Dextromethorphan(DXM) is the antitussive (cough suppressant) ingredient in many over the counter cough syrups, such as Robitussin and Vicks 44. At higher than therapeutic doses, it produces a range of psychoactive effects, so preparations containing DXM are often subject to abuse by middle school and high school students who find it easier to obtain than marijuana or alcohol, and by more mature people who like the unique psychedelic-like effects it produces. DXM is more than just another recreational drug or effective cough syrup, however, as it has a laundry list of potentially useful properties, including antiepleptic activity, potential neuroprotective activity, the ability to potentiate the analgesic effects of morphine and the antiparkinson effects of L-dopa and attenuate the symptoms of opiate and ethanol withdrawal.
History of Dextromethorphan Abuse
Dextromethorphan was first introduced as a cough suppressant in the 1960ís. It was originally marketed as tablets under the name of Romilar. These were taken off the market during the 70’s after people discovered their psychoactive potential and sales soared. (Shulgin 1975) They were replaced by DXM containing cough syrups. Since in order to get even a very low level effect one must drink more than half the bottle, this formulation was intended to discourage recreational use. However, while drinking four ounces of cough syrup is definitely a less appealing way to get a buzz than swallowing a couple of pills, recreational DXM use has continued. There is little statistical data on dextromethorphan abuse available, but it seems to not be an uncommon phenomenon, especially among those with no access to other recreational drugs.(Darboe et al., 1996) At the three junior high schools attended by the author it was common knowledge that you could get “high” off drinking three or four shots of Robitussin, and it was a more accepted practice than sniffing lighter fluid or other inhalants. DXM was apparently somewhat popular in the punk scene during the 1980ís. (WWW 1). There is a sort of underground DXM culture to be found on the internet, with sites discussing DXM experiences, giving reccomended dosage, information on how to trip safely, and warnings about what drug combinations to avoid.
The effects of DXM vary with dosage. At lower doses they are more like those of marijuana and MDMA, and at higher doses they are more like those of dissociatives such as ketamine. There are commonly accepted to be four levels of effects, known in popular DXM culture as “plateaus”, that can be experienced, although like any drug, individual experiences vary. (WWW 2) The first plateau dose is between 1.5-2.5mg DXM per kilogram of body weight, the second plateau dose is between 2.5-7.5mg/kg, the third plateau dose between 7.5-15mg, and the fourth plateau dose about 15-18mg/kg. Anything over 20mg/kg is a very bad idea, as it can cause a very bad trip and could even lead to overdose.
The first plateau consists of mild euphoria, disinhibition, and mild sensory processing changes such as altered perception of sound, altered sense of touch, and altered perception of movement. Music often more pleasurable. A general feeling of wellbeing and peace may often be present. The second plateau has been described as being drunk and stoned at the same time, or as being drunk and high on nitrous oxide. Sound and vision may start to strobe, or become choppy, and motor impairment increases. There may be an increasing emotional detachment from what is going on around one. Closed eye hallucinations are possible, and introspective thoughts and abstract thought patterns are common. The third plateau is more dissociative, with increasing detachment from what is going on around one and in ones own body. Sound and vision become disrupted and chaotic, and coordination and movement are seriously impaired. Internally, thoughts become abstracted and a lot of the normal internal “noise” tends to shut down. Hallucinations are possible at this stage but are usually abstract. The fourth plateau is a full fledged dissociative experience, similar to that caused by sub-anesthetic doses of ketamine. The brain is uncoupled from sensory input, and lifelike hallucinations, out of body experiences, and “trips” to different places are possible. (www2;www3) Bad trips are possible, especially at higher doses, and some people experience side effects including itching, sweating, nausea and vomiting. (www4) DXM trips are not for everyone, as many people don’t care for the dissociative effects they produce.
