Psychotropic Effects of Dextromethorphan Are Altered by the CYP2D6 Polymorphism

[Bajeda]

Psychotropic Effects of Dextromethorphan Are Altered by the CYP2D6 Polymorphism: A Pilot Study

Zawertailo, Laurie A. MSc; Kaplan, Howard L. PhD; Busto, Usoa E. PharmD; Tyndale, Rachel F. PhD; Sellers, Edward M. MD, PhD


Abstract

Dextromethorphan is a nonopioid antitussive metabolized by cytochrome P450 2D6 (CYP2D6) to an active metabolite, dextrorphan.CYP2D6 is polymorphically expressed in humans, with 5 to 10% of Caucasians being homozygous deficient for the active form of the enzyme. In a pilot study, the authors investigated the pharmacologic effects of dextromethorphan in individuals phenotyped and genotyped as extensive metabolizers (EMs, N = 4) and poor metabolizers (PMs, N = 2) of CYP2D6 substrates. Dextromethorphan doses ranged from 0 to 6 mg/kg based on individual subject tolerance. All EMs tolerated 3 to 6 mg/kg dextromethorphan, whereas PMs barely tolerated 3 mg/kg dextromethorphan and therefore received lower doses. As shown in previous studies, plasma kinetics show profound differences in dextromethorphan metabolism between EMs and PMs. Dextromethorphan produced qualitatively and quantitatively different objective and subjective effects in the two groups. Objectively, PMs had greater psychomotor impairment, as measured by a joystick tracking task, compared with EMs on 3 mg/kg dextromethorphan (mean performance +/- SE, 95 +/- 0.5% for EMs vs. 86 +/- 6% for PMs; p < 0.05). At this dose, EMs also reported greater abuse potential compared with PMs (p < 0.05), and PMs reported greater sedation and dysphoria compared with EMs (p < 0.01). These data provide preliminary evidence that dextrorphan contributes to dextromethorphan abuse liability, and therefore PMs may be less likely to abuse dextromethorphan. (J Clin Psychopharmacol 1998;18:332-337)


Full Text

DEXTROMETHORPHAN IS THE METHYLATED dextrorotatory analog of levorphanol (a [micro sign]-opioid agonist), [1] but it does not possess the full range of central nervous system effects common to opioid agonists. [2] The drug has been widely used for its antitussive properties for many years and is available as an over-the-counter preparation in most countries, including Canada and the United States. Dextromethorphan has also been investigated as a possible pharmacotherapy for a variety of neurodegenerative disorders such as amyotrophic lateral sclerosis, [3,4] idiopathic Parkinson disease, [5,6] and Huntington disease. [7] Experimental studies have investigated the analgesic properties of dextromethorphan in humans [8] and its use as possible pharmacotherapy for heroin addiction. [9]

Reports of dextromethorphan abuse have been published in which individuals consume large quantities for the psychotropic effects produced. [10-17] The effects described by these high-dose users include sedation, agitation, dissociative sensations, and visual hallucinations. In some cases, the abuse of dextromethorphan continued for long periods of time, and the individuals had difficulty stopping his or her use of the drug. [17] In addition, there are Internet sites dedicated to representing dextromethorphan as a drug of abuse.

Dextromethorphan has three major metabolites: dextrorphan, 3-hydroxymorphinan (3-HM), and 3-methoxymorphinan (3-MM). [18] Dextrorphan is the major metabolite of dextromethorphan and is produced by an O-demethylation reaction catalyzed predominantly by the enzyme CYP2D6. [19,20] The N-demethylation pathway for dextromethorphan that yields 3-MM is a minor pathway catalyzed mostly by the CYP3A family. [21]

Dextrorphan is an active metabolite with anticonvulsant, sedative, and antitussive properties and an affinity for the phencyclidine (PCP) site of the ligand-gated channel of the N-methyl D-aspartate (NMDA) receptor complex (Ki = 222 nM). [22] The affinity of dextrorphan is similar to that of ketamine (Ki = 200 nM) [23] and is much higher than that of the parent drug, dextromethorphan (Ki = 3500 nM). [24] However, the binding affinity of dextrorphan for the NMDA receptor complex is not as high as that of PCP (Ki = 42 nM), [22] a prototypic NMDA antagonist [25] and a well-known drug of abuse. [26]

