From: [d x m] at [froggy.frognet.net] (Max Tussin) Newsgroups: rec.drugs.psychedelic,alt.drugs Subject: Dextromethorphan FAQ Part 05/06 Date: 7 Apr 1996 23:25:42 -0400 Keywords: DXM DM Robitussin Tussin Dextromethorphan Sigma NMDA P450 X-URL: http://www.frognet.net/dxm/dxm.html affect different people very differently. The receptors and binding sites it affects - sigma, NMDA, and PCP2 - are all new discoveries. All this adds up to a complicated and poorly understood drug. Furthermore, the brain itself is a complicated system, and we're still mostly ignorant of its function. The basics of neurotransmission seem to be understood, but many questions remain. Nobody knows why there are so many different neurotransmitters, nor why there are so many receptor subtypes. The second messenger systems of most receptors are not well understood either. A lot of what happens inside neurons occurs via changes in genetic expression, and that's yet another topic about which little is known. To repeat a commonly quoted (and true) sentiment, if our brains were simple enough for us to easily understand, we would be so simple that we couldn't understand them. I do believe that eventually we will have a good idea of how the brain works, but it may not be in my lifetime. ------------------------------------------------------------------------------ [5.5] How does DXM get metabolized? (Pharmacokinetics) DXM, as the hydrobromide salt, is absorbed quickly from the GI tract; within 30 minutes, all of it may have entered the bloodstream (2,3). The polistirex compound is intended for continuous absorption, and may take 6 to 8 hours to fully enter the bloodstream. o-------------------------------o | | [Note: metabolism proceeds in the "down" | DXM | direction on this graph; the lines from | (P450-2D6) / \ (P450-3A) | DXM to DXO and 3MM, and from DXO to 3HM | / \ | and from 3MM to 3HM, are supposed to | DXO 3MM | have arrowheads on them. Sorry, more | \ / | bad ASCII art. Buy the printed FAQ | (P450-3A) \ / (P450-2D6) | and you get *real* diagrams. ;) ] | 3HM | | | | Figure 4: DXM Metabolism | o-------------------------------o DXM is metabolized via two pathways, both of which lead to the same thing (3-hydroxymorphinan, or 3HM). The first pathway goes from DXM to DXO (dextrorphan) and then to 3HM; the second goes from DXO to 3MM (3-methoxy- morphinan) and then to 3HM. By far most of the DXM (up to 90%) gets metabolized via DXO in normal individuals. DXM is converted to DXO by a liver enzyme called cytochrome P450-2D6 (debrisoquine 4-hydroxylase). Up to 10% of the population has a highly inefficient (70 times slower) version of this enzyme, and cannot metabolize DXM to DXO effectively (10). After being converted to DXO, the enzymes P450-3A4 and P450-3A5 convert DXO to 3-hydroxymorphinan (77). The other pathway goes to 3-methoxymorphinan first (via P450-3A4 and P450-3A5), and then to 3-hydroxymorphinan. Most people do not metabolize much DXM this way, although people who lack the normal P450-2D6 will convert a substantial amount to 3MM. As 3MM is probably not psychoactive, this means that the 5-10% who lack the normal 2D6 enzyme will experience less effect from DXM (or more specifically, won't experience the effects of DXO). P450-2D6 functions by removing the 3-methoxy group and replacing it with a hydroxyl (OH) (or more accurately, pruning the methyl off the oxygen); this step is known as O-demethylation. P450-3A4 and 3A5 replace the 6-methyl group with a hydrogen (H) ; this is the N-demethylation step. Refer to the diagram of the DXM molecule in Section 2.2 for the location of the methyl and methoxy groups. .............................................................................. Factors Affecting DXM's Metabolism As stated above, some people lack the normal P450-2D6 enzyme. In the rest of the population, this enzyme can be inhibited by several factors. Many drugs inhibit P450-2D6, notably including fluoxetine (Prozac[tm]). A partial list of P450-2D6 inhibiting drugs is given in Appendix 1. DXM itself naturally will compete with other drugs for P450-2D6, and importantly, so will 3-methoxymorphinan (3MM) (17,140). In fact, 3MM may have more affinity for the P450-2D6 enzyme than DXM itself does. This may account for the fact that a second "boost" dose of DXM generally produces different effects than the first dose; the competition for P450-2D6 will reduce the amount of DXM converted to DXO in the second dose. The following graphs come from computer simulations of DXM metabolism: [Note: I'm not even going to *try* and put these into ASCII. There were two figures, each consisting of two graphs. In each graph are shown the plasma levels of DXM, DXO, and 3MM. In figure 5, the first graph shows normal DXM metabolism. DXM drops quickly, DXO rises as DXM drops and then slowly drops, and 3MM stays pretty much at zero. The second graph shows abnormal metabolism (no high-efficiency P450-2D6). DXM drops *much* more slowly, DXO rises slowly and only to about 1/2 the maximum in the first graph, and 3MM rises much as DXO does. In figure 6, there are two graphs showing the effect of repeated dosing with DXM. The first graph shows how the second dose of DXM takes much longer to convert to DXO, and therefore less ends up as DXO and more as 3MM. The second graph shows numerous, repeated dosings; DXM eventually rises above DXO.] The first pair represent the metabolism of DXM in a normal individual (on the left) and an individual without the normal P450-2D6 enzyme (on the right). Note the rapid and almost complete conversion of DXM to DXO in the normal individual, as opposed to the less efficient and slower conversion in the P450-2D6 lacking individual. The next pair demonstrate the probable results of taking additional doses (dose boosting). Both graphs correspond to individuals with the normal P450-2D6 variant. Note how the second dose of DXM is not converted to DXO as quickly (thus the shallower slope). The right hand graph shows numerous doses, and the "flattening out" of the metabolism curve for DXM is increasingly evident with each dose. Incidentally, that these are qualitative simulations, not quantitative ones. I have tried to adhere to known KM and VMAX values for the applicable reactions, but the simulation was just a discrete process (to be honest, my differential equation skills are rusty enough that if you stepped on them you'd need a tetanus shot). I did compare my results with what little data I could find, and the comparison seemed reasonable, but then again I could be completely off base. The purpose of these graphs is to demonstrate the relative effects of changes in enzyme activity (via genetic variance and competitive inhibition by 3MM), and hopefully