Properties of Dextromethorphan
Dextromethorphan is a dextrorotary morphinan, a codeine analogue. However, it does not have the normal opiate properties because it doesnít bind the mu and kappa opiate receptors. () It is a ligand for at least four other sites. It has a weak affinity for the NMDA receptor PCP (phencyclidine) site, a strong affinity for the sigma1 site, a weak affinity for the sigma2 site and a strong affinity for one other site. (Connick et al. 19) There is also evidence that it is a calcium channel blocker, but it isnít clear whether this activity is due to sigma site activity or to some other function(Carpenter et al. 1988; Klette et al., 1995)
The PCP site on the NMDA receptor is the binding site for a number of ligands, including the dissociatives phencyclidine (PCP) and ketamine, DXM and another compound called MK-801. (Radjev et al., 1992 )These ligands act as noncompetitive NMDA antagonists, blocking the open channels and preventing ion flow. MK-801 is one of the strongest known ligands for this site, while PCP and ketamine have lower ligand binding curves, and DXM is a relatively weak ligand. However, dextromethorphan undergoes O-demethylation in vivo to form dextrophan, a related compound which has a stronger affinity for the NMDA PCP binding site, and a weak affinity for the sigma sites. (Dematteis et al., 1997)
The functions and characteristics of sigma receptors are still unclear. They were originally thought to be opiate receptors, but they do not bind levorotary morphinans or other opiates. They are stereospecific for dextrorotary morphine analogues such as the benzomorphans (+)cyclazocine and (+). They also bind a variety of other compound such as haldoperidol and some other antipsychotics. Sigma receptors are found in many different locations in the body, not just in the CNS, and their ligands have a wide variety of direct or indirect effects. Studies on preferential binding of various radiolabeled sigma ligands suggest that there are at least two, and probably three sigma sites. Sigma1, which DXM binds to with high affinity, has been implicated in a number of different modulatory roles. Selective sigma1 agonists have been shown to inhibit dopamine release in guinea pig striatal slices, modulate NMDA receptors, and affect serotonin release (Gonzalez and Werling, 1997) New evidence suggests that the sigma1 site is associated with the NMDA receptor, which it regulates either through binding directly to the receptor or through a G- protein coupled receptor.(Yamamato et al. 1995; Whitemore et al., 1997 )The sigma2 site may modulate potassium channels. Sigma receptors are believed to have involvement in schizophrenia. (Debonnel, 1996) Not only do they bind haldoperidol, and several other neuroleptic drugs, but some early sigma ligands proved to be have psychomimetic effects. (Debonnel 1996) They are currently though have an effect through their modulation of NMDA receptors, which have been implicated in regulating serotonin and dopamine levels. (Whitemore et al.,1997)
The second high affinity DXM binding site may have something to do with the amine reuptake transporters, and could be the same as the PCP2 site. (Akunne et al. 1992) Experiments have shown that binding at the DXM2 site is increased in the presence of sodium, and that the distribution of sodium dependent binding of radiolabeled DXM is consistent with the distribution of 5HT reuptake transporters in rat brains.(Meoni et al 1997) DXM has been shown to reduce serotonin depletion caused by p-chloroamphetamine, probably by inhibiting the serotonin reuptake transporter. (Henderson and Fuller, 1992)
Effects of Dextromethorphan
Surprisingly, the most common medical use of DXM is not due to its sigma or NMDA antagonist properties, but to the way it is metabolized. Dextromethorphan is demethylated to form a related compound, dextrophan (DX), in the liver by an enzyme known as P4502D6 that is also involved in metabolizing many other psychoactive drugs such as common antipsychotics and SSRIs.(Woodworth et al. 1987) There are at least two phenotypes for this metabolic pathway, and people can be classified as extensive or poor metabolizes. Since this pathway is so important in determining kinetics of metabolism and therefore the activity of various drugs, many studies have been done on the relative frequencies of the two phenotypes in various different populations. The traditional way to do this is to give subjects a test dose of dextromethorphan then measure the concentrations of DXM and DX in their urine.
