Subj : Dextromethorphan FAQ (Pa ÿ@FROM :BWHITE@OUCSACE.CS.OHIOU.EDU ÿ@SUBJECT:Dextromethorphan FAQ (Part 1/2) Message-ID: Newsgroups: alt.drugs,alt.psychoactives Organization: Ohio University, Computer Science Department (NOTE: This FAQ will be posted roughly biweekly, on the 1st and 15th of each month) This is a fairly comprehensive list of questions and answers relating to the recreational and medical use of dextromethorphan, a sigma and NMDA receptor ligand commonly used as a cough suppressant. The contents of these two files are copyright (C) 1994 by William White, and may be freely reproduced by any means provided that both files are kept intact and are kept together, and are not modified. This is version 1.0, the first release version. Any questions or comments may be addressed to me at bwhite@oucsace.cs.ohiou.edu (finger for PGP2.2 block), or William White, 44 Canterbury Dr., Athens OH 45701 USA. Note that the use of any medicine in any way contrary to instructions may be a violation of local, state, and/or federal laws. I hereby instruct all readers not to violate the law. All factual data herein was obtained from medical journals and references, and was accurate at the time I got it. None of it is guaranteed in any way, shape, or form. This is for informational purposes only; nothing herein is to be taken as a recommen- dation, excepting the instructions in this paragraph. Any actions taken as a result of this text are the responsibility of the reader, and are not the responsibility of me, Ohio University, or any subset of the Usenet/Internet community. Ohio University does not necessarily agree with any views, expressed or implied, in this document. Testimonials and personal data are presented anonymously. I do NOT maintain copies of the sender's name, address, or personal information, either online or offline, and thus I cannot give information as to their identities. Any personal information, testimonials, or reports as to DXM's effects that were or are sent to me will be considered anecdotal and not specifically referring to the sender. I encourage anyone with applicable data to send it to me anonymously. This is part 1/2. Part 2/2 contains: List of Products containing DXM and other active ingredients; Personal Testimonials; and References. FAQ OVERVIEW: Part 1/2 <1> General Information <1.1> What is Dextromethorphan Hydrobromide (DXM)? <1.2> What is Dextromethorphan Polistirex? <1.3> How does one obtain and use DXM? <1.4> What is the content of commonly available DXM preparations? (see also part 2/2) <1.5> What should I know about the other drug ingredients? <1.6> Why are so many of these in liquid form? <1.7> Is recreational DXM usage illegal? <1.8> Other (medical) uses for DXM <1.9> Drug Interactions <2> Subjective Effects and Side Effects of DXM <2.1> What are the effects of a low recreational dose? (see also part 2/2) <2.2> What are the effects of a high recreational dose? (see also part 2/2) <2.3> Why is there so much individual variance in response? <2.4> What are the side effects and risks of recreational DXM? <2.5> How toxic is DXM? What is the LD50? Should I worry? <2.6> Do you recommend DXM for recreation use? <3> Physiological Effects of DXM <3.1> How does DXM inhibit the cough reflex? <3.2> How does DXM cause its psychoactive effects? <3.3> Wow, that sure is complicated, isn't it? <3.4> Pharmacokinetics <4> Sigma, NMDA, and PCP2 receptors <4.1> What are NMDA receptors? <4.2> What are sigma receptors? <4.3> What are PCP2 receptors? <4.4> How does DXM compare to other NMDA/sigma ligands? --------------------------------------------------------------------------- <1> General Information This section covers general information about Dextromethorphan, herein referred to as DXM. Note the following abbreviations: CYA Cover Your Ass. Remember this one! DXM Dextromethorphan GABA Gamma-Aminobutyric Acid (a receptor type) NMDA N-Methyl-D-Aspartate (a receptor type) OTC Over The Counter (as in, non-prescription) PCP [1-(1-phenylcyclohexyl)piperidine] (phencyclidine, also known as "angel dust") PPA Phenylpropanolamine 3-PPP [3-(3-hydroxyphenyl)-N-(1-propyl)piperidine] also note that square brackets denote IUPAC names. If you get nothing else out of this FAQ, let it be this: Remember that the use of DXM is, in general, safe, but please remember the following basic guidelines: - NEVER use a product containing acetaminophen (Tylenol [tm]); large doses of acetaminophen can cause liver damage or death. - NEVER take DXM if you are taking, or have taken within the past two weeks, a monoamine oxidase inhibitor (MAOI). - NEVER take DXM if you are taking the prescription antihistamine terfenadine (Seldane [tm]). - Avoid all products containing DXM and other active ingredients. - Always remember: recreational use of DXM is still a great unknown. The brain you are risking is your own. <1.1> What is Dextromethorphan Hydrobromide (DXM)? DXM is a synthetic morphine analog, similar to levorphanol. DXM has been in use for approximately 30 years, and has replaced codeine as an OTC cough suppressant. It has no traditional opiate-like activity, and is not a substitute for codeine as an analgesic. DXM is [(+)-cis-1,3,4,9, 10,10a-hexahydro-6-methoxy-11-methyl-2H-10,4a-iminoethanophenanthrene], and is also known as 3-methoxy-17-methyl-(9alpha,13alpha,14alpha)- morphinan. CAS-125-71-3. [1] 6-methyl group ---> CH3---N---CH2 : | _____: | Dextromethorphan / \ | _____/ H...