![[dr. bob]](/dr-bob-sm.gif)
Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.orgShown: posts 13 to 37 of 37. Go back in thread:
Posted by undopaminergic on December 4, 2019, at 9:07:46
In reply to Re: What do TRD patients take without an MAIO » undopaminergic, posted by linkadge on December 2, 2019, at 9:11:20
> Nice chat,
>Glad you like it, even though I'm not at my best.
> Amphetamines are not always neurotoxic.
>No, it's dose related. There is a point at which elevated extracellular dopamine begins to produce oxidative stress. Eg. cocaine and even more potent dopamine reuptake inhibitors do not achieve toxic DA elevations. Amphetamines do have that power (again, provided the dose is high enough).
Many people with ADD/ADHD who take it as prescribed continue to enjoy therapeutic benefits in the long term.
> In lower dose paradigms (i.e. stroke rehabilitation) they can actually be neurotrophic. I remember reading a study that low dose meth actually enhanced synaptic plasticity and recovery after TBI.
>Interesting. I didn't know.
> I've never taken selegiline but I often do well by adding the herb FO-TI (purportedly fairly selective towards MAO-B) and it helps quite a bit with energy and focus.
>That's great that you have found something that helps.
> In my own experience with monoamine reuptake inhibitors and MAOIs, MAOIs produce a much different feel to them. For MAO-A, there are other trace amines (such as tryptamine) whose elevation may enhance the clinical effect as dose psychedelics may have antidepressant effects for some individuals.
>I'd really like to try tranylcypromine, or failing that, isocarboxazide or EMSAM, but they aren't available where I live (Nordic countries).
You can safely add NRIs and DRIs to a MAOI. NRIs even counteract tyramine, because they reduce the uptake of tyramine (via the reuptake transporter) into sympathetic nerve terminals.
-undopaminergic
Posted by undopaminergic on December 4, 2019, at 9:19:32
In reply to Re: What do TRD patients take without an MAIO, posted by linkadge on December 2, 2019, at 9:15:25
> I have a bottle of PEA which I use periodically when nothing else works. I prefer it to an MAO-B inhibitor because of half life (much shorter and hence interferes less with sleep).
>It's my understanding that PEA without MAO-B inhibition produces no effects, at a dose up to at least 1 gram. At least that's what Shulgin reports. I haven't tried PEA without selegiline, except via phenylalanine (which gets decarboxylated to PEA).
> The problem is that most doctors just throw SSRIs at you and don't really listen to insights gathered through 'experimentation'.
>Sadly, that is very true.
> I have issues with attention (either bipolar or ADHD). Interestingly PEA calms me down rather than revs me up. It also clears my head and allows me to concentrate (i.e. read for more than 5-10 min at a time).
>That is what amphetamines do in ADHD, often referred to as a "paradoxical calming effect".
I experienced it myself, with the first few doses of PEA.
-undopaminergic
Posted by linkadge on December 6, 2019, at 18:07:55
In reply to Re: What do TRD patients take without an MAIO » linkadge, posted by pedr on December 2, 2019, at 10:07:39
Hey,
Here is a link for PEA supplement on Amazon.com
I live in Canada and they don't have it on Amazon.ca (not sure why). Anyhow, if you're in the US you shouldn't have a problem. If you're in Canada, you may need to search different Amazon vendors to find one that ships to Canada.
Linkadge
Posted by linkadge on December 6, 2019, at 18:15:25
In reply to Re: What do TRD patients take without an MAIO » linkadge, posted by undopaminergic on December 4, 2019, at 9:07:46
Cocaine and amphetamine work in different ways to elevate dopamine levels. It may not be the elevation in dopamine levels (per se) that leads to neurotoxicity. Cocaine works as more of a monoamine reuptake inhibitor whereas amphetamine causes the transport to work in reverse (forcing more dopamine out of the presynaptic neuron).
Interestingly, cocaine (or Ritalin) can actually block the neurotoxic effects of amphetamines!. But, combining the two (can) produce a synergistic elevation in dopamine.
Also, dopamine agonists (like Mirapex) can be neuroprotective.
There may be something else going on with amphetamine because it has other targets (i.e. sigma receptors, and TAAR1 receptors). Sigma agonism (in a certain dose range) can be neurotrophic but at higher doses can be neurotoxic. The sigma actions of amphetamine may be more involved in the neurotoxicity than dopamine elevations.
Another interesting tidbit is that caffeine raises dopamine but is neuroprotective (and can prevent Parkinson like dopamine receptor decline).
But, I really don't know as I am not an expert.
Linkadge
Posted by linkadge on December 6, 2019, at 18:17:06
In reply to Re: What do TRD patients take without an MAIO » linkadge, posted by pedr on December 2, 2019, at 10:07:39
Hey PEDR,
If you do take PEA be VERY careful. It's effects can be highly variable and can (in combination with a MAOI) behave like higher dose amphetamine.
I recommend stating with a tiny measured amount mixed in water. Drink SMALL amounts and see what the effect is.