this is good enough for that purpose. I have no information on what happens to 3-hydroxymorphinan itself. It may be excreted directly by the kidneys, or it may undergo further metabolism. ============================================================================== [6] NEUROPHARMACOLOGY OF DXM ------------------------------------------------------------------------------ [6.1] What is a receptor, anyway? (Basic Neuropharmacology) A neuroreceptor (sometimes just called a receptor) is a location on the surface of a nerve cell (neuron) or other type of cell (e.g., a muscle cell) where a neurotransmitter reacts to cause some change in the nerve cell's activity. This change can either be on the neuron's potential, thus contributing to (or detracting from) its activity directly, or it can be regulatory. o-------------------------------------------------------o | Closed Open | | | | /| |\ /| |\ | | Receptor-> # | | | N.T. -> OO | | | | | | | | | | | | | | | ===========| >< |============| | | |=========== | | ^ | | | | | | | | | | | \| |/ \| |/ | | Cell Wall | | | | Figure 7: Ion Channel before and after binding | | with a neurotransmitter (N.T.) | o-------------------------------------------------------o The directly contributing neuroreceptors typically operate very quickly, and act (and look) somewhat like an iris shutter in a camera. The neuro- transmitter (for example, acetylcholine) binds to a specific area on the channel, which (due to electrostatic forces) causes the channel to snap open. Specific ions then leak into and out of the nerve cell, changing its electrical potential. Different channels allow different ions to pass; some ions (like potassium) excite the nerve cell, others (like sodium) inhibit it. Once the neurotransmitter leaves the receptor, the channel snaps shut, having done its work. These are the receptors involved in fast signal transmission, and in conveying skeletal muscle impulses. The slower domain receptors have a modulatory role. Some of them increase or decrease the number of other types of receptors. Some cause changes in genetic expression in the cell. Some (called autoreceptors) inhibit the release of their own matching neurotransmitter, a process called negative feedback. A thermostat is an example of a negative feedback system - the hotter it gets, the less the furnace is on. Generally, these slower domain receptors operate by second messengers such as G-proteins. Any given neurotransmitter will probably be associated with several different receptors. For example, serotonin (5HT) activates at least twelve receptor subtypes (5HT1A, 5HT1B, 5HT1D, 5HT1E, 5HT1F, 5HT2A, 5HT2C, 5HT3, 5HT4, 5HT5, 5HT6, and 5HT7)! There are several subtypes (instead of just one) because each receptor subtype is involved in a different process on a different type of neuron. Drugs which mimic, block, or otherwise affect activity of a given neurotransmitter will not affect all receptor subtypes equally. For example, LSD operates at 5HT2A and 5HT2C receptors; buspirone operates at 5HT1A receptors. Consequently, they have very different effects; LSD is psychedelic, whereas buspirone is an anti-anxiety drug. Different substances may bind to the same receptor but affect it differently. An agonist is a substance which binds to the receptor and activates it. A partial agonist is an agonist which does not activate the receptor fully. An antagonist binds to the receptor and prevents it from operating. One interesting property of partial agonists is that they tend to "normalize" receptor activity levels. In the presence of a low amount of neurotransmitter, the partial agonist will increase receptor function. In the presence of a high amount of neurotransmitter, however, the partial agonist will limit receptor activity; in fact, many antagonists may really be partial agonists. It is still being debated as to whether LSD is a 5HT2C antagonist or a partial agonist. Antagonists may bind to the same place where the neurotransmitter binds, thus "competing" with the neurotransmitter - these are called competitive antagonists. Or they may bind to a separate place on the receptor complex, so that even if the neurotransmitter reaches its binding site, the receptor won't activate. These are called noncompetitive antagonists. Note that in either case, the binding of the drug is only temporary; if it were permanent (thus effectively destroying the receptor) it would be irreversible antagonism. A rather whimsical analogy can be made between neurotransmitter functioning and toilets. In this case, the toilet is the receptor, you are the neurotransmitter, activating it by pushing the flush handle. If your little brother comes up and flushes the toilet for you, he's is an agonist. If he temporarily sticks the handle halfway down, he's a partial agonist. If he holds the handle up so it won't flush, he's a competitive antagonist. If he plugs up the toilet with toilet paper, he's a noncompetitive antagonist. If he breaks the toilet handle off completely, he's an irreversible antagonist. The biogenic amine neurotransmitters include acetylcholine, noradrenaline, dopamine, serotonin (5HT), and histamine. They are derived from amino acids (choline, tyrosine, tyrosine, tryptophan, and histidine respectively), generally have a modulatory role, and are the common targets of recreational drugs. For example: LSD, DMT, and psilocybin target 5HT receptors; amphetamine causes a release of dopamine and noradrenaline; cocaine blocks the reuptake of dopamine (thus keeping it active longer); MDMA causes a release of 5HT and dopamine; etc. A mostly complete list of recreational drugs and their neuroreceptor activity is given in Appendix 2. The neuropeptide neurotransmitters include a whole slew of peptides (chains of amino acids), such as neuropeptide Y, angiotensin, endorphins, substance P, and so on. The only recreational drugs targeting neuropeptide receptors are the opiates, which target the mu, kappa, and delta opioid receptors. Opioid receptors are (obviously) involved in pain and addiction. Vasopressin, a nootropic ("Smart Drug") is also a peptide neurotransmitter. The amino acid neurotransmitters include GABA (gamma-aminobutyric acid), glutamate, and aspartate. Receptors for these neurotransmitters include the GABA receptors (which come in two main flavors) for GABA, and the NMDA, AMPA (formerly quisqualate), kainate, and metabotropic receptors (all of which respond to glutamate and aspartate). The GABA receptor is the target of benzodiazepines like diazepam (Valiumú), barbiturates, and alcohol; the NMDA receptor is targeted by PCP, ketamine, alcohol, and DXM. And then there are those receptors that don't really fit in anywhere else. The anandamine