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Dr. Bob is Robert Hsiung, MD,
[email protected]Shown: posts 1 to 22 of 22. This is the beginning of the thread.
Posted by NKP on July 23, 2020, at 3:16:56
Apart from its primary effect of being a norepinephrine reuptake inhibitor, atomoxetine is also a mild NMDA receptor antagonist.
To my knowledge, NMDA receptor antagonists are neurotoxic.
Is atomoxetine neurotoxic, or is it a case of dose maketh poison?
Posted by rjlockhart37 on July 23, 2020, at 17:32:26
In reply to Atomoxetine: NMDA receptor antagonist, posted by NKP on July 23, 2020, at 3:16:56
i've been on strattera twice, first in high school, i noticed i was more attentive, but not like adderall. I was attentive to the chemisty boards, periodic tablets. I stopped it and went to wellbutrin
The second time, was not a good experience. I don't know why, but fluoxetine and atmoxetine are very chemically related, so Prozac and Strattera, i was so irrtible and stressed out, saying irrtibility comments alot. Prozac and streattera i know dont mix well
i don't like streattera, and i get a gut feeling about it never to take it again. Yes, you could be right about neurotoxin. nasty drug for me...
Posted by rjlockhart37 on July 23, 2020, at 17:38:50
In reply to Re: Atomoxetine: NMDA receptor antagonist, posted by rjlockhart37 on July 23, 2020, at 17:32:26
i don't have the source to post, but i read atomoxetine is slight serotonin reptake inhibitor, even though its medically classfied on books as a norepinephrine retake inhibitor, just like roboxetine. It was in some research medical journals i read a while back.
that why prozac and strattea combo was not good for me, plus i'm on max dose of fluoxetine
but i've heard roboxeetine is worse, more potent and does not help depression
Posted by linkadge on July 24, 2020, at 19:51:26
In reply to Re: Atomoxetine: NMDA receptor antagonist, posted by rjlockhart37 on July 23, 2020, at 17:38:50
Short answer ... NMDA antagonists not neurotoxic as a class.
For example, magnesium is a NMDA antagonist (and is highly neuroprotective at the right dose) zinc is also and NMDA antagonist.
Some NMDA antagonists display some neurotoxicity i.e. 'angle dust' (Phencyclidine or PCP), ketamine (in high enough doses). However these drugs have many other actions. While many others display no neurotoxicity. NMDA antagonists block the release of glutamate (which generally protects neurons). However, at very high doses, some of these drugs start to do the reverse - i.e. activate glutamate. It's complex and I don't completely understand it all myself.
As for atomoxetine, it is only a weak NMDA antagonist. Also, it acts at the same site as magnesium (meaning it is as harmless as magnesium). If anything, this action is neuroprotective.
Linkadge
Posted by rjlockhart37 on July 24, 2020, at 23:31:41
In reply to Re: Atomoxetine: NMDA receptor antagonist » rjlockhart37, posted by linkadge on July 24, 2020, at 19:51:26
yeah your right'
all i rerember was strattera improved my attention in class, it made me more alert, awake, but not stimulant like or wellbutrin, norephphrpine reptake inhibtor.
I've heard some worse stories about roboxetine, wish there were people here in the past that would post about it. have Go through the archives for expereince of effects, babble has been really toned down, 2000s this place was a powerhouse talk show, 2010s people left
Posted by undopaminergic on July 25, 2020, at 5:54:37
In reply to Atomoxetine: NMDA receptor antagonist, posted by NKP on July 23, 2020, at 3:16:56
> Apart from its primary effect of being a norepinephrine reuptake inhibitor, atomoxetine is also a mild NMDA receptor antagonist.
>
> To my knowledge, NMDA receptor antagonists are neurotoxic.It's known as "Olney's lesions". Many NMDA-antagonists can cause it, but there are at least some exceptions, including memantine and xenon. I don't know about nitrous oxide.
> Is atomoxetine neurotoxic, or is it a case of dose maketh poison?
Yes, I'm pretty certain you'd have to take megadoses for this action to be significant. I don't know about the kappa-opioid effect it also has, but personally I would be more concerned about that.
-undopaminergic
Posted by undopaminergic on July 25, 2020, at 7:11:28
In reply to Re: Atomoxetine: NMDA receptor antagonist » rjlockhart37, posted by linkadge on July 24, 2020, at 19:51:26
>
> Some NMDA antagonists display some neurotoxicity i.e. 'angle dust'Anglo-Saxon dust, to be specific. It was used in battle by the ancient Germanic tribes.
