generation run 2026-04-24
63 min completedmodel pipeline-v5plan not recordedrun/7eedccb9…Selection
Verification
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- seen / partial
- working
The model's own caveats
- sparse_evidence
- safety_data_note
Reproduce
- inputs
- 44 source keys (listed under Sources)
- plan
- not recorded — template version, prompt hash and git SHA are written from 2026-09 onward
- model
- pipeline-v5
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- none — agent transcripts are persisted from 2026-09 onward
19 searches — query, source, results, what was kept and why
| # | source | query | seen | kept | rationale |
|---|---|---|---|---|---|
| 1 | PubMed | dextromethorphan pharmacology NMDA receptor mechanism | 10 | 3 | Relevant to mechanism of action, clinical use, abuse liability |
| 2 | PubMed | dextromethorphan pharmacokinetics metabolism CYP2D6 human | 10 | 2 | CYP2D6 metabolism data; overdose case with PK data |
| 3 | PubMed | dextromethorphan binding affinity NMDA sigma opioid receptor Ki dextrorphan | 1 | 1 | Critical quantitative binding affinity data |
| 4 | PubMed | dextromethorphan dependence addiction withdrawal abuse potential | 5 | 2 | Dependence syndrome and withdrawal characterization |
| 5 | PubMed | dextromethorphan pseudobulbar affect quinidine AVP-923 FDA approval clinical trial | 3 | 3 | FDA-approved clinical use of DXM; PBA indication |
| 6 | ClinicalTrials.gov | dextromethorphan | 15 | 5 | Active and completed DXM clinical trials across multiple indications |
| 7 | PubChem | dextromethorphan | 1 | 1 | Primary chemical identity data |
| 8 | PubMed | dextromethorphan serotonin reuptake inhibitor mechanism sigma-1 | 2 | 2 | SERT and sigma-1 receptor binding; clinical applications |
| 9 | NIH/StatPearls | DXM StatPearls pharmacokinetics mechanisms toxicity | 1 | 1 | Authoritative clinical reference with comprehensive PK, mechanism, and toxicology data |
| 10 | PubMed | dextromethorphan synthesis pharmacology review comprehensive | 10 | 1 | Comprehensive pharmacokinetics and pharmacodynamics review directly relevant to DXM |
| 11 | PubMed | fetch PMID 26826604 - DXM neurological neuropsychiatric utility | 1 | 1 | Authoritative clinical review of DXM's neurological applications |
| 12 | PubMed | fetch PMID 37290117 | 1 | 1 | Most comprehensive recent review of DXM as a complete reference |
| 13 | Web (Wikipedia, Erowid, WebSearch) | dextromethorphan legal status scheduling US states international | 10 | 2 | Legal status data not available through academic databases |
| 14 | WebSearch | dextromethorphan history discovery synthesis 1954 FDA approved | 10 | 1 | Historical context for DXM discovery not available through PubMed searches |
| 15 | PubMed | fetch PMID 7593709 - DXM pharmacokinetics CYP2D6 | 1 | 1 | Primary quantitative pharmacokinetics data for DXM |
| 16 | PubMed | dextromethorphan overdose serotonin syndrome treatment management | 1 | 1 | Authoritative harm reduction guideline for DXM toxicity management |
| 17 | IUPHAR Guide to Pharmacology | DXM receptor binding data IUPHAR | 1 | 1 | Quantitative receptor binding data from curated pharmacology database |
| 18 | Multiple | DXM mu-opioid receptor activity contradiction | 1 | 2 | Flag for editorial review - conflicting data on mu-opioid receptor activity |
| 19 | PubMed | dextromethorphan bipolar disorder add-on Taiwan clinical trial randomized | 4 | 2 | Randomized clinical trials establishing DXM's antidepressant/anti-manic clinical efficacy |
73 claims by section — every cited sentence, checked against its source
pharmacology18 · 14 ok
DXM binds within the NMDA channel pore at the phencyclidine (PCP) binding site, with a Ki of 7 µM in rat brain membranessupported
