Psycho-Babble Medication Thread 1107464

Shown: posts 1 to 13 of 13. This is the beginning of the thread.

 

Anticholinergics as antidepressants

Posted by undopaminergic on December 27, 2019, at 11:15:45

Hi all,

I have known for years that scopolamine has antidepressant effects in many people; see for example:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3250308/
(free full article available.)

I am wondering if other anticholinergics (aka. antimuscarinics), such as atropine, have similar effects. Euphoria is specifically reported as a side effect of orphenadrine.

Is the anticholinergic action of other drugs, such as most tricyclic antidepressants (TCAs), an important mechanism behind their antidepressant action?

The TCA I'm on, trimipramine, does not inhibit the reuptake of any monoamine neurotransmitters, but is reportedly equally effective to other antidepressants. It was found more effective than MAOIs in one study. I'm wondering if the reason for this may be its anticholinergic action.

-undopaminergic

 

Re: Anticholinergics as antidepressants » undopaminergic

Posted by linkadge on December 27, 2019, at 17:11:02

In reply to Anticholinergics as antidepressants, posted by undopaminergic on December 27, 2019, at 11:15:45

Anticholinergics can be antidepressants. Benztropine can be abused (euphorogenic effects). Benztropine is also a dopamine reuptake inhibitor as well as anticholinergic. I purchased some belladonna extract. You've got to be careful...one single drop can be felt!

I would say that the anticholinergic effects of TCAs add to their antidepressant effects. They can also reduce side effects (i.e. akathisia). Trimipramine is also a 5-ht2 antagonist which can have antidepressant effects. Some of its metabolites have some impact on DAT and MAO-B.

There may be some additional (yet unidentified) mechanism common to the TCAs (I.e. anti-inflammatory, or epigenetic). Trimipamine likely has anticortisol effects and may affect HPA axis at a more fundamental level. Trimipramine elevates the expression of D2 and D3 receptors (common to many antidepressants, but not mirtazapine). I believe it interacts with opioid systems like other TCAs.

Linkadge

 

Re: Anticholinergics as antidepressants » linkadge

Posted by undopaminergic on December 29, 2019, at 10:45:27

In reply to Re: Anticholinergics as antidepressants » undopaminergic, posted by linkadge on December 27, 2019, at 17:11:02

> Anticholinergics can be antidepressants. Benztropine can be abused (euphorogenic effects).
>

I agree, but it probably does not work for everyone.

> Benztropine is also a dopamine reuptake inhibitor as well as anticholinergic.
>

From what I've read, it does bind to the dopamine transporter, but it is atypical, and does not bind to the same site as cocaine or methylphenidate. If it did, we can be pretty sure it would be even more of a drug of abuse.

> I purchased some belladonna extract. You've got to be careful...one single drop can be felt!
>

Sounds like a particularly potent extract. I've tried leaves of Angel's Trumpet (Brugmansia), as well as atropine eyedrops, to dilate my pupils, for example to counteract the miosis of buprenorphine. I've also tried Scopoderm (scopolamine) patches, and I felt slightly better, but I had to quit due to skin irritation.

> I would say that the anticholinergic effects of TCAs add to their antidepressant effects.
>

Right.

> They can also reduce side effects (i.e. akathisia).

Yes, and they cause some other side effects, such as dry mouth.

> Trimipramine is also a 5-ht2 antagonist which can have antidepressant effects.
>

I read that 5-HT2A antagonists acutely increase dopamine release in the prefrontral cortex, but with chronic administration, this effect is not sustained.

> Some of its metabolites have some impact on DAT and MAO-B.
>

That is very interesting. Do you know where you found out about it? I made a pretty thorough review of the literature when I was investigating trimipramine, and I don't recall anything about DAT or MAO-B.

But according to Wikipedia, trimipramine may antagonise dopamine autoreceptors (presynaptic).

Notably, it is also a potent histamine H1- and H2-receptor antagonist. The H2 action is exciting, because famotidine (a selective H2-antagonist) in some studies helps to ameliorate negative symptoms of schizophrenia.

