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Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.orgShown: posts 1 to 21 of 21. This is the beginning of the thread.
Posted by Empathy on August 25, 2005, at 1:19:51
As I posted earlier, I had a friend commit suicide almost a month ago - his wife mentioned in passing that he had being using, I believe she said Dextromethorphan. (She said it was in cough syrup, is there something "else" that sounds like that?) She said he was using it for depression and had initially had amazing success.
Does anyone know anything about this drug? I have been trying to figure out what would have led him to try such a thing. I know that there are people here on the board that have a strong grasp of the chemistry of drugs and I wondered if they would explain what effect this drug has on the brain and mood.
I have tried seaching the archives for info on Dextromethorphan and any trance of my friend posting. However, in the archives I continue to get distracted by non-affirming posts that stir emotions in me - and I don't need that. Besides, if my friend was ever here, I am sure he was banned in short order, as he didn't have a very diplomatic nature.
So can someone take pity on me and explain, if they know, what he was doing treating himself with this medication?
Thank you so very much.
Posted by yxibow on August 25, 2005, at 1:42:01
In reply to Dextromethorphan? Why?, posted by Empathy on August 25, 2005, at 1:19:51
> As I posted earlier, I had a friend commit suicide almost a month ago - his wife mentioned in passing that he had being using, I believe she said Dextromethorphan. (She said it was in cough syrup, is there something "else" that sounds like that?) She said he was using it for depression and had initially had amazing success.
I'm not sure where you are located but Dextromethorphan (Robitussin, other brands) is one of the two opiates allowed over the counter in the US, or at least here in California. Its a very weak one for cough syrup. The other one, for random knowledge is Imodium (loperamide) for diarrhea which doesnt cross the blood brain barrier and thus has no opiate brain activity.
>
> Does anyone know anything about this drug? I have been trying to figure out what would have led him to try such a thing. I know that there are people here on the board that have a strong grasp of the chemistry of drugs and I wondered if they would explain what effect this drug has on the brain and mood.I'm sure the Erowid vault has "experiences" on Dextromethorphan or DXM as the street name is called. I imagine it starts out mildly euphoric but it is quickly becomes vomit-making at higher doses and all sorts of unpleasant things.
> So can someone take pity on me and explain, if they know, what he was doing treating himself with this medication?
Ed_uk might add more but I think, and only in my opinion, that he was slowly trying to commit suicide or self-treat depression without knowledge of what he was doing... the dose range of DXM beyond the package label gets into all sorts of nasty feelings, side effects, extreme nausea, etc.
hope that helps... as I say there are plenty of stories you can find about "DXM" in google, but they're not pleasant.
Posted by Empathy on August 25, 2005, at 1:46:11
In reply to Re: Dextromethorphan? Indeed Why ?, posted by yxibow on August 25, 2005, at 1:42:01
Thanks for some input.
Sidenote: My friend did not die from any drug overdose (surprisingly). I would give further details but don't want to "trigger" anyone.
Posted by Empathy on August 25, 2005, at 2:15:42
In reply to Re: Dextromethorphan? Indeed Why ? » yxibow, posted by Empathy on August 25, 2005, at 1:46:11
If something is effecting the Glutamate in one's brain, what is that doing? Anyone know?
Posted by lunesta on August 25, 2005, at 4:05:11
In reply to Dextromethorphan Glutamate? Connection?, posted by Empathy on August 25, 2005, at 2:15:42
Most physiatric diseases have this problem of excess glutamate which is basically our learning/stimulating neurotrainsmitter in the body/brain.
Its either too much glutamate, or too little gaba /magnesium which oppose (opposites) o glutamate.
MOST meds talked about here block some pathway o glutamate (a sodium channel, or calicum channel etc..)
OR if you use benzos etc.. your augmenting your inhibitory vs glutamate.
The ultimate solution is probably finding a glutamqate antgonist but remember that you need to glutamate to survive and to be functional and learn etc. So it is a fine balance of inhbition vs stimulation that gets upset in most of our disorders.
DXm is an NMDA antagonist. NMDA is excitatory, opposed by gaba and magnesium.
DXM also eects sigma receptors i believe.
Posted by Declan on August 25, 2005, at 7:29:19
In reply to Re: Dextromethorphan Glutamate? Connection?, posted by lunesta on August 25, 2005, at 4:05:11
Somewhwhere I read about DXM and ketamine as both being NMDA antagonists. Does that sound right? DXM and ketamine are asserted to cause the same brain damage, I've forgotten what to.
