From: [d x m] at [froggy.frognet.net] (Max Tussin) Newsgroups: rec.drugs.psychedelic,alt.drugs Subject: Dextromethorphan FAQ Part 04/06 Date: 7 Apr 1996 23:25:41 -0400 Keywords: DXM DM Robitussin Tussin Dextromethorphan Sigma NMDA P450 X-URL: http://www.frognet.net/dxm/dxm.html .............................................................................. Kidney damage I have found no evidence of liver or kidney toxicity from DXM itself. This doesn't mean that there isn't any, just that I haven't found any references indicating this. DXM tends to be metabolized fairly well, and neither it nor its metabolites seem to be toxic to the body. On the other hand, the large amounts of "inert" ingredients may be dangerous to the kidneys and/or pancreas, especially if taken on an empty stomach. At least one chronic (9 month) user became unable to take any type of cough syrup (containing DXM or not) without severe kidney pain and bloody urine. Gel-caps failed to induce this adverse effect. Another two former users have reported similar effects, so this may be something to worry about. .............................................................................. Bromide poisoning Although some authors have suggested the possibility of DXM-induced bromism (147), actual blood tests have revealed little danger to occasional users, even with large doses of DXM (137). Daily use might lead to a dangerous buildup. Notable symptoms of bromide poisoning include headache, irritation, slurred speech, psychosis, weight loss, hallucinations, and an acne-like rash. .............................................................................. Miscellaneous DXM may decrease immune function due to sigma activity (51). Chronic use of NMDA antagonists seems to modify 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. A recent paper supports the ability of DXM to affect alcohol tolerance (53), although this paper was concerned with a different effect, i.e., prevention of learned tolerance by NMDA antagonists. At least one user has reported that very long-term regular use of DXM (recreationally) can lead to a constant hacking dry cough. I have not been able either to confirm or to disprove this. ------------------------------------------------------------------------------ [4.3] Is DXM addictive? From one viewpoint, of course, anything can be addictive - television, chocolate, masturbation, self-mutilation, etc. So in that sense, yes, DXM can be addictive. Somewhat more relevant are the degree to which DXM is addictive, and how such addiction manifests itself. The quick answer is, DXM can be addictive if you use too much, too often. The traditional distinction made with respect to addiction is between physical addiction and psychological addiction. As examples, alcohol is physically addictive, whereas marijuana is psychologically addictive. Unfortunately this distinction has its problems - not the least of which is that since the brain is a physical construct, any addiction is in some sense "physical." As physical addiction is a somewhat nebulous concept at best, I prefer to use the concrete ideas of tolerance and serious withdrawal symptoms. Tolerance is a process by which the body and brain adjust to a drug so that the dosage must be increased to achieve the same effect (some drugs, such as nitrous oxide, exhibit reverse tolerance). "Serious" withdrawal symptoms is somewhat less clear, unfortunately. Note that it is possible to become tolerant to a drug without being psychologically addicted; in fact, some people lose the desire to use a drug when tolerance takes away its more interesting effects. There is considerable evidence based on personal reports that tolerance to DXM's more interesting dissociative effects builds quickly. This is a result of upregulation or sensitization of NMDA receptors, as well as possible changes in other receptors and systems indirectly affected by DXM. Cross-tolerance exists between DXM, PCP and ketamine, naturally. Some people seem to be immune to tolerance to dissociatives including DXM (lucky them). Usually it takes several doses before tolerance is noticeable, although a few people have noted tolerance after just one dose. Larger doses will lead to quicker tolerance. Once tolerance has built, it takes at least three weeks before receptors will reregulate to normal levels. To avoid this problem, it is probably best to dose only once a week at most. Also, some people believe that receptors which are upregulated (or downregulated) for long periods of time may tend to stay that way. The practical upshot is you should take a month off every now and then (a good idea with any drug, incidentally). Interestingly, the first plateau music euphoria effect also seems to disappear with repeated use of DXM. It's also one of the last effects to come back. This may be due to downregulation of dopamine receptors rather than upregulation of NMDA receptors. The practical upshot is, don't do DXM all the time. Again, some people are luckily immune to this tolerance effect. For information on withdrawal and withdrawal symptoms, see the next section. Psychological addiction to DXM has been noted a few times, and can theoretically lead to physical addiction. Generally, though, dissociatives aren't considered particularly habit-forming, since they tend to have such "heavy" effects. Low-dose DXM might be an exception due to its moderate to strong stimulant effect; in practicality, it's probably too hard to consistently hit the first plateau. There are exceptions, some of them notable. One case report (133) involved a 23-year old male who maintained an incredible daily dose of 30mg/kg to 40mg/kg DXM (plus a six-pack of beer)! Needless to say, after maintaining this dose long enough, he had become addicted, although the authors consider it a "psychological" addiction, with withdrawal symptoms such as dysphoria, depression, and anxiety. Most people who use DXM have noticed little or no addiction, and only mild tolerance (don't let that scare you; remember that coffee produces both tolerance and withdrawal symptoms). A few unfortunate people have developed problems with DXM. Prolonged, heavy use of DXM seems to induce dysphoria, anxiety, and/or depression in some people; as the dosage is increased, the problem gets worse. Unfortunately, at this point, there may be withdrawal problems (see the next section). If this happens to you, seek medical