wellbutrin + sertraline to block DAT efficiently

[trainman04]

The occupancy of dopamine transporter (DAT) sites by bupropion and its metabolites in the human brain as measured by positron emission tomography was 26% according to GlaxoSmithKline researchers .

in any case, the above findings suggest that, although weak DAT occupation may occur, oral bupropion at clinically-used doses does not have the actual capacity to elevate dopamine levels in the human brain.[14] In accordance with this finding, based on analogy with serotonin reuptake inhibitors, higher than 50% inhibition of DAT would be needed for the dopamine reuptake mechanism to be a significant mechanism of the drug's action. Moreover, 65%75% DAT occupancy is necessary for euphoria and abuse potential.[82]
Ki values of sertraline at the human SERT, DAT, and NET of 0.29, 25, and 420 nM, respectively.[93] The selectivity of sertraline for the SERT over the DAT was 86-fold.[93] In any case, of the wide assortment of antidepressants assessed in the study, sertraline showed the highest affinity of them all for the DAT, even higher than the norepinephrinedopamine reuptake inhibitors (NDRIs) nomifensine (Ki = 56 nM) and BUPROPION (Ki = 520 nM).[93][104] Sertraline also has similar affinity for the DAT as the NDRI methylphenidate (Ki = 24 nM).[93][104] Tametraline (CP-24,441), a very close analogue of sertraline and the compound from which sertraline was originally derived, is an NDRI that was never marketed.[109]

So if wellbutrin alone is 27% on DAT and sertraline has higher affinity for dat than wellbutrin it should equal more than 50% if taken together thus block DAT efficiently and increase dopamine neurotransmission right and produce anti depressant effect? The text say sertraline has similar affinity for the DAT as the NDRI methylphenidate (ritalin).. I dont know how much that is .But the good thing with sertraline is its long half life 26 hours and ritalin has very short 7 hours or something similar. wellbutrin + sertraline block DAT to increase dopamine together they block over 50% dopamine transporter enough to produce an anti depressant effect im asking if i am correct if this makes sense would this work the way im thinking it would?

 

[Hodor]

How about you read the next paragraph in that Wikipedia article? Unlike methylphenidate, almost all of your sertraline dose is quickly bound to plasma proteins. That means that even at high doses of 200+ mg/day, there is barely any DAT inhibition.

What's more, Sertraline is first and foremost a SEROTONIN REUPTAKE INHIBITOR.
By the time you're getting noticeable dopaminergic effects, you're on the threshold of serotonin syndrome.

 

[trainman04]

How about you read the next paragraph in that Wikipedia article? Unlike methylphenidate, almost all of your sertraline dose is quickly bound to plasma proteins. That means that even at high doses of 200+ mg/day, there is barely any DAT inhibition.

What?s more, Sertraline is first and foremost a SEROTONIN REUPTAKE INHIBITOR.
By the time you?re getting noticeable dopaminergic effects, you?re on the threshold of serotonin syndrome.

oh damn.................. good that you are here to correct me.

whats a good drug to block DAT?

 

[AlphaMethylPhenyl]

affinity vs efficacy...

 

[Hodor]

affinity vs efficacy...

The problem in this case isn't just efficacy, it's mostly sertraline's ridiculously high protein binding rate of 98.5%.

Here is the following paragraph from the Wikipedia article that OP was quoting:

Single doses of 50 to 200 mg sertraline have been found to result in peak plasma concentrations of 20 to 55 ng/mL (65–180 nM),[102] while chronic treatment with 200 mg/day sertraline, the maximum recommended dosage, has been found to result in maximal plasma levels of 118 to 166 ng/mL (385–542 nM).[83] However, sertraline is highly protein-bound in plasma, with a bound fraction of 98.5%.[83] Hence, only 1.5% is free and theoretically bioactive.[83] Based on this percentage, free concentrations of sertraline would be 2.49 ng/mL (8.13 nM) at the very most, which is only about one-third of the Ki value that Tatsumi et al. found with sertraline at the DAT.[93] A very high dosage of sertraline of 400 mg/day has been found to produce peak plasma concentrations of about 250 ng/mL (816 nM).[83] This can be estimated to result in a free concentration of 3.75 ng/mL (12.2 nM), which is still only about half of the Ki of sertraline for the DAT.[93]