I'd heard that the Manson murders had been committed under the influence of DXM and thought it might be worth trying (Romilar). It was really awful. (Not like ketamine subjectively. Not remotely like opiates either.)Declan
Posted by Shawn. T. on August 25, 2005, at 15:10:14
In reply to Dextromethorphan? Why?, posted by Empathy on August 25, 2005, at 1:19:51
Dextromethorphan (DXM) exhibits relatively high affinity binding activity as a sigma-1 receptor agonist and serotonin reuptake inhibitor. DXM is also a low affinity, noncompetitive NMDA receptor antagonist. The active metabolite of DXM, dextrorphan, is a more potent noncompetitive NMDA antagonist and sigma-1 agonist than DXM. In addition, dextrorphan is a serotonin reuptake inhibitor. Dextrorphan and DXM also bind with low affinity to sigma-2 receptors. DXM and dextrorphan noncompetitively block alpha3beta4 neuronal nicotinic acetylcholine receptors; other nicotinic receptor subtypes may also be affected by these drugs. Serotonin reuptake, sigma-1 agonism, and NMDA antagonism are all mechanisms of action that can lead to an antidepressant effect. Also, DXM is not an opiate.
Shawn
Posted by yxibow on August 25, 2005, at 15:39:57
In reply to Re: Dextromethorphan? Why?, posted by Shawn. T. on August 25, 2005, at 15:10:14
Also, DXM is not an opiate.
>
> ShawnI erred. Technically not a opiate in the classic heroin sense, but it is the d-isomer of levorphanol, and i erred, loperamide is the congener not of levorphanol but meperidine. Today's trivia lessons.
Posted by chemist on August 25, 2005, at 17:36:32
In reply to Dextromethorphan? Why?, posted by Empathy on August 25, 2005, at 1:19:51
Posted by SLS on August 25, 2005, at 17:38:54
In reply to Re: Dextromethorphan? Why?, posted by Shawn. T. on August 25, 2005, at 15:10:14
> Dextromethorphan (DXM) exhibits relatively high affinity binding activity as a sigma-1 receptor agonist and serotonin reuptake inhibitor. DXM is also a low affinity, noncompetitive NMDA receptor antagonist. The active metabolite of DXM, dextrorphan, is a more potent noncompetitive NMDA antagonist and sigma-1 agonist than DXM. In addition, dextrorphan is a serotonin reuptake inhibitor. Dextrorphan and DXM also bind with low affinity to sigma-2 receptors. DXM and dextrorphan noncompetitively block alpha3beta4 neuronal nicotinic acetylcholine receptors; other nicotinic receptor subtypes may also be affected by these drugs. Serotonin reuptake, sigma-1 agonism, and NMDA antagonism are all mechanisms of action that can lead to an antidepressant effect. Also, DXM is not an opiate.
>
> Shawn
What do sigma receptors do?
- Scott
Posted by Empathy on August 25, 2005, at 18:22:23
In reply to Re: Dextromethorphan? Why?, posted by Shawn. T. on August 25, 2005, at 15:10:14
Hhhmmm... I remain puzzled by why someone would attempt to use this as an anti-depressant. Seems like it would make you feel all goofy and out of focus. I got the impression from his wife he felt energized and motivated on it (kind of hard to believe) - at least for awhile until he (obviously) crashed. I am relatively certain that he wasn't treating a manic state, but quite the opposite.
I would assume it would be toxic with any other "traditional" anti-depressants that work on the Serotonin, right? (Serotonin overload)
Any thoughts regarding the effects of this drug with alcohol? I am pretty sure he had been drinking.
Posted by Shawn. T. on August 25, 2005, at 18:22:25
In reply to Re: Dextromethorphan? Why?, posted by SLS on August 25, 2005, at 17:38:54
>What do sigma receptors do?
Su TP, Hayashi T.
Understanding the molecular mechanism of sigma-1 receptors: towards a hypothesis that sigma-1 receptors are intracellular amplifiers for signal transduction.
Curr Med Chem. 2003 Oct;10(20):2073-80.
