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Dextromethorphan

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Collated from PsychonautWiki, TripSit, Pharmacology, DrugCentral. Where sources differ (e.g. dosing), Compare shows them side by side.

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DissociativeSubstituted morphinansHabit-formingCommonPW

Also known as DXM, DMO, DM, Dex, Robitussin, Delsym, DexAlone, Duract, robo, syrup, robotussinPW

Commonly found in certain over the counter cough medicines. Has dissociative effects similar to ketamine or MXE, though also shares properties with opioids and alcohol. Make sure DXM is the only active ingredient in the preparation.TS

Addiction potentialPW
produces dependence with chronic use and has moderate abuse potential
ToxicityPW
exact toxic dosage is unknown
TolerancePW
full tolerance develops with prolonged and repeated use; half after 3 - 7 days; baseline after 1 - 2 weeks
Cross-tolerancePW
dissociatives

Oral

Route dataPsychonautWiki

Dose
WeakerStronger
ThresholdLightCommonStrongHeavy
75 mg100–200 mg200–400 mg400–700 mg700 mg+
0875 mg
LightCommonStrongHeavy
Duration
ShorterLonger
Onset30–120 minutes
Come-up60–120 minutes
Peak3–6 hours
Offset2–4 hours
Total8–12 hours
After-effects4–24 hours
OnsetCome-upPeakOffset

Caution / uncertainPWTS

BenzodiazepinesCannabisCaffeine

🧬 Receptor activityPHDC

TargetActionAffinitySource
Sodium-dependent serotonin transporter—Ki 1.44 nMCHEMBL
Sigma non-opioid intracellular receptor 1—Ki 10 nMCHEMBL
Unchecked—Ki 1636 nMCHEMBL
Glutamate NMDA receptor—Ki 2246 nMCHEMBL
Muscarinic acetylcholine receptor M2—Ki 10000 nMCHEMBL
Glutamate receptor ionotropic, NMDA 2C (GRIN2C)Blocker6.33 IC50DRUGCENTRAL
Glutamate receptor ionotropic, NMDA 3A (GRIN3A)Antagonist5.699 IC50DRUGCENTRAL
Sigma non-opioid intracellular receptor 1 (SIGMAR1)Agonist6.458 D2DRUGCENTRAL
Cytochrome P450 2D6 (CYP2D6)—4.48 KsDRUGCENTRAL
Glutamate NMDA receptor (Grin1)—5.65 KiDRUGCENTRAL
Sigma non-opioid intracellular receptor 1 (Sigmar1)—5.29 KiDRUGCENTRAL
Sodium channel alpha subunits; brain (Types I, II, III) (Scn1a)—5.89 IC50DRUGCENTRAL
Sodium-dependent serotonin transporter (SLC6A4)—8.842 KiDRUGCENTRAL
Solute carrier family 22 member 1 (SLC22A1)—4.98 IC50DRUGCENTRAL
Taste receptor type 2 member 46 (TAS2R46)—4.51 EC50DRUGCENTRAL
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Mechanism of actionPH