As such, it seems unlikely that sertraline would produce much inhibition of dopamine reuptake even at clinically used dosages well in excess of the recommended maximum clinical dosage.[106] This is in accordance with its 86-fold selectivity for the SERT over the DAT according to Tatsumi et al. and hence the fact that nearly 100-fold higher levels of sertraline would be necessary to also inhibit dopamine reuptake.

So even though sertraline is a potent serotonin reuptake inhibitor, most people need a dose of 100-200 mg/d or more to achieve a noticeable antidepressant effect - ten times the typical dosage of e.g. Lexapro... so you can imagine that inhibiting DAT (which sertraline is at best mediocre at) to a significant extent is going to require such staggering doses that you'd probably be sending yourself straight into a serotonergic delirium for even a mild dopamine buzz 8(

 

[trainman04]

The problem in this case isn't just efficacy, it's mostly sertraline's ridiculously high protein binding rate of 98.5%.

Here is the following paragraph from the Wikipedia article that OP was quoting:


So even though sertraline is a potent serotonin reuptake inhibitor, most people need a dose of 100-200 mg/d or more to achieve a noticeable antidepressant effect - ten times the typical dosage of e.g. Lexapro... so you can imagine that inhibiting DAT (which sertraline is at best mediocre at) to a significant extent is going to require such staggering doses that you'd probably be sending yourself straight into a serotonergic delirium for even a mild dopamine buzz 8(

hodor do you know if taking 600mg wellbutrin will increase dopamine ? that should add up over 50% dopamine transporter inhibition. when wellbutrin first came out the starting dose was 600mg Im assuming thats because they knew at that dose it increases dopamine but they had to lower the dose since it caused seizurez and now the max is 300mg which is 27% affinity on dat.. if you have no family history of seizures i think it would be safe for me to take 600mg.

 

[Pomzazed]

if you have no family history of seizures i think it would be safe for me to take 600mg.

No...

 

[sekio]

buproprion is actually mostly metabolised to hydroxybuprorpion & the levels of OH-buproprion can be some 20x of the levels of buproprion in blood. what's interesting to note is that OH-buproprion is inactive as a DA releaseing agent and this likely underlies why buproprion is effectively not a good dopamine reuptake inhibitor, especially when taken orally.

Otherwise you'd see effects that were like that of methcathinone or mephedrone... those are strong monoamine releasers.

 

[trainman04]

i have a question about wellbutrin on its wiki page under Pharmacology
it says

DA uptake	100%	ND	ND	ND	ND
NE uptake	27%

shouldnt it be the other way around? 27% DAT inhibtion and 100% NET inhibtion?

 

[trainman04]

would wellbutrin + concerta (methylphenidate ) work? that would inhibit over 50% right

 

[Hodor]

would wellbutrin + concerta ([FONT="]methylphenidate ) work? that would inhibit over 50% right[/FONT]

Methylphenidate is a stimulant, and one that tends to cause more anxiety than amphetamine at that. You'd probably just end up giving yourself stim psychosis.

And bupropion's in-vitro affinity for the dopamine transporter means very little in practice - what matters are its effects in-vivo, where it is rapidly metabolized into hydroxybupropion, which is more or less a selective noradrenaline reuptake inhibitor with little to no effects on dopamine levels.

 

[trainman04]

Methylphenidate is a stimulant, and one that tends to cause more anxiety than amphetamine at that. You'd probably just end up giving yourself stim psychosis.