Linkadge
Posted by linkadge on December 6, 2019, at 18:21:59
In reply to Re: What do TRD patients take without an MAIO » linkadge, posted by undopaminergic on December 4, 2019, at 9:19:32
From my standpoint it is not really accurate to say that PEA is inactive without an MAOI.
There are likely sizable variations in individual (functional) MAOB activity that can influence individual reactions to PEA.
I have a huge reaction to PEA (to the point that I need to dissolve a 90mg cap and take tiny sips).
Mind you, I do consume quite a bit of dark chocolate, coffee and green tea daily (both of which have some documented MAOI properties (stronger towards MAO-B in the case of chocolate and green tea).
Linkadge
Posted by pedr on December 6, 2019, at 18:25:06
In reply to Re: What do TRD patients take without an MAIO » pedr, posted by linkadge on December 6, 2019, at 18:17:06
> Hey PEDR,
>
> If you do take PEA be VERY careful. It's effects can be highly variable and can (in combination with a MAOI) behave like higher dose amphetamine.
>
> I recommend stating with a tiny measured amount mixed in water. Drink SMALL amounts and see what the effect is.
>
> Linkadge
Dosing was actually going to be my next question - thank you. Pete
Posted by pedr on December 6, 2019, at 18:27:27
In reply to Re: What do TRD patients take without an MAIO » undopaminergic, posted by linkadge on December 6, 2019, at 18:21:59
> From my standpoint it is not really accurate to say that PEA is inactive without an MAOI.
>
> There are likely sizable variations in individual (functional) MAOB activity that can influence individual reactions to PEA.
>
> I have a huge reaction to PEA (to the point that I need to dissolve a 90mg cap and take tiny sips).
>
> Mind you, I do consume quite a bit of dark chocolate, coffee and green tea daily (both of which have some documented MAOI properties (stronger towards MAO-B in the case of chocolate and green tea).
>
> Linkadge
>I tried eating lots of dark chocolate and didn't respond.
W.r.t. Dosing, I've ended up in the ER (with my young kids...) because of misjudging a Vyvanse dose whilst on Nardil so I'll tread carefully. Cheers.
Posted by linkadge on December 7, 2019, at 8:03:41
In reply to Re: What do TRD patients take without an MAIO » linkadge, posted by pedr on December 6, 2019, at 18:27:27
Yeah, if you're taking Nardil, then PEA dosing would definitely need to be adjusted downwards. If you purchase in capsules, DO NOT take an entire capsule to start.
You can easily adjust upwards, but not so well downwards.
Linkadge
Posted by undopaminergic on December 9, 2019, at 9:14:33
In reply to Re: What do TRD patients take without an MAIO » undopaminergic, posted by linkadge on December 6, 2019, at 18:15:25
> Cocaine and amphetamine work in different ways to elevate dopamine levels.
>Of course. I hesitate to call myself an expert, because the more I learn, the more I realise there is so much more to learn, but at least relatively speaking, stimulants are one of my areas of expertise.
> It may not be the elevation in dopamine levels (per se) that leads to neurotoxicity.
>No, it is not the elevated dopamine *itself* that is neurotoxic. Rather, it is the metabolism thereof, which leads to oxidative stress. But now, stumbling across this article:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3870191/
I realise it is more complex than I had thought. See, that's what I meant when I said the more I learn, the more I realise how much more there is to learn.> Cocaine works as more of a monoamine reuptake inhibitor ...
>Of course. There may be less important actions as well, including modestly increased dopamine release. As a matter of fact, you called my attention to this in a debate many years ago!
> whereas amphetamine causes the transport to work in reverse (forcing more dopamine out of the presynaptic neuron).
>Of course.
> Interestingly, cocaine (or Ritalin) can actually block the neurotoxic effects of amphetamines!.
>Yes, it is interesting, but it follows from the fact that amphetamines need the DAT (dopamine transporter) in order to produce their effects, and cocaine inhibits that transporter.
> But, combining the two (can) produce a synergistic elevation in dopamine.
>"can" is the keyword. This is complex, and I don't have a good understanding of it.
> Also, dopamine agonists (like Mirapex) can be neuroprotective.
>Yes, but these agonists are not identical to dopamine; their metabolism does not produce oxidative stress. Indeed pramipexole (Sifrol; Mirapex?) has been show to have antioxidant properties.
> There may be something else going on with amphetamine because ...
>Many things, it seems, including increased release of glutamate; see the article I referenced above.
> it has other targets (i.e. sigma receptors, and TAAR1 receptors). Sigma agonism (in a certain dose range) can be neurotrophic but at higher doses can be neurotoxic. The sigma actions of amphetamine may be more involved in the neurotoxicity than dopamine elevations.
>I did not know amphetamines modulate sigma. Cocaine definitely does, and it is apparently associated with the seizures sometimes resulting from cocaine overdose. Although cocaine seems to be a more potent sigma-agonist (amph. do not produce seizures), it does not produce the same neurotoxicity as the amphetamines.