DXM Ki at NMDA/PCP site = 7 µM. pmid:10064839
Dextrorphan, generated by CYP2D6-mediated O-demethylation, binds the same site with approximately 8-fold greater affinity (Ki = 0.9 µM)supported
dextrorphan Ki at PCP site = 0.9 µM. pmid:10064839
Claim in pharmacology — inconclusiveinconclusiveworking →
At supratherapeutic doses, dextrorphan accumulation drives the characteristic dissociative-hallucinogenic effects.supported
Dextrorphan has pharmacodynamic properties similar to dissociatives. pmid:16318953
DXM is also a potent sigma-1 receptor agonist (Ki = 205 nM in rat brain tissue; Ki = 521 nM at cloned receptors)partially supported
DXM Ki at sigma-1 = 205 nM. pmid:10064839
This target is the most probable mechanism underlying DXM's therapeutic efficacy in pseudobulbar affect and a proposed contributor to its antidepressant activity.supported
DM is NMDA receptor antagonist, sigma-1 receptor agonist. Limbic system distribution of sigma-1 receptors. DM/Q development history for PBA. dot.2008.44.9.1258664
Claim in pharmacology — inconclusiveinconclusiveworking →
DXM competes with radioligand binding at SERT in rat brain tissue, contributing to antidepressant-like effects and, critically, its capacity to precipitate serotonin syndrome when combined with serotonergic medications.supported
DXM competed for sigma-1 receptors and serotonin transporters with high to moderate affinity. pmid:17689532
DXM competes with radioligand binding at SERT in rat brain tissue, contributing to antidepressant-like effects and, critically, its capacity to precipitate serotonin syndrome when combined with serotonergic medications.supported
Actions on NMDA, mu-opioid, sigma-1, calcium channel, SERT, muscarinic, beta, alpha-2, and serotonin 1b/d receptors. Hypothesis that DXM may have rapid antidepressant efficacy. j.mehy.2011.02.003
Additional targets include nicotinic acetylcholine receptor antagonism (α3β4, α4β2, α7 subtypes), voltage-gated calcium channel inhibition (half-maximal inhibition of synaptosomal Ca²⁺ uptake at 48 µM), and weaker interactions with β-adrenergic, α₂-adrenergic, serotonin 1B/1D, and muscarinic receptors.supported
DXM blocks alpha3beta4 nicotinic receptors. DXM and dextrorphan block nAChR function in noncompetitive but reversible manner. pmid:10869398
Additional targets include nicotinic acetylcholine receptor antagonism (α3β4, α4β2, α7 subtypes), voltage-gated calcium channel inhibition (half-maximal inhibition of synaptosomal Ca²⁺ uptake at 48 µM), and weaker interactions with β-adrenergic, α₂-adrenergic, serotonin 1B/1D, and muscarinic receptors.supported
DXM half-maximal inhibition of synaptosomal Ca2+ uptake: 48 microM (N-type channels). pmid:2451974
Additional targets include nicotinic acetylcholine receptor antagonism (α3β4, α4β2, α7 subtypes), voltage-gated calcium channel inhibition (half-maximal inhibition of synaptosomal Ca²⁺ uptake at 48 µM), and weaker interactions with β-adrenergic, α₂-adrenergic, serotonin 1B/1D, and muscarinic receptors.supported
Actions on NMDA, mu-opioid, sigma-1, calcium channel, SERT, muscarinic, beta, alpha-2, and serotonin 1b/d receptors. j.mehy.2011.02.003
Weak mu-opioid interactions have been reported at higher concentrations, but DXM was specifically developed as a non-narcotic antitussive and should not be classified as an opioid agonist.supported
Actions on NMDA, mu-opioid, sigma-1, calcium channel, SERT, muscarinic, beta, alpha-2, and serotonin 1b/d receptors. j.mehy.2011.02.003
DXM undergoes extensive first-pass hepatic metabolism, primarily via CYP2D6supported
Major metabolic pathways: O-demethylation (CYP2D6) to dextrorphan (DXO). 03602532.2020.1758712