\__|__ (note : and .. are // \\ / | \ dotted lines). // \\_____/...CH2 \ \ / \ / The 6-methyl and the CH3O__\_____/ \_____/ 3-methoxy group are ^ ----- marked for later notes. | 3-methoxy group <1.2> What is Dextromethorphan Polistirex? Dextromethorphan Polistirex is a time-release formulation of DXM; the "polistirex" refers to a sulfonated styrene-divinylbenzene copolymer complex. It is occasionally spelled polystirex or polystyrex. Unlike the HBr salt, which is absorbed fairly quickly, this compound is intended for longer duration cough suppression. Most, but not all, people who use DXM recreationally tend to prefer the HBr form (which is also much more readily available). <1.3> How does one obtain and use DXM? DXM is widely available in cough syrups, both brand-name (such as Robitussin [tm] or Vicks Formula 44 [tm]) and store brands. Most DXM containing cough syrups also contain one or more of the following active ingredients: nasal decongestants, antihistamines, acetaminophen, or guaifenesin (see <1.5>). As a rule, you want to avoid all of them. There are "gelcaps" (liquid or gel filled capsules) available that contain DXM, but they tend to be fairly expensive and contain other active ingredients. Capsule/tablet formulations of DXM are not usually available in the USA. Drixoral Cough Caps [tm] are the notable exception (30mg DXM per capsule). It is worth noting that some drugstores keep tabs on people who frequently buy DXM-containing preparations, especially if they buy multiple bottles at once or tend not to buy other things at the same time. This is less common in larger supermarket/drug stores. DXM has been popular as an "underground" recreational drug for at least 10 years, probably longer. It is probably one of the few OTC medicines with any serious recreational use potential (ephedrine might also qualify). It is both extremely safe and very effective as a cough suppressant. The recreational use potential of DXM has not, in general, been well known, either by drug users or by physicians. Not too long ago, many physicians denied that dextromethorphan was psychoactive at all; whether this was out of ignorance or a desire to prevent recreational use, I do not know. At present, there is an increasing body of knowledge about DXM's potential for recreational use (and abuse) available in medical journals. DXM is unique among recreational drugs for several reasons. First, it is pharmacologically unlike most other recreational drugs (PCP and ketamine being its nearest relatives). Second, its effects can vary considerably from individual to individual. Finally, it can cause quite different effects at low and at high dosage levels. <1.4> What is the content of commonly available DXM preparations? NOTE: The following list is incomplete. If you have information to add to this list (esp. outside the USA), please email me. Note also that I do NOT recommend ANY of the following for recreational use. Finally, note that all expressions are metric. 1tsp is approx. 5ml. Preparations containing DXM only: (SAFEST) Drixoral Cough Caps [tm] ???? Dextromethorphan HBr 30mg per capsule Vicks Pediatric Formula 44 [tm] Richardson-Vicks Dextromethorphan HBr 1mg/ml Robitussin [tm] Pediatric Cough Suppressant Robins Dextromethorphan HBr 1.5mg/ml Benylin DM [tm] Cough Syrup Parke-Davis Dextromethorphan HBr 2mg/ml Robitussin [tm] Maximum Strength Robins Dextromethorphan HBr 3mg/ml Vicks Formula 44 [tm] Richardson-Vicks Dextromethorphan HBr 3mg/ml Kroger [tm] Cough Formula Kroger Dextromethorphan HBr 3mg/ml Note: DXM is misspelled "dextromethrophan" on the bottle. Preparations containing DXM and other products: This list is presented in Part 2/2 of the FAQ. <1.5> What should I know about other drug ingredients? There are five main classes of ingredients that are present in OTC DXM-containing products: decongestants, antihistamines, guaifenesin, analgesics, and alcohol. Each will be discussed in turn. With the exception of alcohol, all should be avoided, although for differing reasons. DECONGESTANTS: There are three nasal decongestants that are used in OTC cough formulas in the USA: PPA, pseudoephedrine, and phenyleprine (the latter is almost always found with antihistamines). PPA is also known as phenylpropanolamine (from which the acronym PPA is derived), norephedrine, and the IUPAC name [alpha-(1-aminoethyl)benzyl alcohol]. Pseudoephedrine, known by the brand name Sudafed [tm], is [(+)alpha-(1-methylamino)benzyl alcohol]. Phenyleprine is [(-)-3-hydroxy-alpha-(methylaminomethyl)benzyl alcohol]. These decongestants belong to a class of chemicals known as the phenethylamines; this class also includes amphetamine, methamphetamine, MDMA, MDA, etc., and tend to be DEA scheduled. The above three are not scheduled by the DEA (this is USA laws) because they do not have significant psychostimulant activity. Ephedrine, which is similar to pseudoephedrine, and is available throughout truck stops and mail-order pharmaceutical companies in the USA, does have mild stimulant properties; thus its popularity as a form of "legal speed". All of these drugs stimulate the sympathetic nervous system and are thus called sympathomimetics. What nasal decongestants do share with the more potent amphetamines is the peripheral activity common to sympathomimetics, such as vasoconstric- tion and decreased nasal secretions (the good side), and -- with larger doses -- insomnia, hypertension, heart rhythm abnormalities, hemmorhaging, stroke, or death (the bad side). Note that these are extreme reactions, and that individual tolerance to sympathomimetics tends to vary considerably. Tolerance can build quickly, and a fatal dose for one person may have only a mild effect on another person. Because of the potential danger of hypertension, exceeding the recommended dose of DXM and decongestant containing preparations may be asking for trouble. Most people can probably handle it in smaller recreational doses, but the peripheral "speediness" can be distinctly unpleasant. Anyone with high blood pressure or the like has no business taking large quantities of decongestants. TRY TO AVOID THESE DRUGS. ANTIHISTAMINES: The antihistamines operate by blocking histamine receptors. Peripherally, this has the effect of reducing the symptoms of histaminergic activity (stuffy and runny nose, itchy eyes, hives, rashes, etc.) associated with infections and allergies. In the CNS, histamine is partially responsible for wakefulness, and antihistamines that cross the blood-brain barrier will cause sleepiness. In fact, OTC "sleeping pills" are really just antihistamines. There are antihistamines that do not cross the blood-brain barrier (Seldane [tm] is one) but these are prescription drugs in the USA. High doses of antihistamines can result in dizziness, impairment of concentration, extreme sedation (or, paradoxically, insomnia), headache, heart palpitations, dry mouth, gastric discomfort, delusions, and abnormally high blood pressure. Doses of 30-60mg/kg have been fatal in very young