(kidding)
> (Phencyclidine or PCP), ketamine (in high enough doses). However these drugs have many other actions. While many others display no neurotoxicity. NMDA antagonists block the release of glutamate
>They block the NMDA-subtype of ionotropic glutamate *receptors*. As far as I know, they don't block the release of the neurotransmitter.
> (which generally protects neurons).
>Can you clarify that? I don't think you mean glutamate protects neurons.
-undopaminergic
Posted by undopaminergic on July 25, 2020, at 7:13:09
In reply to Re: Atomoxetine: NMDA receptor antagonist, posted by rjlockhart37 on July 24, 2020, at 23:31:41
>
> I've heard some worse stories about roboxetine, wish there were people here in the past that would post about it. have Go through the archives for expereince of effects, babble has been really toned down, 2000s this place was a powerhouse talk show, 2010s people left
>I've taken reboxetine. I was left with persistent depersonalisation.
-undopaminergic
Posted by NKP on July 25, 2020, at 8:12:39
In reply to Re: Atomoxetine: NMDA receptor antagonist, posted by undopaminergic on July 25, 2020, at 7:13:09
What is one to make of a study like this?
https://www.nature.com/articles/s41598-019-49609-9
Are these negative effects only observed with very high doses?
I'm taking atomoxetine so am concerned when I read such things.
Posted by undopaminergic on July 25, 2020, at 8:24:26
In reply to Re: Atomoxetine: NMDA receptor antagonist, posted by NKP on July 25, 2020, at 8:12:39
> What is one to make of a study like this?
>
> https://www.nature.com/articles/s41598-019-49609-9
>
> Are these negative effects only observed with very high doses?The 10 micromol dose is larger than the typical drug doses measured in *nano*mol.
I am not advanced enough to translate 10 mcmol to an equivalent human peroral dose.
> I'm taking atomoxetine so am concerned when I read such things.
Well, I've heard mostly bad things about it... including heart problems and nausea, but you have to decide for yourself whether it is good enough for you personally. If it makes you feel better, I'd say it is worth taking some risk -- but that's just what *I* would do.
-undopaminergic
Posted by linkadge on July 25, 2020, at 9:46:54
In reply to Re: Atomoxetine: NMDA receptor antagonist, posted by undopaminergic on July 25, 2020, at 5:54:37
Kappa opioid agonists are neuroprotective too (although they can induce dysphoria). However, I don't know if the kappa agonism for clinical doses of atomoxetine would reach any significance.
Linkadge
Posted by linkadge on July 25, 2020, at 10:09:06
In reply to Re: Atomoxetine: NMDA receptor antagonist, posted by undopaminergic on July 25, 2020, at 7:11:28
Yes typo. Angel dust.
>Can you clarify that? I don't think you mean >glutamate protects neurons.
Right. Glutamate, which is critical for proper neurotransmission in a certain concentration range, can become neurotoxic at elevated concentrations. You are correct in saying that NMDA antagonists, block glutamate receptors, but the net effect is a reduction in 'glutamate neurotransmission' (usually - at least in lower doses). However, as the concentration increases other things begin to happen. I haven't read enough on this topic, but I understand blocking NMDA can increase dopamine (hence the application of amantadine in Parkinson's). At certain doses, drugs like PCP and ketamine can increase glutamate release. I'm not sure of the mechanism here (AMPA receptors or GABA inhibition or something). I'm not sure too, if there are NMDA autoreceptors which try to offset the NMDA blockade. I'm not sure if this is homeostatic, or if it results in a net *increase* in glutamate neurotransmission. Increasing glutamate may be part of the antidepressant effect. I know that some of the neurogenic properties of ketamine require a glutamate increase, which can trigger BDNF. Acute lithium often has antidepressant effects. In the short term, lithium decreases glutamate reuptake (increasing glutamate) over time (perhaps as BDNF levels rise) glutamate reuptake is actually enhanced (more stabilizing). It's very complex. In some cases, reducing glutamate improves depression, in other cases, increasing it does. Of course, much of it is region specific. Some studies have tried combinations of NMDA antagonists and NMDA agonists (i.e. d-cycloserine). See below for the use of d-cycloserine to prolong the antidepressant effect of ketamine. Very strange.