Recently, we showed large pharmacokinetic differences with respect to the metabolism and elimination of 30 mg of dextromethorphan, administered orally, between those individuals who have high CYP2D6 activity (extensive metabolizers, EMs) and those who do not express an active form of this enzyme (poor metabolizers, PMs). [27] The t1/2 of dextromethorphan was significantly increased in PMs (mean +/- SE, 30 +/- 8 hours) compared with EMs (16 +/- 4 hours, p < 0.05), and in PMs the area under the curve (AUC) plasma dextrorphan concentration was significantly lower than in EMs (p < 0.05).

We hypothesized that the psychotropic effects of dextromethorphan are partially dependent on its biotransformation patterns. Since CYP2D6 is expressed polymorphically in humans, [28] we anticipated that the resulting interindividual variation in dextromethorphan metabolism could result in qualitatively and quantitatively different dextromethorphan effects among individuals of known phenotype and genotype and could also affect the abuse liability of dextromethorphan. Therefore, we conducted a pilot study to compare the subjective and psychomotor effects of dextromethorphan in four EM and two PM subjects.
Methods
Subjects

The subjects were six male volunteers (four EMs and two PMs) recruited from a population of several hundred phenotyped healthy volunteers. Phenotyping was done by the method described by Otton and associates [29] using dextromethorphan as the probe drug. Subjects were also genotyped for the CYP2D6 gene using allele-specific polymerase chain reaction amplification. [28] Subjects' ages ranged from 25 to 30 years. They were healthy, with no history of serious medical or psychiatric problems. All subjects had limited experience with a variety of psychotropic drugs, but none met DSM-III-R diagnostic criteria for abuse of or dependence on any drug, except nicotine, either currently or in the past.
Study design

The research protocol was approved by the Human Subjects Review Committee of the Addiction Research Foundation and the University of Toronto, and informed written consent was obtained from the subjects. This study consisted of 4 study days each separated by at least 3 and not more than 7 nonstudy days. The study was designed as a single-blind study. For the first 2 study days, all subjects received placebo on the first study day and dextromethorphan 3.0 mg/kg orally on the second study day. The doses of dextromethorphan on study days 3 and 4 were based on the response of the subjects to the 3.0-mg/kg dose. If this dose was well-tolerated, the subject received doses of 4.5 and 6.0 mg/kg on study days 3 and 4. If the 3.0-mg/kg dose of dextromethorphan was not well-tolerated, the subject received 1.33 and 2.0 mg/kg on subsequent study days. The judgment of whether the subject tolerated the drug on study day 2 was made by a study physician who was blind to subject phenotype. The goal of this study design was to maximize the number of clinically safe but behaviorally interesting doses taken by each subject.

The subjects participated as outpatients in the Biobehavioral Research Department of the Addiction Research Foundation. They were told that the purpose of the study was to find out how different drugs affected their mood and behavior. The subjects were told not to take any drugs or alcohol for 24 hours preceding any study day. They arrived for each study day by 8:30 a.m., having fasted since midnight. After their vital signs were taken and a urine drug screen and blood alcohol test were administered to ensure compliance with the protocol, the subjects completed objective tests and subjective questionnaires (described in detail elsewhere [30]) once before drug administration to obtain baseline measures and then once every hour after drug administration for 6 hours. An indwelling venous catheter was inserted into a forearm vein, and a blood sample (7 mL) was taken just before test cycles at baseline and at 1, 2, 3, 4, 5, and 6 hours after drug administration. The samples were held in glass tubes containing EDTA as the anticoagulant. Plasma was separated by centrifugation within 2 hours after collection and stored at -20[degree sign]C until analyzed. A maximum of two subjects could be tested on any 1 study day, offset by 30 minutes.
Drugs and chemicals

The following drugs were given to the study subjects: placebo; dextromethorphan 1.33, 2.0, 3.0, 4.5, or 6.0 mg/kg (within 10%) in capsule form administered orally in four identical capsules. Dextromethorphan HBr was supplied by Hoffman-LaRoche (Mississauga, Canada). Placebo capsules consisted of dextrose filler in gelatin capsules. All drug and placebo capsules were identical in size, color, and taste and were specially prepared for this study by the Pharmacy of the Addiction Research Foundation.