children; most adults, however, are very unlikely to overdose on antihistamines. Death, when it does occur, is from cardiovascular collapse or respiratory arrest. The danger of an antihistamine overdose is very low when using a DXM-containing product recreationally. However, you will most likely experience some unpleasant symptoms, such as sleepiness, dry mouth, heart palpitations, etc. For this reason, I RECOMMEND AGAINST PRODUCTS CONTAINING ANTHISTAMINES. GUAIFENESIN: Guaifenesin [3-(2-methoxyphenoxy)-1,2-propanediol] is an expectorant; it increases the production of respiratory tract fluids, thus making phlegm less viscous and easier to cough up. Guaifenesin has been shown effective as an expectorant, but is of no use as a cough suppressant. It is often combined with dextromethorphan. Guaifenesin should not be used for chronic coughs or coughs accompanied by excessive phlegm. High doses of guaifenesin tend to induce emesis (i.e., you puke). Other effects from high guaifenesin doses are not well known, but probably not serious. However, as most people do not enjoy vomiting, I WOULD RECOMMEND AVOIDING GUAIFENESIN-CONTAINING PRODUCTS. ANALGESICS: Acetaminophen is the most common analgesic present in cough suppressant formulas. It is closely related to the NSAIDs (non- steroidal anti-inflammatory drugs) of which aspirin and ibuprofen are the two most common examples. Unlike the OTC NSAIDs, however, acetaminophen does not tend to irritate the stomach, and thus its inclusion in cough syrups. An acetaminophen overdose can be very dangerous. Normally, acetaminophen is metabolized in the body by two separate pathways, both of which lead to harmless metabolites. However, these two pathways can only metabolize so much before saturating. At that point, the remaining acetaminophen is metabolized by a cytochrome P450 liver enzyme. The metabolite via the P450 pathway is toxic to the liver. Furthermore, this doesn't happen right away; it can take 16 hours before any signs of liver damage show up. This delayed toxic effect has been responsible for the deaths of some people who (accidentally or not) overdose on acetaminophen, and then think they are fine when no immediate problems occur. There is an antidote (acetylcystine), but it must be administered within the first 12 to 16 hours. The toxic dose of acetaminophen can be as low as 50mg/kg; for a 60kg person this is only six acetaminophen tablets. DO NOT UNDER ANY CIRCUMSTANCES USE RECREATIONALLY ANY DXM PRODUCT WHICH ALSO CONTAINS ACETAMINOPHEN! As for aspirin and ibuprofen, the other two OTC painkillers, both tend to irritate the stomach at high doses. I recommend against them, especially if you have an irritable stomach. Never take large doses of aspirin or ibuprofen if you have an ulcer. ALCOHOL: Most cough syrups contain some alcohol, to act as a carrier and to numb the throat. With a few exceptions (such as Nyquil [tm]), the amount of alcohol is not usually very great. While alcohol does not, in general, mix well with DXM as a recreational drug, the amount in cough syrups should not cause trouble unless you are specifically sensitive to, or attempting to avoid, alcohol. There are alcohol-free preparations available. <1.6> Why are so many of these in liquid form? Cough preparations are in liquid form for one reason: most people have the (mistaken) belief that in order for a cough suppressant formula to work, it must coat the throat. This is complete bunk. If consumers were a bit smarter, we wouldn't have to gag down cough syrup. There are, in fact, gel-capsule cough suppressants on the market, and I expect that tablet or capsule dextromethorphan will eventually be common. In the mean time, we're all stuck with that lovely medicinal cherry taste. Note: there is some (reliable) evidence that tablet-form DXM preparations have been kept from the market in an attempt to prevent their recreational use. <1.7> Is recreational use of DXM illegal? Possibly. There are laws making it a crime to use OTC medicines in any way other than directed on the label. Not that this stops people from using ephedrine (a bronchodilator) as a stimulant. Nor are you likely to get caught and/or prosecuted; the authorities are much too busy infringing upon our civil rights looking for the illegal drugs. But, remember -- I SPECIFICALLY instruct you NOT to use any medicine in a manner inconsistent with its labelling. Furthermore, suggesting to someone that they use DXM as a recreational drug could also be violating a law -- against prescribing drugs as a layperson. Again, it's not likely to happen, but it is possible. DXM is a prescription drug in Sweden. It may become prescription in other countries. <1.8> Other (medical) uses for DXM Dextromethorphan has been used to determine cytochrome P450-2D6 activity. Cytochrome P450-2D6 is a liver enzyme which converts DXM into dextrorphan, and is extensively involved in the metabolism of other drugs. Some people lack P450-2D6 entirely; others have a highly efficient version of it. By looking for the metabolites of DXM, a physician can determine whether a person has P450-2D6, and if so, how efficient it is. This information can then be used to titrate the dosage of drugs which are metabolized by P450-2D6. One area in which DXM (as well as other NMDA blockers; see <4.1> below) shows great promise is in the prevention of brain damage resulting from excitotoxicity (overstimulation of nerve cells to the point of cell death). This excitotoxicity may be partially or wholly responsible for the damage associated such wide conditions as fever, hypoxia (lack of oxygen), infection (such as poliomyelitis, encephalitis, and meningitis), stroke, siezure, physical injury, and withdrawal from long-term dependence upon certain drugs (notably alcohol, barbiturates, and benzodiazepines). In the case of infection (and in particular poliomyelitis), it has been demonstrated that the damage to the CNS often occurs not from the infection, but from the body's own defenses, and notably from a chemical called quinolinic acid (a metabolite of tryptophan). Quinolinic acid is a very potent agonist at excitatory amino acid receptors, of which NMDA is one type; DXM prevents it from activating NMDA