Dextromethorphan Dampens Neonatal Astrocyte Activation and Endoplasmic Reticulum Stress Induced by Prenatal Exposure to Buprenorphine.

Prenatal exposure to buprenorphine renders offspring vulnerable to cerebral impairments. In this study, our data demonstrate, for the first time, that prenatal exposure to buprenorphine escalates astrocyte activation concurrent with indications of endoplasmic reticulum (ER) stress in the hippocampi of neonates, and this can be prevented by the coadministration of dextromethorphan with buprenorphine. Furthermore, dextromethorphan can inhibit the accumulation of GPR37 in the hippocampus of newborns caused by buprenorphine and is accompanied by the proapoptotic ER stress response that involves the procaspase-3/CHOP pathway. Primary astrocyte cultures derived from the neonates of the buprenorphine group also displayed aberrant ER calcium mobilization and elevated basal levels of cyclooxygenase-2 (COX-2) at 14 days in vitro while showing sensitivity to lipopolysaccharide-activated expression of COX-2. Similarly, these long-lasting defects in the hippocampus and astrocytes were abolished by dextromethorphan. Our findings suggest that prenatal exposure to buprenorphine might instigate long-lasting effects on hippocampal and astrocytic functions. The beneficial effects of prenatal coadministration of dextromethorphan might be, at least in part, attributed to its properties in attenuating astrocyte activation and hippocampal ER stress in neonates.

Dextromethorphan - A widely-used cough suppressant - Induces local anaphylaxis via MRGPRX2 on mast cells.

Dextromethorphan (DM) is a cough suppressant available in many prescribed and over-the-counter medications. Adverse reactions induced by DM have been regularly reported, including allergic skin reactions in some cases. However, the underlying mechanisms of local anaphylaxis induced by DM have not been elucidated. In this study, we found that DM could activate mast cells to increase calcium mobilization and release ß-hexosaminidase, histamine, tumor necrosis factor-α, MCP-1, and IL-8 in a dose-dependent manner. The allergic reactions were confirmed by hind paw swelling and extravasation assay in vivo. Furthermore, DM was revealed to induce local anaphylaxis via MRGPRX2 by the mast cell-deficient kitW-sh/W-sh mice and MRGPRX2 knockdown mast cells. And the MRGPRX2-HEK293/CMC analysis and frontal analysis also showed that DM has a considerable affinity with MRGPRX2. Together, our findings suggest that close monitoring should be drawn on patients with DM for its potential anaphylaxis via MRGPRX2.

Food-Drug Interaction between the Adlay Bran Oil and Drugs in Rats.

Adlay (Coix lachryma-jobi L. var. ma-yuen Stapf) contains various phytonutrients for treating many diseases in Asia. To investigate whether orally administered adlay bran oil (ABO) can cause drug interactions, the effects of ABO on the pharmacokinetics of five cytochrome P450 (CYP) probe drugs were evaluated. Rats were given a single oral dose (2.5 mL/kg BW) of ABO 1 h before administration of a drug cocktail either orally or intravenously, and blood was collected at various time points. A single oral dose of ABO administration did not affect the pharmacokinetics of five probe drugs when given as a drug cocktail intravenously. However, ABO increased plasma theophylline (+28.4%), dextromethorphan (+48.7%), and diltiazem (+46.7%) when co-administered an oral drug cocktail. After 7 days of feeding with an ABO-containing diet, plasma concentrations of theophylline (+45.4%) and chlorzoxazone (+53.6%) were increased after the oral administration of the drug cocktail. The major CYP enzyme activities in the liver and intestinal tract were not affected by ABO treatment. Results from this study indicate that a single oral dose or short-term administration of ABO may increase plasma drug concentrations when ABO is given concomitantly with drugs. ABO is likely to enhance intestinal drug absorption. Therefore, caution is needed to avoid food-drug interactions between ABO and co-administered drugs.

MK-801, but not naloxone, attenuates high-dose dextromethorphan-induced convulsive behavior: Possible involvement of the GluN2B receptor.

Dextromethorphan (DM) is a dextrorotatory isomer of levorphanol, a typical morphine-like opioid. When administered at supra-antitussive doses, DM produces psychotoxic and neurotoxic effects in humans. Although DM abuse has been well-documented, few studies have examined the effects of high-dose DM. The present study aimed to explore the effects of a single high dose of DM on mortality and seizure occurrence. After intraperitoneal administration with a high dose of DM (80mg/kg), Sprague-Dawley rats showed increased seizure occurrence and intensity. Hippocampal expression levels of N-methyl-d-aspartate (NMDA) receptor subunits (GluN1

Protective effect of Lycium Barbarum polysaccharides on dextromethorphan-induced mood impairment and neurogenesis suppression.