assistance. ------------------------------------------------------------------------------ [4.4] Is DXM withdrawal dangerous? Withdrawal from occasional DXM use is almost certainly not dangerous, and in fact any "symptoms" felt are probably just "jonesing" - the same sort of withdrawal "symptoms" felt with marijuana, television, sex, etc. At this point it's a matter of willpower more than anything else. Once tolerance has built, withdrawal has the potential to cause more serious problems. Mild tolerance to DXM is probably no more dangerous than mild tolerance to alcohol (tolerance at the level of "being able to hold your liquor"). Withdrawal may produce boredom and mild anxiety, but rarely anything more troubling than that. Beyond the mild tolerance level, things get rapidly worse. There is evidence that significant NMDA upregulation can lead to excitotoxic rebound (101), and many of the symptoms of opiate withdrawal may occur via a similar mechanism (110,134). The good news is, studies generally haven't found any significant evidence of brain damage from heroin withdrawal, so withdrawal from DXM probably wouldn't be much trouble. The bad news is, heroin withdrawal isn't particularly enjoyable. Interestingly, one person who developed addiction and tolerance to DXM also compared the withdrawal symptoms to those of heroin (although DXM never produced any of the positive effects of opiates in this individual). These symptoms included watery eyes, stuffy nose, gooseflesh, muscle spasms, increased pain sensitivity, nausea, anxiety, and depression. Furthermore, the individual eventually began to develop some of these symptoms even while using DXM. This is definitely something to avoid. If you happen to develop a significant degree of tolerance to DXM, it might be a good idea not to quit "cold turkey" (all at once). Build down slowly over a few weeks, and avoid all other drugs in the mean time. One person who had been using DXM twice daily reported no withdrawal symptoms after decreasing the dosage 10% per day, and stopping at 180mg. This should prevent any excitotoxic rebound. ------------------------------------------------------------------------------ [4.5] DXM hangovers - avoiding and alleviating Hangovers from DXM trips are not common at lower dosage ranges (first and second plateau). Instead, many people report feeling energetic and refreshed the next day, although it seems that getting enough sleep is important here. At higher dosage levels (third and fourth plateau), hangovers are more frequent. Hangover effects reported consist of lethargy, sleepiness, amotivation, mild sensory dissociation, muscle rigidity, muscle tics (especially in the jaw and hands), dizziness, loss of balance, headache, photophobia, and sharply diminished sense of taste. Some people say that everything tastes like slightly salty tepid water, or like MSG (monosodium glutamate, the flavor enhancer). Note that you're very unlikely to get all, or even most, of these symptoms. Some of the hangover effect from high dosage trips is almost certainly due to residual DXM or dextrorphan, especially in individuals who lack P450-2D6, or in whom it is inhibited (e.g., by fluoxetine). To my knowledge there doesn't seem to be any way to speed up the metabolism; the best I can suggest is to exercise, drink plenty of water, take a multivitamin every day (don't overdo it, one is plenty) and possibly a small iron supplement (which just might increase cytochrome turnover), get enough sleep, and eat right. Don't take too much iron; iron is very toxic. Other hangover effects may be due to neurotransmitter depletion (due to induction of 5HT and dopamine release), temporary inactivation of NMDA receptors (I doubt it, but there's been speculation), or just plain lack of sleep. Again, treating your body well is probably the best you can do. Preventing hangovers may be possible to some degree. Certainly, make sure you are in good physical condition to start with, and don't try to stay up too late during your trip. Drink plenty of fluids (it is possible to get dehydrated; this can slow down the kidneys), and don't mix DXM with anything that could further deplete neurotransmitters (e.g., amphetamines, MDMA, etc.). Try to avoid going to sleep while still tripping hard - it seems to reduce the quality of sleep. Eat something before you go to sleep; usually DXM kills the appetite. Another possibility is the use of nootropics ("Smart Drugs") to help prevent and alleviate hangovers. A good place to start for information is alt.psychoactives; another good place is Dean and Morganthaler's text on the subject. A healthy dose of skepticism is probably a good idea here; some of it might be placebo effect. There's evidence for and against; check Medline if you're interested. Note that unless otherwise specified, everything I mention should be available at health-food or mail-order vitamin suppliers (this is USA; I don't know about other countries). Several people have reported beneficial effects from cholinergics, specifically choline (the precursor to acetylcholine), and DMAE (also a precursor, and a choline oxidase inhibitor). In both cases the bitartrate salt seems to be the usual (there is a liquid DMAE para-aminobenzoic acid formulation that tastes nasty and evidently doesn't work). Note that some people with depression, primarily endogenous, react very poorly to cholinergics. Also note that they can make you really, really irritable if you're susceptible. Regular use of DMAE seems to be the most effective, although that's something that you have to build up for a couple of weeks (Dean and Morganthaler suggest around 800mg per day in divided doses; please consult alt.psychoactives for nootropic information). One-time use of DMAE or choline immediately before, during, or after the trip has also been reported to work, (in that order of preference), although not as well. Recommendations given to me have been 800mg DMAE, or 1500mg choline; in either case with 350mg vitamin B-5 (pantothenic acid) which acts as the relevant cofactor here. Don't go much above that. There is some preliminary evidence (still haven't found the reference) that supplementary tyrosine may actually be useful in the case of dopamine depletion. Normally, the rate-limiting enzyme in the process is nearly saturated, so boosting tyrosine doesn't work. It's hypothesized that more enzyme may be produced in response to dopamine depletion. Furthermore, sigma activity may enhance synthesis of dopamine (115), so taking supplemental tyrosine is even more likely to be a good idea. Vasopressin might also be useful; it seems to have a fair amount of success in combating intoxicants, possibly by affecting long-term potentiation (how I don't know). It's prescription in the USA, and it does have side effects. One final note - do not take tryptophan! Although this isn't established, it's possible that NMDA receptors may be upregulated after a DXM trip (especially in chronic users). Tryptophan, in addition to leading to 5HT, also leads (along a much more efficient pathway) to a substance called quinolinic acid, which is very toxic to neurons, and acts via NMDA receptors. ------------------------------------------------------------------------------ [4.6] 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, for a total dose of 3000mg). 