Josie Kins

# Ketamine · #383
 
Removed: -  "summary": "",
Added: +  "summary": "",
Removed: -      "NMDA receptor antagonist (noncompetitive)",
Added: +      "NMDA receptor antagonist (uncompetitive)",
Added: +      "κ-opioid receptor agonist",
Added: +      "Norepinephrine reuptake inhibitor",
Added: +      "Dopamine D2 receptor agonist (partial)",
Removed: -      "Mu-opioid receptor antagonist (high doses)"
Added: +      "5-HT2 receptor antagonist",
Added: +      "5-HT1A receptor antagonist",
Added: +      "Nicotinic acetylcholine receptor antagonist"
Removed: -      "Glutamate receptor ionotropic, NMDA 3A": "antagonist",
Removed: -      "5-hydroxytryptamine receptor 3A": "potentiator",
Removed: -      "Neuronal acetylcholine receptor subunit alpha-7": "antagonist",
Removed: -      "Cholinesterase": "inhibitor",
Removed: -      "Nitric oxide synthase 1": "inhibitor",
Removed: -      "Substance-P receptor": "antagonist",
Removed: -      "D(2) dopamine receptor": "agonist",
Removed: -      "Sodium-dependent noradrenaline transporter": "inhibitor",
Removed: -      "Kappa-type opioid receptor": "agonist",
Removed: -      "5-hydroxytryptamine receptor 2": "antagonist",
Removed: -      "5-hydroxytryptamine receptor 1": "antagonist"
Added: +      "NMDA (racemic)": "Ki = 119 nM",
Added: +      "NMDA (S-ketamine)": "Ki = 300 nM",
Added: +      "NMDA (R-ketamine)": "Ki = 1.4 μM",
Added: +      "GluN2A": "IC50 = 330 nM",
Added: +      "GluN2B": "IC50 = 310 nM",
Added: +      "GluN2C": "IC50 = 510 nM",
Added: +      "GluN2D": "IC50 = 830 nM",
Added: +      "D2": ">10 μM (low affinity)",
Added: +      "α7 nAChR": "No significant binding (metabolites active)",
Added: +      "5-HT3A": "potentiator",
Added: +      "κ-opioid": "agonist",
Added: +      "μ-opioid": "binder (no agonist activity)",
Added: +      "δ-opioid": "binder",
Added: +      "NET": "inhibitor"
Removed: -    "metabolism": "",
Removed: -    "metabolites": [],
Added: +    "metabolism": "Primarily hepatic via CYP3A4 and CYP2B6. Undergoes N-demethylation to norketamine, which is subsequently converted by CYP2A6 and CYP2B6 to hydroxynorketamine and dehydronorketamine. Additional metabolic pathways include hydroxylation of the cyclohexone ring, conjugation to glucuronic acid, and dehydration of hydroxylated metabolites.",
Added: +    "metabolites": [
Added: +      "Norketamine (active, primary metabolite)",
Added: +      "Dehydronorketamine (DHNK)",
Added: +      "(2R,6R)-hydroxynorketamine (active, implicated in antidepressant effects)",
Added: +      "Hydroxynorketamines (HNKs)",
Added: +      "Conjugated hydroxylated derivatives"
Added: +    ],
Removed: -    "bioavailability_notes": "",
Removed: -    "bioavailability": "",
Removed: -    "protein_binding": "",
Removed: -    "volume_of_distribution": ""
Added: +    "bioavailability_notes": ""
Added: +  "tolerance": {
Added: +    "full_tolerance": "",
Added: +    "half_tolerance": "",
Added: +    "baseline_tolerance": "",
Added: +    "cross_tolerance": []
Added: +  },
Removed: -    "addiction_liability": "Moderate to high abuse potential with significant risk of psychological dependence. The short duration of effects promotes bingeing, and compulsive redosing is commonly reported. Daily use patterns are not uncommon among those with regular access, making ketamine more psychologically compelling than most other psychedelics.",
Removed: -    "dependence_liability": "Physical dependence can develop with chronic use. Some daily users reported withdrawal symptoms including anxiety, tremor, sweating, and palpitations following attempts to stop.",
Added: +    "addiction_liability": "Moderate to high abuse potential with significant risk of psychological dependence. The short duration of effects promotes bingeing, and compulsive redosing is commonly reported. Ketamine is considered more psychologically compelling than most other psychedelics, and daily use patterns are not uncommon among those with regular access.",
Added: +    "dependence_liability": "Physical dependence can develop with chronic use. Some daily users reported withdrawal symptoms including anxiety, tremor, sweating, and palpitations following attempts to stop. Psychological dependence is more widely reported than physical dependence.",
Removed: -      "organ_toxicity": "Chronic use causes severe bladder damage (ketamine-induced ulcerative cystitis) in 20-30% of frequent users, including reduced bladder capacity to as low as 10-150 mL, urinary incontinence, painful urination, and blood in urine. Severe cases may require surgical bladder removal. Liver toxicity occurs in approximately 10% of heavy users. Acute kidney injury has also been documented.",
Added: +      "organ_toxicity": "Chronic use causes severe bladder damage (ketamine-induced ulcerative cystitis) in 20-30% of frequent users, including reduced bladder capacity to as low as 10-150 mL, urinary incontinence, painful urination, and blood in urine. All reported cases involving greater than 5 grams daily showed lower urinary tract symptoms. Severe cases may require surgical bladder removal. Liver toxicity occurs in approximately 10% of heavy users. Chronic use has also been associated with acute kidney injury, biliary colic, and gastrointestinal diseases.",