receptor is the recently-identified target for the THC in marijuana. The adenosine receptor, which tends to inhibit nerve activity, is blocked by caffeine (by which it exerts its stimulant effect). The sigma receptor was originally classified as an opioid receptor, but is now thought to be separate. Gamma-hydroxybutyrate, GHB, seems to target a specific receptor as well. Each receptor can have more than one binding site. For example, the NMDA channel/receptor complex has seven (glutamate, glycine, magnesium ion, zinc ion, PCP open channel site, polyamine site, and phosphorylation site). Most have fewer than this; the NMDA channel is an extremely complicated receptor. Voltage Dependent Ion Channels are similar to the fast-domain, shutter-like receptors, except that they are opened by voltage potentials across the cell membrane. They usually transmit signals along nerve fibers, or to cause the end of an axon to release its neurotransmitter. Sodium, potassium, calcium, and chloride (Na+, K+, Ca2+, and Cl-) are the usual ions in question. Tetrodotoxin, the active ingredient in "zombie powder", is a sodium channel blocker. The NMDA receptor has some features of a voltage dependent ion channel (see below). ------------------------------------------------------------------------------ [6.2] What are Sigma Receptors? Sigma receptors (sigma is often written in Greek) are probably one of the most elusive entities in neuropharmacology. Our knowledge of sigma receptors pales in comparison to our ignorance; in fact, what we absolutely know (or at least think we absolutely know) can be summed up very briefly in the following paragraph: Scattered throughout the brain and body there are places (sigma binding sites) where a bunch of chemicals (sigma ligands) happen to stick. We don't know if they're on the outside or inside of cells. We don't know if sticking a chemical to them does anything or not, except in the vas deferens. We don't really know what they do, if they do anything. We don't know what they're for, why they're there, or whether the body uses them. They may be neuroreceptors, steroid receptors, intracellular messenger receptors, growth regulators, enzymes, or something else entirely. In other words, prepare to be confused. Don't worry, everyone else is as well. Sigma receptors were originally thought of as opioid receptors, since many morphine derivatives bind there. However, this classification is probably false, and the endogenous opioid peptides show little sigma activity. The usual characteristics of opiates are mediated by the mu, kappa, and delta receptors. There are at least two sigma receptors, and a third one (sigma3, appropriately enough) has been discovered recently (115). Some researchers have speculated that sigma receptors aren't really receptors at all, but just enzyme binding sites (84). On the other hand, sigma ligands affect the guinea pig vas deferens muscles, which probably wouldn't happen unless sigma receptors really were receptors (98). Sigma receptors may be intended for hormones or intracellular messengers rather than neurotransmitters, as they are present on microsomes rather than on the cell surface (130). ............................................................................. Sigma 1 Receptors and General Sigma Information Much of what is known about sigma receptors seems to apply more to sigma1 than sigma2 (though this is by no means universal). I grouped the following information with sigma1 receptors, but don't take this as gospel. I expect that a lot will turn out to be wrong. Fortunately, we may not have to wait long; research in sigma receptors is proceeding rapidly. Endogenous Ligands The neurotransmitter for sigma1 receptors has not been found, although there are speculations and evidence (82-86;99-100). The usual term for the (unidentified) sigma1 neurotransmitter is "endopsychosin" (100), formerly known as "angeldustin". Progesterone targets sigma1 receptors in the placenta, and it and other steroid hormones may be natural ligands for sigma1 receptors (98,103,104). If this is true, it is possible that some of the effects of sex hormones on the brain may be mediated by the sigma1 receptor (98). Substance P (a peptide neurotransmitter) was considered but rejected as an endogenous sigma1 ligand (112). Location and Function in the Brain Sigma receptors are densest in the cerebellar cortex, accumbens nucleus, and cortex, and also present at lower density in the limbic areas and extrapyramidal motor system. This is interesting because some of the bizarre effects of DXM on motion may be related to sigma activity in the cerebellar cortex and extrapyramidal motor system. Sigma1 receptors (and possibly sigma2) appear to be functionally coupled to some other receptors, notably nicotinic acetylcholine receptors (98,117) and NMDA receptors (107-110). The nicotinic receptor coupling may be direct, with sigma activation causing a change in the function of nicotinic receptors. Whether modulation of nicotinic receptors would alter the effects of nicotine on the brain, I don't know; some people have indicated that tobacco induces strong responses during DXM use. Sigma agonists (and/or possibly antagonists) seem to affect memory function, reversing the impairment in memory caused by drugs such as p-chloroamphetamine and MK-801 (a drug similar to ketamine) (131,132). DTG, (+)-pentazocine, and SKF-10047 all improved memory impairment due to MK-801. On the other hand, NE-100, which is considered a sigma antagonist, seems to help with NMDA antagonist induced memory impairment as well (107-108). DTG, a sigma agonist, reversed the memory impairment caused by carbon monoxide (118). Many drugs now considered sigma antagonists or agonists may in fact be partial agonists. Another possibility is that the optimal level of sigma activity may be a healthy medium; one study found a bell-curve dose response on sigma agonists (118). This is similar to the effect of many nootropics (smart drugs), specifically the cholinergics - taking too much can be worse than taking none at all. This similarity may be further evidence for the link between sigma receptors and acetylcholine receptors. Both sigma1 agonists and antagonists may protect NMDA receptors from glutamate toxicity (109). One study found that sigma antagonists protected hippocampal cells from hypoxia and hypoglycemia (105), and this may be related to NMDA receptors as well. Morphine has indirect effect on NMDA receptors that seems to be mediated via sigma receptors, probably sigma1 (110). It is possible that all these effects are mediated via the nicotinic receptor, i.e., sigma1 may not directly control NMDA functioning. Behavioral Effects The behavioral effects