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. Liver levels of DXM were about an order of magnitude higher. In both cases, the ratio of DXM to dextrorphan was about 3 (9). On the other hand, a dosage of 42mg/kg/day has been used in children (33), which would be 2500 to 3000mg for a 60-70kg adult. There is also a very low incidence of death associated with DXM use. Since a 42mg/kg dose in an adult may be stronger than the equivalent dose in a child (I have no reason to believe this, but it is possible), caution is advisable in taking this as an indication of safety. The highest daily dose of DXM I've come across is from a case study of a 23-year old male (133). His daily dose was 3 to 4 12oz bottles of Robitussin DM[tm], for a total of 2160mg (31mg/kg) to 2880mg (41mg/kg). He was, of course, considerably addicted to DXM, and had built up this dose over a long period of time. It is reasonable to expect, given the data, and the available data on the effects of high DXM doses, that DXM starts becoming toxic around 25 to 30 mg/kg (about 2000g for adult of 150lb). 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 (54). ------------------------------------------------------------------------------ [4.7] Do you recommend DXM for recreational 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 labeling. 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 as mentioned above. 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 USA, 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. ------------------------------------------------------------------------------ [4.8] Help! What do I do if... This section covers suggestions for undesirable, unexpected, and emergency situations. Always remember, though, if you feel there is an emergency, get to a hospital. While DXM-related deaths are very, very rare, they have occurred. Nobody wants to see any more happen. None of this is intended to be medical advice or replace the judgment of a physician, nor should it be taken as such. These are general guidelines only, compiled from reports of DXM users. Neither I nor anyone else take responsibility for any injury, death, or other misfortune, resulting from this advice. There, have I covered my ass well enough? Probably not. Just remember, please use common sense and be careful! .............................................................................. Itching (the "Robo Itch") Some people get the itch, some don't. Unfortunately, I still haven't been able to correlate it with anything, so I still can't figure out whether it comes from the DXM itself, or from a dye or other additive. It very well may be a reaction to dissociative anesthesia. In any case, from all reports the best thing seems to be to wait for it to go away, and try to think about something else. Scratching is OK, so long as you don't injure yourself in the process (remember, you many not be feeling pain as you normally would). A loofah can be quite enjoyable, actually, should you feel the urge to take a bath (which evidently can itself be enjoyable on DXM. Just be careful!) You can try a topical antihistamine spray, but I doubt it will do any good. If the itch is accompanied by a rash, swelling, or other symptoms of an allergic reaction, you should definitely take an oral antihistamine (not a prescription one), and make sure there is someone with you. If the allergic reaction continues, or you feel you may be going into shock, get to a hospital. To my knowledge this type of allergic reaction has never occurred. .............................................................................. Fast Heartbeat and Panic Attacks Many times this is more a problem of perception than anything else. Still, it does happen. As far as I have been able to determine, DXM itself can raise the heart rate somewhat, about as much as a mild to moderate stimulant (e.g. a few cups of coffee to a "coffee virgin"). Reports have indicated a range of 90 to 120 beats per minute as the relevant range. Panic attacks also can occur on DXM, especially in naive users or users rushing in to higher doses. A panic attack can increase the heart rate significantly, sometimes as much as 200 beats per minute! Unfortunately, panic attacks can be hard to control; the best thing to do seems to be to try to relax, go somewhere you feel comfortable, and focus on your environment. A panic attack is a positive feedback situation; once you start having one, the symptoms themselves can feed the fear. Breaking this vicious cycle can be difficult. If you are predisposed to panic attacks you should probably avoid DXM in the first place. Prolonged very fast heartbeat, or fast heartbeat accompanied by chest pain or tightness, should be taken seriously and may be cause for medical attention (note that a panic attack can also cause a feeling of chest tightness). If in doubt, go to the hospital. Note also that people with existing heart problems should avoid recreational DXM use. Incidentally, neither of the recorded deaths due to DXM overdose were attributed to heart attack (respiratory failure was considered the cause). .............................................................................. Irregular Heartbeat, or "Skipped Beats" An irregular heartbeat, like a fast heartbeat, may be a problem of perception more than anything else. Remember that, especially at higher doses, there can be a "sensory echo" effect which may influence your measurements. An occasional feeling that your heart "skipped a