paper

“Based on studies that detail the onset of drug-induced effects in humans, ketamine (0.5 mg/kg i.v. over 40 minutes) produces illusory experiences, increases in perceptual acuity, and paranoia within 10 minutes of treatment initiation, which supports rapid brain entry of ketamine in humans”

What the sources say

• ?Not checked — no full text of the sourcecites Krystal et al., 1994 source

In the paper

“Notably, this study also found that the effects of Ro25-6981 were not sustained for as long as ketamine (two weeks post-treatment) which suggests that NMDARs may not be the only locus for the mechanism of action of the long-term actions of ketamine.”

What the sources say

• ?Not checked — no full text of the sourcecites Maeng et al., 2008 source

In the paper

“Importantly, the magnitude of ketamine block appears to be modulated by many factors, including membrane potential, subunit composition, extracellular pH, and the presence of obligatory agonists”

In the paper

“Given these findings, it is likely that the effects of ketamine on NMDAR function are influenced by the presence of Mg2+, agonist concentration, subunit composition, and pH, all of which may vary as a function of brain region.”

In the paper

“This phenomenon corresponded to an increase in the key synaptic proteins ARC, synapsin 1, PSD95, and GluA1 (the obligatory AMPAR subunit) two hours post-treatment and an increase in excitatory postsynaptic current (EPSC) amplitude at thalamocortical and intracortical synapses 24 hours post-treatment.”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites Li et al., 2010

In the paper

“Intriguingly, Ro25-6981 (10 mg/kg i.p.) mimicked the effects of ketamine on mTOR signaling components one hour post-treatment and synaptic proteins (synapsin1, PSD95, and GluA1) six hours post-treatment.”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites Li et al., 2010

In the paper

“One of the effects of ketamine administration in rodents is a facilitation of AMPAR-mediated signaling and the strength of glutamatergic synapses, which is associated with antidepressant-like effects”

What the sources say

• ?Not checked — no full text of the sourcecites Alt et al., 2006 source

In the paper

“Importantly, the GluN2B subunit confers the highest relative Ca2+ permeability among NMDAR subunits while also reducing deactivation rate and open probability”

What the sources say

• ?Not checked — no full text of the sourcecites Paoletti et al., 2013 source

In the paper

“The IC50 observed in striatal neurons is higher than at hippocampal neurons at 0.92 μM, which suggests that the potency of ketamine to inhibit NMDARs may differ across individual brain regions”

What the sources say

• ?Not checked — no full text of the sourcecites Parsons et al., 1996 source