receptors. (Incidentally, the function of quinolinic acid -- if it has any -- is not currently known; it may be involved in the immune response). As for physical trauma, hypoxia, siezure, stroke, etc., there are several experiments which indicate that the majority of the damage again comes from excitotoxicity at excitatory amino acid receptors. While DXM has shown somewhat less success there (possibly due to other receptors being involved), it still has potential. DXM has also shown interesting potential in treating some of the problems associated with mental retardation. It may also be of use in treating Parkinson's disease. DXM may be useful in conjunction with opiates for alleviation of both acute and chronic pain. It may even be useful in fighting lung cancer. <1.9> Drug Interactions and Contraindications DXM should not be used (either recreationally or at normal dosage levels) by people who are taking a monoamine oxidase inhibitor (either a prescription MAOI or a recreational one such as harmaline). Combining DXM and a MAOI has resulted in death. Fluoxetine (Prozac [tm]) is a cytochrome P450 inhibitor, and will change the characteristics of a DXM trip somewhat (see <1.8>; see also the testimonials in Part 2/2). Other P450 inhibiting drugs will probably do the same. The duration of the trip may be greatly extended by P450-2D6 inhibitors; some users have reported effects lasting 12 to 24 hours past the normal duration. Avoid DXM if taking the prescription antihistamine terfenadine (Seldane [tm]). This combination has resulted in death. Terfenadine has been implicated in other drug interactions, incidentally. Like other psychoactive drugs, DXM should not be used by people who are mentally or emotionally unstable. I tend to believe that NO recreational drug (legal or not) should be used unless the user is in a calm, rational mood, free from anxiety or negative emotions, and is in a controlled setting where s/he will not have to drive. Speaking of which, as DXM is an intoxicating drug, don't drive under the influence. Ever. But I shouldn't have to tell you that, right? Some people are allergic to tartrazine (FD&C Yellow #5), which is present in several cough syrups. Sensitivity to tartrazine is rare, but is frequent in people sensitive to aspirin. Avoid tartrazine if you are, or think you might be, allergic to it or to aspirin. <2> Subjective Effects and Side Effects of DXM This section discusses some of the effects you might expect to feel if you were to use DXM (which I again do not recommend). Note that people with an abnormal P450-2D6 enzyme variant may experience no effects from DXM, or may have a very long-duration (2-3 days), mild, irritating intoxication. Neither of these two possibilities occur frequently, but they should be mentioned. <2.1> What are the effects of a low recreational dose? Exactly what constitutes a low dose of DXM will vary from person to person, but is usually in the range of 120mg to 360mg; this corresponds to one third to one full 4oz bottle of "maximum strength" cough syrup. The effects of DXM can vary considerably depending on the person, their set and setting, and probably numerous other factors. There is no "typical" DXM trip, although there are some common phenomena which do occur. These will be discussed separately, below. Low dose DXM trips usually take between 30 and 60 minutes to start, peak about two hours later, and last between 5 and 6 hours. Hangovers are rare; if present, there is a general feeling of being lethargic and/or slightly "off". A low dose DXM trip has been compared with marijuana and MDMA, although neither is really all that similar to DXM. SENSORY CHANGES: Many of the initial effects of DXM relate to the senses. The best known, and probably responsible for a good deal of DXM's popularity, is its effects upon hearing. Sounds may seem to be "richer" or "deeper" in content. Music is particularly affected; music -- especially powerful, intense (but not necessarily fast) music -- can become a euphoric experience. Music may develop a very rich "texture" to it, and some users feel as if the music were lifting them up to great heights. Some people find this happens only with a certain type or tempo or structure of music. Classical music seems to be popular, as is rave music (of course), and Irish/Celtic/Folk (such as Enya and Lorenna McKennit). Your mileage may vary considerably. Some people find the music euphoria only happens within a narrow dosage range. Body position and kinetic senses are also greatly distorted. Large, fluid movements may also be euphoric, and DXM users may find it enjoyable to move around a lot. The sense of balance tends to be adversely affected, and coordination may as well. Taste and smell may be distorted. Stimulation of the sense of touch often is pleasurable. There is some anaesthetic effect at low dosages; it has been likened to wearing a body-suit of open-cell foam. Vision may be affected. Colors may seem brighter or more "real". There may be loss of ability to focus or track objects. Double vision may occur if the eyes lose their ability to track the same item, although this tends to occur more at higher dosages. Overall, users may feel their senses have improved; certainly, sensory input may be pleasurable or even euphoric. The ability to process the senses remains; objects are still identifiable, although it may take longer than usual due to visual focussing problems. There is a slight "phasing" or "flanging" effect of hearing and vision (see <2.2>). There are few if any hallucinations, although imagination often becomes far more powerful. Eidetic imagery (the ability to see clearly what you imagine, as if it were there) may occur. Some users have reported their skin feeling very hot or flushed, especially in the face and hands. INTELLECTUAL FUNCTION: Because DXM tends to have some "stoning" or intoxicating effect, there is often some adverse effect upon higher mental function, especially at larger doses. Language is particularly affected. Words, phrases, or syllables may be repeated, especially when similar-sounding syllables are next to each other (e.g., "animated it" becoming "animatedididit"). The user may not be immediately aware of this. Speech may develop