The chemicals used as reference compounds for the high-performance liquid chromatography (HPLC) assay for plasma determination of dextromethorphan, dextrorphan, 3-MM, and 3-HM (described in detail elsewhere [27]) were dextromethorphan HBr (Sigma, St. Louis, MO), norfluoxetine as internal standard, dextrorphan tartrate, 3-MM, and 3-HM (Hoffman-LaRoche, Nutley, NJ). [small beta, Greek]-Glucoronidase (type H-1, containing sulfatase) was purchased from Sigma (St. Louis, MO). All other chemicals were of analytical reagent grade. The assay recoveries of dextromethorphan, dextrorphan, 3-MM, 3-HM, and internal standard were 97, 99, 87, 87, and 95%, respectively. The sensitivity of the assay was 10 pmol/mL for dextromethorphan and 3-MM and 100 pmol/mL for dextrorphan and 3-HM in plasma. The coefficients of variation within-days (N = 2) were 0.6, 1.9, 2.5, and 1.7%, and between-days (N = 5) were 3.6, 3.4, 2.5, and 1.8% for dextromethorphan, dextrorphan, 3-MM, and 3-HM, respectively.
Data analysis

All data were analyzed using the General Linear Models procedure of SAS 6.10 for Windows [31] and Microsoft Excel 6.0 for Windows. [32] The plasma drug and metabolite concentrations were determined using HPLC methodology described above and the AUC was determined using the trapezoidal rule. The baseline score for the day on each scale or measure was subtracted from the maximum score; this value was taken as the peak score for the day. This peak score did not always occur at the same time point for each group or drug condition, but it did always occur between 1 and 3 hours after drug administration. The mean postdrug score for each measure was also calculated, and the baseline score was subtracted. Since the test cycles were all separated by 1 hour, this method is similar to the method for calculating the AUC. Subsequently, t-tests were performed comparing both peak and mean scores on the 3.0-mg/kg dextromethorphan dose of EMs and PMs. In addition, correlation analyses were performed for selected scales versus plasma dextromethorphan and dextrorphan concentrations. The null hypothesis was rejected when the p value was less than or equal to 0.05.
Results
Subject characteristics

All six subjects completed the study. All subjects were male between the ages of 25 and 30 years (mean age +/- SD: EMs, 28 +/- 2; PMs, 26.5 +/- 1; p = not significant [NS]). The range of O-demethylation metabolic ratios for the four EMs was -2.9 to -2.5 and for the two PMs was 0.06 and 0.4. Three EMs were genotyped as homozygous wild type (*1/*1) and one was heterozygous wild type (*1/*4). Both PMs were genotyped as homozygous for the *4 mutation (*4/*4). Drug use history in all subjects consisted of alcohol use and some limited experience with illicit substances including cannabis. Three of the six subjects were regular cigarette smokers.
Drug doses

All four EMs tolerated 3.0 mg/kg dextromethorphan well and proceeded to receive 4.5 mg/kg and 6.0 mg/kg dextromethorphan on subsequent study days. However, the PMs barely tolerated 3.0 mg/kg dextromethorphan, experiencing nausea, vomiting, and dizziness. As a result, these subjects received 1.33 mg/kg and 2.0 mg/kg dextromethorphan on subsequent study days. Therefore, only the placebo and the 3.0-mg/kg dextromethorphan drug conditions are identical between the two groups, and these are the doses used to explore between-group differences.
Pharmacokinetic effects