Metabolic phenotype is important not only in determining drug dosages, but also in determining the effects of DXM on the central nervous system, both as a recreational drug and as a medical drug. Although DX recognizes the same sites as DXM, it has different ligand binding curves. DX is a stronger NMDA PCP site ligand, but a weaker sigma ligand. (Church et al. 1989;) Research has shown that poor metabolizers of DXM are much less prone to abusing the drug.( Zawertailo et al, 1998) Poor metabolizers seldom attempt to use DXM recreationally more than once (www2). The conversion to dextrophan in the body can pose challenges to researchers because properties of DXM observed in vitro on brain slices, where metabolism is slight, may not be reproducible in vivo, because it is readily converted into DX by extensive metabolizers. There are several ways in which this effect has been circumvented. Dextromethorphan analogues have been developed which retain most of its properties but arenít converted into dextrophan.(Tortella et al. 1994) Another way to prevent conversion to DX is to coadminister a low dose of quinidine, an inhibitor of P4502D6 (Zhang et al. 1992; Schadel et al, 1995)
Little research has been done on the psychoactive effects of DXM experienced by recreational users. Although the effects are well characterized by users, and there is awareness of its abuse potential as shown by numerous letters to medical journals, few from the scientific community has seen fit to examine its effects. One study was done comparing the effects of oral DXM in extensive metabolizers with its effects in poor metabolizers. (Zawertailo et al., 1998) It was found that poor metabolizers could tolerate lower doses, and had more sedation and more feeling of dysphoria. They also did not perform as well on a test of psychomotor function. The extensive metabolizers reported greater abuse potential. Dark Agouti rats, who are poor DXM metabolizers, will exhibit similar behavior while when either PCP or DX, but not DXM. This suggests some of the euphoria and some other more enjoyable properties of DXM are actual caused by its metabolite DX. It is likely that a combination of DXís NMDA antagonist properties and DXMís sigma site and DM2 site affinity that create the unique effects of a DXM trip. The more ketamine-like effects are probably due to DX, given its similar binding affinities, while the initial motor impairment may be caused by DXM binding the sigma2 site (Walker and Bowen, 1993) The dissociative effects of ketamine, and presumably also PCP and DX are caused by NMDA receptor blockade. (Oye, 1992; Szekely, 1991) DXM binding at the sigma sites may be responsible for changes in though processes, as other sigma ligands have been known to cause schizophrenia-like states. Without the other effects caused by DX to balance it, this could be unpleasant and explain the lack of appeal of of DXM use to poor metabolizers. The euphoria and other MDMA-like effects could be due to inhibited serotonin reuptake, possibly caused by binding at the DM2 site, since this is consistent with the actions of traditional psychedelics on serotonin receptors and MDMA on the serotonin reuptake transmitter.
Dextromethorphan is an effective cough suppressant. Studies have shown that is at least as effective as codeine, if not more so Matthys, H et al. 1985). The antitussive activity appears to be caused by modulation of the serotonergic neurons in the respiratory centers by a sigma site, either directly or through NMDA channel modulation. (Kamei, J 1996)
The first neurological use of DXM to be discovered was its anticonvulsant properties. It has been shown to prevent seizures caused by kindling, triggered by electroshock or induced by cocaine in lab rats.(Feeser et al, 1988; Leander, JD, 1989; Witkin and Tortella, 1991) This is probably due to NMDA inhibition, either through the channel blocking site or through the sigma 1 site. Glutamatinergic neurons make up the main excitatory pathways in the brain, and NMDA receptors are responsible for long term potentiation (LTP) of synapses. LTP has been implicated in animal models of epilepsy in which the seizure threshold is lowered by repeated weak stimulation of the amygdala, known as kindling. (Purves, D et al. 1997) A reduction in LTP, conversely, may prevent lowering of the seizure threshold.