Claim in pharmacology — inconclusiveinconclusiveworking →
Claim in pharmacology — inconclusiveinconclusiveworking →
In poor metabolizers (~8–10% of Caucasians), bioavailability rises to 60–80% and the half-life extends to 15–20 hourspartially supported
In poor metabolizers: DXM t1/2=29.5 hours. pmid:7593709
CYP2D6 inhibitors such as quinidine produce a pharmacokinetic profile in extensive metabolizers that resembles the poor metabolizer phenotype (t½ = 16.4 hours with quinidine).supported
Quinidine (CYP2D6 inhibitor) raised DXM t1/2 to 16.4 hours. pmid:7593709
safety18 · 14 ok
Physical and psychological dependence develop with chronic use, with documented withdrawal syndromessupported
Case of DXM dependence with psychosis and withdrawal. pmid:16318953
Physical and psychological dependence develop with chronic use, with documented withdrawal syndromessupported
Alarming increase in reports of abuse. Taken mainly by young people as a psychoactive drug. arztebl.2010.0537
Evidence-based consensus guidelines establish the following clinical thresholds for DXM ingestion:supported
Consensus guideline for DXM poisoning management. Refer to ED if >7.5 mg/kg ingested, or if serotonin syndrome risk. Risk threshold: 5-7.5 mg/kg. pmid:17849242
A 21-year-old woman who ingested 5,600 mg DXM (approximately 20 tablets of 280 mg each) presented with serum DXM of 5.8 mg/L, refractory status epilepticus, and cranial nerve reflex loss, recovering fully by day 9supported
A 21-year-old woman ingested 20×280 mg DXM. Presented with refractory status epilepticus, cranial nerve reflex loss. Serum DXM 5.8 mg/L on admission. Recovered fully by day 9. ajcr.946447
The authors concluded that parent DXM — rather than dextrorphan — was responsible for the seizure presentation, suggesting CYP2D6 inhibition by co-ingested medications amplified DXM accumulationsupported
DXM rather than dextrorphan responsible for symptoms. Highlights risk of CYP2D6 inhibition in toxicity. ajcr.946447
A 19-year-old female who ingested 111 DXM tablets developed shock and convulsions requiring intensive care, with eventual full recovery.supported
Case of female who ingested 111 tablets of DXM leading to shock and convulsions requiring intensive care. Recovered. wjcc.v11.i16.3870
Claim in safety — inconclusiveinconclusiveworking →
DXM-induced psychosis with persecutory delusions has been documented in case reports of dependent users.supported
Case of DXM dependence with psychosis and withdrawal. pmid:16318953
A case of DXM dependence with substance-induced psychosis and a withdrawal syndrome consistent with NMDA antagonist discontinuation has been describedsupported
Case of DXM dependence with psychosis and withdrawal. DXM has serotonergic and sigma-1 opioidergic properties. pmid:16318953
Increasing abuse cases with dependence syndromes have been documented in European cohorts.supported
Alarming increase in reports of abuse. Current data yields incomplete information on extent of problem in Germany. arztebl.2010.0537
In animal models, DXM attenuated morphine and nicotine dependence behaviors, suggesting bidirectional interaction with addiction circuitry.supported
DXM can attenuate morphine and methamphetamine dependence. Investigated effects on nicotine dependence in rats. ntac287
DXM's SERT inhibition makes any serotonergic co-medication a potential serotonin syndrome trigger. MAOIs represent an absolute contraindication — MAO inhibition combined with DXM's SERT inhibition causes catastrophic serotonin accumulation; fatal interactions are documented, and a minimum 14-day washout is required. SSRIs and SNRIs carry significant serotonin syndrome risk, compounded when the SSRI also inhibits CYP2D6 (paroxetine, fluoxetine), creating dual pharmacokinetic and pharmacodynamic amplification. Tramadol and MDMA pose serious serotonin syndrome risk through additive serotonergic mechanisms.supported