Linkadge
Posted by linkadge on July 25, 2020, at 10:56:38
In reply to Re: Atomoxetine: NMDA receptor antagonist, posted by NKP on July 25, 2020, at 8:12:39
I was a little bit concerned when I read this too. However, most of the effects were occurring at concentrations of 10uM and above. According to my calculations this would require fairly high doses (in poor metabolizers). The upper dose range (80mg in poor metabolizers) would start to enter the range of some of these negative effects.
Linkadge
Posted by linkadge on July 25, 2020, at 11:49:56
In reply to Re: Atomoxetine: NMDA receptor antagonist, posted by undopaminergic on July 25, 2020, at 8:24:26
According to the study, a twice-daily dose 2045 mg of ATX, Cmax detected ranged from 174 to 1221 ng/ml. **This is a total daily dose of 40 - 90mg.
1) This is in adolescents (concentrations would be lower in adults taking equivalent doses).
2) Poor metabolizers have much higher blood levels than the normal metabolizers. This is why there is almost a 10x difference in concentration range.
To go from ng/mL --> uMol / L you just divide by the molar mass of atomoxetine (255).
40-90 mg (total) daily dose produced concentrations of 174 to 1221 ng/mL.
174ng/mL ÷ 255 g/mol = 0.68uM
1221ng/mL ÷ 255 g/mol = 4.78uMThus, a 90mg daily dose in poor metabolizing adolescents could result in a concentration of 4.78uM. This would be a level where *some* of the negative effects could be observed (there was a small increase in cell death between 1-5 uM). However, the more pronounced negative effects required 10-50 uM concentrations. This would require (much) higher doses. That being said, an non-poor metabolizing adult taking < 90mg would be expected to have *much* lower concentrations (possibly more than 10x lower for normal metabolizers). So, all this being said, you could get a genotype test to see if you are a low CYP2D6 (I think it is) metabolizer. If you were, then a 50mg dose could be on the threshold of some mild negative effects. If not, then the concentration would be far below the test concentrations used.
The first question to ask is whether the drug is helping you. If it isn't then case closed. If it is helping you, then consider the dose and, if you're really concerned, think about getting a metabolism genotype test. This would give you an idea of the concentration.
Linkadge
Posted by linkadge on July 25, 2020, at 11:59:07
In reply to Re: Atomoxetine: NMDA receptor antagonist, posted by undopaminergic on July 25, 2020, at 8:24:26
Most NRIs have some impact on the cardiovascular system. You have to monitor cardiac function to make sure that all the parameters are in acceptable ranges.
Linkadge
Posted by NKP on July 27, 2020, at 8:23:56
In reply to Re: Atomoxetine: NMDA receptor antagonist » undopaminergic, posted by linkadge on July 25, 2020, at 11:59:07
Also, the study by Corona to which I linked above is an in vitro study. Human neuron-like cells were grown in a lab. Even in the control group, a substantial proportion of the cells died within a week. Their reaction to atomoxetine in vitro does not necessarily match their reaction to atomoxetine in the human body.
I've seen a number of studies that seem to suggest that atomoxetine is, if anything, neuroprotective.
Posted by linkadge on July 27, 2020, at 9:28:59
In reply to Re: Atomoxetine: NMDA receptor antagonist, posted by NKP on July 27, 2020, at 8:23:56
Yes, norepinephrine (in general) activates growth / protective factors in the brain (like nerve growth factor NGF and brain derived neurotrophic factor).
A few other things to keep in mind
1) Even if atomoxetine had some toxicity, tolerance to this effect may occur over time. For example, in rats you can prevent many of the the neurotoxic effects of high dise methamphetamine simply by increasing the dose more slowly.
https://www.nature.com/articles/1300247.pdf?origin=ppub
2) The study is looking at cells cultured in a dish. In the human brain, there would potentially by more protective factors (i.e. antioxidants) floating around. The study itself mentions that antioxidants could offset some of the effects seen with high doses.
3) This is not a 'disease model'. In other words, drugs may work differently in the brains of people who need them who may have biochemical abnormalities which the drugs ameliorate. For example, since starting atomoxetine, my sleep has improved quite a bit. Insomnia can be neurotoxic. Also, it feels like my brain is firing more rhythmically. Sure if norepinephrine becomes excessive, it may cause problems, but if the drug is normalizing the level of norepinephrine, this could actually lead to a net improvement.
Linkadge
Posted by undopaminergic on July 27, 2020, at 10:49:22
In reply to Re: Atomoxetine: NMDA receptor antagonist » NKP, posted by linkadge on July 27, 2020, at 9:28:59
> Yes, norepinephrine (in general) activates growth / protective factors in the brain (like nerve growth factor NGF and brain derived neurotrophic factor).