AUC plasma dextromethorphan and metabolite concentrations for 6 hours after administration of dextromethorphan 3 mg/kg in EMs and PMs are shown in Table 1. In EMs, very little parent compound is detected in the plasma, whereas in PMs, the parent compound is the major component found (p < 0.001). For AUC plasma dextrorphan concentrations, PMs produced negligible dextrorphan compared with EMs (p < 0.01). For the other metabolites at this dose, PMs produced twice as much 3-MM as EMs (p < 0.01) and 3-HM concentrations were 18 times higher in EMs than in PMs (p < 0.001). Plasma dextrorphan concentration increases with increasing doses in EMs and PMs (data not shown); however, PMs have minimal plasma dextrorphan concentration levels compared with EMs at all doses. In contrast, plasma dextromethorphan concentration increases appreciably as a function of dose in both EMs and PMs. The slope of this curve is steeper for PMs, with 2 mg/kg dextromethorphan resulting in plasma dextromethorphan concentrations similar to that in EMs after administration of three times the dose (6 mg/kg dextromethorphan) (mean +/- SE [nanomoles per milliliter x hour]: PMs, 2.4 +/- 0.3; EMs, 2.2 +/- 0.4; p = NS).

Graphic
[Help with image viewing] Table 1. Area under the curve (0 to 6 hours) plasma concentrations for dextromethorphan and metabolites after oral administration of 3.0 mg/kg dextromethorphan HBra
Objective effect

Psychomotor performance, as measured by a joystick manual tracking task (described elsewhere [33]), was the objective measure of drug effect in this study. There was no significant decrement in psychomotor performance in EMs at any dose of dextromethorphan tested compared with placebo. However, in PMs the 3.0-mg/kg dose produced greater mean psychomotor impairment than in EMs (mean +/- SE: PMs, 86 +/- 6%; EMs, 95 +/- 0.5%; p < 0.05) and compared with placebo (92 +/- 2%; p < 0.01). Psychomotor impairment in PMs at 2 mg/kg was equivalent to that in EMs at 6 mg/kg (90 +/- 2% vs. 91 +/- 2%; p = NS), which are the same doses that produced equivalent plasma dextromethorphan concentrations.
Subjective effects

(Figure 1) shows mean effects from selected subscales of the Addiction Research Center Inventory (ARCI), the Cole/ARCI, and the Visual Analog Scales (VAS) for EMs versus PMs after oral administration of 3 mg/kg dextromethorphan. On subjective measures of sedation (ARCI Pentobarbital-Chlorpromazine-Alcohol [PCAG] scale) (p < 0.05) and dysphoria (ARCI Lysergic Acid Diethylamide [LSD] scale) (p < 0.07, NS), VAS scales of "bad" drug effects (p < 0.03) and overall strength of drug effect (p < 0.05), PMs reported greater overall effects. On the other hand, EMs reported greater effects on the Cole/ARCI Abuse Potential scale (p < 0.02) and the VAS scales of "good" drug effects (p < 0.03) and drug "liking" (p < 0.06, NS).

Graphic
[Help with image viewing] Figure 1. Scores on selected ARCI and VAS subjective effects scales, corrected for baseline effects (mean +/- SD) after oral administration of 3 mg/kg dextromethorphan HBr in EM (filled bars) and PM (open bars) subjects. *A significant difference in score between EMs and PMs (p < 0.05). PCAG, sedation scale; LSD, dysphoria scale; ABPOT, abuse potential scale; VAS BAD, VAS "bad" effects scale; VAS GOOD, VAS "good" effects scale; VAS LIKING, VAS drug liking scale.

When subjective effects were compared at doses that produced comparable mean plasma dextromethorphan concentrations (i.e., 2 mg/kg in PMs and 6 mg/kg in EMs), although EMs also had much higher plasma dextrorphan concentrations at this dose compared with PMs, there were comparable mean scores on measures of dysphoria using the ARCI LSD scale (mean +/- SE: PMs, 3.2 +/- 1.5; EMs, 3.7 +/- 1.6) and sedation using the ARCI PCAG scale (PMs, 3.5 +/- 3.3; EMs, 3.7 +/- 1.6). However, on scales measuring positive subjective effects, EMs reported increased effects compared with placebo, whereas PMs did not.