Removed: -      "other": "Neurotoxicity demonstrated in primate studies, with indicators of increased cell death in the prefrontal cortex after six months of daily use at recreational-equivalent doses (1 mg/kg IV). Brain damage including reduction in both white and grey matter observed on MRI imaging in frequent users. Increased neuronal apoptosis in developing brains with prolonged exposure. Cognitive deficits including impaired verbal, short-term, and visual memory reported in frequent users, though these may be reversible upon discontinuation."
Added: +      "other": "Neurotoxicity demonstrated in primate studies, with indicators of increased cell death in the prefrontal cortex after six months of daily use at recreational-equivalent doses (1 mg/kg IV). Brain damage including reduction in both white and grey matter and atrophy has been observed on imaging in frequent users. Increased neuronal apoptosis in developing brains with prolonged exposure. Cognitive deficits including impaired verbal, short-term, and visual memory reported in frequent users, though these may be reversible upon discontinuation."
Removed: -      "psychosis": "At anesthetic doses, 10-20% of adults experience emergence delirium with hallucinations and dysphoria. Long-term chronic use may lead to psychosis, paranoia, and increased delusional thinking. Increased dissociation and delusions observed in frequent recreational users even after periods of abstinence.",
Added: +      "psychosis": "At anesthetic doses, 10-20% of adults experience emergence delirium with hallucinations and dysphoria. Long-term chronic use may lead to psychosis. Increased dissociation, delusions, paranoia, and egocentrism observed in frequent recreational users even after periods of abstinence.",
Removed: -        "Contraindicated in severe cardiovascular disease, uncontrolled psychosis, increased intracranial pressure, severe liver disease, and pregnancy",
Added: +        "Contraindicated in severe cardiovascular disease, uncontrolled psychosis, increased intracranial or intraocular pressure, severe liver disease, and pregnancy",
Removed: -  "tolerance": {
Removed: -    "full_tolerance": "",
Removed: -    "half_tolerance": "",
Removed: -    "baseline_tolerance": "",
Removed: -    "cross_tolerance": []
Added: +  "history_culture": {
Added: +    "content": "",
Added: +    "sections": [
Added: +      {
Added: +        "heading": "Discovery and Development",
Added: +        "content": "Ketamine was first synthesized in 1962 by the American scientist Calvin Stevens at Parke Davis Laboratories while searching for a safer anesthetic to replace phencyclidine (PCP), which produced severe hallucinogenic effects upon recovery of consciousness. Initially designated \"CI581,\" ketamine was found to produce comparatively minor hallucinogenic effects and shorter psychotomimetic episodes than its predecessor. In 1965, Edward Domino identified ketamine as a useful anesthetic and coined the term \"dissociative anesthetic\" to describe its unique pharmacological profile.\n\nThe United States Food and Drug Administration approved ketamine for human use in 1970. Due to its favorable sympathomimetic properties and wide margin of safety, it was extensively administered as a field anesthetic to soldiers during the Vietnam War. It remains on the World Health Organization's \"Essential Drugs List,\" a catalog of the safest and most effective medicines required for a basic healthcare system.\n"
Added: +      },
Added: +      {
Added: +        "heading": "Rise in Recreational Use",
Added: +        "content": "Recreational use of ketamine was first reported among medicinal chemists in the United States in 1967. By the early 1970s, patients receiving ketamine anesthesia began reporting unwanted visions, raising concerns about its recreational potential. The publication of John C. Lilly's book \"The Scientist\" in 1978, which detailed his extensive personal experiments with ketamine, contributed to growing interest in the substance throughout the 1980s.\n\nIn the 1990s, ketamine became more widespread in Europe, gaining popularity as an adulterant in ecstasy tablets and becoming closely associated with the nightclub and rave scenes. In 1995, the United States Drug Enforcement Administration added ketamine to its \"emerging drugs list\" due to its involvement in electronic music culture. By 1998, it was being characterized alongside GHB as both a \"date rape drug\" and a \"club drug\" in media coverage, leading to its emergency scheduling as a Schedule III controlled substance in August 1999.\n"
Added: +      },
Added: +      {
Added: +        "heading": "Antidepressant Discovery",
Added: +        "content": "The discovery of ketamine's rapid antidepressant action in 2000 has been described as the single most important advance in the treatment of depression in over 50 years. Studies have demonstrated that even small doses can produce immediate effects within two hours, consistently relieving depressive and suicidal symptoms for up to three days following a single administration. This breakthrough has sparked significant interest in NMDA receptor antagonists for depression treatment and fundamentally shifted the direction of antidepressant research and development."