Although sigma receptors were discovered in 1982, the biochemical and physiological roles of sigma receptors have just begun to unveil. Sigma receptors are non-opioid, non-phencyclidine receptors that contain two subtypes: sigma-1 and sigma-2 receptors. The sigma-1 receptor has been cloned and its sequence does not resemble that of any mammalian protein. Sigma-2 receptors have not been cloned. The focus of this review will be on sigma-1 receptors. Sigma-1 receptors contain 223 amino acids and reside primarily at the endoplasmic reticulum. Sigma-1 receptors exist mainly in the central nervous system, but also in the periphery. Sigma-1 receptor ligands include cocaine, (+)-benzomorphans like (+)-pentazocine and (+)N-allyl-normetazocine (or (+)-SKF-10047), and endogenous neurosteroids like progesterone and pregnenolone sulfate. Many pharmacological and physiological actions have been attributed to sigma-1 receptors. These include the regulation of IP3 receptors and calcium signaling at the endoplasmic reticulum, mobilization of cytoskeletal adaptor proteins, modulation of nerve growth factor-induced neurite sprouting, modulation of neurotransmitter release and neuronal firing, modulation of potassium channels as a regulatory subunit, alteration of psychostimulant-induced gene expression, and blockade of spreading depression. Behaviorally, sigma-1 receptors are involved in learning and memory, psychostimulant-induced sensitization, cocaine-induced conditioned place preference, and pain perception. Notably, in almost all the aforementioned biochemical and behavioral tests, sigma-1 agonists, while having no effects by themselves, caused the amplification of signal transductions incurred upon the stimulation of the glutamatergic, dopaminergic, IP3-related metabotropic, or nerve growth factor-related systems. Thus, it is hypothesized that sigma-1 receptors, at least in part, are intracellular amplifiers creating a supersensitized state for signal transduction in the biological system.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12871086
Posted by Shawn. T. on August 25, 2005, at 18:30:01
In reply to Re: Dextromethorphan? Why? » Shawn. T., posted by Empathy on August 25, 2005, at 18:22:23
Yes, it could cause serotonin syndrome if mixed with serotoninergic antidepressants. There is some danger of respiratory depression if a high dose of dextromethorphan is mixed with a high amount of alcohol. Taking alcohol after a large dose of dextromethorphan seems to reduce some of the effects of the alcohol, but it could cause increased dissociation in some people.
Shawn
Posted by linkadge on August 27, 2005, at 9:51:50
In reply to Re: Dextromethorphan? Why? » Empathy, posted by Shawn. T. on August 25, 2005, at 18:30:01
Without delving much into the subject, I have read some article headlines about the neurotoxicity of NMDA antagonists.
Could somebody tell me if this is an effect of all NMDA antagonists or just certain ones. Or is it a result of overdosing on an NMDA antagonist.
What is the mechanism anyway, I thought NMDA antagonists were neruoprotective ?
Linkadge
Posted by Declan on August 27, 2005, at 15:45:34
In reply to Are all NMDA antagonists neurotoxic ?, posted by linkadge on August 27, 2005, at 9:51:50
Linkadge I dunno about this. Memantine shouldn't be neurotoxic, should it? It's used for Alzheimers, I think.
Declan
Posted by Mistermindmasta on August 27, 2005, at 23:35:22
In reply to Are all NMDA antagonists neurotoxic ?, posted by linkadge on August 27, 2005, at 9:51:50
> Without delving much into the subject, I have read some article headlines about the neurotoxicity of NMDA antagonists.
>
> Could somebody tell me if this is an effect of all NMDA antagonists or just certain ones. Or is it a result of overdosing on an NMDA antagonist.
>
> What is the mechanism anyway, I thought NMDA antagonists were neruoprotective ?
>
>
> LinkadgeAs I understand it, DXM could be an antidepressant by lowering the activity of glutamate, thus preventing glutamate induced neurotoxicity - a key step to depression. Therefore, neurogenesis is allowed to occur and activity in many areas of the brain improves due to increased connectivity. However, more doesn't necessarily equal better and the problem with depression might not actually lie in too much glutamate - too much glutamate might just be a symptom or an effect of whatever really causes depression. The problem you run into is this - indeed, NMDA antagonists can be neuroprotective, but when you antagonize it too much, you start to run into problems because too much antagonism can burn out dopamine receptors and maybe serotonin receptors, from too much activity there. The NMDA receptor has a U curve kinda thing going on - too much glutamate causes cell death, just the right amount and cells thrive, and too little and you see to run into problems of neurotoxicity from dopamine, not glutamate. Also, schizophrenia is thought to arise partially from underactive NMDA receptors. So many the guy had an acute psychotic episode from this whole self medication thing. Or, he abruptly stopped using DXM... which obviously could have many bad effects.
Posted by Shawn. T. on August 28, 2005, at 14:51:06
In reply to Re: Are all NMDA antagonists neurotoxic ?, posted by Mistermindmasta on August 27, 2005, at 23:35:22
I don't believe that NMDA antagonism "burns out" dopamine or serotonin receptors. Farber et al. (2002) have suggested that NMDA antagonists disinhibit inhibitory GABA neurons in subcortical areas that modulate other neurons that release glutamate and acetylcholine into the cerebral cortex (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11803444&dopt=Abstract). They also suggested that the simultaneous activation of M3 muscarinic acetylcholine receptors and AMPA/kainate glutamate receptors in the cerebral cortex is involved in NMDA antagonist neurotoxicity. Initially, the neurotoxicity occurs in the retrosplenial cortex and posterior cingulate, but much higher doses may affect other regions of the cortex.