>One major problem with adrenergics is the vascular effects. People have strokes and ischaemic heart attacks from cocaine. Not sure whether cocaine is a more potent NRI than atomoxetine.
> A few other things to keep in mind
>
> 1) Even if atomoxetine had some toxicity, tolerance to this effect may occur over time. For example, in rats you can prevent many of the the neurotoxic effects of high dise methamphetamine simply by increasing the dose more slowly.
>
> https://www.nature.com/articles/1300247.pdf?origin=ppubThanks, I found that useful.
> For example, since starting atomoxetine, my sleep has improved quite a bit.
That is peculiar. I had early awakenings from reboxetine. It seemed I didn't sleep as deeply.
-undopaminergic
Posted by SLS on July 27, 2020, at 11:51:26
In reply to Re: Atomoxetine: NMDA receptor antagonist, posted by undopaminergic on July 25, 2020, at 7:13:09
> >
> > I've heard some worse stories about roboxetine, wish there were people here in the past that would post about it. have Go through the archives for expereince of effects, babble has been really toned down, 2000s this place was a powerhouse talk show, 2010s people left
> >
>
> I've taken reboxetine. I was left with persistent depersonalisation.
>
> -undopaminergic
Reboxetine made my depression *much* worse and added anxiety.
- Scott
Posted by SLS on July 27, 2020, at 11:59:08
In reply to Re: Atomoxetine: NMDA receptor antagonist » undopaminergic, posted by linkadge on July 25, 2020, at 10:09:06
> Yes typo. Angel dust.
>
> >Can you clarify that? I don't think you mean >glutamate protects neurons.
>
> Right. Glutamate, which is critical for proper neurotransmission in a certain concentration range, can become neurotoxic at elevated concentrations. You are correct in saying that NMDA antagonists, block glutamate receptors, but the net effect is a reduction in 'glutamate neurotransmission' (usually - at least in lower doses). However, as the concentration increases other things begin to happen. I haven't read enough on this topic, but I understand blocking NMDA can increase dopamine (hence the application of amantadine in Parkinson's). At certain doses, drugs like PCP and ketamine can increase glutamate release. I'm not sure of the mechanism here (AMPA receptors or GABA inhibition or something). I'm not sure too, if there are NMDA autoreceptors which try to offset the NMDA blockade. I'm not sure if this is homeostatic, or if it results in a net *increase* in glutamate neurotransmission. Increasing glutamate may be part of the antidepressant effect. I know that some of the neurogenic properties of ketamine require a glutamate increase, which can trigger BDNF. Acute lithium often has antidepressant effects. In the short term, lithium decreases glutamate reuptake (increasing glutamate) over time (perhaps as BDNF levels rise) glutamate reuptake is actually enhanced (more stabilizing). It's very complex. In some cases, reducing glutamate improves depression, in other cases, increasing it does. Of course, much of it is region specific. Some studies have tried combinations of NMDA antagonists and NMDA agonists (i.e. d-cycloserine). See below for the use of d-cycloserine to prolong the antidepressant effect of ketamine. Very strange.
>
> https://www.nature.com/articles/s41386-019-0480-y#:~:text=D%2Dcycloserine%20(DCS)%2C,as%20a%20depression%20augmentation%20treatment.
>
> Linkadge
Don't forget about the other two glutamate receptors. I don't know how they figure in.Lithium has recently reported to have a biphasic effect on glutamate activity. At low dosages, it stimulates glutamate activity. At higher dosages, it inhibits it. I imagine that's why low dosages have antidepressant effects for me (300 mg/day) and higher dosages consistently make me feel worse (450 mg/day and higher).
- Scott
Posted by linkadge on July 27, 2020, at 14:02:51
In reply to Re: Atomoxetine: NMDA receptor antagonist » linkadge, posted by SLS on July 27, 2020, at 11:59:08
You might benefit from theanine. It is a glutamate reuptake inhibitor.
Linkadge
Posted by SLS on August 1, 2020, at 14:35:51
In reply to Re: Atomoxetine: NMDA receptor antagonist » SLS, posted by linkadge on July 27, 2020, at 14:02:51
> You might benefit from theanine. It is a glutamate reuptake inhibitor.
>
> Linkadge
Thanks!- Scott
This is the end of the thread.
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