of sigma1 receptors have not been fully established. However, sigma1 (and sigma2) receptors seem to have effects on motor function, producing an increase in locomotion (113,114,121). Part of this effect may occur at the cerebellum (113); the release of dopamine may also be involved (114,129). This is probably the origin of DXM's curious effects on motions and gait, including "sea legs" and the "Robo Shuffle". Sigma1 activation may counteract some of the analgesic effects of opioids (119). Pentazocine (Talwin), a synthetic opiate, is a potent sigma1 agonist which tends to be self-limiting; when too much is taken, the sigma activity reverses the opiate activity. It is possible that the gradual loss of euphoric effects experienced by morphine and heroin users may be related to changes caused by sigma activity. Sigma receptors seem to be involved in psychotomimetic (literally "psychosis-like") effects from schizophrenia and drugs (46-49). Amphetamine psychosis, a temporary condition resulting from heavy use of psychostimulants, may be due to sigma1 activity (80,126). Sigma, and in particular sigma1, receptors may be altered by schizophrenia. An alternative possibility which is being studied is that some sort of chemical - produced by the body itself, or by a virus or other foreign agent - causes prolonged activation of sigma receptors, and this is one of the causes for schizophrenia (47,49). Many neuroleptics, including some of the atypical ones, are sigma antagonists (47). In addition to DXM, other recreational drugs such as PCP, cocaine, and opiates all show activity at sigma receptors (72). Chronic amphetamine use increases the number of sigma receptors (80), while chronic antidepressant and antipsychotic treatments decrease the number of sigma receptors (47,74). Sigma receptors are involved in the limbic areas of the brain (81), and thus may be involved in emotion. They are also involved in the cough reflex, and probably involved in seizures (or at least their prevention). Location and Function in the Body Sigma1 receptors are also present throughout the body. Most tumor cells express both sigma1 and sigma2 receptors (38,106). Liver and kidney cells also contain sigma receptors (124), as do heart cells (125). As stated above, the placenta contains sigma1 receptors. Sigma receptors are also present in the immune system and endocrine glands, and may be responsible for modulating these systems. There is some evidence that sigma agonists may inhibit the immune system. The widespread presence of sigma receptors may indicate some involvement in development, cellular regulation, or other basic biological process. .............................................................................. Sigma 2 Receptors Much of what was stated about sigma1 receptors may apply to sigma2 receptors as well. There hasn't been much time to differentiate between the two receptor types. The neurotransmitter for sigma2 receptors may be zinc ions (78), and sigma2 receptors seem related to potassium ion channels (79). The sigma2 receptor is less affected by DXM than the sigma1 receptor (58). Some of the sigma-induced potentiation of NMDA function may be due to sigma2 receptors (117). One study found that chronic exposure to sigma ligands, both agonists and antagonists, caused brain cells to degenerate and die (102). The deterioration occurred as a gradual loss of cellular shape; cells eventually became spherical (and died soon after). Interestingly, some drugs, including DXM, seemed to be very weak in this effect. While haloperidol induced significant changes and cell death in a few hours, it took DXM 3 days to produce any changes at all, which reversed when the DXM was removed. The potency of different sigma ligands seems to point towards sigma2 receptors as the culprit in this effect. By the way, I wouldn't worry too much about this. The concentration of DXM required to induce any change at all was extremely high, and it took 3 days of constant exposure. All changes were reversible, even after the cells had assumed a spherical shape. Haloperidol and other sigma ligands, which seem to be up to 100 times as potent as DXM at producing brain cell degeneration, are used medically used without substantial evidence of brain damage. Finally, steroid hormones may very well cause the same sort of effects if present at sufficient levels (another reason not to use anabolic steroids, I guess). .............................................................................. Sigma 3 Receptors Sigma3 receptors are a new discovery (115). They seem to be linked to the conversion of tyrosine to dopamine, and sigma3 agonists may increase the rate of dopamine synthesis. DXM's potency at the sigma3 receptor is unknown, but if it binds strongly there, then increased dopamine synthesis may be partially responsible for DXM's stimulant effects. ------------------------------------------------------------------------------ [6.3] What are NMDA Receptors? NMDA and Other Glutamate Receptors Most of the better known neurotransmitter systems - dopamine, noradrenaline, serotonin (5HT), and acetylcholine in particular - have modulatory roles. They are produced by a few neurons located in specific clusters, and drugs affecting them often have specific effects (recreational or medical, or both). Receptors for these neurotransmitters tend to operate fairly slowly, taking milliseconds or longer to communicate. Rather than directly changing the potential of the neuron, they often trigger second-messenger responses. On the other hand, most of the brain's regular function operates quickly, and involves the excitatory and inhibitory amino acids (EAAs and IAAs, respectively). The receptors for amino acids are generally ion channels; when the receptor is activated, ions enter or exit the cell which change its potential. EAA and IAA receptors generally correspond to the positive and negative synaptic connections in electronic and computer neural networks. The excitatory amino acid neurotransmitters include glutamate and aspartate. GABA is the only established inhibitory amino acid neurotransmitter in the brain; the spinal column also uses glycine. Generally, glutamate is more prominent (or at least better understood) than aspartate, although they have similar effects at EAA receptors. Thus, the receptors for EAAs are called glutamate receptors. There are currently four identified type of glutamate receptors. Two of them, the AMPA (formerly quisqualate) and kainate receptors, are ion channel receptors which increase neuron activity in response to EAAs. A third, the metabotropic glutamate receptor, is a newer discovery, and seems to involve second messenger systems and produce metabolic