Dextromethorphan is a low-affinity uncompetitive NMDA antagonist and sigma-1 receptor agonist. It is also an antagonist of α3/β4 nicotinic receptors. However, the mechanism by which dextromethorphan's receptor agonism and antagonism translate to a clinical effect is not well understood.
Dextromethorphan (DXM) is the dextro isomer of levomethorphan, a semisynthetic morphine derivative. Although structurally similar to other /CNS depressants/, DXM does not act as a mu receptor opioid (eg, morphine, heroin). DXM and its metabolite, dextrorphan, act as potent blockers of the N-methyl-d-aspartate (NMDA) receptor.
Amantadine and dextromethorphan suppress levodopa (L-DOPA)-induced dyskinesia (LID) in patients with Parkinson's disease (PD) and abnormal involuntary movements (AIMs) in the unilateral 6-hydroxydopamine (6-OHDA) rat model. These effects have been attributed to N-methyl-d-aspartate (NMDA) antagonism. However, amantadine and dextromethorphan are also thought to block serotonin (5-HT) uptake and cause 5-HT overflow, leading to stimulation of 5-HT(1A) receptors, which has been shown to reduce LID. We undertook a study in 6-OHDA rats to determine whether the anti-dyskinetic effects of these two compounds are mediated by NMDA antagonism and/or 5-HT(1A) agonism. In addition, we assessed the sensorimotor effects of these drugs using the Vibrissae-Stimulated Forelimb Placement and Cylinder tests. Our data show that the AIM-suppressing effect of amantadine was not affected by the 5-HT(1A) antagonist WAY-100635, but was partially reversed by the NMDA agonist d-cycloserine. Conversely, the AIM-suppressing effect of dextromethorphan was prevented by WAY-100635 but not by d-cycloserine. Neither amantadine nor dextromethorphan affected the therapeutic effects of L-DOPA in sensorimotor tests. We conclude that the anti-dyskinetic effect of amantadine is partially dependent on NMDA antagonism, while dextromethorphan suppresses AIMs via indirect 5-HT(1A) agonism. Combined with previous work from our group, our results support the investigation of 5-HT(1A) agonists as pharmacotherapies for LID in PD patients.
Dextromethorphan (DM) is a dextrorotatory morphinan and an over-the-counter non-opioid cough suppressant. We have previously shown that DM protects against LPS-induced dopaminergic neurodegeneration through inhibition of microglia activation. Here, we investigated protective effects of DM against endotoxin shock induced by lipopolysaccharide/d-galactosamine (LPS/GalN) in mice and the mechanism underlying its protective effect. Mice were given multiple injections of DM (12.5 mg/kg, s.c.) 30 min before and 2, 4 hr after an injection of LPS/GalN (20 ug/700 mg/kg). DM administration decreased LPS/GalN-induced mortality and hepatotoxicity, as evidenced by increased survival rate, decreased serum alanine aminotransferase activity and improved pathology. Furthermore, DM was also effective when it was given 30 min after LPS/GalN injection. The protection was likely associated with reduced serum and liver tumor necrosis factor alpha (TNF-alpha) levels. DM also attenuated production of superoxide and intracellular reactive oxygen species in Kupffer cells and neutrophils. Real-time RT-PCR analysis revealed that DM administration suppressed the expression of a variety of inflammation-related genes such as macrophage inflammatory protein-2, CXC chemokine, thrombospondin-1, intercellular adhesion molecular-1 and interleukin-6. DM also decreased the expression of genes related to cell-death pathways, such as the DNA damage protein genes GADD45 and GADD153. In summary, DM is effective in protecting mice against LPS/GalN-induced hepatotoxicity, and the mechanism is likely through a faster TNF-alpha clearance, and decrease of superoxide production and inflammation and cell-death related components. This study not only extends neuroprotective effect of DM, but also suggests that DM may be a novel compound for the therapeutic intervention for sepsis.
/The investigators/ showed that dextromethorphan (DM) provides neuroprotective/anticonvulsant effects and that DM and its major metabolite, dextrorphan /DX/, have a high-affinity for sigma(1) receptors, but a low affinity for sigma(2) receptors. In addition, we found that DM has a higher affinity than DX for sigma(1) sites, whereas DX has a higher affinity than DM for PCP sites. We extend our earlier findings by showing that DM attenuated trimethyltin (TMT)-induced neurotoxicity (convulsions, hippocampal degeneration and spatial memory impairment) in rats. This attenuation was reversed by the sigma(1) receptor antagonist BD 1047, but not by the sigma(2) receptor antagonist ifenprodil. DM attenuates TMT-induced reduction in the sigma(1) receptor-like immunoreactivity of the rat hippocampus, this attenuation was blocked by the treatment with BD 1047, but not by ifenprodil. These results suggest that DM prevents TMT-induced neurotoxicity, at least in part, via sigma(1) receptor stimulation.
Dextromethorphan (DEX) is a widely used non-opioid antitussive. However, the precise site of action and its mechanism were not fully understood. We examined the effects of DEX on AMPA receptor-mediated glutamatergic transmission in the nucleus tractus solitarius (NTS) of guinea pigs. Excitatory postsynaptic currents (evoked EPSCs: eEPSCs) were evoked in the second-order neurons by electrical stimulation of the tractus solitarius. DEX reversibly decreased the eEPSC amplitude in a concentration-dependent manner. The DEX-induced inhibition of eEPSC was accompanied by an increased paired-pulse ratio. Miniature EPSCs (mEPSCs) were also recorded in the presence of Cd(2+) or tetrodotoxin. DEX decreased the frequency of mEPSCs without affecting their amplitude. Topically applied AMPA provoked an inward current in the neurons, which was unchanged during the perfusion of DEX. BD1047, a sigma-1-receptor antagonist, did not block the inhibitory effect of DEX on the eEPSCs, but antagonized the inhibition of eEPSCs induced by SKF-10047, a sigma-1 agonist. Haloperidol, a sigma-1 and -2 receptor ligand, had no influence on the inhibitory action of DEX. These results suggest that DEX inhibits glutamate release from the presynaptic terminals projecting to the second-order NTS neurons, but this effect of DEX is not mediated by the activation of sigma receptors.