And bupropion's in-vitro affinity for the dopamine transporter means very little in practice - what matters are its effects in-vivo, where it is rapidly metabolized into hydroxybupropion, which is more or less a selective noradrenaline reuptake inhibitor with little to no effects on dopamine levels.

but it still inhibits 27% and with concerta XL you can have constant over 50% dopamine transporter inhibition

 

[browri]

but it still inhibits 27% and with concerta XL you can have constant over 50% dopamine transporter inhibition

That's true, but that much dopamine activation like @hodor said would precipitate psychosis.

If we entertained the idea though that someone wanted to make themselves psychotic, because bupropion is a poor dopamine releasing agent, theoretically combining low dose bupropion (150mg qd) with a more efficient releasing agent like dextroamphetamine may enhance bupropion's inhibitory effects on the dopamine transporter. Then to make sure you don't get psychotic, you take an antipsychotic with it. I've actually seen several people take bupropion even at high doses with a dopamine partial agonist like aripiprazole.

 

[trainman04]

That's true, but that much dopamine activation like @hodor said would precipitate psychosis.

If we entertained the idea though that someone wanted to make themselves psychotic, because bupropion is a poor dopamine releasing agent, theoretically combining low dose bupropion (150mg qd) with a more efficient releasing agent like dextroamphetamine may enhance bupropion's inhibitory effects on the dopamine transporter. Then to make sure you don't get psychotic, you take an antipsychotic with it. I've actually seen several people take bupropion even at high doses with a dopamine partial agonist like aripiprazole.

psychosis at 50% DAT inhibition? Really? I thought it would be more like somewhere around 80%-90% inhibition that would cause psychotic / Schizophrenia .

 

[Hodor]

psychosis at 50% DAT inhibition? Really? I thought it would be more like somewhere around 80%-90% inhibition that would cause psychotic / Schizophrenia .

Methylphenidate (Concerta/Ritalin) is a stimulant. Trying to use it to constantly elevate your dopamine levels is going to result in sleep deprivation, and sleep deprivation can easily lead to or exacerbate mental disturbances, especially in susceptible individuals (ex.: a bipolar person going manic).

Carefully dosed stims can be used to combat symptoms such as depressive anhedonia, and dextroamphetamine (more specifically the prodrug form Vyvanse) has been trialled against "negative"* symptoms of schizophrenia, but trying to use them to stimulate dopamine receptors to counteract overactive serotonergic neurons (as you seem to be planning) sounds like a recipe for disaster.

*note: Negative symptoms of schizophrenia are those where the illness "takes away" things like joy and motivation; positive symptoms are the ones where it "gives" you things like hallucinations and paranoid delusions.

 

[browri]

psychosis at 50% DAT inhibition? Really? I thought it would be more like somewhere around 80%-90% inhibition that would cause psychotic / Schizophrenia .

Well it would likely depend more on subsequent receptor occupancy due to the increased amount of dopamine in the synapse. And this could be variable from person to person. As Hodor indicated, someone with bipolar disorder or schizophrenia who sufficiently inhibits the transporter could overactivate post-synaptic dopamine receptors and induce psychosis. Genetics would play a major role in this as well. Someone who is Val/Val for COMT V158M would have high levels of catechol-o-methyltransferase which would result in accelerated breakdown of dopamine. So more DAT inhibition would be required to achieve therapeutic effect on anhedonia, and it would be much more difficult for COMT Val/Val individuals to go psychotic via over-activation of the dopamine system.

 

[sekio]

Why are we trying to block DAT anyway? More often than not DAT blockers are stimulants and produce stereotypical "moreish" behavior by messing with reward systems. Cf. cocaine, methylphenidate, methcathinone, MDPV... Those are not what I'd class as antidepressants.

 

[trainman04]

Why are we trying to block DAT anyway? More often than not DAT blockers are stimulants and produce stereotypical "moreish" behavior by messing with reward systems. Cf. cocaine, methylphenidate, methcathinone, MDPV... Those are not what I'd class as antidepressants.

do you know what causes the stimulants effects from smart drugs? is it the dopamine?
well im hoping that if I can increase my dopamine maybe it can shift and my serotonin will go down . Right now I have high serotonin low dopamine.