Dextromethorphan (DXM) is one of the common drugs abused by adolescents. It is the active ingredient found in cough medicine which is used for suppressing cough. High dosage of DXM can induce euphoria, dissociative effects and even hallucinations. Chronic use of DXM may also lead to depressive-related symptoms. Lycium barbarum, commonly known as wolfberry, has been used as a traditional Chinese medicine for the treatment of ageing-related neurodegenerative diseases. A recent study has shown the potential beneficial effect of Lycium barbarum to reduce depression-like behavior. In the present study, we investigated the role of Lycium barbarum polysaccharide (LBP) to alleviate DXM-induced emotional distress. Sprague Dawley rats were divided into 4 groups (n=6 per group), including the normal control (vehicles only), DXM-treated group (40 mg/kg DXM), LBP-treated group (1 mg/kg LBP) and DXM+ LBP-treated group (40 mg/kg DXM and 1 mg/kg LBP). After two-week treatment, the DXM-treated group showed increased depression-like and social anxiety-like behaviors in the forced swim test and social interaction test respectively. On the other hand, the adverse behavioral effects induced by DXM were reduced by LBP treatment. Histological results showed that LBP treatment alone did not promote hippocampal neurogenesis when compared to the normal control, but LBP could lessen the suppression of hippocampal neurogenesis induced by DXM. The findings provide insights for the potential use of wolfberry as an adjunct treatment option for alleviating mood disturbances during rehabilitation of cough syrup abusers.

High-dose dextromethorphan produces myelinoid bodies in the hippocampus of rats.

Dextromethorphan (DM) administered at supra-antitussive doses produce psychotoxic and neurotoxic effects in humans. We administered DM (80 mg/kg) to rats intraperitoneally to determine the ultrastructural change induced by DM, because intraperitoneal route is sensitive for the behavioral responses. Treatment with DM resulted in mitochondrial dysfunction and formation of myelinoid bodies in the hippocampus. MK-801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate] attenuated DM-induced cytosolic oxidative burdens. However, neither MK-801 nor naloxone affected DM-induced mitochondrial dysfunction and formation of myelinoid bodies, indicating that the neurotoxic mechanism needs to be further elucidated. Therefore, the spectrum of toxicological effects associated with DM need to be reassessed.

A Prospective Observation Study of Medical Toxicology Consultation in a U.S. Combat Theater.

OBJECTIVES: Since 2001, U.S. military personnel and active duty, uniformed physicians providing medical support have been deployed to Afghanistan. Medical toxicologists are among the physicians deployed. There is a paucity of information present in the literature that has documented cases treated by toxicologists in theater. This prospective observational study describes 15 male patients treated in theater by a military medical toxicologist. METHODS: We performed a prospective observational study in which a medical toxicologist consulted and reported on deployed toxicology cases occurring during a 5-month deployment to Bagram, Afghanistan. RESULTS: Fifteen toxicology cases were collected during the 5-month period. The patients included three Afghan civilians, three U.S. civilians, and nine U.S. military personnel. Eight cases were attempts at recreational euphoria, two were self-harm attempts, two were from performance-enhancing supplements, two were accidental occupational exposures and one was alcohol withdrawal. Methanol was the most common exposure followed by dextromethorphan, supplements, opiates, and chlorine gas. CONCLUSION: In our study, we found that toxic alcohols and nonprescription medications were the most common exposures. In addition, this is the first study to describe bedside toxicology consults for U.S. combat forces in theater and the use of an observation unit for critically ill patients.

Repeated, high-dose dextromethorphan treatment decreases neurogenesis and results in depression-like behavior in rats.

Abuse of cough mixture is increasingly prevalent worldwide. Clinical studies showed that chronic consumption of cough mixture at high dosages may lead to psychiatric symptoms, especially affective disturbances, with the underlying mechanisms remain elusive. The present study aims at exploring the effect of repeated, high-dose dextromethorphan (DXM, a common active component of cough mixture) treatment on adult hippocampal neurogenesis, which is associated with pathophysiology of mood disturbances. After treatment with a high-dose of DXM (40 mg/kg/day) for 2 weeks, Sprague-Dawley rats showed increased depression-like behavior when compared to the control animals. Neurogenesis in the hippocampus was suppressed by DXM treatment, which was indicated by decreases in number of proliferative cells and doublecortin (an immature neuron marker)-positive new neurons. Furthermore, the dendritic complexity of the immature neurons was suppressed by DXM treatment. These findings suggest that DXM induces depression- and anxiety-like behavior and suppresses neurogenesis in rats. The current experimental paradigm may serve as an animal model for study on affective effect of cough mixture abuse, rehabilitation treatment options for abusers and the related neurological mechanisms.