effects. The fourth is the NMDA receptor. .............................................................................. NMDA Receptor Function and Structure o-----------------------------------------------------------o | Mg++ Zn++ | | ____ __ Asterisks (*) | | | \* _*| | indicate location | | | |_ | | of binding sites | | EAA --> * > => _> | | on the NMDA channel | | | | _| _| | | | | <_ <= \* <-- Gly | | | | | | | | OOOOOOOOOOO | | | | OOOOOOOOOOO | | ||||||||||| | / | | ||||||||||| | | ||||||||||| | <* | | ||||||||||| <-- Cell Wall | | OOOOOOOOOOO | PCP\ | | OOOOOOOOOOO | | | | | | | | | | | | | | | _ | | | <-- NMDA Channel Complex | | \/*\/ *\___/ | | | | Polyamine Mg++ | | | | Figure 8: NMDA Channel | o-----------------------------------------------------------o This drawing represents the structure of the NMDA receptor, according to current knowledge. The NMDA receptor has seven distinct binding sites. Three of these are located on the exterior surface of the cell, two are located on the cell interior, one on the inside of the channel, and one (the magnesium ion site) is present both on the inside and outside surfaces. There are two agonist sites on the exterior are the cell, denoted EAA and Gly; they correspond to the excitatory amino acids (glutamate and aspartate) and glycine. Both sites must be occupied before the channel can open enough for any ions to pass through. A third site is the target of zinc ions (Zn2+), which block the channel when present. The exterior of the channel contains a magnesium ion site. This site is also present on the inside of the cell (alternatively, it may be located within the channel itself). A magnesium ion normally occupies the exterior site; the interior site is probably empty under biological conditions. The interior of the cell contains two binding sites. One binds to polyamines (spermine and spermidine), and its function is unknown. The other, not shown in this diagram, is a phosphorylation site. Enzymes can bind to this site and enhance or reduce the activity of the receptor. o---------------------------------o o---------------------------------o | /:\ | | /::\ | | ____ : __ | | ____ :: __ | | | Mg : __| | | | | | :: __| | | | | | : | | | | | | ::| | | | EAA | : | | | | EAA | ::| | | | | | : | | | | | | ::| | | | | | : | Gly | | | | ::| Gly | | | | : | | | | | | ::| | | | OOOOO | | : | | OOOOO | | OOOOO | | ::| | OOOOO | | ||||| | / : | | ||||| | | ||||| | / ::| | ||||| | | ||||| | < : | | ||||| | | ||||| | < ::| | ||||| | | OOOOO | \ : | | OOOOO | | OOOOO | \ ::| | OOOOO | | | | : | | | | | | ::| | | | | | : | | | | | | ::| | | | | _ | : | | | | | _ | ::| | | | \/ \/ : \___/ | | \/ \/ :: \___/ | | : | | :: | | \:/ | | \::/ | | Na+, K+ ions | | Na+, K+, Ca++ ions | | | | | | Figure 9: Partially Open | | Figure 10: Fully Open | | NMDA Channel | | NMDA Channel | o---------------------------------o o---------------------------------o Finally, inside the channel itself is the PCP1 site, where PCP, ketamine, MK-801 (dizocilpine), DXM, and dextrorphan all bind. The channel must be fully open for these drugs to enter; once in place they "clog up" the channel. NMDA receptors are unique for several reasons. Unlike most receptors, they require two agonists (glutamate or aspartate, plus glycine) before the channel opens. These two agonists (Glu and Gly in the diagram) bind to two different locations on the NMDA receptor. After both agonists have bound to the channel, it opens enough for potassium to enter, and the receptor operates much like AMPA and kainate receptors. This is shown in Figure 9. The most important and unique characteristic of NMDA receptors, though, is what happens next (Figure 10). Normally, a magnesium ion is bound to a specific location at the opening of the channel; this ion allows potassium to pass through but prevents calcium, possibly due to its size. This binding is due to electrostatic forces; the same electrostatic attraction that causes potassium ions to enter the cell makes the magnesium ion cling to the channel. Once the cell becomes activated enough, however, the cell potential rises enough that the magnesium ion is no longer stuck to the cell. Calcium can enter (and exit, although this doesn't happen) the cell through the fully open NMDA channel. Once inside, calcium sets into motion a series of responses which enhance the strength of the synapse. So what's the point? Well, if the neuron is only slightly active, the NMDA channel may open partially, but the magnesium ion won't get a chance to leave its binding site. However, if the neuron should be rapidly or substantially activated, the magnesium ion will be released, and calcium can enter the cell, enhancing synaptic strength. This process, called Long-Term Potentiation (LTP), is one of the mechanisms by which neurons can change their functioning and "learn". LTP in the hippocampus is probably responsible for short-term memory. Learning capacity may in fact be directly related to the number of NMDA receptors in the hippocampus (where short-term memory is thought to be stored) (88). LTP is reversible, and long-term memory seems to be stored via more permanent changes in genetic expression and synaptic shape. 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) (87). There is also some speculation that the NMDA receptor's ion channel may (for reasons unknown) become "uncoupled" from the receptor itself (63). Noncompetitive antagonism of NMDA receptors by the open channel blockers is known to induce changes throughout the brain. NMDA blockade causes an increase in dopamine release in the midbrain and prefrontal cortex (63). NMDA blockade also causes activation of 5HT systems specifically targeting the 5HT1A receptor (90). .............................................................................. NMDA and Excitotoxicity NMDA receptors are involved in excitotoxicity (nerve cell death via over-stimulation). The chemicals which agonize (activate) NMDA receptors can also kill the very same nerve cells they are activating (19). 