> Another interesting tidbit is that caffeine raises dopamine but is neuroprotective (and can prevent Parkinson like dopamine receptor decline).
>Yes (I knew about the DA elevation but not the neuroprotection), and caffeine-like stimulants (primarily adenosine-receptor antagonists) have been researched as a treatment for Parkinson's.
I have personal (first-hand) experience with this. At some point, cocaine-like stimulants (in my case, ethylphenidate and desoxypipradrol) alone seemed to lose most of their effects, but when combined with ~ 500-1000 mg of caffeine, I get excellent effects. Severely nootropic!
> But, I really don't know as I am not an expert.
>You are certainly one of the more well-informed people I've met regarding these issues.
-undopaminergic
Posted by undopaminergic on December 9, 2019, at 9:36:36
In reply to Re: What do TRD patients take without an MAIO » undopaminergic, posted by linkadge on December 6, 2019, at 18:21:59
> From my standpoint it is not really accurate to say that PEA is inactive without an MAOI.
>Apparently, you are right. However, given Shulgin's report, it seems typical that it is inactive.
> There are likely sizable variations in individual (functional) MAOB activity that can influence individual reactions to PEA.
>Apparently. It would be interesting to study this further. People like you, who are highly sensitive to PEA, must have differing neurology than those who experience no effect.
> I have a huge reaction to PEA (to the point that I need to dissolve a 90mg cap and take tiny sips).
>It's nice to hear you've found a (legal) stimulant that works for you.
> Mind you, I do consume quite a bit of dark chocolate, coffee and green tea daily (both of which have some documented MAOI properties (stronger towards MAO-B in the case of chocolate and green tea).
>I didn't know these substances had MAOI properties. I did know, however, that cocoa is particularly high in PEA content. It is sometimes called the "chocolate amphetamine".
-undopaminergic
Posted by linkadge on December 9, 2019, at 17:15:19
In reply to Re: What do TRD patients take without an MAIO » linkadge, posted by undopaminergic on December 9, 2019, at 9:14:33
>No, it is not the elevated dopamine *itself* that >is neurotoxic. Rather, it is the metabolism >thereof, which leads to oxidative stress. But now, >stumbling across this article:
Right. There is the possibility of amphetamine (and related substances) as being directly neurotoxic (in a manner that substances like MTPP are). Anything that leads to excessive glutamate function, in theory can be neurotoxic.
However, I've never heard of cocaine blocking the high associated with amphetamine (although I only know a few people personally that would have mixed the two), even though, it appears it can block the neurotoxicity. I would imagine, however, that cocaine would lead to increased glutamate levels (at least in some brain regions).
>Yes, it is interesting, but it follows from the >fact that amphetamines need the DAT (dopamine >transporter) in order to produce their effects, >and cocaine inhibits that transporter.
I don't know if cocaine only blocks the transporter within the synaptic junction, or whether it also enters the presynaptic neuron and prevents the dopamine transporter function there. Complicating the picture is the action of the presynaptic dopamine autoreceptor system. Cocaine can actually calm hyperactive mice in a similar fashion to Ritalin. This may be via stimulation of dopamine autoreceptors. Amphetamine too may lower dopamine release (in ADHD) via TAAR1's interaction with presynaptic dopamine autoreceptors. TAAR1 agonsits actually reduce dopamine release. Hence the anti-hyperkinetic effects of amphetamines may have nothing to do with their direct actions on the dopamine transporter.
>Yes, but these agonists are not identical to >dopamine; their metabolism does not produce >oxidative stress. Indeed pramipexole (Sifrol; >Mirapex?) has been show to have antioxidant >properties.
True, and it may depend on the degree (and location) of dopaminergic stimulation. Caffiene, adenosine antagonists, and MAO-B inhibitors are typically neuroprotective but they increase dopamine to a lesser degree than amphetamine.
I don't know the relative potency of amphetamines vs. cocaine for sigma receptors, and there are two subtypes of sigma receptors that have different effects. Some sigma agonsits are neuroprotective (sigma-1?) and others have more neurotoxic effects. The neurotrophic effects (and cognitive enhancing effects of amphetamines) may be via sigma-1 receptors. There is an increased propensity for schizohprenics to use amphetamines. I have wondered if the TAAR1 agonism and sigma-1 agonism (which have antipsychotic qualities in some paradigms) may control certain psychotic symptoms (in a certain dose range). Wikipedia lists meth as a sigma agonist, but I believe I have seen this property for amphetamines as well.
https://en.wikipedia.org/wiki/Sigma_receptor
Amphetamines have other targets (like inhibition of MAO-A) which may exert some anticonvulsant effect. Fenfluramine (amphetamine derivative) has anticonvulsant effects (which may be related to 5-ht2c agonism). It has been used with some success for Dravet syndrome. I believe amphetamines can interact with 5-ht2c as well, which might mediate with anorexigenic and anticonvulsant properties. Or, as you mention, sigma receptors could be involved.