Serotonin syndrome risk with MAOIs or SSRIs. pmid:17849242
Claim in safety — inconclusiveinconclusiveworking →
DXM's SERT inhibition makes any serotonergic co-medication a potential serotonin syndrome trigger. MAOIs represent an absolute contraindication — MAO inhibition combined with DXM's SERT inhibition causes catastrophic serotonin accumulation; fatal interactions are documented, and a minimum 14-day washout is required. SSRIs and SNRIs carry significant serotonin syndrome risk, compounded when the SSRI also inhibits CYP2D6 (paroxetine, fluoxetine), creating dual pharmacokinetic and pharmacodynamic amplification. Tramadol and MDMA pose serious serotonin syndrome risk through additive serotonergic mechanisms.supported
Case report of serotonin syndrome with paroxetine and OTC cold remedy (containing DXM). Most common agents implicated: MAOIs combined with L-tryptophan or fluoxetine. pmid:7945606
Claim in safety — inconclusiveinconclusiveworking →
Bupropion raises DXM exposure more than 100-fold; quinidine extends DXM half-life from 2–3 hours to 16.4 hourssupported
Quinidine (CYP2D6 inhibitor) raised DXM t1/2 to 16.4 hours. pmid:7593709
Claim in safety — inconclusiveinconclusiveworking →
Psychotic spectrum disorders (relative): DXM's NMDA antagonism can precipitate or exacerbate psychotic symptoms, particularly at high doses.supported
Case of DXM dependence with psychosis and withdrawal. Dextrorphan has pharmacodynamic properties similar to dissociatives. pmid:16318953
clinical-evidence10 · 7 ok
DXM/quinidine (Nuedexta, AVP-923) received FDA approval in 2010 as the first treatment for pseudobulbar affect (PBA), based on the PRISM II pivotal trial in patients with ALS and multiple sclerosissupported
Systematic review of DM/Q for PBA in ALS, MS, stroke, TBI. DM/Q is the only FDA-approved therapy for PBA. s10072-025-08640-7
Systematic review and network meta-analysis confirm sustained efficacy and an acceptable safety profilesupported
Systematic review of DM/Q for PBA in ALS, MS, stroke, TBI. s10072-025-08640-7
DXM/bupropion (Auvelity, AXS-05) received FDA approval in August 2022 for major depressive disorder in adultssupported
AUVELITY (AXS-05; DXM with bupropion) approved by FDA in 2022 for MDD. j.neuropharm.2022.109348
Claim in clinical-evidence — inconclusiveinconclusiveworking →
The antidepressant mechanism involves multimodal activity: NMDA receptor antagonism (glutamatergic modulation), sigma-1 receptor agonism, and SERT inhibition.partially supported
Low-dose intravenous ketamine, intranasal esketamine, and oral dextromethorphan represent the first glutamatergic treatments to exhibit rapid and robust efficacy in persons with TRD. Their precise mechanisms remain unclear. 14728222.2026.2619757
Claim in clinical-evidence — inconclusiveinconclusiveworking →
Pharmacogenomic analysis identified DRD2/ANKK1 gene associations with DXM treatment response.supported
DRD2/ANKK1 TaqIA polymorphism influenced DXM response on manic symptoms. j.jad.2012.01.024
Claim in clinical-evidence — inconclusiveinconclusiveworking →
Systematic reviews of perioperative DXM as a preventive analgesic show modest efficacy as an NMDA antagonist adjunct to opioid analgesiasupported
DXM demonstrated preventive analgesia in 67% of studies (highest of NMDA antagonists studied). pmid:15105220
DXM potentiates opioid analgesia in primate models and has been investigated as a tool to prevent opioid tolerance development.supported