Mean values for selected subjective scales were plotted against AUC plasma dextromethorphan concentration for both EMs and PMs. There was a high correlation (r = 0.84, p = 0.07) between dextromethorphan concentration and VAS ratings of "bad" drug effects, but no correlation with VAS ratings of "good" drug effects (r = 0.40, p = 0.35). AUC plasma dextromethorphan concentration (nanomoles per milliliter x hour) was also correlated with VAS drug strength (r = 0.87, p = 0.05) and ARCI PCAG scale for sedation (r = 0.88, p = 0.02), whereas AUC plasma dextrorphan concentration (nanomoles per milliliter x hour) was correlated with ARCI Abuse Potential (r = 0.86, p = 0.06) and VAS drug liking (r = 0.85, p = 0.07) scales.
Discussion

This study provides preliminary evidence for pharmacodynamic differences of dextromethorphan based on CYP2D6 phenotype and genotype. Although there have been studies of the effect of CYP2D6 phenotype on the pharmacokinetics of dextromethorphan and its metabolites, [27,34] these studies have been conducted using therapeutic doses of dextromethorphan, and no pharmacodynamic measures were included. Our study combines both kinetic and dynamic measures of multiple high doses of dextromethorphan in a within-subjects design and examines the effects of a range of dextromethorphan doses compared with placebo in both EM and PM subjects.

Previous studies have shown that PMs produce slightly more 3-MM than EMs, but this increase does not compensate for their lack of ability to metabolize dextromethorphan through the major metabolic pathway, resulting in higher plasma dextromethorphan concentrations in PMs compared with EMs. [21,35] Our study confirms this: the major component in the plasma of PMs was unchanged dextromethorphan and in EMs was the primary metabolite dextrorphan.

The pharmacodynamic profile of dextromethorphan differed substantially between EMs and PMs, with EMs reporting more positive subjective effects and PMs reporting more negative subjective effects and demonstrating greater psychomotor impairment. Furthermore, EMs seemed more able to tolerate higher doses of dextromethorphan compared with PMs. These differences in subjective effects and tolerance between EMs and PMs are presumably due to pharmacokinetic differences. The ratings of "bad" drug effects on a VAS scale correlated with plasma dextromethorphan concentrations, whereas VAS "good" drug effects ratings did not. At doses that produced equivalent AUC plasma dextromethorphan concentrations in the two groups (i.e., 2 mg/kg in PMs and 6 mg/kg in EMs), there were also equivalent mean subjective ratings of dysphoria and sedation and equivalent decreases in psychomotor performance. However, 6 mg/kg of dextromethorphan resulted in very high plasma dextrorphan concentrations in EMs, and at this dose subjects continued to report significant increases in positive subjective effects compared with placebo. Because equivalent concentrations of dextrorphan did not occur in the PMs, drawing conclusions regarding the contribution of dextrorphan to specific drug effects is difficult, but the data strongly suggest that unchanged dextromethorphan is responsible for sedation, dysphoria, and motor impairment after oral dextromethorphan administration, whereas the positive subjective effects reported by the EM subjects may be mediated by the active metabolite dextrorphan.

Preclinical evidence suggests that dextrorphan has a different psychoactive profile than dextromethorphan. In animal drug discrimination studies, dextrorphan substitutes as a discriminative stimulus in rats trained to discriminate PCP from placebo [36] and in rats trained to discriminate dizocilpine (MK-801) from placebo. [37] However, dextromethorphan did not substitute for the discriminative stimulus in either of these studies. In another study in which rats were trained to discriminate 2.0 mg/kg PCP from saline, dextrorphan given intraperitoneally and subcutaneously and dextromethorphan given intraperitoneally showed complete stimulus generalization, whereas dextromethorphan given subcutaneously did not, [38] suggesting that first-pass metabolism plays a role in the discriminative effects of dextromethorphan. Dextrorphan is an active metabolite with a higher affinity for the NMDA receptor complex than dextromethorphan. [22,24] The affinity of dextrorphan is moderate compared with that of known selective NMDA antagonists MK-801 and PCP but is comparable with that of ketamine. [23] Therefore, it is possible that dextrorphan exerts at least some of its effects by binding to this receptor. Comparing the effects of oral dextromethorphan with those of an NMDA antagonist such as ketamine in EMs and PMs should provide additional support for this hypothesis. However, to determine clearly whether dextromethorphan and dextrorphan have different pharmacologies, one would have to administer both compounds intravenously and compare subjective effects.