a sense of rhythm. Some users find they are more creative, more insightful, and more capable of non-linear thought while under the influence. I do not know if this is in fact true. I would like to see more research done on this subject, as DXM tends to be an unusual drug. MEMORY: Memory tends to be slightly affected at lower dosage levels. Working memory (the "train of thought") can become stuck in repetitive thoughts; on the other hand, some users find that they are easily distracted. Short term memory tends to be degraded. Recall of events prior to the trip is usually not affected, but encoding of what happens during the trip (and subsequent recall) may be diminished (again, this is not universal). The "break in continuity" feeling described in <2.2> (under MEMORY) may occur at low to medium dosage levels. EMOTION: Mood enhancement is typical; many users find themselves quite bouncy and happy. Unlike many other drugs, there is much less of a let-down in mood when the drug wears off. Accompanying the euphoria is often a sense of energy or drive. Users may find formerly boring, tedious tasks to be far more tolerable, or even enjoyable, under the influence of DXM. There may be some sense of fear, although this is not common at lower dosages. <2.2> What are the effects of a high recreational dose? At the higher dosage level (around 720mg, or one 8oz bottle of the same strength as in <2.1>), DXM takes on a very "heavy" character. At this level it is very "stoning" -- cognitive, sensory, and memory functions are all strongly disrupted. Some say it acts a bit like ketamine at this level; others compare it to a heavy LSD trip. Individual response varies enormously at high dosage levels. Some love it, some hate it. A high dose trip may last between 6 and 8 hours, peaking about three hours in. SENSORY CHANGES: Hearing, vision, and touch become subject to "flanging" effects -- sensory input seems to be chopped into regular, rhythmic bits, with some echo or persistence effects. This is similar, but more profound, to the flanging from nitrous oxide intoxication. The closest sober approximation would be listening to the world through a delay-line flanger. This effect, and especially the echo/persistence effects, occur both on a "raw" level (e.g., sounds, sights) and on a more complex level (shapes, faces, words). If extreme, it makes it impossible to process sensory input at all. Individual objects and sounds may still have meaning but the user may find it impossible to connect them into a coherent whole. Double vision is common; the eyes tend to lose the ability to track objects. At very high doses, vision can become disrupted and confused to the point where the user is effectively blind. It may take a very long time to process sensory input. Body position and kinetic sense are usually distorted to the point of being useless. It is often difficult if not impossible to walk. Taste and smell may be similarly affected. Do not attempt to drive or operate any complex machinery. Some users find themselves wiggling or alternatively tensing and relaxing their muscles, especially those in the feet and toes; it may feel "wrong" to stop. Sensory distortions similar to that from fever may occur. Objects may seem both too big and too small, and both too far away and too close. This may, or may not, be extremely disturbing. Actual hallucinations also occur at high dosage levels, and users have reported everything from simple geometric patterns to full-blown, lifelike hallucinations. INTELLECTUAL FUNCTION: The "stoning" effect is profound at this level. Complex, tedious functions (such as arithmetic) are very difficult. Reaction time is significantly delayed. Decision-making is somewhat degraded, although conceptual thinking is less affected than more concrete thinking. Again, the intellectual effects are sometimes unpleasant, and have been compared to those deriving from a high fever. Language changes can be quite profound. Sentences may stretch on for quite a long time or be very terse (I call this the "Hemingway effect"). Words are very often repeated. This may be related to problems with working and short-term memory. Speech may often occur in a very rigid (but not necessarily simple) rhythm; the user may not respond to speech unless it is in a similar rhythm. Some users believe this state induces rhythm-based creativity (music, poetry, etc). MEMORY: Working and short-term memory are seriously impaired. It is typical for thoughts to get stuck in a "loop". While some users report little or no short-term memory loss, others find that they cannot remember what happened even a few seconds ago. Long-term memory recall is not necessarily degraded, although encoding is usually bad. Expect to forget a lot of what happened during the trip. The sense of time can be quite distorted, incidentally, both in terms of chronological placement of events and the sense of the passage of time. The day after the DXM trip, some users feel as if there has been a break in the continuity of their memories, almost like the close of one chapter and the beginning of another. Some find this feeling a very positive one, like a rebirth or transition. It can be disconcerting if you experience it without being prepared. MOOD: Mood can range from mania to panic. Irrational fears may occur, especially in users naive of the bodily effects of this dosage range. There may be a great increase in approach behaviour, as if every event and object were a new experience. At this dosage level, DXM can have an almost "shamanic" feel to it; the user may find himself or herself confronting aspects of the self for which he/she is unprepared. This can range from interesting to terrifying. At least one user has reported recall of repressed memories (later verified to be true). At very high levels, some users have reported feeling that they have "lost" themselves for a time. The amount of control over this will tend to relate to experience with this drug and hallucinogens in general. Several people have reported that high dosage DXM trips have a definite "spiritual" component. I cannot comment on the validity of this type of observation, as I am not knowledgeable on the subject of shamanic use of