Added: +      }
Added: +    ]

# Dextromethorphan · #282
 
Removed: -      "NMDA receptor antagonist",
Removed: -      "serotonin reuptake inhibitor"
Added: +      "NMDA receptor antagonist (uncompetitive)",
Added: +      "Serotonin-norepinephrine reuptake inhibitor (SNRI)",
Added: +      "Sigma-1 receptor agonist",
Added: +      "Nicotinic acetylcholine receptor antagonist"
Removed: -      "Sigma non-opioid intracellular receptor 1": "agonist",
Removed: -      "Glutamate receptor ionotropic, NMDA 3A": "antagonist",
Removed: -      "Aromatase": "inhibitor",
Removed: -      "Neuronal acetylcholine receptor subunit alpha-2": "antagonist",
Removed: -      "Sodium-dependent serotonin transporter": "inhibitor",
Removed: -      "Neuronal acetylcholine receptor subunit alpha-3": "antagonist",
Removed: -      "Neuronal acetylcholine receptor subunit alpha-4": "antagonist",
Removed: -      "Neuronal acetylcholine receptor subunit beta-4": "antagonist",
Removed: -      "Neuronal acetylcholine receptor subunit beta-2": "antagonist",
Removed: -      "Neuronal acetylcholine receptor subunit alpha-7": "antagonist",
Removed: -      "Mu-type opioid receptor": "agonist",
Removed: -      "Delta-type opioid receptor": "agonist",
Removed: -      "Kappa-type opioid receptor": "agonist",
Removed: -      "NADPH oxidase": "inhibitor",
Removed: -      "Sodium-dependent noradrenaline transporter": "inhibitor"
Added: +      "SERT": "40 nM (DXM), 484 nM (DXO)",
Added: +      "Sigma-1": "150 nM (DXM), 118 nM (DXO)",
Added: +      "NET": "6000 nM (DXM), 6200 nM (DXO)",
Added: +      "NMDA": "2120 nM (DXM), 892 nM (DXO)",
Added: +      "α1D-adrenergic": "830 nM (DXM)",
Added: +      "α1A-adrenergic": "3000 nM (DXM)",
Added: +      "Sigma-2": "11,060 nM (DXM), 11,325 nM (DXO)"
Removed: -    "metabolism": "",
Removed: -    "metabolites": [],
Removed: -    "half_life": "",
Removed: -    "bioavailability_notes": "",
Removed: -    "bioavailability": "",
Removed: -    "protein_binding": "",
Removed: -    "volume_of_distribution": ""
Added: +    "metabolism": "Rapidly absorbed from the gastrointestinal tract with extensive first-pass hepatic metabolism. Primary pathway is O-demethylation to dextrorphan via CYP2D6, accounting for approximately 80% of dextrorphan formation. Secondary pathway is N-demethylation to 3-methoxymorphinan via CYP3A4, accounting for approximately 90% of 3-MM formation. Both metabolites converge to form 3-hydroxymorphinan. Dextrorphan and 3-hydroxymorphinan undergo conjugation with glucuronic acid and sulfate ions as phase II metabolism.",
Added: +    "metabolites": [
Added: +      "Dextrorphan (active, primary mediator of dissociative effects, approximately 10x more potent NMDA antagonist than parent compound, less active as serotonin reuptake inhibitor)",
Added: +      "3-Methoxymorphinan (local anesthetic effects, CYP2D6 inhibitor)",
Added: +      "3-Hydroxymorphinan (neuroprotective and neurotrophic effects)"
Added: +    ],
Added: +    "half_life": "3-30 hours (highly variable due to CYP2D6 polymorphism; approximately 4 hours in extensive metabolizers, up to 13 hours in poor metabolizers or with CYP2D6 inhibition)",
Added: +    "bioavailability_notes": "Rapidly absorbed from the gastrointestinal tract with brain concentrations significantly exceeding serum levels. Volume of distribution is 5-6.7 L/kg with 60-70% protein binding. Approximately 1 in 10 Caucasian individuals are CYP2D6 poor metabolizers, resulting in prolonged elevated drug levels and altered metabolite ratios favoring the parent compound over dextrorphan."