What were we originally talking about :)
Linkadge
Posted by linkadge on December 9, 2019, at 17:26:32
In reply to Re: What do TRD patients take without an MAIO » linkadge, posted by undopaminergic on December 9, 2019, at 9:36:36
The catechins in cocoa are MAO inhibitors (more selective to MAO-B). They also have some monoamine reuptake effects (more selective for norepinephrine). I've felt that the combination of a MAO-B inhibitor and a NET inhibitor would be particularly good for cognitive problems.
I'm not sure what degree of MAO-B inhibition one would get through regular chocolate consumption, but polyphenols like catechin can build up in the system over time.
Cocoa (and coffee) also contain beta carbolines which are MAOIs (more selective towards MAO-A). The beta carbolines are also benzodiazepine antagonists (can increase anxiety). I believe the beta carbolines were originally identified as the first endogenous benzodiazepine antagonists. There is another endogenous compound called isatin which is both a MAOI and a benzodiazepine receptor antagonist. It is released during stress (I presume to give a quick fight / flight response).
If you gave me 10-20 mg of PEA in a capsule and an identical placebo, I could identify the PEA 100% of the time. The problem is that the effects are fairly short lasting. However, if I use the energy boost to get exercising, it can help improve mood for a longer duration.
Linkadge
Posted by undopaminergic on December 10, 2019, at 12:12:24
In reply to Re: What do TRD patients take without an MAIO, posted by linkadge on December 9, 2019, at 17:15:19
>
> Right. There is the possibility of amphetamine (and related substances) as being directly neurotoxic (in a manner that substances like MTPP are).
>MPTP, which is metabolised into the MPP+ ion by MAO-B. The ion is the neurotoxic principle.
If amphetamines were neurotoxic in this manner, then cocaine would not prevent that toxicity.
> Anything that leads to excessive glutamate function, in theory can be neurotoxic.
>Excitotoxic, to be specific.
> However, I've never heard of cocaine blocking the high associated with amphetamine (although I only know a few people personally that would have mixed the two), even though, it appears it can block the neurotoxicity. I would imagine, however, that cocaine would lead to increased glutamate levels (at least in some brain regions).
>I don't know; as I said, this is complex. In principle, too high a dose of cocaine (or the like) would prevent amphetamines from getting taken up into the nerve terminals. There is still the possibility for the amph. to passively diffuse into the terminal, but then it would not reach much higher concentrations within than outside the terminal. So, the key would be to take a large dose amph. and a small (but not insignificant) dose of cocaine. Then there would be enough DAT function remaining for the amph. to be taken up into the terminal. At the same time, the cocaine would augment the reuptake inhibition produced by the amph. itself. Amph. is also a (modest) reversible MAOI.
> >Yes, it is interesting, but it follows from the >fact that amphetamines need the DAT (dopamine >transporter) in order to produce their effects, >and cocaine inhibits that transporter.
>
> I don't know if cocaine only blocks the transporter within the synaptic junction, or whether it also enters the presynaptic neuron and prevents the dopamine transporter function there.The DAT is located at the membrane and can be blocked from outside or within. Cocaine does not get taken up into the terminal actively, but I believe it might enter in small quantities through passive diffusion. At least this is my understanding.
> Complicating the picture is the action of the presynaptic dopamine autoreceptor system.
>Yes. Combining sulpiride with cocaine results in significantly higher extracellular dopamine elevation.
> Cocaine can actually calm hyperactive mice in a similar fashion to Ritalin. This may be via stimulation of dopamine autoreceptors.
>I don't know for sure if there is something to that. While autoreceptors reduce the release (and synthesis -- I think) of dopamine, cocaine still elevates (rather than reduces) the synaptic levels thereof and the net effect is an increase in postsynaptic DA receptor stimulation.
As I understand it, it is through one of the trace amine receptors that amph. (and PEA) reduce the spontaneous firing of the presynaptic neuron.
As for calming effects, those happen in some people and in some strains of rodents, but not in others. I don't know why. It may have something to do with the particular configuration of stimulatory (D1 and D5) vs. inhibitory (D2, D3, and D4) dopamine receptors.
> Amphetamine too may lower dopamine release (in ADHD) via TAAR1's interaction with presynaptic dopamine autoreceptors. TAAR1 agonsits actually reduce dopamine release.
>Yes, I am quite sure TAAR agonists do that (ie. reduce spontaneous firing of presynaptic neurons).
Do TAARs interact with the autoreceptor system, or do these receptors produce their effect independently of each other?
> Hence the anti-hyperkinetic effects of amphetamines may have nothing to do with their direct actions on the dopamine transporter.
>You may be right, but I have some evidence that the calming effect happens through stimulation of postsynaptic receptors, when the synaptic dopamine concentrations are high enough. See above regarding inhibitory and stimulatory DA.
> >Yes, but these agonists are not identical to >dopamine; their metabolism does not produce >oxidative stress. Indeed pramipexole (Sifrol; >Mirapex?) has been show to have antioxidant >properties.