drugs. However, enough people have mentioned it that I have included it here. Increased contact with the spirit world, spiritual journeying, etc. are the usual fare. Many find this dosage level to be quite enjoyable. A lot probably has to do with familiarity with psychoactive drugs in general. Some people have reported mystical experiences on high dosage levels (e.g., connection with the spirit world or with other beings). <2.3> Why is there so much individual variance in response? Several reasons. First off, there is a liver enzyme known as cytochrome P450IID6 (commonly P450) which metabolizes DXM. Some people have a different variant than others, or none at all (see above, question <1.8>). Thus, while one person may metabolize DXM quickly, another may not. Certain drugs -- such as fluoxetine (Prozac [tm]) -- can inhibit P450 activity. Secondly, it is hypothesized that some of the effects of DXM, especially at higher dosage levels, may actually be due to dextrorphan, which is more similar to PCP and ketamine in its neuroreceptor activity. Some individuals may metabolize high doses of dextromethorphan to dextrorphan. Incidentally, my opinion -- based on anecdotal evidence of recreatioanl DXM use while on fluoxetine -- is that DXM, and not dextrorphan, is responsible for the psychoactive effects. Third, NMDA receptors are intimately involved in most areas of the brain, unlike the biogenic amine neurotransmitters (serotonin, dopamine, noradrenaline, histamine, and acetylcholine); the biogenic amines are usually secreted by small, distinct bundles of nerves. It is possible that, due to this extensive involvement, many different cortical and limbic circuits may be affected. There are probably a gazillion other reasons why DXM has such a wide range of effects. The involvement of NMDA receptors in long-term potentiation may be part of the reason. Subtle differences in brain chemistry, notably in terms of sigma receptors, may also be involved. I don't know; I doubt anyone does. <2.4> What are the side effects and risks of recreational DXM? Physical side effects are usually fairly mild, although at higher dosage levels, there can be a heavy "body feel". Heart rate may be increased. At very high dosages, siezures may occur -- you want to avoid this. Hangovers are not common but do occur. Don't plan on doing anything too intensive or strenuous the next day. Amotivation and lethargy are common hangover effects. There are occasionally memory problems the next day, such as forgetting words or experiencing frequent deja vu. If a hangover continues for a long time, this may indicate that you have difficulty metabolizing DXM. Be patient; it may take several days (this is very rare). Take a multivitamin each day, and drink a lot of water (the former helps with enzyme activity, the latter helps your body get rid of things). Exercise daily. Psychological side effects can be quite varied. Bad trips are certainly possible, as with any drug. As with other psychoactive drugs, especially hallucinogens, there is always the chance that a mental illness may be triggered by the experience. No drug, recreational or not, can *cause* schizophrenia; most any drug can trigger it if it is latent. DXM is no exception. Prolonged, regular use of DXM has some definite risks. The most common is mania; this has been reported in people who used large amounts of DXM (especially to self-medicate depression). Some research has linked sigma receptors to schizophrenia, and chronic use of NMDA antagonists has been shown to upregulate (increase) dopamine receptors. This could theoretically mean that DXM could trigger schizophrenia in susceptible individuals, although nobody knows for sure. One thing that is known is that neither DXM nor PCP nor ketamine cause any change in PCP or sigma receptors. Chronic use of NMDA antagonists may also increase alcohol tolerance; this is based mostly on anecdotal evidence and theory, but it appears to be a very real phenomenon. If true, then it is important to note that the GABA receptor effects of alcohol may NOT be changed; in practical terms, you might be a lot drunker than you feel, and this could possibly lead to alcohol poisoning. Be careful, and limit yourself to as little alcohol as possible when using DXM. <2.5> How toxic is DXM? What is the LD50? Should I worry? The LD50 of DXM is not well known. In searching medical literature, I found only two cases of death associated with DXM use, both in Sweden. In one case, a girl was found dead in a public bathroom with two bottles of 30mg DXM tablets (the number of tablets is believed to be 50/bottle, but may be 15 or 25). She had previously tried to commit suicide using a bottle of 50 tablets (this leads me to believe that she had, in fact, taken 100 tablets). The other case involved a 27 year old man, and few details were specified. In both cases, death was apparently due to inhibition of respiration. Plasma levels of DXM were 9.2 and 3.3 micrograms per gram (cases 1 and 2); plasma levels of dextrorphan were 2.9 and 1.5 micrograms per gram. In both cases, the ratio of DXM to dextrorphan was about 3. It is reasonable to expect, given this data, and the available data on the effects of high DXM doses, that DXM starts becoming toxic around 2000 to 3000mg (for an adult). This corresponds to between 5 and 8 4oz bottles of 3mg/ml cough syrup, i.e., a fairly large amount, but still within the realm of hardcore experimenters. Keep this in mind before you consider large doses. IV naloxone is considered the antidote for DXM overdose. <2.6> Do you recommend DXM for recreation use? No. Definitely not. Use of medicine, OTC or not, contrary to instructions may be a violation of local, state, and/or federal law. I hereby specifically tell you not to use any DXM-containing product (or any other product) in a manner inconsistent with its labelling. Even if DXM *were* legal for recreational use, I still wouldn't recommend it for frequent use, nor for high-dosage use. Frequent use may bring about undesirable changes (upregulation of dopamine receptors, for example). High-dosage use carries with it all the risks of any hallucinogen, and can be distinctly unpleasant. Very little is known about sigma, PCP, or NMDA