beat" is usually not cause for worry. Sometimes it is due to spasms of the esophagus, stomach, or bronchial tubes and has nothing to do with the heart; it's hard to distinguish sensations among internal organs. More frequent heart irregularity, or irregularity with chest pain, may require medical attention. Go to the hospital if in doubt. .............................................................................. Nausea, vomiting, gas, and diarrhea Ah, the joys of ingesting large amounts of thickening agents. Nausea is to be expected, especially with cough syrups. It usually goes away. Do not take anti-nausea medication. Some antiemetics are anticholinergics and/or CNS depressants, neither one of which you want to mix with DXM (meclizine would probably be okay, although I don't advise it). The best response seems to be to tough it out, or switch to gel-caps. Incidentally, avoid taking DXM with greasy or heavy foods. Vomiting occasionally occurs, usually for the same reason as nausea. Again, not much to worry about. If you do vomit, just make sure to drink lots of water to replace what you just lost. Both guaifenesin and large amounts of alcohol tend to contribute to the tendency to vomit. Gas and diarrhea, especially after the trip, are also fairly common with syrups. Not much to do, unfortunately; just tough it out and drink water. .............................................................................. Unconsciousness This is mostly advice for the designated sober person; obviously it won't do you much good if you're unconscious. Unconsciousness with DXM is to my knowledge extremely rare (I've heard of it happening once). Generally if someone passes out, the first thing to do is make sure they don't fall and hit their head. Yes, DXM may protect brain cells somewhat from the effects of head trauma, but let's not try out that theory ourselves. Make sure the unconscious person is lying down with their feet elevated, and that someone (sober) is with them. If you feel there is any danger of vomiting, roll the person onto his or her side. At this point, if the individual is breathing well, and seems OK (other than being unconscious), you can wait it out if you feel comfortable doing so. The unconscious person may be flying around in a mental dreamscape, oblivious to you and the rest of the world. If there is any indication of irregular breathing, slow or weak heartbeat, or other problems (e.g., his face is blue), get to a hospital immediately. You may wish to indicate that IV naloxone is considered antidotal for DXM (naloxone is also used for opiate overdose, incidentally). I suppose it would be possible to have a syringe of naloxone on hand (it's actually fairly safe, being an opiate antagonist; to my knowledge it's not possible to overdose on it). However, it's not exactly something you can get at your local drugstore, and in any case other measures may be necessary which would require hospitalization. Remember, if there is any indication or suspicion of an overdose, get medical assistance immediately! .............................................................................. High body temperature / fever First, make sure you actually have a fever. DXM can mess with your sense of temperature. On the other hand, I have received one report of DXM-induced hyperthermia that could have been dangerous. A temperature at or above 102 F (39 C) is entering the danger zone. If this happens to you (or someone you are with), the best way to cool down is by taking a cool bath or shower (make sure it feels cool to a normal person!), and drinking cold water. Incidentally, speaking from personal experience (with the flu, not DXM), the "cool" water will feel damn cold. In the case of a fever at or above 105 F (40.5 C) you've got a real emergency on your hands. Immediately contact a doctor or hospital, and try to reduce the body temperature as quickly as possible. Ice-water baths are acceptable providing there is someone (sober) there to make sure the person doesn't pass out and drown. Expect to hear a lot of screaming; this is a significantly unpleasant experience even without a fever. .............................................................................. Shortness of breath Again this is usually a perceptional problem, and sometimes is related to panic attacks. There is also evidence that dissociative anesthetics in general cause a transient phase of shortness of breath, possibly because the body is beginning to "take over" breathing from conscious control. Take deep, even, and slow breaths; hyperventilating won't help, and can make you feel even worse. It should clear up by itself. In the case of hyperventilation, the "breathing into a paper bag" trick really does work, by increasing blood CO2 levels. .............................................................................. Sensation of choking one's tongue If you start feeling like you are choking on your tongue, make sure someone can assist you, or call a doctor if you believe you really are choking. There is actually very little danger of choking on your tongue; it's pretty much physically impossible. Nonetheless it can seem frightening. If you are in the position of trying to assist someone in this situation, open the person's mouth, tilt their head back slightly, and grasp and hold their tongue out of the way of their airway until they feel better. Avoid putting anything in their mouth; this could easily fall and cause much worse choking. .............................................................................. Nosebleeds If you are prone to nosebleeds this probably isn't a problem and may be due to nasal irritation. If possible, check your blood pressure. If the nosebleed is prolonged, your blood pressure is high, you notice any burst capillaries in your eyes, or you experience sharp pains in your head or lungs, go to the hospital. I'm not familiar with any cases of DXM-induced hypertension, although it might be possible, especially when mixed with stimulants or MAOIs. .............................................................................. Feeling "dead" / losing one's body Remember, DXM at high levels can be very dissociative. You're not dead, you just can't feel your body right now. This state can have a lot in common with certain lucid dream states. A feeling of "being dead" is common with third and fourth plateau DXM doses. The best thing