>
> True, and it may depend on the degree (and location) of dopaminergic stimulation. Caffiene, adenosine antagonists, and MAO-B inhibitors are typically neuroprotective but they increase dopamine to a lesser degree than amphetamine.
>I guess you mean "caffeine [and other] adenosine antagonists"? Or are you thinking of other pharmacodynamic actions of caffeine?
> I don't know the relative potency of amphetamines vs. cocaine for sigma receptors,
>Well, as I recall, amphetamines do not produce seizures. So, if cocaine does (in overdose) through sigma receptors, it must be more potent.
> and there are two subtypes of sigma receptors that have different effects. Some sigma agonsits are neuroprotective (sigma-1?) and others have more neurotoxic effects.
>I need to learn more about that.
> The neurotrophic effects (and cognitive enhancing effects of amphetamines) may be via sigma-1 receptors.
*Some* of the cognitive enhancing effects. Remember they primarily act via dopamine.
> There is an increased propensity for schizohprenics to use amphetamines.
>Yes, but as far as I can tell, there is a combination of deficiency and excess of dopamine in schizoprenia, in different bran regions; eg. excess in limbic regions and shortage in the prefrontal cortex. The excess seems to cause positive symptoms while the shortage seems produces negative symptoms. Indeed, many of the negative symptoms are identical to Parkinsonian symptoms. If schizophrenics have increased incidence of amphetamine use, it is probably because they treat the negative symptoms.
> I have wondered if the TAAR1 agonism and sigma-1 agonism (which have antipsychotic qualities in some paradigms) may control certain psychotic symptoms (in a certain dose range). Wikipedia lists meth as a sigma agonist, but I believe I have seen this property for amphetamines as well.
>Meth *is* an amphetamine. I suppose you mean amphetamine itself (unsubstituted). The reason why amphetamines is used in the plural is to cover other substances with an amphetamine structure. This can sometimes be misleading; ie. you typically mean to refer to amphetamine and methamphetamine, and not others like MDMA and MDA.
> https://en.wikipedia.org/wiki/Sigma_receptor
>I read it. This article is rather scarce given how much there is to know about sigma-receptors.
> Amphetamines have other targets (like inhibition of MAO-A) which may exert some anticonvulsant effect.
>I didn't know MAO inhibition had anticonvulsant effects.
> Fenfluramine (amphetamine derivative) has anticonvulsant effects (which may be related to 5-ht2c agonism). It has been used with some success for Dravet syndrome.
>Interesting.
> I believe amphetamines can interact with 5-ht2c as well, which might mediate with anorexigenic and anticonvulsant properties. Or, as you mention, sigma receptors could be involved.
>I don't recall seeing that mentioned (5-HT2x actions of amph.).
> What were we originally talking about :)
>Judging by the title, it was something about treatment-resistant depression.
-undopaminergic
Posted by undopaminergic on December 10, 2019, at 12:41:16
In reply to Re: What do TRD patients take without an MAIO, posted by linkadge on December 9, 2019, at 17:26:32
> The catechins in cocoa are MAO inhibitors (more selective to MAO-B).
>And the catechins in green tea are COMT inhibitors?
It would be interesting to combine them.
What about bioavailability of these substances? I read green tea catechins are poorly absorbed.
> I've felt that the combination of a MAO-B inhibitor and a NET inhibitor would be particularly good for cognitive problems.
>Reboxetine on selegiline was rather unpleasant in my experience. I have reason to believe I may have excessive levels of noradrenaline. I also did not fare well on mirtzapine, which increases noradrenaline release by blocking alpha2-adrenergic autoreceptors. I almost got some kind of cramps in my neck (I do not recall clearly).
> Cocoa (and coffee) also contain beta carbolines which are MAOIs (more selective towards MAO-A).
>Tobacco too, it seems:
https://en.wikipedia.org/wiki/Harmala_alkaloid> The beta carbolines are also benzodiazepine antagonists (can increase anxiety).
>That's news to me. Good to learn something.
> I believe the beta carbolines were originally identified as the first endogenous benzodiazepine antagonists. There is another endogenous compound called isatin which is both a MAOI and a benzodiazepine receptor antagonist. It is released during stress (I presume to give a quick fight / flight response).
>Interesting. Apparently it (isatin) is a metabolite of adrenaline.
> If you gave me 10-20 mg of PEA in a capsule and an identical placebo, I could identify the PEA 100% of the time. The problem is that the effects are fairly short lasting. However, if I use the energy boost to get exercising, it can help improve mood for a longer duration.
>How often do you take it? Is there any tolerance?
-undopaminergic
Posted by pedr on December 10, 2019, at 13:33:39
In reply to Re: What do TRD patients take without an MAIO » linkadge, posted by undopaminergic on December 10, 2019, at 12:41:16
Hey undopaminergic,
> Reboxetine on selegiline was rather unpleasant in my experience. I have reason to believe I may have excessive levels of noradrenalineI had 24/7 suicidal ideation for the 2 weeks I was on Reboxetine. It was possibly the worst med I've ever been on (and that's a lot of meds to beat). I also suspect I have too much noradrenaline flowing around. What meds do you think would be good for such a situation?