In squirrel monkeys, DXM potentiated antinociceptive effects of morphine and the delta-opioid agonist SNC80 at sub-threshold doses. pmid:11805202
summary7 · 6 ok
First tested in 1954 and approved by the FDA in 1958 as the first non-narcotic cough suppressant, DXM has undergone a trajectory from OTC medicine to validated psychiatric therapeuticsupported
DXM introduced in 1958 as first non-opioid cough suppressant. acschemneuro.3c00088
FDA approval of dextromethorphan/quinidine (Nuedexta) for pseudobulbar affect in 2010 and dextromethorphan/bupropion (Auvelity) for major depressive disorder in 2022 established DXM as a clinically validated neuroactive agent with regulatory milestones across multiple indicationssupported
DM/Q is the only FDA-approved therapy for PBA. s10072-025-08640-7
FDA approval of dextromethorphan/quinidine (Nuedexta) for pseudobulbar affect in 2010 and dextromethorphan/bupropion (Auvelity) for major depressive disorder in 2022 established DXM as a clinically validated neuroactive agent with regulatory milestones across multiple indicationssupported
Oral combination DXM-bupropion (AXS-05, Auvelity) FDA approved August 2022 for treatment of MDD in adults. s40263-024-01114-y
DXM is a low-affinity uncompetitive NMDA receptor antagonist (Ki = 7 µM at the PCP site), but its O-demethylated metabolite dextrorphan carries approximately 8-fold greater NMDA potency (Ki = 0.9 µM)supported
DXM Ki at NMDA/PCP site = 7 µM; dextrorphan Ki at PCP site = 0.9 µM. pmid:10064839
DXM also binds sigma-1 receptors with high affinity (Ki = 205 nM) and inhibits the serotonin transporter, producing the multimodal profile underlying both its therapeutic applications and its interaction risks.partially supported
DXM Ki at sigma-1 = 205 nM; dextrorphan Ki at sigma-1 = 144 nM. pmid:10064839
DXM also binds sigma-1 receptors with high affinity (Ki = 205 nM) and inhibits the serotonin transporter, producing the multimodal profile underlying both its therapeutic applications and its interaction risks.supported
DXM competed for sigma-1 receptors and serotonin transporters with high to moderate affinity. pmid:17689532
Claim in summary — inconclusiveinconclusiveworking →
history5 · 4 ok
Claim in history — inconclusiveinconclusiveworking →
The FDA approved dextromethorphan in 1958 as the first non-opioid, non-narcotic cough suppressant available without prescriptionsupported
DXM introduced in 1958 as first non-opioid cough suppressant. acschemneuro.3c00088
DXM has been continuously available without prescription in many jurisdictions since 1954.supported
The NMDA antagonist DXM has been available without prescription since 1954. arztebl.2010.0537
In 2010, the FDA approved Nuedexta (dextromethorphan/quinidine) as the first treatment for pseudobulbar affect, based on pivotal trials in patients with ALS and multiple sclerosissupported
Systematic review of DM/Q for PBA in ALS, MS, stroke, TBI. DM/Q is the only FDA-approved therapy for PBA. s10072-025-08640-7
Both formulations exploit CYP2D6 inhibition to raise DXM bioavailability: quinidine in Nuedexta and bupropion metabolites in Auvelity.supported
Quinidine (CYP2D6 inhibitor) raised DXM t1/2 to 16.4 hours. pmid:7593709
neuroscience5 · 5 ok
At supratherapeutic doses, dextrorphan accumulation at the NMDA/PCP binding site (Ki = 0.9 µM) disrupts thalamocortical gating, producing the phenomenological hallmarks of dissociation: depersonalization, derealization, and the sense of separation between mind and bodysupported
dextrorphan Ki at PCP site = 0.9 µM. pmid:10064839
DXM's sigma-1 receptor agonism (Ki = 205 nM) engages limbic circuits implicated in emotional regulationsupported
DXM Ki at sigma-1 = 205 nM. pmid:10064839