seems to be to try to make contact with some part of your body (this can take a lot of effort), to reassure you that you're still there. Then, relax and enjoy your trip. This is another reason why you should a sober person with you. If you are in any real danger, he or she should take care of you. Note: see also the guidelines on shamanic journeying in Section 3.12. .............................................................................. Hangovers (lethargy and feeling "not all there") Hangovers can occur from higher doses. Usually you can expect to feel very relaxed if not lethargic for the next day after a heavy trip. You may also might experience dizziness, muscle rigidity, loss of balance, slight double-vision, and a general feeling of being "not all there". Again, it goes away. Sleep seems to improve things a great deal. Make sure to drink a lot of liquids, get plenty of rest, take a multivitamin, and exercise. As DXM is metabolized differently in different people, some may experience hangovers (and trips) a lot longer than others. For more details, see Section 4.5. .............................................................................. Prolonged dissociation from the real world Very rarely, someone will come out of a DXM trip and seem to be very dissociated from the real world, behaving a little like a robot. Whenever this has been reported to me, the person in question had always taken a high (third to fourth plateau) dose, and in most cases had tried to achieve an out-of-body state (draw your own conclusions). Make sure the person is relaxed, and try to engage him or her in a familiar activity. Familiar environmental cues should go a long way towards bringing him or her back to the "real world". Also keep in mind that the person may be slow to metabolize DXM and thus still be tripping. If, after a couple of days, the person still hasn't returned to normal, it's time to get worried. Contact your nearest psychologist, priest, shaman, or other equivalent. Note that I don't think there's any biological reason for this to happen. ============================================================================== [5] PHYSIOLOGICAL EFFECTS OF DXM This section explains some of what is currently known about DXM and its physiological effects. As the recreational use of DXM is not well studied, most of that information is speculation, some of it on my part. ------------------------------------------------------------------------------ [5.1] How does DXM inhibit the cough reflex? This is a complex problem. 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 can be blocked. Sigma receptors are evidently involved in this pathway (42,49,55,56). This may be a direct involvement - sigma activation may directly inhibit the cough reflex signals - or it may be an indirect one. The cough suppressant effect of opiates (such as codeine) is not related to the same effect of non-opiate morphinans like DXM (49); instead, it seems to be governed by traditional opiate receptors (mu, kappa, or delta). There is some evidence that 5HT1A receptors (a serotonin receptor type) are involved somewhere in this pathway, and that cough suppressants may increase 5HT1A activity (57), possibly via NMDA antagonism (90). This could explain some of DXM's mood-altering activity. 5HT1A receptors are involved in anxiety states and in resilience to aversive events. Buspirone, a 5HT1A receptor partial agonist, is an anti-anxiety drug less potent (but considerably safer) than the benzodiazepines such as diazepam (Valium[tm]). ------------------------------------------------------------------------------ [5.2] How does DXM cause its psychoactive effects? General Information DXM binds to at least four sites in the brain (58), which can be arbitrarily labeled DM1, DM2, DM3, and DM4; there is probably also a fifth binding site (DM5). Some of these sites are sensitive to pentazocine, a known sigma ligand; some are sensitive to haloperidol, another sigma ligand. On the following table, information from several sources has been gathered and combined. The binding affinity of DXM, DTG, and 3-PPP are listed (58), along with (+)-pentazocine sensitivity (60), and haloperidol displacement ability (58), (binding values in nM unless otherwise specified). "Low" means micromolar binding affinity. o-------------------------------------------------------------------o | DXM Site | DM1 | DM2 | DM3 | DM4 | |-----------------------+----------+----------+----------+----------| | Probable Binding Site | Sigma1 | PCP2 | Sigma2 | NMDA | |===================================================================| | DXM | 50-83 | 8-19 | low | low | |-----------------------+----------+----------+----------+----------| | (+)-3-PPP | 24-36 | low | 210-320 | low | |-----------------------+----------+----------+----------+----------| | DTG | 22-24 | ??? | 13-16 | ??? | |-----------------------+----------+----------+----------+----------| | Pentazocine Sensitive | Yes | No | ??? | ??? | |-----------------------+----------+----------+----------+----------| | Haloperidol Displaced | Yes | ??? | Yes | ??? | o-------------------------------------------------------------------o Table 2: DXM Binding Sites What this table demonstrates is that DXM binds to four separate places, two with high affinity. The first receptor is accepted to be the sigma1 receptor based on the binding to pentazocine and haloperidol, and the potency of (+)-3-PPP. The second receptor is almost certainly the PCP2 receptor, given the insensitivity to pentazocine, and the very high affinity for DXM. The third site is probably sigma2 (based on the potency of DTG) but it is possible that "DM1" in this table represents both sigma1 and sigma2 and that the third site is something else. The fourth site is probably the NMDA receptor's open channel site, although it might be the ion channel binding site (59). I don't have information on the binding of DXO (dextrorphan), unfortunately. It would probably show strongest binding at DM4 (NMDA open channel site), followed by DM1 (sigma1), and then by DM3 (sigma2) and/or DM2 (PCP2), or both. I'm looking for this information currently. .............................................................................. Contribution of the PCP2 Binding Site The PCP2 binding site is probably the dopamine reuptake complex, so blocking it would prevent the uptake of dopamine in much the same way that the antidepressant bupropion (Wellbutrin[tm]) or cocaine does (73). Of course, DXM is considerably weaker than cocaine (and stronger than bupropion, incidentally) at this site. This probably accounts for the euphoric effects of a low recreational dose, and almost certainly explains the stimulant effects of a low dose. Interestingly, the stimulant effect seems qualitatively different from amphetamines to most people (I have no comparison information on cocaine). One user compared DXM and bupropion favorably in stimulant effect. The music euphoria and motion euphoria are probably partly due to PCP2 activity, and partly due to other activity. As NMDA blockade and sigma activity can both lead to dopaminergic activity (see below), reuptake inhibition would potentiate these effects. 