My current rx is (in mg) 40 Fetzima, 30 Lexapro, 30 Ritalin, 60 Adderall, 2.5 Abilify, 45 Buspar, 300 Lyrica, 300 Trazodone, 40 Percocet.
Cheers.
Posted by linkadge on December 10, 2019, at 15:06:45
In reply to Re: What do TRD patients take without an MAIO » linkadge, posted by undopaminergic on December 10, 2019, at 12:12:24
>If amphetamines were neurotoxic in this manner, >then cocaine would not prevent that toxicity
Absence of MPTP-induced neuronal death in mice lacking the dopamine transporter.
https://www.ncbi.nlm.nih.gov/pubmed/10072302
Dopamine transporter is required for in vivo MPTP neurotoxicity: evidence from mice lacking the transporter.
https://www.ncbi.nlm.nih.gov/pubmed/9282960
Linkadge
Posted by linkadge on December 10, 2019, at 15:36:19
In reply to Re: What do TRD patients take without an MAIO » linkadge, posted by undopaminergic on December 10, 2019, at 12:12:24
>As I understand it, it is through one of the trace >amine receptors that amph. (and PEA) reduce the >spontaneous firing of the presynaptic neuron.
Yes, it may be a dopamine autoreceptor agonist (or functionally interact via TAAR1). Again, amphetamine can have this property too (within a certain dose range, I believe).
>Do TAARs interact with the autoreceptor system, >or do these receptors produce their effect >independently of each other?
I'm not sure. TAAR1 agonist have antidepressant and antipsychotic properties. So, in some ways, amphetamine may counteract some of its psychotomimetic effects.
https://www.ncbi.nlm.nih.gov/pubmed/29636691
"In general, TAAR1 agonists specifically inhibited the rewarding and reinforcing effects of drugs of abuse and drug-abuse related behaviors. Details of the mechanism of TAAR1 remain elusive; however, it is thought to be regulated by its interactions with D2 receptors."
https://www.ncbi.nlm.nih.gov/pubmed/29066851
"We show, first, that the full TAAR1 agonist, RO5256390, dose-dependently blocked cocaine-induced inhibition of DA clearance in slices of the nucleus accumbens."
"Second, subthreshold inhibition of PKA or PKC phosphorylation did not prevent TAAR1 suppression of cocaine effects whereas subeffective doses of the DA D2 receptor antagonist, L-741,626, rescued cocaine's ability to produce changes in DA uptake in the presence of full TAAR1 activation, thus indicating that TAAR1 modulation of cocaine effects requires simultaneous DA D2 receptor activation."
It seems that taar1 agonist somehow interact with (likely?) presynaptic d2 receptors to inhibit dopamine release (?). It suggested that there is an interaction between TAAR1 and gsk-3. Gsk-3 inhibitors (like lithium) have mood stabilizing and (in some cases) antipsychotic qualities and also seems to regulate dopamine systems.
LSD inhibits dopamine firing via TAAR1 receptors.
https://www.ncbi.nlm.nih.gov/pubmed/27544651
I've often wondered if cannabis interacts with TAAR1 in some way. I know that CB2 receptor agonists also inhibit dopamine firing and can prevent sensitization from drugs like cocaine.
"Postsynaptic D2 dopamine receptor supersensitivity in the striatum of mice lacking TAAR1."
https://www.ncbi.nlm.nih.gov/pubmed/25721394
Hence it seems that TAAR1 receptors also regulate post synaptic d2 receptor sensitivity (as do GSK3 inhibitors like lithium / valproate).
There are case reports of amphetamine calming mania. This could be via taar1 agonism. Perhaps some manics have supersentive TAAR1 receptors, leading to an increased sensitivity to this target of amphetamine.
"Low phenethylamine levels and low activation of TAAR1 can cause attention deficit hyperactivity disorder."
https://www.bocsci.com/tag/trace-amine-associated-receptor-1-taar1-430.html
" Methamphetamine is a psychostimulant that is known to exhibit moderate affinity for sigma-1 receptors (σ-1R) expressed in most neuronal cells "
https://jneuroinflammation.biomedcentral.com/articles/10.1186/s12974-015-0250-7
Linkadge
Posted by linkadge on December 10, 2019, at 15:38:36
In reply to Re: What do TRD patients take without an MAIO, posted by linkadge on December 10, 2019, at 15:36:19
Just to add, Ritalin may also act via a 5-ht related mechanism. A metabolite of Ritalin acts as a 5-ht1a agonist. 5-ht1a agonists (like buspirone) can also reduce hyperactivity (but perhaps not improve cognition to the same degree).