PharmacodynamicsPH

Dextromethorphan is an opioid-like molecule indicated in combination with other medication in the treatment of coughs and pseudobulbar affect. It has a moderate therapeutic window, as intoxication can occur at higher doses. Dextromethorphan has a moderate duration of action. Patients should be counselled regarding the risk of intoxication.

Pharmacokinetics

Half-lifePH

Dextromethorphan has a half life of 3-30 hours.
The half life of /dextromethorphan/ is approximately 2 to 4 hours in people with normal metabolism.

AbsorptionPH

A 30mg oral dose of dextromethorphan reaches a Cmax of 2.9 ng/mL, with a Tmax of 2.86 h, and an AUC of 17.8 ng\*h/mL.
The volume of distribution of dextromethorphan is 5-6.7L/kg.
Dextromethorphan is rapidly absorbed from the GI tract and exerts its antitussive effect in 15-30 minutes after oral administration. The duration of action is approximately 3-6 hours with conventional dosage forms.
Dextromethorphan and its metabolites are excreted via the kidney. Depending on the metabolism phenotype up to 11% may be excreted unchanged or up to 100% as demethylated conjugated morphinan compounds. In the first 24 hours after dosing, less than 0.1% is eliminated in the feces.
Dextromethorphan is well absorbed from the gastrointestinal tract with maximum serum level occurring at 2.5 hours. Peak concentration of the major metabolite dextrorphan) was 1.6 to 1.7 hours.
Dextromethorphan hydrobromide (DM) is a widely used antitussive. This study determined, for the first time, the basic pharmacokinetic profile of DM and its active metabolite, dextrorphan (DP) in children and adolescents. Thirty-eight male and female subjects at risk for developing an upper respiratory tract infection (URTI), or symptomatic with cough due to URTI, were enrolled in this single-dose, open-label study: ages 2-5 years (Group A, n = 8), 6-11 years (Group B, n = 17), 12-17 years (Group C, n = 13). Subjects were genotyped for cytochrome P450 (CYP) 2D6 polymorphisms and characterized as poor (PM) or non-poor metabolizers (non-PM). Groups A and B were dosed using an age-weight dosing schedule (DM range 7.5-24.75 mg); a 30-mg dose was used for Group C. Average exposures to total DP increased as age group increased, and average exposure to DM was highest in the adolescent group. One subject in that group was a PM. The terminal half-life values were longer in the adolescent group due in part to the single PM subject. No relationship between body weight and pharmacokinetic parameters was noted. This is the first evaluation of the pharmacokinetic characteristics of DM in children and adolescents. A single dose of DM in this population was safe, and well tolerated at all doses tested. The data are used to model and compare pediatric DM exposures with those of adults.