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 active at related receptors (sigma, PCP) (71,74,75); it is possible that the PCP2 site may be a target of some antidepressants. .............................................................................. Contribution of the Sigma Binding Sites As the sigma2 site is a fairly recent discovery, it is not known what sigma-related effects and behaviors are attributable to which receptor (sigma1 or sigma2). There is very little data on the subjective effects of sigma ligands, in part because only recently have selective ligands become available, and in part because most researchers aren't very willing to dose themselves to find out. DXM binds to the sigma1 receptor and is generally considered to be an agonist at this receptor. DXM is probably also an agonist (as opposed to an antagonist) at sigma2, though it is much weaker there. The disruption of sensory processing is probably partly due to sigma activation (and partly due to NMDA blockade) (63-65). Sigma receptors may be specifically involved in the auditory effects of DXM (65), and these effects may relate to a disruption of sensory input persistence. The psychotomimetic (literally "psychosis-like") effects of DXM may be a result of sigma activity (sigma receptors may be involved in schizophrenia) (46-49). People who have used both DXM and ketamine have remarked that DXM is much more likely to induce delusional and hyper-abstract thought patterns. Interestingly, sigma receptors seem to temporarily modulate cholinergic receptors (98), so sigma activity may produce temporary effects somewhat like the delusional anticholinergics. The effects on motor skills may be a result specifically of sigma2 receptors (69). Expect to see more data on this subject as sigma2 receptors are investigated more fully. There may also be a contribution from NMDA receptors, of course. .............................................................................. Contribution of the NMDA Receptor Most of the effects on the NMDA receptor are due to DXO (dextrorphan), DXM's main metabolite. DXO, and to a lesser extent DXM, block the NMDA receptor once it opens, essentially by "plugging it up". Most of the "stoning" or intoxicating effects of DXM are probably due to NMDA receptor blockade. Alcohol's intoxicating effect seems to be mediated in part by NMDA receptor blockade (its depressant effect is due to GABA activity; DXM has no activity at GABA receptors) (28,61,62). The dissociative anesthesia of high DXM doses is also likely due to NMDA receptor blockade (63). As stated before, sensory processing disruption, especially at higher doses, is probably due in part to NMDA receptors and partly to sigma (63-65). Flanging, in particular visual flanging, probably derives from NMDA blockade. The effects on memory are almost certainly due to NMDA blockade. NMDA receptors are intimately involved in long-term potentiation (64,66-68), a part of (probably short-term) memory. By blocking NMDA receptors, long-term potentiation, and thus short-term memory, is disrupted. DXM's ability to suppress respiration at toxic levels, is most likely due to NMDA receptor blockade or (in my opinion) ion channel blockade. Some of the effects from very high dosage levels may be due to overall disruption of neural networks. There is some preliminary evidence that both the "spontaneous memory" effect and the sensations similar to near-death experiences may occur as general neural networks are disrupted. Most drugs target specific clusters of neurons, whereas NMDA receptors tend to be more evenly distributed within certain areas of the brain, so blockade of NMDA receptors may be responsible for disruption of some of the brain's neural networks. .............................................................................. Contributions of Indirect Activity 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 has a fairly strong ability to increase dopamine activity (both from activating sigma receptors, and from preventing dopamine reuptake at PCP2 sites) (72,76). NMDA receptor blockade also has been shown to increase dopaminergic activity, as well as activity of other neurotransmitter systems (101). .............................................................................. Flanging One of DXM's most prominent effects if the flanging of sensory input. This happens to some extent with many drugs, and I have a hypothesis on this. Note in particular the relation of flanging to "stoning" and "buzzing" - in some ways, flanging is a more profound degree of stoning. Some people have noticed a flanging or strobing effect after smoking a great deal of cannabis, and nitrous oxide users are also familiar with flanging of sounds. Even alcohol can produce it. What it seems many of these drugs have in common is the ability to inhibit short-term memory, almost certainly via blocking long-term potentiation (in the case of nitrous oxide, of course, the inhibition lasts for such a short period that it is generally not noticeable). Other drugs, such as the benzodiazepines, block short-term memory as well, but this is more likely due to an overall depressant effect on the brain. Current theories point towards the hippocampus as the main location for short-term memory, and although other parts of the brain are probably involved, I will refer to it exclusively. The hippocampus is one of the most regular neural networks in the brain, and seems ideally suited for storing temporary associations. It also is to some extent "self-feeding" (although not necessarily directly); as such it is capable of very complex, nonlinear associations