Effects of dextromethorphan on glial cell function: proliferation, maturation, and protection from cytotoxic molecules.

Dextromethorphan (DM), a sigma receptor agonist and NMDA receptor antagonist, protects neurons from glutamate excitotoxicity, hypoxia and ischemia, and inhibits microglial activation, but its effects on differentiation and protection of cells in the oligodendroglial lineage are unknown. It is important to protect oligodendroglia (OL) to prevent demyelination and preserve axons, and to protect oligodendroglial progenitors (OPC) to optimize myelination during development and remyelination following damage. Enriched glial cultures from newborn rat brain were used 1-2 days or 6-8 days after shakeoff for OPC or mature OL. DM had large effects on glial proliferation in less mature cultures in contrast to small variable effects in mature cultures; 1 µM DM stimulated proliferation of OPC by 4-fold, microglia (MG) by 2.5-fold and astroglia (AS) by 2-fold. In agreement with increased OPC proliferation, treatment of OPC with DM for 3 days increased the % of OPC relative to OL, with a smaller difference by 5 days, suggesting that maturation of OPC to OL was "catching up" by 5 days. DM at 2 and 20 µM protected both OL and OPC from killing by glutamate as well as NMDA, AMPA, quinolinic acid, staurosporine, and reactive oxygen species (ROS). DM did not protect against kynurenic acid, and only modestly against NO. These agents and DM were not toxic to AS or MG at the concentrations used. Thus, DM stimulates proliferation of OPC, and protects both OL and OPC against excitotoxic and inflammatory insults.

"How high do they look?": identification and treatment of common ingestions in adolescents.

Adolescents have access to a variety of legal or illicit substances that they use to alter their mood or "get high." The purpose of this review is to provide an overview of common substances adolescents use to get high, including the illicit substances synthetic marijuana or "Spice," salvia, MDMA, synthetic cathinones, and 2C-E. Dextromethorphan and energy drinks are easily accessible substances that teenagers abuse. The toxic effects of common ingestions and treatment of overdose is discussed to inform pediatric providers who provide care for adolescents.

Neuropsychotoxic and neuroprotective potentials of dextromethorphan and its analogs.

Dextromethorphan (3-methoxy-17-methylmorphinan) has complex pharmacologic effects on the central nervous system. Although some of these effects are neuropsychotoxic, this review focuses on the neuroprotective effects of dextromethorphan and its analogs. Some of these analogs, particularly dimemorfan (3-methyl-17-methylmorphinan) and 3-hydroxymorphinan, have promising neuroprotective properties with negligible neuropsychotoxic effects. Their neuroprotective effects, the mechanisms underlying these effects, and their therapeutic potential for the treatment of diverse neurodegenerative disorders are discussed.

Developmental toxicity of dextromethorphan in zebrafish embryos/larvae.

Dextromethorphan is widely used in over-the-counter cough and cold medications. Its efficacy and safety for infants and young children remains to be clarified. The present study was designed to use zebrafish as a model to investigate the potential toxicity of dextromethorphan during embryonic and larval development. Three sets of zebrafish embryos/larvae were exposed to dextromethorphan at 24, 48 and 72 h post fertilization (hpf), respectively, during the embryonic/larval development. Compared with the 48 and 72 hpf exposure sets, the embryos/larvae in the 24 hpf exposure set showed much higher mortality rates which increased in a dose-dependent manner. Bradycardia and reduced blood flow were observed for the embryos/larvae treated with increasing concentrations of dextromethorphan. Morphological effects of dextromethorphan exposure, including yolk sac and cardiac edema, craniofacial malformation, lordosis, non-inflated swim bladder and missing gill, were also more frequent and severe among zebrafish embryos/larvae exposed to dextromethorphan at 24 hpf. Whether the more frequent and severe developmental toxicity of dextromethorphan observed among the embryos/larvae in the 24 hpf exposure set, as compared with the 48 and 72 hpf exposure sets, is due to the developmental expression of the phase I and phase II enzymes involved in the metabolism of dextromethorphan remains to be clarified. A reverse transcription-polymerase chain reaction analysis, nevertheless, revealed developmental stage-dependent expression of mRNAs encoding SULT3 ST1 and SULT3 ST3, two enzymes previously shown to be capable of sulfating dextrorphan, an active metabolite of dextromethorphan.