In conclusion, we have investigated both the pharmacokinetic and the pharmacodynamic effects of dextromethorphan in healthy volunteers who were phenotyped and genotyped as PMs and EMs of CYP2D6 substrates. Qualitative and quantitative differences in the subjective effects profiles of dextromethorphan in these two populations exist, suggesting that EMs may have a greater risk of abuse of this drug than PMs because of the positive subjective effects reported, whereas PMs may be at greater risk of adverse effects and toxicity of dextromethorphan at higher than therapeutic doses.

[Bajeda]

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[aaronitotheburrito]

i dont understand...
english please

[Bajeda]

^^^^^^ Just ignore this for now if you have trouble comprehending it.

This was supposed to be uploaded to the file archive but I couldnt get it in pdf form and someone wanted it so I put it here. If you don't usually read through the scientific literature in the file archive then you shouldn't feel a need to read through this. The interested parties will read it and if there is something they find important they should articulate it to everyone else, either here or in an applicable thread.

[Bajeda]

Agh, fine... I'll try to summarize quickly.

Originally Posted by Study

Dextromethorphan is a nonopioid antitussive metabolized by cytochrome P450 2D6 (CYP2D6) to an active metabolite, dextrorphan.CYP2D6 is polymorphically expressed in humans, with 5 to 10% of Caucasians being homozygous deficient for the active form of the enzyme. In a pilot study, the authors investigated the pharmacologic effects of dextromethorphan in individuals phenotyped and genotyped as extensive metabolizers (EMs, N = 4) and poor metabolizers (PMs, N = 2) of CYP2D6 substrates. Dextromethorphan doses ranged from 0 to 6 mg/kg based on individual subject tolerance. All EMs tolerated 3 to 6 mg/kg dextromethorphan, whereas PMs barely tolerated 3 mg/kg dextromethorphan and therefore received lower doses.

Ok, DXM is metabalised by the CYP450 enzyme 2D6. This particular enzyme is expressed polymorphically in humans, meaning its mechanism of action and efficiency level can vary between different people. Thus, people with CYP2D6 enzymes that function differently will experience DXM differently, as it will be metabolised in a different fashion.

The scientists wanted to test this so they found people whose phenotypes and genotypes expressed varying tendencies of metabolism with this enzyme, i.e. they tested whether the genes/alleles signalled that the tendency for either metabolism would be present, and then they tested the person directly for phenotype to see if it actually worked the way the genotype hinted that it would. Here is how they did this: "Phenotyping was done by the method described by Otton and associates using dextromethorphan as the probe drug. Subjects were also genotyped for the CYP2D6 gene using allele-specific polymerase chain reaction amplification." Knowing how the person's CYP2D6 metabolism worked, they then gauged how much dextromethorphan each person would optimally tolerate so they would have a dose to use in the experiment. Apparently the Extensive Metabolisers group could tolerate more dextromethorphan than the Poor Metabolisers group, hence the former group getting higher doses and the latter getting lower doses.

Originally Posted by Study

As shown in previous studies, plasma kinetics show profound differences in dextromethorphan metabolism between EMs and PMs. Dextromethorphan produced qualitatively and quantitatively different objective and subjective effects in the two groups. Objectively, PMs had greater psychomotor impairment, as measured by a joystick tracking task, compared with EMs on 3 mg/kg dextromethorphan (mean performance +/- SE, 95 +/- 0.5% for EMs vs. 86 +/- 6% for PMs; p < 0.05). At this dose, EMs also reported greater abuse potential compared with PMs (p < 0.05), and PMs reported greater sedation and dysphoria compared with EMs (p < 0.01). These data provide preliminary evidence that dextrorphan contributes to dextromethorphan abuse liability, and therefore PMs may be less likely to abuse dextromethorphan. (J Clin Psychopharmacol 1998;18:332-337)

First part is pretty obvious. People metabolised dextromethorphan differently so they experienced different physical and mental effects that could be measured and observed both quantitatively and subjectively.