in much the same way that "self-feeding" functions can give rise to fractals. Simulations of self-feeding neural nets often show that information is processed in a finite number of "cycles" before the output state settles down (this sophisticated behavior may derive from some very simple rules, and has even been observed in bulk optical material (138). Interestingly, the hippocampus has a "sweep frequency" of unknown nature which may be related to this cycling. The activity of NMDA receptors certainly helps to maintain the normal functioning of the hippocampus. As NMDA receptors become increasingly blocked, individual neurons in the associative network of the hippocampus lose part of their positive input. Although they may compensate by reducing negative input (at GABA receptors, perhaps), the plastic or "learnable" component of neural input will diminish in comparison to the ordinary input (via AMPA and kainate glutamate receptors). Thus it may take more cycles to reach a stable output state. In cortex, NMDA receptors could be much less important, and some aspects of "consciousness" may function mostly via "ordinary" glutamate receptors. If this is the case, then cortical networks would still be operating at normal (or near normal) speed, while the hippocampus slowed down. It is also likely that unstable output from the hippocampus is ignored, or at least dealt with differently than stable, final associative output. Finally, note that raw sensory input probably needs some associative processing before it can reach consciousness, since what we perceive is to some extent "written" in the mental language of our past experiences. Thus, as the hippocampal output slows down and becomes increasingly less stable, one becomes conscious of increasingly less frequent sensory input. Eventually, this becomes infrequent enough that flanging occurs. Finally, with sufficient loss of NMDA function, the hippocampus may never reach a stable state, leading only to chaotic output, totally unconnected to sensory input. But more on that later. This is all just a SWAG (scientific wild-assed guess), of course. But I think this hypothesis has some merit, and in the next several years I hope to further elaborate on it in my studies on hippocampal neurons. .............................................................................. Hyper-Abstraction Another interesting effect of DXM is its ability to induce peculiar cognitive disturbances, which I lump together under the term of "hyper-abstraction". Two examples: o A meme is a "particle" or "virus" of thought - an idea which is in some ways self-contained, and which spreads like a virus. For example, the idea of civil liberties is a meme, which at some point sprang into existence, spread rapidly, and has now become an integral part of our consciousness. One user during a DXM trip suddenly became aware of (or thought up) "The self-invoking, self-creating meme", which was the concept of a meme whose identification creates and invokes it. It seemed that this meme was timeless in the sense that it must have always existed, or it could not have come to mind. o Another user wrote of thinking about convergent infinite sums (e.g., 1/2 + 1/4 + 1/8 + etc., which sums up to 1). Although one can add these terms up forever, it's easier to abstract the process and get the answer that way. This user imagined an infinite series of abstractions, and then imagined abstracting that infinite series to get a new level or plane of abstraction. Many DXM thought patterns involve what some have called "Strange Loops" in logic (139). Like the self-contradicting statement "this statement is false", some of them cannot be embodied in logical form; others can be, but cannot be derived without presenting them as hypothesis. Thinking at this degree of abstraction is very difficult (unless you are fortunate enough to be Kurt G”del). Several people who have written first-person accounts of psychosis and schizophrenia have mentioned increasingly abstract thought patterns (Zen and the Art of Motorcycle Maintenance springs to mind). This may of course be complete bunk, and it may be that the increasingly "abstract" thoughts are just increasingly loony (and thus difficult to relate to concrete ideas). On the other hand, it may be that something about schizophrenia and psychotic states is related to a blurring between levels of abstraction. Once blurred sufficiently, a thought which cannot be represented at a concrete degree of abstraction could be representable in the mind. Thus, DXM may induce a sort of temporary blurring of these levels of abstraction. Whether this is due to NMDA or sigma activity, I don't know, although I suspect the latter, since other NMDA antagonists don't tend to induce such changes in thought patterns. .............................................................................. Delusions and Memory Problems As stated above, sigma activity may modulate cholinergic receptors in the brain (98), leading to a temporary decrease in cholinergic function similar to (but considerably safer than) that caused by anticholinergics like atropine, scopolamine, cyclizine (Marezine), etc. It is known that cholinergic activity is important in memory, and many nootropics ("Smart Drugs") enhance cholinergic function. Sigma activity may very well cause temporarily lowered effectiveness in some cholinergic receptors, thus distorting memory and thought processes. Some people have in fact said that DXM makes them feel temporarily stupid ("Dumb Drugs", anyone?) although this by no means happens to everyone. Many of the biogenic amine systems seem to have a modulatory role, and some researchers think these modulating systems operate much like "control knobs". For example, one theory on LSD is that it upsets the "gain control" on sensory recognition networks, so that the random noise input (necessary for any pattern matching network) becomes much stronger than the sensory input. As a consequence, sensory recognition becomes increasingly less and less precise - ergo, hallucinations. LSD's effects are almost certainly more complex than this, but there may be some truth to the "control knob" idea of the biogenic amine systems. If so, then the cholinergic systems may be the "control knobs" for cognitive networks in much the same way that 5HT2A/5HT2C systems are for sensory recognition networks. Delusions may simply be the cognitive