 

[sekio]

do you know what causes the stimulants effects from smart drugs? is it the dopamine?

Dopamine is more of a reward salience horomone[ref], rather than promoting wakefulness, it's used to govern movement in the motor cortex (excessive dopamine can cause motor tics, Parkinsons/dopamine blockade by antipsychotic will cause rigidity and inability to move properly), and to help your brain learn how to engage in pleasurable activities (when an unexpected reward occurs during a task your brain releases dopamine - dopamine is why slot machines, sex, food, etc are "addictive".)

Generally speaking the "stimulant" (wakefulness promoting) effects of most drugs comes from their action on norepinephrine (generally speaking, NE release causes arousal/wakefulness). Some drugs produce wakefulness-promoting effects other ways, e.g. stimulation of nicotinic acetylcholine receptors (nicotine, arecoline), blockade of adenosine receptors (caffeine, theobromine), positive modulation of AMPA receptors (racetam drugs), alpha-adrenergic autoreceptor blockade (yohimbine), histamine release (some opiates and modafinil) and so on. There are many many ways your brain governs arousal and no single receptor or drug can explain it all.

Right now I have high serotonin low dopamine.

And you've measured this how? PET scans with radioactive L-DOPA/5-HTP? Microdialysis with a probe stuck inside your brain? Or are you just inferring it from how you feel? I've probably said this a thousand times, emotions and mental states are governed by much more than simply "if you have X amount of neurotransmitter ABC, you will feel happy". As a corollary, you can't derive "I have low dopamine" from emotional states alone.

Besides, if you were truly dopamine deficient, you'd have severe movement disorders and presentation of Parkinsons symptoms.





'

 

[trainman04]

Dopamine is more of a reward salience horomone[ref], rather than promoting wakefulness, it's used to govern movement in the motor cortex (excessive dopamine can cause motor tics, Parkinsons/dopamine blockade by antipsychotic will cause rigidity and inability to move properly), and to help your brain learn how to engage in pleasurable activities (when an unexpected reward occurs during a task your brain releases dopamine - dopamine is why slot machines, sex, food, etc are "addictive".)

Generally speaking the "stimulant" (wakefulness promoting) effects of most drugs comes from their action on norepinephrine (generally speaking, NE release causes arousal/wakefulness). Some drugs produce wakefulness-promoting effects other ways, e.g. stimulation of nicotinic acetylcholine receptors (nicotine, arecoline), blockade of adenosine receptors (caffeine, theobromine), positive modulation of AMPA receptors (racetam drugs), alpha-adrenergic autoreceptor blockade (yohimbine), histamine release (some opiates and modafinil) and so on. There are many many ways your brain governs arousal and no single receptor or drug can explain it all.



And you've measured this how? PET scans with radioactive L-DOPA/5-HTP? Microdialysis with a probe stuck inside your brain? Or are you just inferring it from how you feel? I've probably said this a thousand times, emotions and mental states are governed by much more than simply "if you have X amount of neurotransmitter ABC, you will feel happy". As a corollary, you can't derive "I have low dopamine" from emotional states alone.

Besides, if you were truly dopamine deficient, you'd have severe movement disorders and presentation of Parkinsons symptoms.





'

I Think the brain is more complicated than that. You could be dopamine deficient and not have any parkinsons symptoms. its not as simple as -Ok you have low dopamine then you must have this and that or else you dont qualify.
I told you before I came to the conclusion of high serotonin from researching and testing different drugs .

I Know im DOPAMINE deficient and I KNOW I have some overactive serotonin receptors in the amygdala.

question is how can I fix it? shift it around . Increase DOPAMINE neurotransmission by blocking DAT over 50% inhibition would decrease serotonin activity. High dopamine you end up with less serotonin and other way around.

im wondering with your expertise do you think it will work?