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 (30-31). DXM is not a particularly effective NMDA open channel blocker, but DXO, PCP, ketamine, and MK-801 (dizocilpine) are all very effective blockers. Unfortunately, nothing in life is ever free. Lowered NMDA activity, called NMDA Receptor Hypofunction (NRH), seems to be itself responsible for excitotoxicity to other neurons. The theory is that normal NMDA activity keeps other neurotransmitters (glutamate and acetylcholine, and possibly dopamine) from being over-secreted. NRH releases this inhibition, and can therefore lead to hyperactivity at some neurons. It is possible that chronic NRH may be a cause for, or at least a factor in, schizophrenia and Alzheimer's disease (101). Acute, strong NRH of the type produced by the dissociative anesthetics has not been studied. My hunch is that it probably isn't nearly as traumatic to the brain as long-term NRH; otherwise, John Lilly would be a lot dumber than he is. DXM in particular may be safer due to counteracting effects of sigma activity. On the other hand, PCP has been shown to be toxic to neurons in the posterior cingulate, retrosplenial cortex, and cerebellum (136). This is probably a result of NRH, although sigma receptors may be involved. Infants may be particularly susceptible to this effect, so use of any NMDA antagonist during pregnancy or nursing is probably a bad idea (113). ------------------------------------------------------------------------------ [6.4] 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). Their use by the body (if they have one) has not been determined. Most research indicates that the PCP2 receptor is the dopamine reuptake complex, the very same one targeted by cocaine and the antidepressant bupropion (Wellbutrin[tm]) (70,127). A reuptake complex (or reuptake site), incidentally, is a structure on a cell which takes used neurotransmitter back into the cell for recycling or breakdown. By blocking reuptake of a neurotransmitter, its activity can be increased. The tricyclic antidepressants block the reuptake of noradrenaline, dopamine, and/or serotonin (5HT). Fluoxetine (Prozac[tm]) is a serotonin-specific reuptake inhibitor (SSRI), as are several other newer antidepressants. The dopamine reuptake site seems to be the only reuptake site targeted by recreational drugs (primarily cocaine). Curiously, bupropion, a dopamine reuptake inhibitor, seems to have little recreational use potential; then again, it isn't a particularly strong dopamine reuptake inhibitor. ------------------------------------------------------------------------------ [6.5] What are Na+ and Ca2+ channels? Sodium and calcium ion channels are two types of voltage dependent ion channels. These channels open or close not due to neurotransmitters, but instead due to voltage differences between the inside and outside of the cell. Voltage dependent sodium channels are typically involved in the action potential - a domino-effect propagation of nerve impulses along the axon. The sodium channel opens when the voltage reaches a certain activation threshold; the resulting influx of sodium then further activates the neuron (leading to more sodium channels opening). Eventually a second part of the sodium channel closes (otherwise they would keep themselves open forever). Incidentally, voltage dependent potassium channels are involved in bringing the neuron back to its resting state. Voltage dependent calcium channels are similar to voltage dependent sodium channels, and typically open on activation voltages. Their effect, however, is to cause calcium to enter the cell; the calcium then acts as a messenger to intracellular mechanisms. The most common example is at the end of the axon, where calcium influx causes neurotransmitters to be released. NMDA receptors may be structurally related to voltage dependent calcium channels. DXM has recently been found to block sodium and calcium channels, although it is not particularly potent in this capacity. Because of their extensive presence, blockade of these ion channels could have overall depressant effect upon brain function, and might explain DXM's toxic effects at very high dosages. ------------------------------------------------------------------------------ [6.6] How does DXM compare to other drugs at these receptors? PCP and ketamine both bind more strongly to NMDA, and less strongly to the PCP2 and sigma sites, than DXM. In fact, some users report that DXM, at higher dosages, begins to resemble ketamine and PCP. The resemblance is still fairly limited. DXM's unique characteristics are most likely due to the PCP2 and sigma sites. ------------------------------------------------------------------------------ [6.7] Endopsychosin and the Big Picture For whatever reason, some people involved in biological sciences like to talk about the "big picture." I'm one of them. I think the reason why the "big picture" seems so important is that science, especially biological science, has become so specialized and compartmentalized that it's difficult to keep one's perspective, especially when considering the possible relevance of things. Endopsychosin (en-doe-sy-KOE-sin) is the name given to an endogenous ligand for the NMDA open channel site (PCP1) and/or sigma receptors. The search for endopsychosins started several years ago in an attempt to find the endogenous ligand for PCP; at the time, the term was "angeldustin". Recently, the search for endopsychosins has resumed as NMDA and sigma receptors have become increasingly understood. As I write this, nobody has managed to positively identify an endopsychosin, although there are several candidates. The most promising candidates for the NMDA PCP1 site seem to be series of peptides (99-100). The endogenous ligand for the sigma1 site may be an unknown aromatic chemical (98,100). The original idea behind endopsychosin (or angeldustin, if you prefer) was that the body was capable of secreting a substance which would mimic the effects of PCP on the brain. It may be secreted in times of extreme stress, leading to a sort of detached, dreamy feeling. Endopsychosin may be responsible for such altered states of consciousness as religious ecstasy, speaking in tongues, possession, astral projection, and other paranormal experiences. Spontaneous releases of endopsychosin may account for experiences such as alien abductions, encounters with ghosts, and that sort of thing. Note the similarity of these experiences with aspects of DXM, ketamine, and PCP drug trips. In particular, the "emergence phenomenon" identified with ketamine (and present also with PCP and DXM) often consists of experiences with spiritual or alien beings. What's going on here? Why the hell would the human brain secrete a chemical that makes us think we've been talking to Elvis and Jim Morrison on the far side of Mars? What's the big picture? Well, to be honest, nobody knows. One potential clue is that the perforant path of the hippocampus (a neural circuit) seems to release endopsychosin when stimulated (141). Perhaps endopsychosin is a part of the memory process; or perhaps it is involved in dreaming and the conversion of short-term to long-term memories. Another possibility is that endopsychosin is one of the brain's natural defenses against injury. I find it interesting that sigma/NMDA agents often mimic fever hallucinations; common characteristics include Lilliputian