equivalent of hallucinations. Or to put it another way, the difference between thinking you look like a flower and thinking you are a flower may be a question of which network is disrupted. Memory problems derive to some extent from NMDA blockade, although some users of ketamine have remarked that DXM can have a stronger effect on memory than ketamine. It is possible that, in addition to inducing delusional thoughts, a decrease in cholinergic function could be responsible for some of the memory problems. This is certainly consistent with the effects of the delusional anticholinergics. Incidentally, the anticholinergics also affect acetylcholine receptors that govern the functioning of the heart and respiration (these receptors do not seem to be modulated by sigma activity). Recreational use of anticholinergics can be extremely dangerous, leading to collapse of respiration or heart failure. ------------------------------------------------------------------------------ [5.3] Why does DXM exhibit plateaus? Plateaus 1-3: Multiple Receptors This graph illustrates a potential effect of multiple receptors. Note that it is a qualitative drawing, not a quantitative one; the actual degree of saturation on different receptors for a given strength of DXM is still mostly unknown. The lines represent saturation levels at the PCP2, sigma1, and NMDA open channel sites, with full saturation at a given receptor indicated by the "flattening out" of the curve. o------------------------------------------------o | | | S | Pla | Plateau 2 | Plateau 3 _ | | a | tea | | __-- | | t | 1 | | __-- | | u | | | __--.......... | | r | | ..._.-.... | | a | ......__-- | | t | ***.*.*.**_*-********************** | | i | ** .. __-- | | o |* .. __-- ** = PCP2 .. = sigma | | n |*._-- -- = NMDA | | |______________________________________ | | DXM Dose | | | | Figure 2: Possible Basis of Plateaus | o------------------------------------------------o [Note on text version: This graph didn't make it into ASCII very well. Basically, you've got three curves; the first -- PCP2 -- reaches a maximum value very quickly; the second -- sigma -- reaches a higher maximum but takes somewhat longer; the third -- NMDA -- reaches the highest maximum but takes the longest time. In "plateau 1", the PCP2 curve is the highest; in "plateau 2", it is the sigma curve that is highest; and in "plateau 3" the NMDA curve is highest.] Due to its increasing affinity for PCP2, sigma1, and NMDA receptors respectively (sigma2 is not represented), a low dose will tend to have proportionally more effect on PCP2 receptors, whereas as the dosage increases, these receptors will saturate. Taking more DXM won't change PCP2 levels much, but will still have a fair effect on other receptors. Furthermore, the more subtle effects on the PCP2 receptors may be all but obliterated by the effects on sigma1 and NMDA receptors (the differing vertical maxima of the three curves represent this effect). This is entirely reasonable, since sigma1 and NMDA activity seem to both produce fairly profound behavioral effects, the latter more so than the former. Thus, the first plateau probably corresponds to predominantly PCP2 activity with some sigma activity and a little NMDA blocking effect; the second plateau to sigma and some NMDA effects; and the third to profound NMDA blockade. This is, of course, a simplification, and it certainly doesn't take into account individual variations in receptors. Some people probably have receptors for which DXM has a stronger (or weaker) affinity. A person with PCP2 receptors strongly bound by DXM may enjoy its stimulant effects a great deal more than someone whose PCP2 receptors are only weakly affected. Additionally, both ion channels and sigma2 receptors are omitted from this graph. They undoubtedly contribute, and some people have asserted that there are plateaus in between the first three. Some of these may be so subtle as to be unnoticeable by most users. .............................................................................. The Fourth Plateau o-------------------------------------------------------------------o | | | o-------o-------o o-------o o o-------o o | | | \ / | \ / | | / | \ | / | | | | | X | X | | / | \ | / | | | | | / \ | / \ | | / | \ | / | | | | o-------o-------o o o o o o o | | | | 100% intact 50% intact 20% intact | | | | Figure 3: Fourth Plateau Pruning Hypothesis | o-------------------------------------------------------------------o [Another bad ASCII drawing. The original showed three "nets" or "meshes", the first with all links in place, the second with 50% removed, and the third with 80% removed. The first and second were both fully connected, i.e., you could get from any node to any other. In the third, there were isolated nodes and groups of nodes.] What about the fourth plateau? Well, once again, here's another little drawing that will hopefully clear up everything (yeah, right). This drawing represents a neural network; the dots are the neurons and the lines are their connections. Like most of the brain, this network is highly interconnected. The percentage numbers show the number of functional links remaining. As enough NMDA receptors are blocked, one neuron may lose enough input from another that the connection is effectively severed. Initially this isn't such a problem, since both neurons and connections are dense enough so that others can take over the job (although the end result will probably be a slower and less accurate network). At some point, enough connectivity is lost that the network no longer functions. Compare this to the dissociation of the fourth plateau. At some level, some part of the brain (possibly the hippocampus) loses enough functionality that it can no longer operate as a cohesive unit. Sensory processing halts, and raw sensory input cannot be converted to an appropriately parsed output. The consciousness is then left without any real sensory input; instead, the chaotic, unstable patterns are provided. Ergo, dissociative anesthesia. ------------------------------------------------------------------------------ [5.4] Why is this so complicated? DXM itself is a very complex drug; most drugs only bind to one or two receptors (or at least one class of receptors). Its recreational abuse potential, although known for years, has not been well studied, and it can ----------------------------------------------------------------------