Linkadge
Posted by undopaminergic on December 11, 2019, at 9:05:54
In reply to Re: What do TRD patients take without an MAIO » undopaminergic, posted by pedr on December 10, 2019, at 13:33:39
> Hey undopaminergic,
Hello pedr.
> I had 24/7 suicidal ideation for the 2 weeks I was on Reboxetine. It was possibly the worst med I've ever been on (and that's a lot of meds to beat). I also suspect I have too much noradrenaline flowing around. What meds do you think would be good for such a situation?
>Guanfacine without question, or failing that, clonidine. Possibly prazosin or doxazosin.
You can combine (one of) the former 2 with (one of) the latter 2.
> My current rx is (in mg) 40 Fetzima, 30 Lexapro, 30 Ritalin, 60 Adderall, 2.5 Abilify, 45 Buspar, 300 Lyrica, 300 Trazodone, 40 Percocet.
>That's quite a cocktail!
If you haven't already you may wish to experiment to find the right ratio of Adderall to Ritalin. Ritalin can (dose-dependently, to a degree) inhibit the action of Adderall.
If you have trouble with opioid tolerance, I recommend trying memantine or opioid rotation.
-undopaminergic
Posted by undopaminergic on December 11, 2019, at 9:17:04
In reply to Re: What do TRD patients take without an MAIO, posted by linkadge on December 10, 2019, at 15:06:45
I realised this after I had already posted.
> Absence of MPTP-induced neuronal death in mice lacking the dopamine transporter.
>
> https://www.ncbi.nlm.nih.gov/pubmed/10072302
>
> Dopamine transporter is required for in vivo MPTP neurotoxicity: evidence from mice lacking the transporter.
>
> https://www.ncbi.nlm.nih.gov/pubmed/9282960
>
> LinkadgeYes.
Before looking, I knew I would find an article like this:
https://www.ncbi.nlm.nih.gov/pubmed/3875884
"Cocaine blocks the dopamine depletion induced by MPTP."Selegiline (l-deprenyl) also prevents MPTP toxicity but I have trouble finding a succinct abstract. Likewise do other MAOIs (such as tranylcypromine) that inhibit MAO-B.
-undopaminergic
Posted by undopaminergic on December 11, 2019, at 10:31:16
In reply to Re: What do TRD patients take without an MAIO, posted by linkadge on December 10, 2019, at 15:36:19
> >As I understand it, it is through one of the trace >amine receptors that amph. (and PEA) reduce the >spontaneous firing of the presynaptic neuron.
>
> Yes, it may be a dopamine autoreceptor agonistIf you mean "indirect autoreceptor agonist", I definitely agree. On the other hand, if you mean direct agonist, I'm quite sure it isn't, because that is something we would have read about already if it were so.
> (or functionally interact via TAAR1). Again, amphetamine can have this property too (within a certain dose range, I believe).
>Probably. Meth and "regular" amphetamine have very similar pharmacology.
> >Do TAARs interact with the autoreceptor system, >or do these receptors produce their effect >independently of each other?
>
> I'm not sure. TAAR1 agonist have antidepressant and antipsychotic properties.
>That is interesting. The antipsychotic effect is also consistent with the conclusion that TAARs reduce DA neuronal firing. However, *anti*depressant and reduced DA? That is counterintuitive.
> So, in some ways, amphetamine may counteract some of its psychotomimetic effects.
>Yes.
> https://www.ncbi.nlm.nih.gov/pubmed/29636691
>
> "In general, TAAR1 agonists specifically inhibited the rewarding and reinforcing effects of drugs of abuse and drug-abuse related behaviors. Details of the mechanism of TAAR1 remain elusive; however, it is thought to be regulated by its interactions with D2 receptors."
>
> https://www.ncbi.nlm.nih.gov/pubmed/29066851
>
> "We show, first, that the full TAAR1 agonist, RO5256390, dose-dependently blocked cocaine-induced inhibition of DA clearance in slices of the nucleus accumbens."
>I don't understand how TAAR-agonists would inhibit cocaine's effects on clearance. If they did, they would have to activate the DAT in face of cocaine's inhibition thereof. I think that the authors may mean that TAAR-agonists inhibit the cocaine-induced *accumulation* of synaptic dopamine.
> "Second, subthreshold inhibition of PKA or PKC phosphorylation did not prevent TAAR1 suppression of cocaine effects whereas subeffective doses of the DA D2 receptor antagonist, L-741,626, rescued cocaine's ability to produce changes in DA uptake in the presence of full TAAR1 activation, thus indicating that TAAR1 modulation of cocaine effects requires simultaneous DA D2 receptor activation."
>Yes, I think this goes a long way to establish that these two classes of presynaptic receptors interact.
> It seems that taar1 agonist somehow interact with (likely?) presynaptic d2 receptors to inhibit dopamine release (?).
>Agreed.
> It suggested that there is an interaction between TAAR1 and gsk-3. Gsk-3 inhibitors (like lithium) have mood stabilizing and (in some cases) antipsychotic qualities and also seems to regulate dopamine systems.