hallucinations (feeling too big and/or too small), geometrical and linear hallucinations, and psychosis-like effects. Perhaps the brain secretes endopsychosins during high fever in an attempt to prevent neurotoxicity. In addition to potential neuroprotective roles, these substances may have significant roles in regulating cognition and (in the body) the immune and endocrine systems. A dysfunction of an endopsychosin, or of the sigma receptors (or both) may be one of the causes of schizophrenia. And if some steroids (e.g., progesterone and testosterone) turn out to be endopsychosins, this could explain a lot about the long-term behavioral effects of steroid use. Or, it may simply be that altered states of consciousness are a natural part of animal life, and that our culture's fear of such states is abnormal. Certainly one doesn't need drugs to achieve altered states; even profoundly dissociative states can be achieved with a certain amount of ritual and faith. Most "primitive" cultures have some experience with dissociative states such as astral projection, shamanic journeying, possession, and that sort of thing. They may very well know something that we don't. So it is entirely possible that the similarity between NMDA PCP1 and sigma receptors has a purpose. In any case, data about the effects of sigma-specific agonists (or antagonists for that matter) are limited, but our understanding of these receptors should improve in the next few years as research continues. Not to mention the possibility of some brave and/or stupid psychonaut deciding to experiment with sigma-specific agonists. (+)-3-PPP and SKF-10,047 are good sigma-specific ligands; more sigma1 specific ligands include 1-phenylcycloalkanecarboxylic acid derivatives (123,128). Anyone feeling brave? Maybe you can become the next Shulgin ("Endopsychosins I Have Known And Loved" anyone?). Then again, maybe you'd better not; I don't need to be sued if you develop a stubborn case of insanity. ============================================================================== [7] DXM CHEMISTRY AND EXTRACTION This section has been completely rewritten, as new information has been received about acid-base extraction and about extraction of DXM+guai- fenesin preparations. Please remember to always wear safety goggles when working with chemicals, and be generally careful with these procedures. My thanks to all who did research on this subject. ----------------------------------------------------------------------------- [7.1] How can I extract DXM from cough formulae? I'm going to present this as "kitchen chemistry" as I feel most people with adequate chemistry knowledge (and equipment) will be able to do it correctly anyway. The older procedure for extracting DXM was to basify it with NaOH (sodium hydroxide), and filter out the precipitated DXM using a coffee filter. This tended to fail for several reasons. First, the DXM precipitate was often so fine that it went through the filter paper. Second, many syrups contain propylene glycol, and DXM free base seems to be moderately soluble in propylene glycol. You can, of course, still use the precipitation procedure; I just don't recommend it. If you do choose to precipitate DXM, try to get actual filter paper rather than a coffee filter -- it will help. ............................................................................. Acid-Base Extractions The acid-base extraction process is a common method for isolating a desired chemical from undesirable "gunk". The theory is that certain chemicals (generally, alkaloids) occur in two forms: a water-soluble complex with an acid, and an oil-soluble free base form. For example, pseudoephedrine (Sudafed[tm]), a decongestant, is usually supplied as the hydrochloride salt (pseudoephedrine HCl). It can also exist as a base, without an acid molecule (thus the term "free base"). You can convert an alkaloid from acid salt to free base (or vice versa) using a base (or acid). The practical upshot is you take your chemical and "gunk", and lower the pH until the chemical converts to free base form and precipitates out (since it's no longer soluble in water). Now you add a nonpolar solvent (an "oily" layer) for the chemical to dissolve in, shake for a long time, and all the chemical you want is in the nonpolar layer. Discard the polar (i.e., water) layer, and you're left with a nonpolar layer full of your chemical ..... Plus anything else that might be oil-soluble. So you reverse the process, by adding an acid until the free base turns into an acid salt, and precipitates out of the nonpolar layer. Add water, shake, and you can discard your nonpolar layer. This is the acid-base extraction, and it's very frequently used to extract the active ingredients from plants (free clue: the THC in marijuana is not an alkaloid and thus won't extract this way). ............................................................................. Acid-Base Extraction of DXM So how do we apply this to DXM? Well, it turns out that DXM is an alkaloid, and you can extract DXM from cough syrups using the same process. Furthermore, this procedure even works for DXM plus guaifenesin syrups, e.g., Robitussin DM[tm], and generic equivalents (invariably called Tussin DM). The "DM" syrups usually only contain 10mg/5ml of DXM, so you won't get as much yield, but they're usually cheaper (and more commonly available). Do NOT try this extraction procedure with cough syrups or formulations containing acetaminophen/paracetamol, pseudoephedrine, other decongestants, or antihistamines. (I'm working on it) For this procedure you will need: o Cough syrup (obviously) or some other DXM-containing preparation. The only active ingredients that should be listed are dextrometh- orphan and guaifenesin. Avoid alcohol (check the inactive ingredients). If you can get DXM-only preparations, do so; the DXM+ guaifenesin preparations tend to contain less DXM than the DXM-only ones. o A mason (canning) jar with a complete lid, big enough to contain twice the volume of cough syrup/formula you have. o A glass container to make your sodium hydroxide solution in (a mason jar works; you can also use a drinking glass). o Two plastic freezer bags with lock closures (e.g., Ziploc[tm] freezer bags) -- the larger the better. o A nonpolar solvent. The easiest to get is Zippo[tm] lighter fluid (or an equivalent) -- note that this is cigarette lighter fluid, not charcoal lighter fluid. You want your solvent to evaporate quickly, leaving no residue. The easiest way to test it is by placing a drop or two onto a pocket mirror, and letting it evaporate; if it leaves no residue or smell, you can use it. o Sodium hydroxide (NaOH). Photography supply stores carry this. In a