receptors. You dork with them at your own risk, and that risk may be considerable. Sound like a CYA answer? It sure is. Right now, in the country in which I live, there are many people with nothing better to do than support legal paternalism and legal moralism. For whatever reason, some people feel that they have the right to tell a legal adult what she or he can and cannot do that involves only her/his body. And as long as this goes on, I'm going to make sure I'm not thrown into prison so they can free murderers and rapists to make room for me. So, I'm telling you -- don't break the law. <3> Physiological Effects of DXM This section governs the effects of DXM on the body. Unfortunately, knowledge of NMDA/sigma ligands is far from complete. Much of this information will undoubtedly turn out to be wrong. <3.1> How does DXM inhibit the cough reflex? This is a complex question. The cough reflex involves a series of signals originating from the throat, lungs, and nasal passages, and ending up in the muscles. At any point in this pathway, signals are susceptible to the effect of inhibitory transmission. Sigma receptors are evidently involved in this pathway. This may be a direct involvement -- sigma receptors may directly inhibit the cough reflex signals -- or it may be an indirect one. There is some evidence that 5HT1a receptors (a type of serotonin receptors) are involved somewhere in this pathway, and that cough suppressants may increase 5HT1a activity. This could explain some of DXM's mood-altering activity. 5HT1a receptors are involved in anxiety states and in resilience to aversive events. <3.2> How does DXM cause its psychoactive effects? Upon comparison with 3-PPP (similar to PCP), DXM has been found to bind with at least three types of neuroreceptors; these have been labelled DM1, DM2, and DM3 (remember, these are binding sites, not necessarily receptors). At the DM1 binding site, 3-PPP and DXM both have nanomolar potency; at DM2, DXM is nanomolar while 3-PPP is micromolar (i.e. less potent than DXM); and at the DM3 binding site, DXM is micromolar while 3-PPP is nanomolar. Given what is currently known about sigma and PCP receptors, the DM1 binding site is most likely the sigma receptors and the DM3 binding site is most likely the NMDA/PCP1 receptor (see <4> below). The DM2 binding site is likely the PCP2 receptor, but some research has suggested another site of DXM action separate from this receptor. Most of the "stoning" or intoxicant effects of DXM are likely the result of NMDA receptor blockade. Part of alcohol's intoxicant effect seems to be mediated by NMDA receptor blockade; this may explain some of the similarity. Unlike alcohol, DXM does not affect GABA receptors. The severe disruption of sensory processing is also most likely due to NMDA blockade. Some analogy to auditory disturbances in schizophrenia have been drawn, and potential mechanisms for "flanging" of sensory input and for persistence/echo are being investiaged. These, as well, are likely due to NMDA activity. Memory inhibition is almost certainly due to NMDA blockade; NMDA receptors are involved in long-term potentiation (a cellular component of memory). The psychotomimetic (literally "psychosis-like") effects of DXM may be a result of sigma activity. For better or for worse, little if any data is available on the effects of sigma agonists without NMDA activity on humans. However, sigma agonism is likely much more "subtle" than NMDA block. Finally, if (as some researchers believe) PCP2 "receptors" are in fact a biogenic amine reuptake site, then many of DXM's euphoric, mood- enhancing, and stimulant effects could result from occupancy (and thus blockade) of this site. Interestingly, DXM seems to be much more potent at this site than other sigma/NMDA ligands (such as PCP or ketamine) in comparison to activity at other sites. Also interestingly, at least one tricyclic antidepressant has been found to be a sigma ligand; it is possible that this reuptake site is in the same category as those targeted by antidepressants. It is my belief that many of the effects felt at lower dosages may be due to reuptake inhibition. Many of DXM's effects are undoubtedly due to indirect activity. For example, it may indirectly increase 5HT activity, especially at the 5HT1a receptor. This could explain some of its mood-altering properties. Another example is dopaminergic activity; DXM seems to increase activity at certain dopamine receptors. Note that DXM itself may not be responsible for the psychoactive effects, especially at higher dosage levels. DXM may be converted within the body to dextrorphan (see <2.3>). <3.3> Wow, that sure is complicated, isn't it? Yes. And unfortunately, it doesn't really say as much as you might think. What it means, basically, is that DXM works via at least three neuroreceptors, one of which (the NMDA receptor) is involved in learning and in higher reasoning, and one of which (the sigma receptor) may be involved in schizophrenia and in psychotomimetic effects. The third receptor (PCP2) may be the same reuptake site (or a similar one) as that targetted by antidepressants. But, beyond that, nobody really knows why or how DXM (or any other complex, psychoactive drug) works. <3.4> Pharmacokinetics DXM is absorbed quickly from the GI tract; within 30 minutes, all of it may have entered the bloodstream. The polistirex compound will obviously take longer to be absorbed. DXM is subject to two first-pass metabolic changes: O-demethylation (replacement of the 3-methoxy group with OH), and N-demethylation (replacement of the 6-methyl group with H). Refer to <1.1> and the diagram of the DXM molecule. The O-demethylation pathway can occur either via cytochrome P450-2D6, or another (unidentified) enzyme which works at about 70 times slower. The enzyme responsible for the N-demethylation pathway has not been identified. The product of O-demethylation of DXM is dextrorphan, a chemical which many believe to be responsible for DXM's psychoactive effects. N-demeth- ylation of DXM produces 3-methoxymorphinan (3MM). O-demethylation of 3MM or N-demethylation of dextrorphan produces 3-hydroxymorphinan. I could not find any further information on DXM metabolism. Incidentally, the