MetabolismPH

Dextromethorphan can be N-demethylated to 3-methoxymorphinan by CYP3A4, CYP2D6, and CYP2C9 or O-demethylated to dextrorphan by CYP2D6 and CYP2C9. Dextrorphan is N-demethylated by CYP3A4 and CYP2D6, while 3-methoxymorphinan is O-demethylated by CYP2D6. Both are metabolized to form 3-hydroxymorphinan. Dextrorphan and 3-hydroxymorphinan are both O-glucuronidated or O-sulfated.
Genetic polymorphism has profound effects on its metabolism. Dextromethorphan undergoes polymorphic metabolism depending on variation in cytochrome P-450 enzyme phenotype. The specific cytochrome P-450 enzyme is P450 2D6(CYP2D6). Fast metabolizers constitute about 84% of the population. After a 30 mg dose plasma levels are less than 5 ng/mL four hours postingestion. Intermediate metabolizers constitute about 6.8% of the population. After an oral dose of 30 mg plasma levels are 10 to 20 ng/mL at 4 hours and less than 5 ng/mL at 24 hours postingestion. Poor metabolizers constitute 5% to 10% of the Caucasian population. The ratio of metabolite to parent drug in 8 hour urine sample is less than 10 to 1 after a 15 mg dose. After an oral dose of 30 mg plasma levels are greater than 10 ng/mL at 4 hours and greater than 5 ng/mL at 24 hours.
There is a clear first pass metabolism and it is generally assumed that the therapeutic activity is primarily due to its active metabolite, dextrophan.
It is metabolized in the liver by extensive metabolizers to dextrorphan. Dextrorphan is itself an active antitussive compound. Only small amounts are formed in poor metabolizers. Less than 15% of the dose form minor metabolites including D-methoxymorphinane.
The pentose phosphate pathway (PPP) is involved in the activity of glucose-6-phosphate dehydrogenase (G6PD) and generation of NADPH, which plays a key role in drug metabolism. The aim of this study was to investigate the effects of modulation of the PPP on drug metabolism capacity in vitro. A pair of hepatic cell lines, ie, the cancerous HepG2 cells and normal L02 cells, was used. The expression of CYP450 enzymes, p53 and G6PD in the cells were analyzed. The metabolism of testosterone (TEST, 10 umol/L) and dextromethorphan (DEM, 1 umol/L), the two typical substrates for CYP3A4 and CYP2D6, in the cells was examined in the presence of different agents. Both the expression and metabolic activities of CYP3A4 and CYP2D6 were considerably higher in HepG2 cells than in L02 cells. The metabolism of TEST and DEM in HepG2 cells was dose-dependently inhibited by the specific CYP3A4 inhibitor ketoconazole and CYP2D6 inhibitor quinidine. Addition of the p53 inhibitor cyclic PFT-alpha (5, 25 umol/L) in HepG2 cells dose-dependently enhanced the metabolism of DEM and TEST, whereas addition of the p53 activator NSC 66811 (3, 10, 25 umol/L) dose-dependently inhibited the metabolism. Furthermore, addition of the G6PD inhibitor 6-aminonicotinamide (5, 15 umol/L) in HepG2 cells dose-dependently inhibited the metabolism of DEM and TEST, whereas addition of the PPP activity stimulator menadione (1, 5, 15 umol/L) dose-dependently enhanced the metabolism. Modulation of p53 and the PPP alters the metabolism of DEM and TEST, suggesting that the metabolic flux pattern of PPP may be closely involved in drug metabolism and the individual variance.
Dextromethorphan has known human metabolites that include 3-methoxymorphinan and Dextrorphan.

Protein bindingPH

Dextromethorphan is 60-70% protein bound in serum.

Plan when to take Dextromethorphan — see where onset, peak and comedown land on the clock

Fact-sheets from PsychonautWiki. Harm-reduction reference only — not medical advice.