# Ketamine · #383
 
Removed: -    "dependence_liability": "Physical dependence can develop with chronic use. Withdrawal symptoms include anxiety, tremor, sweating, and palpitations following cessation attempts.",
Added: +    "dependence_liability": "Physical dependence can develop with chronic use. Some daily users reported withdrawal symptoms including anxiety, tremor, sweating, and palpitations following attempts to stop.",
Removed: -      "organ_toxicity": "Chronic use causes severe bladder damage (ketamine-induced ulcerative cystitis) in 20-30% of frequent users, including reduced bladder capacity to as low as 10-150 mL, urinary incontinence, painful urination, and blood in urine. Severe cases may require surgical bladder removal. Liver toxicity occurs in approximately 10% of heavy users. Kidney damage including acute kidney injury has been documented.",
Added: +      "organ_toxicity": "Chronic use causes severe bladder damage (ketamine-induced ulcerative cystitis) in 20-30% of frequent users, including reduced bladder capacity to as low as 10-150 mL, urinary incontinence, painful urination, and blood in urine. Severe cases may require surgical bladder removal. Liver toxicity occurs in approximately 10% of heavy users. Acute kidney injury has also been documented.",
Removed: -      "other": "Neurotoxicity demonstrated in primate studies, with cell death in the prefrontal cortex after six months of daily use at recreational doses. Brain damage including reduction in both white and grey matter observed on MRI imaging in heavy users. Increased neuronal apoptosis in developing brains with prolonged exposure. Cognitive deficits including impaired verbal, short-term, and visual memory reported in frequent users."
Added: +      "other": "Neurotoxicity demonstrated in primate studies, with indicators of increased cell death in the prefrontal cortex after six months of daily use at recreational-equivalent doses (1 mg/kg IV). Brain damage including reduction in both white and grey matter observed on MRI imaging in frequent users. Increased neuronal apoptosis in developing brains with prolonged exposure. Cognitive deficits including impaired verbal, short-term, and visual memory reported in frequent users, though these may be reversible upon discontinuation."
Removed: -      "psychosis": "At anesthetic doses, 10-20% of adults experience emergence delirium with hallucinations and dysphoria. Chronic use may lead to persistent psychosis, paranoia, and delusional thinking. Increased dissociation and delusions observed in frequent recreational users even after abstinence.",
Removed: -      "self_harm": "Loss of pain sensation and motor control significantly increases injury risk. Multiple drowning deaths documented from unsupervised use near water or in bathtubs. Traffic accidents and suicides also implicated in ketamine-related fatalities.",
Removed: -      "seizure": "Seizures rare but reported at very high doses or overdose.",
Added: +      "psychosis": "At anesthetic doses, 10-20% of adults experience emergence delirium with hallucinations and dysphoria. Long-term chronic use may lead to psychosis, paranoia, and increased delusional thinking. Increased dissociation and delusions observed in frequent recreational users even after periods of abstinence.",
Added: +      "self_harm": "Loss of pain sensation and motor control significantly increases injury risk. Multiple drowning deaths documented from unsupervised use near water or in bathtubs. Traffic accidents and suicides have also been implicated in ketamine-related fatalities.",
Added: +      "seizure": "Seizures are rare but have been reported at very high doses or overdose.",
Removed: -        "Aspiration risk from vomiting while unconscious",
Removed: -        "Positional asphyxia from rapid loss of consciousness and suppressed pain response",
Removed: -        "Respiratory depression including brief apneic episodes, especially with rapid IV injection",
Removed: -        "Contraindicated in severe cardiovascular disease, uncontrolled psychosis, increased intracranial pressure, severe liver disease, and pregnancy"
Added: +        "Aspiration risk from vomiting while unconscious or sedated",
Added: +        "Positional asphyxia from rapid loss of consciousness combined with suppressed pain response",
Added: +        "Respiratory changes including deeper, slower breathing and brief apneic episodes, especially with rapid IV injection",
Added: +        "Contraindicated in severe cardiovascular disease, uncontrolled psychosis, increased intracranial pressure, severe liver disease, and pregnancy",
Added: +        "Amnesia and confusion effects have been exploited for date rape"