Dextromethorphan and other NMDA antagonists have shown potential as neuroprotectant agents in cases of stroke, trauma to the CNS, and hypoxia. According to current theories, much of the neurological damage triggered by these events is caused by glutamate excitotoxicity. (Olney 1990) Excess glutamate causes activation of a variety of excitatory amino acid receptors, including NMDA. This somehow leads to cell degeneration or death. The activation of large numbers of NMDA channels lead to a massive influx of calcium ion into the cell. One theory is that this produces an influx in chloride and potassium ions in response to the electrical imbalance, which in turn creates an osmotic imbalance which causes water to enter the cell, causing it to swell and rupture. (Olney 1990)
NMDA channel blockers attenuate the calcium influx, and can block glutamate exitotoxicity in vitro (Choi et al, 1987) Sigma ligands have also been shown to prevent exitotoxicity. In an in vitro study, PCP site ligands and sigma/PCP ligands such as DXM attenuated both neurotoxicity caused by direct exposure of the cells to NMDA and that caused by hypoxia (lack of oxygen). Specific sigma ligand only protected against neurotoxicity induced by hypoxia. (Lockhardt et al., 1995) This suggests that sigma ligands act as neuroprotectants by reducing presynaptic glutamate release. In vivo studies in rats and mice have confirmed the neuroprotectant effects of DXM, and it seems to be one of the more promising neuroprotectant agents. (Steinberg et al. 1991; Steinberg et al. 1993)
Preliminary clinical trials are being done in humans to determine whether it can prevent neuronal damage. A small study in which infants undergoing major heart surgery with a cardiopulmonary bypass were given 36mg/kg DXM or placebo showed some protective effects but was inconclusive because of differences between the control and experimental groups. A tolerance and safety study that was performed on neurosurgery patients showed that theoretically neuroprotective levels of DXM in the brain can be achieved safely and without serious side effects.(Steinberg et al, 1996) Interestingly, the major unpleasant side effect reported was nausea and vomiting in 270f patients. The DXM was administered to some patients in the form of Robitussin DM, which also contains guaifenesin, an expectorant which causes nausea and vomiting in higher doses. Most recreational users of DXM know to stay away from cough syrups with guaifenesin (www5), but surprisingly the researchers at Stanford University who performed the study didnít recognize that it might be better to use a formula such as Robitussin Maximum Strength Cough (the common cough syrup of abuse) which is more concentrated and contains only DXM as its active ingredient. They even failed to comment in their paper on guaifenesin as a possible cause of the vomiting even though they noted it as an ingredient in the syrup. One hopes that by the time they start trials on the efficacy of DXM as a neuroprotectant, they will have reassessed their method of delivery.
DXM has also proved useful in the relief of certain types of pain. Alone, it shows potential in relieving neuropathic pain. Neuropathic pain is hyperalgesia (decrease in pain threshold) and allodynia (pain from a light touch) resulting from a nerve injury. (Chaplin et al., 1997) The spinal cord dorsal horn NMDA receptors are believed to be involved in modulating abnormal afferent input that results from nerve damage, and NMDA channel blockers have been shown to help attenuate neuropathic pain. Studies on rats with ligated nerves showed effective analgesia, and a pilot study of patients with diabetic neuropathy showed that DXM was effective in pain relief. (Nelson et al., 1997) DXM also potentates the effects of morphine, improving its effectiveness while reducing the necessary dose. (Grass, S et al., 1996) This may have something to do with the sigma receptors, as it is more effective in potentiating morphine than ketamine, a stronger NMDA channel blocker, in rats. (Plesan et al. 1998) One study suggested that it may partially prevent morphine tolerance. (Manning et al. 1996) In clinical trials, DXM given before tonsillectomy surgery reduced postoperative pain and painkiller requirements. (Kawamata, T. et al., 1998) In another trial in laparotomy patients it reduced morphine requirements while under anesthesia when given before surgery, but didnít alter morphine needs during recovery. (Grace et al, 1998) However, since the DXM was administered before surgery and was not continued during the recovery period, another trial should probably be attempted in which DXM is coadministered with the morphine, or administered repeatedly during recovery period, which would better stimulate the conditions under which the animal studies showed an effect.