O-demethylation of 3MM is also performed by P450-2D6. Note that anecdotal evidence from recreational users of DXM who take fluoxetine leads me to believe that dextrorphan is not, in fact, responsible for DXM's psychoactive effects. In fact, fluoxetine (which inhibits P450-2D6) tends to extend the DXM trip. This is consistent with DXM's effects being due to the dextromethorphan itself and not a metabo- lyte such as dextrorphan. <4> Sigma, NMDA, and PCP2 receptors This section covers some of the basics about the three receptor types that DXM targets. I apologize if this may get a bit complicated; I'm not all that good at explaining this sort of thing. I assume a basic knowledge of neurotransmitters and neuroreceptors (consult any biological psychology, psychophysiology, or psychopharmacology text). <4.1> What are NMDA receptors? When most people discuss neurotransmitters and neuroreceptors in the context of drug activity, they usually refer to the biogenic amines: acetylcholine, dopamine, noradrenaline, serotonin (5HT), and histamine. From a psychopharmacological standpoint, these are probably the best understood. These neurotransmitters tend to have a regulatory function; they modulate behaviour, mood, activity level, etc. In general, the receptors are slow and are not involved in the sort of high speed information processing that takes place in the cortex. The bulk of neurotransmission takes place not with the biogenic amines but with excitatory amino acids (glutamic acid and aspartic acid) and inhibitory amino acids (GABA). Unlike most biogenic amine receptors, many receptors for excitatory and inhibitory amino acids are very fast, and operate by directly polarizing or depolarizing the nerve membrane. NMDA is one type of excitatory amino acid receptor (quisqualate and kainate are the others). NMDA receptors are unique in that, in addition to the normal chemical signal, they also require a Mg ion in order to function. NMDA receptors are involved in long-term potentiation, the mechanism by which individual nerve cells "learn". Long-term potentiation is probably the basis of learning and memory, at least short-term. NMDA receptors operate, and look, a bit like an iris or camera aperture. There are five subunits, which normally fit together to close the channel; each of the subunits has a spot where neurotransmitters attatch. When they do attatch, electrostatic forces snap the channel open, and ions can flow in and out of the cell. DXM, as well as PCP and ketamine, are "open channel blockers"; they bind to a spot in the open channel (blocking it), but have little or no effect upon a closed one. Their activity is thus dependent upon the channel opening. The "PCP1" receptor is the name for this open channel attatchment site. There are at least three types of NMDA receptors (in the rat, at least; this probably extends to humans as well). One type is found in the cerebellum, one in the thalamus, and one in the cortex. These types differ subtly, but it is possible that DXM may show a different spectrum of effect on these types than other NMDA antagonists (such as ketamine or PCP). NMDA receptors are also involved in excitotoxicity (nerve cell death via overstimulation). The chemicals which agonize (activate) NMDA receptors can also kill the very same nerve cells they are activating. Many substances, such as quinolinic acid (a metabolite of tryptophan) are so potent that very small amounts can devastate great numbers nerve cells. Others, like glutamic and aspartic acid, are less potent but still capable of doing damage if present in sufficient amounts. This excitotoxicity is directly responsible for much of the damage attributed to various types of trauma and insult to the CNS. Polio is a good example; by blocking the activity of quinolinic acid, all the damage resulting from poliomyelitis can be prevented. <4.2> What are sigma receptors? Sigma receptors are a type of opioid receptor, the others being mu, kappa, and delta. This classification may, in fact, be false; there is some evidence that, while many opioids show sigma activity, the sigma receptor is not involved in the same domain as other opioid receptors (reward mechanisms and painkilling). Sigma receptors are known to be involved in psychotic states and in the cough reflex (I doubt the two are related). Sigma receptors are probably involved in schizophrenia. Neither the actual "purpose" of sigma receptors, nor the endogenous neurotransmitter that fits the sigma receptor, has been identified. <4.3> What are PCP2 receptors? PCP2 receptors were, obviously, the second PCP receptor to be positively identified (the first is the open channel site on the NMDA receptor; see <4.1>). Their use (if they have one) has not been determined, nor has their significance. PCP2 receptors could represent the closed state of NMDA channels (or some other receptor). They could be an entirely new receptor. One possibility which has received considerable support is that PCP2 receptors are reuptake sites -- areas where "used" neurotransmitters are taken back into the cells to be used again. Reuptake sites are the target for antidepressants (except for monoamine oxidase inhibitors), as well as the target for cocaine. Reuptake inhibition by DXM would result in some of the same effects as antidepressants or cocaine, and could explain the euphoria. <4.4> How does DXM compare to other NMDA/sigma ligands? DXM, especially at higher dosages, begins to resemble ketamine and PCP. However, it still is very different (especially at lower dosages). This is most likely due to the DM2 binding site (the PCP2 reuptake site), where DXM is far stronger in effect than either PCP or ketamine, as well as the DM3 binding site (the NMDA/PCP1 site) where PCP and ketamine are far stronger in effect than DXM. This is probably why DXM has a much stronger mood-enhancing effect, and a much weaker dissociative anaesthetic effect, than PCP or ketamine. -- | Bill White +1-614-594-3434 | bwhite@oucsace.cs.ohiou.edu | | 44 Canterbury, Athens OH 45701 | finger for PGP2.2 block | | SCA: Erasmus Marwick, Dernehealde Pursuivant, Dernehealde, Middle Kingdom | -------------------------------------------------------------------------------