>Interesting. I haven't read much about the pharmacodynamics of lithium.
I would expect a reduction in mania to result in a reduction of the development of delusions. Then again, this is in rodents, I assume.
> LSD inhibits dopamine firing via TAAR1 receptors.
>Good to know. I haven't read much about LSD pharmacology either.
> https://www.ncbi.nlm.nih.gov/pubmed/27544651
>
> I've often wondered if cannabis interacts with TAAR1 in some way.
>If so, it doesn't seem to have been reported yet. This PubMed search: <<cannabinoid[tiab] AND (taar[tiab] OR trace amine[tiab])>> turns up nothing interesting.
> I know that CB2 receptor agonists also inhibit dopamine firing and can prevent sensitization from drugs like cocaine.
>That is also good to know. I would like to add, however, that cocaine pharmacology is complex, and this drug also induces DA downregulation, and this may happen through increased dynorphin (the primary endogenous kappa-opoid).
> "Postsynaptic D2 dopamine receptor supersensitivity in the striatum of mice lacking TAAR1."
>If TAARs are presynaptic, how do they produce postsynaptic supersensitivity? Seems to me that it has to be through reducing synaptic dopamine, preventing DA-induced downregulation of the postsynaptic receptors.
> https://www.ncbi.nlm.nih.gov/pubmed/25721394
>
> Hence it seems that TAAR1 receptors also regulate post synaptic d2 receptor sensitivity (as do GSK3 inhibitors like lithium / valproate).
>Interesting. I think in the case of TAARs, this is indirect, through modulation of synaptic DA.
> There are case reports of amphetamine calming mania. This could be via taar1 agonism. Perhaps some manics have supersentive TAAR1 receptors, leading to an increased sensitivity to this target of amphetamine.
>Very possible. Such supersensitivity would likely exist in many ADDers too.
> "Low phenethylamine levels and low activation of TAAR1 can cause attention deficit hyperactivity disorder."
>Maybe lack of PEA leads to less development of TAAR-downregulation (tolerance)? And hence, amphetamines would be more effective in calming subjects with this condition via increased TAAR-activation.
> https://www.bocsci.com/tag/trace-amine-associated-receptor-1-taar1-430.html
>
> " Methamphetamine is a psychostimulant that is known to exhibit moderate affinity for sigma-1 receptors (σ-1R) expressed in most neuronal cells "
>
> https://jneuroinflammation.biomedcentral.com/articles/10.1186/s12974-015-0250-7
>It seems this article examines meth-induced astrocyte (not neuron) activation by meth?
-undopaminergic
Posted by undopaminergic on December 11, 2019, at 10:37:00
In reply to Re: What do TRD patients take without an MAIO, posted by linkadge on December 10, 2019, at 15:38:36
> Just to add, Ritalin may also act via a 5-ht related mechanism. A metabolite of Ritalin acts as a 5-ht1a agonist. 5-ht1a agonists (like buspirone) can also reduce hyperactivity (but perhaps not improve cognition to the same degree).
>
> LinkadgeThat is a new piece of knowledge about Ritalin to me. In any case, I have read that activation of 5-HT1A is pro-dopaminergic (opposite to 5-TH2C). These facts almost certainly also play an important role in the pharmacology of SSRIs.
-undopaminergic
Posted by pedr on December 12, 2019, at 14:38:39
In reply to Re: What do TRD patients take without an MAIO, posted by undopaminergic on December 11, 2019, at 9:05:54
> Hello pedr.
> Guanfacine without question, or failing that, clonidine. Possibly prazosin or doxazosin.
>
> You can combine (one of) the former 2 with (one of) the latter 2.Thanks! I will bring these up with my PDoc. He is very "by the book' however so I don't expect to get anywhere. IIRC we did look at Guanfacine but he didn't like it in the end for some reason.
> > My current rx is (in mg) 40 Fetzima, 30 Lexapro, 30 Ritalin, 60 Adderall, 2.5 Abilify, 45 Buspar, 300 Lyrica, 300 Trazodone, 40 Percocet.
> >
>
> That's quite a cocktail!:( it's the "best" I've found to date and it's only the stimulants that make me semi-functional.
>
> If you haven't already you may wish to experiment to find the right ratio of Adderall to Ritalin. Ritalin can (dose-dependently, to a degree) inhibit the action of Adderall.Oo-er, I didn't know that. My mood (and pain and IBS) is so unpredictable, even when on a constant regimen, that I'm afraid I'll never be able to discover the best ratio.
>
> If you have trouble with opioid tolerance, I recommend trying memantine or opioid rotation.Cool, thanks I'll look into that. Thank you for your help, it's much appreciated.
Pete>
> -undopaminergic
>
Posted by greg rizzo on January 9, 2020, at 21:19:39
In reply to Re: What do TRD patients take without an MAIO » linkadge, posted by undopaminergic on December 9, 2019, at 9:14:33
See my recent posts about non MAOI STRATAGIES.
This is the end of the thread.
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