Yet another possible use for DXM is to attenuate the withdrawal symptoms of various physically addicting drugs. There have been mixed results administering it to heroin addicts going through detox. It is used clinically in some places, in one study DXM was shown to be more effective than another common treatment, ( chlorpromazine), but other studies show it has little effect on withdrawal triggered by naloxone injection (Rosen et al 1996). A recent study showed that DXM also significantly attenuated symptoms of withdrawal in ethanol dependent rats. (Erden et al., 1999)
NMDA channel blockers such as dextromethorphan may have potential uses in treating Parkinsonís disease. When administered in conjunction with the standard combination of L-dopa and dopa decarboxylase inhibitor to mice in which Parkinson symptoms have been induced by reserpine, dextromethorphan reduced the dose of L-dopa necessary to overcome akinesia. (Kaur and Starr, 1995) Small scale human studies have shown that DXM can reduce the incidence of L-dopa induced diskinesias (involuntary movements) in Parkinson patients.(Verhagen Metman et al, 1998) In this case the effects appear to be solely due to the actions of dextromethorphan rather than dextrophan, because quinidine was given to inhibit conversion.
Negative effects of DXM
Most research has focused on the benefits and possible clinical uses of DXM. However, there are some findings which show that DXM use has possible long term side effects. Although NMDA channel blockers have neuroprotective properties, at higher concentration they can cause NMDA antagonist neurotoxicity, or Olneyís lesions (Olney, 1994) These are damage to the posterior cingulate cortex and retrosplenial cortex of rats that have been given massive doses of NMDA antagonists, which show up as vacuoles (tiny holes) in fixed brain slices. This has only been shown to occur with massive, short term doses, and it is not known if long term lower level doses have toxic effects. These effects are blocked by a number of different chemicals, including alpha-adrenergic receptor agonists such as clonidine, and 5HT-2A agonists, including psychedelics such as LSD (Farber et al. 1998; Jevtovic-Todorovic 1998) They are also blocked by low level, sub-anesthetic doses of general anesthetics such as isoflurane and propofol, which could be administered with an NMDA channel blocker such as DXM or DX in the management of stroke or brain trauma to achieve neuroprotection without risk of NMDA antagonist neurotoxicity.(Jevtovic-Todorovic, V et al., 1997)
Other possible problems of long term use have been observed in chronic recreational users and in animal models. Side effects include memory impairment; rats who were given DXM in levels below that required to seriously impair motor function showed impaired learning which increased with increasing doses. (Bane et al., 1996) This is logical considering the role of the NMDA receptors in long term potentiation, which is involved in learning and memory. However, these rats were receiving DXM while they were learning the maze, so this is not evidence to suggest that there is long term cognitive impairment. However, anecdotal reports in humans suggest that very high doses for long periods of time can lead to cognitive impairment, including problems with word recall and short term memory (WWW 4, Hinsberger et al., 1994). Physical addiction to DXM appears to be possible after long term regular use at high doses.(WWW 4) Overdose is possible, as at a certain point respiratory function is depressed enough that a DXM user can stop breathing. Naloxone will reverse a severe DXM overdose, but it is not understood why this works.(Schneider and Michaelson, 1991) There does not seem to be a clear LD50 dose, but deaths have occured at doses of about 35mg/kg. (WWW4)
Dextromethorphan is a complex psychoactive drug with many potential clinical uses. However, very little is known about its long term effects at various doses, and these need to be established before extended use can be advised. A good first step in examining this problem would be to recruit habitual users and former users to screen for neurological changes.
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WWW 2. http://www.frognet.net/dxm/dxm_experience.html
WWW3 http://third-plateau.lycaeum.org/
WWW 4.http://www.frognet.net/dxm/side_effects.html#toc.6
WWW5 http://www.frognet.net/dxm/general_info.html#toc.4
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