Systemic dextromethorphan and dextrorphan are less toxic in rats than bupivacaine at equianesthetic doses.

PURPOSE: Dextrorphan, a major metabolite of dextromethorphan, produces the duration of spinal and cutaneous anesthesia similar to bupivacaine. The purpose of this study was to test the central nervous system and cardiovascular toxicity of bupivacaine, dextromethorphan, and dextrorphan. METHODS: First, dose-response curves for dextromethorphan, dextrorphan, and bupivacaine (n = 8 at each testing point) were determined for cutaneous analgesia on the rat back, and equipotent doses were calculated. Next, during continuous intravenous infusion of equipotent doses of bupivacaine, dextromethorphan, and dextrorphan (n = 8 in each group), we observed the time to seizure, apnea, and complete cardiac arrest. A saline group (n = 7) was used for comparison. Mean arterial blood pressure (MAP), heart rate (HR), stroke volume (SV), and cardiac output (CO) were also monitored. RESULTS: Bupivacaine, dextromethorphan, and dextrorphan produced dose-dependent cutaneous anesthesia. A longer duration of equipotent infusion doses was required to produce seizures in the dextromethorphan group (10.6 ± 1.3 min) than in the bupivacaine group (7.6 ± 2.1 min) (P = 0.005). Dextrorphan did not produce any seizures. Compared with bupivacaine, time to apnea and complete cardiac arrest was longer with dextrorphan (P < 0.001) and with dextromethorphan (P = 0.001). Cardiovascular collapse, defined as a decline in MAP, HR, CO, and SV, was slower in the dextromethorphan and dextrorphan groups than in the bupivacaine group (P < 0.001 for both comparisons). CONCLUSION: At equipotent doses for local anesthesia, dextromethorphan and dextrorphan were less likely than bupivacaine to induce central nervous system and cardiovascular toxicity.

Effects of common antitussive drugs on the hERG potassium channel current.

A common over-the-counter (OTC) non-opioid antitussive drug, clobutinol, was recently withdrawn from the market due to its potential to induce cardiac arrhythmias by a blockade of the potassium channel coded by the human ether-à-go-go-related gene (hERG). In this study, we investigated the effects of a number of antitussive compounds on the hERG ion channel current using patch-clamp electrophysiology, and compared the effects to that of clobutinol. The compounds clobutinol, pentoxyverine, dextromethorphan, and codeine inhibited the outward current in hERG transfected cells with half-maximal inhibition concentrations (IC50) of 1.9 microM, 3.0 microM, 5.1 microM, and 97 microM, respectively. For theobromine, no significant effect on the hERG current at a concentration up to 100 microM was detected. Safety margins between the effects of the drugs on the hERG ion channel current and their calculated maximal free therapeutic plasma concentration were calculated. These results were compared to assess potential risks of the compounds to induce torsade de pointes-type arrhythmias.

An evaluation of the genotoxicity of the antitussive drug Dextromethorphan.

Dextromethorphan (DMP) is an effective and widely used antitussive drug. While DMP has over a 50 year safe-marketing history, the only available genotoxicity data was an unpublished, negative Ames assay (Roche). Lack of a complete genotoxicity profile on DMP, specifically covering the chromosomal damage endpoint, prompted a regulatory request for an in vitro chromosome aberration assay. In accordance with EC and CPMP Guidance, we evaluated data for a number of chemicals with a structural relationship to DMP. DMP contains no structural alerts for genotoxicity or carcinogenicity using the Deductive Estimation of Risk from Existing Knowledge (DEREK) software tool, confirming the negative results obtained in the existing Ames assay. This is also consistent with the mostly negative genotoxicity and carcinogenicity data available on structurally related chemicals including morphine, codeine, nalbuphine, buprenorphine, naloxone, hydromorphone, levorphanol, and oxycodone. A state-of-the-science, in vitro chromosome aberration assay was also conducted, which demonstrated a lack of genotoxicity for DMP. The overall weight of evidence for DMP and its structural analogues, supports the conclusion that this class of phenanthrene-based chemicals, and DMP, in particular, are not genotoxic in vitro or in vivo, and do not represent a carcinogenic risk to patients.

Effects of dextromethorphan on dopamine dependent behaviours in rats.