No one has ever shown that dextromethorphan or memantine causes NMDA antagonist neurotoxicity. A serotonin reuptake inhibitor, fluoxetine, inhibits the development of NMDA antagonist neurotoxicity in the rat brain (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10812043&dopt=Abstract). So it could be the case that the serotonin reuptake inhibition caused by dextromethorphan prevents the drug from inducing neurotoxicity; however, this will remain speculation until someone actually examines dextromethorphan's potential for neurotoxicity.
Shawn
Posted by Mistermindmasta on August 28, 2005, at 16:30:18
In reply to Re: Are all NMDA antagonists neurotoxic ? » Mistermindmasta, posted by Shawn. T. on August 28, 2005, at 14:51:06
> I don't believe that NMDA antagonism "burns out" dopamine or serotonin receptors. Farber et al. (2002) have suggested that NMDA antagonists disinhibit inhibitory GABA neurons in subcortical areas that modulate other neurons that release glutamate and acetylcholine into the cerebral cortex
Ok, this is a case where I was trying to remember this stuff from memory and my memory obviously failed. Anyway, in addition to the idea that lowering activity at NMDA receptors increases glutamate and acetylcholine, dopamine was "possibly" involved. Not serotonin, though, I'm wrong on that.
>(http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11803444&dopt=Abstract). They also suggested that the simultaneous activation of M3 muscarinic acetylcholine receptors and AMPA/kainate glutamate receptors in the cerebral cortex is involved in NMDA antagonist neurotoxicity. Initially, the neurotoxicity occurs in the retrosplenial cortex and posterior cingulate, but much higher doses may affect other regions of the cortex.
>
> No one has ever shown that dextromethorphan or memantine causes NMDA antagonist neurotoxicity.True. But it seems to be that way, at least in theory.
>A serotonin reuptake inhibitor, fluoxetine, inhibits the development of NMDA antagonist neurotoxicity in the rat brain (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10812043&dopt=Abstract). So it could be the case that the serotonin reuptake inhibition caused by dextromethorphan prevents the drug from inducing neurotoxicity; however, this will remain speculation until someone actually examines dextromethorphan's potential for neurotoxicity.
>
> ShawnGood post.
Posted by linkadge on August 28, 2005, at 17:11:45
In reply to Re: Are all NMDA antagonists neurotoxic ?, posted by Mistermindmasta on August 28, 2005, at 16:30:18
Zinc and magnesium are NMDA antagonists (Am I right on that ?) But would either of these cause neurotoxicity, or is it like a dose dependant thing, (ie no neurotoxcity at biological doses).
Linkadge
Posted by Chairman_MAO on August 30, 2005, at 10:03:16
In reply to Are all NMDA antagonists neurotoxic ?, posted by linkadge on August 27, 2005, at 9:51:50
They are neuroprotective--against neurotox caused by excessive glutaminergic activity . The problem is that there is a "downstream" neurotoxicity associated with their neurprotecitve mechanism--it has to do with the induction of something called HSP (heat shock protein) 70 which I believe ultimately leads to apoptosis if the cell cannot recover normal functioning. This could be mediated by Read William White's "this is your brain on dissociatives" for a detailed explanation of this mechanism. I am not sure if the rest of the document holds water, though.
BTW, the jury is still out as to whether this even occurs in humans. At any rate, the strenght of the blockade caused by therapeutic concentrations of memantine I believe is too weak to cause neurotoxicity. Also, this neurotoxicity in animals likely has something to do with NDMA antagonism preventing normal GABAergic inhibition; thus, benzodiazepines and gabanergic drugs (such as muscimol) prevent the neurotoxicity. Many, many agents can do this via various means: a2 agonists, LSD (seriously), BZDs, clozapine (IIRC), etc.
Posted by linkadge on August 30, 2005, at 15:26:13
In reply to Re: Are all NMDA antagonists neurotoxic ? » linkadge, posted by Chairman_MAO on August 30, 2005, at 10:03:16
Strange, I thought the induction of heat shock protiens (by things like fasting, vitamin D, curry spice, and lithium) was neuroprotective.
Huntington's research is focusing on the induction of heat shock proteins to slow disease progression.
http://hdlighthouse.org/research/brain/updates/1113heatshock.php
Are there different HSP's with different functions ?
Sorry, my curiosity is overtaking my ignorance.
Linkadge
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