pinch, some people have been known to use Red Devil[tm] Lye. I do not advise this! Lye is likely to be impure. If you must use lye, make sure you let your sodium hydroxide solution settle (see below). Note that sodium hydroxide is caustic and severely damaging to the eyes, so wear your safety goggles! o A heat-resistant glass baking dish (smaller is better). o Distilled water (tap water won’t work very well due to the chlorine ions) o A pair of scissors o Access to the outdoors. To speed up the process (from overnight to about 30 minutes), you will have to evaporate the solvent with heating. For this you will require: o An electric wok or skillet, or a hot plate with a pot of water on it. Basically, you want a flameless (electric) source of heat that will heat up a volume of water, which you can put your baking dish in (the hot water will heat the baking dish). o A hair dryer o An OSHA-certified organic vapor mask. A brief word about organic vapors. The solvents you will in all likeli- hood be dealing with (hexane, heptane, petroleum ether, whatever) are bad for you. Really bad for you. You do NOT want to breathe the fumes. Get it? So, if you want to speed up the process, pony up US$30.00 or so for an OSHA organic vapor gas mask (tell `em you'll be painting with oil- based paint). Sure, it's uncomfortable and looks dorky. But it sure beats brain damage! Additionally, you must do the evaporation outdoors (unless you happen to have a fume cabinet handy. And NO, the stove or bathroom fan does NOT count as a fume cabinet). Okay, here we go: 1. Form a solution of sodium hydroxide (NaOH) by placing one tablespoon (15ml) of solid sodium hydroxide in one cup (about 236ml) of distilled water in the sodium hydroxide solution container. Stir until dissolved. If you are using lye (I don't recommend it), wait awhile to let any impurities settle out to the bottom. Note that dissolving the NaOH will generate some heat. 2. Empty your cough syrup or formula into the mason jar, rinsing the bottle out with distilled water. If using gelcaps, break them open and rinse out the inside of the capsules. 3. Add one tablespoon (15ml) of sodium hydroxide solution to the mason jar. You should see a rapid formation of a milky precipitate. Swirl the mason jar gently to mix the syrup evenly, and the precipitate should redissolve (because there's not enough base yet). 4. Repeat step 3, until the precipitate doesn't redissolve with swirling. The entire solution should be cloudy (stir well to make sure the base is evenly distributed). 5. Add one more tablespoon (15ml) of sodium hydroxide solution to the mason jar. 6. Add a small volume of nonpolar solvent (e.g., Zippo[tm] lighter fluid) to the mason jar. How much? Well, as a suggestion, start with 1/4 cup (60ml); you want a layer roughly 3/8" (1cm) thick in the jar. It will float on top of the water layer. (You may have to pry open the pour spout to get a good flow rate on the lighter fluid container). 7. Cut one of the plastic bags along the seam so that you end up with a quare of plastic. Place that over the mason jar, and then place the lid on top of that. Close the lid tightly. The plastic protects the rubber seal, which would otherwise dissolve in the lighter fluid. 8. Shake the mason jar for about 5 minutes, or until you feel like your arms are going to fall off. 9. Place the mason jar on a flat surface and wait for the layers to separate (this may take awhile). If they don't seem to separate easily, try salting it (really). 10. Carefully pour the contents of the mason jar into the intact sealable plastic bag, and close it shut ("yellow and blue make green--it's sealed!"). Hold the bag up so that one of the bottom corners (not a corner with the seal) points down. 11. Let the two layers separate again (this should only take a few seconds). 12. Cut off the tip of the bottom corner and allow the water layer (the bottom layer) to drain out of the bag. When the water layer has drained out, pinch the bag shut. 13. Hold the bag over the baking dish, and allow the nonpolar solvent layer to drain out into the baking dish. 14. Take the baking dish outdoors. At this point, if you don't have a gas mask and a way to heat the baking dish, you’ll have to let the solvent evaporate (which may take a day or so), so go on to step 19. 15. Put on your gas mask 16. Place the baking dish into the container of water (electric wok, electric skillet, hot plate with pan of water, whatever), and set it to simmer. If you can't set the temperature low enough, you'll have to turn the heater on and off manually to maintain a near-boiling temperature. 17. Plug in the hair dryer and gently blow hot air into the baking dish. Take care not to splash solvent over the sides of the dish. Incidentally, make sure you don't overload your circuit; it might be a good idea to alternate heating with the hot plate/wok/skillet and heating with the hair dryer. 18. Continue heating until all the solvent evaporates. At this point you may see a thin layer of crystalline material; you might see a shiny layer of goo that looks a lot like the glass itself (which can be confusing); or you might see a layer of brown gunk. Whatever. Anyway, make sure all the solvent has evaporated. 19. If your baking dish is covered with an oily substance (goo, gunk, whatever), you in all likelihood managed to extract some propylene glycol (or something else) along with the DXM. Blow hot air from the hair dryer onto the surface of the dish until the material dries completely (this may take 5 to 10 minutes). This should evaporate the propylene glycol, leaving behind only DXM. 20. Scrape the DXM off the baking dish with a razor blade or other convenient sharp edge. You now have DXM free base. A few comments. First, guaifenesin seems to itself convert to an oily free base layer if you add too much sodium hydroxide, so don’t overdo it. Second, if you happen to have lab equipment you can of course use a separatory funnel (which is what the plastic baggie is for). Third, if you don’t think you got anything, make sure the baking dish is completely dry; sometimes the DXM free base plus propylene glycol can look a lot like the glass itself. Precipitation Method If you want to use the precipitation method, all you have to do is add sodium hydroxide to the cough formula as described above, until the DXM precipitates out. Let it stand (or centrifuge it), and filter. The (very fine) powder that hopefully was caught by the filter paper is the DXM free base. I don't know if the precipitation method works with DXM + guaifenesin preparations. ----------------------------------------------------------------------------- ----------------------------------------------------------------------