Dextromethorphan, a noncompetitive blocker of N-methyl-D- aspartate (NMDA) type of glutamate receptor, at 7.5-75 mg/kg, ip did not induce oral stereotypies or catalepsy and did not antagonize apomorphine stereotypy in rats. These results indicate that dextromethorphan at 7.5-75 mg/kg does not stimulate or block postsynaptic striatal D2 and D1 dopamine (DA) receptors. Pretreatment with 15 and 30 mg/kg dextromethorphan potentiated dexamphetamine stereotypy and antagonised haloperidol catalepsy. Pretreatment with 45, 60 and 75 mg/kg dextromethorphan, which release 5-hydroxytryptamine (5-HT), however, antagonised dexamphetamine stereotypy and potentiated haloperidol catalepsy. Apomorphine stereotypy was not potentiated or antagonised by pretreatment with 7.5-75 mg/kg dextromethorphan. This respectively indicates that at 7.5-75 mg/kg dextromethorphan does not exert facilitatory or inhibitory effect at or beyond the postsynaptic striatal D2 and D1 DA receptors. The results are explained on the basis of dextromethorphan (15-75 mg/kg)-induced blockade of NMDA receptors in striatum and substantia nigra pars compacta. Dextromethorphan at 15 and 30 mg/kg, by blocking NMDA receptors, activates nigrostriatal dopaminergic neurons and thereby potentiates dexampetamine stereotypy and antagonizes haloperidol catalepsy. Dextromethorphan at 45, 60 and 75 mg/kg, by blocking NMDA receptors, releases 5-HT and through the released 5-HT exerts an inhibitory influence on the nigrostriatal dopaminergic neurons with resultant antagonism of dexampetamine stereotypy and potentiation of haloperidol catalepsy.

Ovariectomy ameliorates dextromethorphan--induced memory impairment in young female rats.

We have previously found that dextromethorphan (DM), over-the-counter cough suppressant, impairs memory retention in water maze task, when it is repeatedly administrated to adolescent female rats at high doses. In this study we examined first if ovariectomy ameliorates the DM-induced memory impairment in female rats, and then whether or not the DM effect is revived by estrogen replacement in ovariectomized female rats. Female rat pups received bilateral ovariectomy or sham operation on postnatal day (PND) 21, and then intraperitoneal DM (40 mg/kg) daily during PND 28-37. Rats were subjected to the Morris water maze task from PND 38, approximately 24 h after the last DM injection. In probe trial, goal quadrant dwell time was significantly reduced by DM in the sham operated group, however, the reduction by DM did not occur in the ovariectomy group. When 17beta-estradiol was supplied to ovariectomized females during DM treatment, the goal quadrant dwell time was significantly decreased, compared to the vehicle control group. Furthermore, a major effect of estrogen replacement was found in the escape latency during the last 3 days of initial learning trials. These results suggest that ovariectomy may ameliorate the adverse effect of DM treatment on memory retention in young female rats, and that estrogen replacement may revive it, i.e. estrogen may take a major role in DM-induced memory impairment in female rats.

Dextromethorphan psychosis, dependence and physical withdrawal.

As part of a synthesis of evidence regarding the abuse and addiction liability of dextromethorphan (DM), an over-the-counter cough medicine available in over 140 preparations, an uncommonly published case of dextromethorphan dependence (addiction) is described, with specific, rarely published complications. The individual was interviewed and several medical databases were also reviewed (Medline, 1966-present; PubMed) for all content relating to the Keywords: dextromethorphan, abuse, dependence, cough medicine, addiction, withdrawal, psychosis. The patient evidenced history suggesting substance dependence, substance-induced psychosis and substance withdrawal in relation to DM. A literature review revealed that DM has specific serotonergic and sigma-1 opioidergic properties. Dextrorphan (DOR), the active metabolite of DM, has similar properties; however, DOR is a weaker sigma opioid receptor agonist, and a stronger NMDA receptor antagonist. DM and DOR display specific biological features of addiction, and are capable of inducing specific psychiatric sequelae. A specific, reproducible toxidrome with significant psychiatric effects occurred, when DM was abused at greater than indicated doses, with more profound and potentially life-threatening effects at even higher doses. DM withdrawal appears evident. DM's active metabolite, DOR, has pharmacodynamic properties and intoxication effects similar to dissociatives, and may be more responsible for the dissociative effect that this DM abuser sought. However, it is this same metabolite that may be fraught with the potentially life-threatening psychoses and dissociative-induced accidents, as well as addiction. While DM has been hypothesized as the most commonly abused dissociative, health-care providers seem largely unaware of its toxidrome and addiction liability.