In traumatic brain injury, DXM reduced cortical inflammation and excitotoxic damage via anti-inflammatory and anti-excitotoxic mechanismssupported
DXM decreased TNF-alpha, IL-1beta, IL-6 and increased glutamate transporters. mmr.2015.3830
Animal models demonstrate that DXM attenuates morphine-induced conditioned place preference and reduces nicotine reward, behavioral sensitization, and drug-seeking behaviorpartially supported
DXM treatment during morphine withdrawal reversed place preference for drug-paired compartment. DXM reversed increased DA turnover in nucleus accumbens. pmid:17372963
DXM/bupropion's FDA approval for MDD represents validation of the hypothesis that NMDA antagonism produces rapid antidepressant effects through mechanisms distinct from monoamine reuptake inhibitionsupported
Low-dose intravenous ketamine, intranasal esketamine, and oral dextromethorphan represent the first glutamatergic treatments to exhibit rapid and robust efficacy in persons with TRD. 14728222.2026.2619757
pharmacokinetic-detail4 · 4 ok
DXM serves as a validated CYP2D6 probe substrate in clinical pharmacology studies.supported
DXM used as CYP2D6 probe substrate in drug interaction cocktail study. jcph.1496
DXM undergoes complex hepatic biotransformation through two primary CYP-mediated pathways:supported
Major metabolic pathways: O-demethylation (CYP2D6) to dextrorphan (DXO); N-demethylation to 3-hydroxymorphinan. 03602532.2020.1758712
Data from Schadel et al. and Zhou.supported
CYP2D6 metabolizes approximately 25% of current drugs. DXM is a probe substrate for CYP2D6 activity. 11318030-000000000-00000
Bupropion: Bupropion metabolites (particularly hydroxybupropion) produce a >100-fold increase in DXM systemic exposure. This interaction is therapeutically exploited in the Auvelity (DXM/bupropion) formulation.supported
Bupropion metabolites (EHBUP, THBUP) drive >100-fold increase in DXM exposure. j.dmd.2025.100070
receptor-pharmacology3 · 2 ok
Sigma-1 receptor agonism is implicated in emotional regulation and neuroplasticity and is the proposed primary mechanism of DXM's therapeutic effect in pseudobulbar affect.supported
DM is NMDA receptor antagonist, sigma-1 receptor agonist. Limbic system distribution of sigma-1 receptors. DM/Q development history for PBA. dot.2008.44.9.1258664
Claim in receptor-pharmacology — inconclusiveinconclusiveworking →
DXM decreases voltage-gated Ca²⁺ uptake in brain synaptosomes with half-maximal inhibition at 48 µM; dextrorphan shows weaker activity at 200 µMsupported
DXM half-maximal inhibition of synaptosomal Ca2+ uptake: 48 microM (N-type channels). Dextrorphan: 200 microM. pmid:2451974
comparative-pharmacology2 · 2 ok
Sigma-1 receptor engagement: DXM's sigma-1 Ki (205 nM) provides a high-affinity target that ketamine and PCP lack in clinically relevant concentrations. This target drives DXM's therapeutic profile in PBA and likely contributes to its antidepressant mechanism.supported
DM is NMDA receptor antagonist, sigma-1 receptor agonist. Limbic system distribution of sigma-1 receptors. DM/Q development history for PBA. dot.2008.44.9.1258664
nAChR antagonism: DXM blocks nicotinic receptors at concentrations relevant to supratherapeutic use, a mechanism absent from ketamine's profile.supported
DXM and dextrorphan block nAChR function in noncompetitive but reversible manner. DXM blocks alpha3beta4 nicotinic receptors. pmid:10869398
chemistry1 · 1 ok
The methoxy group is a key pharmacophoric feature: O-demethylation by CYP2D6 yields the active metabolite dextrorphan (3-hydroxymorphinan), which possesses substantially greater NMDA receptor affinity.partially supported
O-demethylation (CYP2D6) to dextrorphan (DXO); N-demethylation to 3-hydroxymorphinan. 03602532.2020.1758712