For instance, it says that the people with poorer metabolism of DXM had greater psychomotor impairment. This means their motor-coordination (i.e. being able to move around and use muscles effectively) was impaired, and the reason for this impairment was of cognitive origin rather than having a physical basis (as in the muscles or nervous system being damaged). This was measured quantitatively with a joystick, and not by asking the participants whether or not they felt impaired, so the data is fairly objective and was referred to as such.

Now, it also says the Extensive Metabolisers experienced more "abuse potential" than the Poor Metaboliser group. What this means is that on a subjective rating survey completed by the participants (or something of that nature), the people in the Extensive Metaboliser group basically found they got better effects on the whole than the other group and enjoyed the experienced more, hence there being more "abuse potential" for that group than the group that didn't get as many good effects.

An example of the less desirable effects experienced by the Poor Metabolisers group is the increased sensations of sedation and dysphoria, which aren't on the top of recreational drug users' wish lists for the most part!!


So basically if your CYP2D6 enzyme metabolises DXM into detrorphan efficiently you will probably enjoy it more as a recreational substance and be more likely to abuse it but if you don't metabolise it effectively you will get more nasty effects and have a lesser chance of abusing the drug.


I am quite tired at the moment, so that may not be the best explanation (I'm sure Paracelsus or someone will come around to clarify further if I missed something), but I hope it helped.

[Paracelsus]

A bit simpler: some people (CYP2D6 deficients) don't metabolize DXM to dextrorphan. DXM itself causes more sedation and bad effects, while dextrorphan (DXO) is responsible for the 'good' effects. So the CYP2D6 deficients get less good effects from DXM.

I asked someone to upload this file because many still think DXM is the 'good' drug and DXO a less active metabolite. Just clarifying another misunderstanding.

[sterling77]

Then would it be advantageous to choose DXO products (e.g. Delsym in the U.S.) over regular DXM products?

[Paracelsus]

Long-release DXM preparations increase the DXM: DXO ratio by constantly releasing new DXM into the body. Which would be closer to the effects of DXM in CYP2D6 poor metabolizers.

[radiometer]

So, this helps explain why CYP2D6 deficiency apparently has much more effect on DXM use compared to MDMA.

[El Calico Loco]

It would also seem to make DXM potentiation a bad idea, given that most of the methods rely on saturating the 2d6 enzyme so that the DXM is processed more slowly. Come to think of it, most of Swim's most unpleasant (but also most intense) experiences have been when he used the grapefruit juice trick with a good 3rd plateau dose.


ECL

[Paracelsus]

Grapefruit juice saturates CYP3A, not CYP2D6 (this might be helpful). This results in lower rate of N-demethylation rate, which means less DXM >> 3-methoxymorphinan and less DXO >> 3-hydroxymorphinan. Overall more effects and not necessarily more effects of DXM itself (because few DXM gets metabolized into 3-MM).

[sirlaughman]

Well, hmmmmmm lol SWIM wishes he could understand this, SWIM want to know more about the scientific part of drugs. He's am fairly knowledgable on the subjects of drugs and the interactions with the body, but not in scientific terms like this. SWIM is looking to go into the field of pharmacology.

In a positive and random note, SWIM just injested a little over 700mg of DXM

[Stradivarius]

One guy had this crazy theory that DXM and DXO counted for different plateaus.One for the lower ones(stoned,high) and one for the higher ones(trippy,CEVs).He thought that DXM gives him a trip and DXO the high.Is this possible or he's crazy?

[iAmRellySmartzL0l]

Hmm... I foresee pharmacogenetics playing a role in drug-use in the near future.