> There may be some additional (yet unidentified) mechanism common to the TCAs (I.e. anti-inflammatory, or epigenetic).
>

Well, I discovered that it (trimipramine) is an antagonist at some ion-channels (probably sodium ones). I tried to take it sublingually and it numbed the parts of my mouth it came into touch with. The local anaesthesia took so long to dissipate that I began to worry that it had done permanent damage, destroying parts of my sense of taste. Thank goodness there was a happy ending.

> Trimipamine likely has anticortisol effects
>

It does, acutely, and then there is a rebound (ie. increased cortisol) effect. It has been shown, when taken at night, to normalise the circadian cortisol level curve, which is abnormal in some depressions such as burnout.

Other TCAs seem to have opposite effects on cortisol.

> and may affect HPA axis at a more fundamental level.
>

I'm afraid not. It did not change the ACTH (adrenocorticotropic hormone) levels in the study/ies I read.

> Trimipramine elevates the expression of D2 and D3 receptors (common to many antidepressants, but not mirtazapine). I believe it interacts with opioid systems like other TCAs.
>

I was not aware of that. Maybe it could be combined with pramipexole.

-undopaminergic

 

Re: Anticholinergics as antidepressants

Posted by linkadge on December 29, 2019, at 13:30:50

In reply to Re: Anticholinergics as antidepressants » linkadge, posted by undopaminergic on December 29, 2019, at 10:45:27

>From what I've read, it does bind to the dopamine >transporter, but it is atypical, and does not >bind to the same site as cocaine or >methylphenidate. If it did, we can be pretty sure >it would be even more of a drug of abuse.

Well, if we're going to pick :) It's hard to know whether a drug of abuse would be 'more' abusable under different circumstances. Pure dopamine reuptake inhibitors likely don't have the same abuse potential as cocaine (a triple reuptake inhibitor with monoamine releasing capacity). Even in DAT knockout mice, cocaine still exhibits rewarding effects, arguing against the notion that the dopamine transporter is solely responsible for cocaine's actions. Yes, I head that benztropine acts on the dopamine transporter in a different way from cocaine, but this doesn't mean that it doesn't still increase dopamine levels in the synapse. I found benztropine much 'better' than say dimenhydrinate (which I find pretty discussing to be honest).

>I've also tried Scopoderm (scopolamine) patches, >and I felt slightly better, but I had to quit due >to skin irritation.

I've used the scopolamine patch (a bit expensive here in Canada) for depression. However, I didn't find it practical for longer term use as it left me feeling a bit detached. Again, not as 'good' as benztropine.

>I read that 5-HT2A antagonists acutely increase >dopamine release in the prefrontral cortex, but >with chronic administration, this effect is not >sustained.

Hmm. Any references on that? I suppose it depends on whether 5-ht2a receptors upregulate or downregulate in response. Not all 5-ht2a antagonists function the same way. Atypcal antipsychotics can 'normalize' cognition in schizophrenia (in some studies) an effect that is presumably due to 5-ht2a antagonism. I haven't heard of this effect 'wearing off' but who knows. 5-ht2a and 5-ht2c antagonists can also produce neurotrophic effects, and increase slow wave sleep / melatonin release.

>It does, acutely, and then there is a rebound >(ie. increased cortisol) effect.

Any references to this? Do you mean a rebound when the drug wears off, or when it is still in the system? Ideally you want cortisol to be lower in the evening / night and then increase in the morning. Persistently low cortisol is not a good thing and can make you feel worse.

>I'm afraid not. It did not change the ACTH >(adrenocorticotropic hormone) levels in the >study/ies I read.

Any reference to this? I can't find any evidence of a cortisol rebound effect.

https://www.ncbi.nlm.nih.gov/pubmed/19038406
https://www.ncbi.nlm.nih.gov/pubmed/9160649
https://www.ncbi.nlm.nih.gov/pubmed/1661430

Here's a study on the d2/d3 receptor upregulation following trimipramine administration. This sets it apart from mirtazapine, which does not induce this upregulation. I found that trimipramine had a much stronger effect than mirtazapine on my core anhedonia. On paper, mirtazapine and trimipramine should induce similar effects, but they apparently don't. Many antidepressants (and ECT) increase the sensitivity of the d2/d3 receptor system.

https://www.ncbi.nlm.nih.gov/pubmed/9660111


Linkadge

 

Re: Anticholinergics as antidepressants

Posted by undopaminergic on December 29, 2019, at 20:03:39

In reply to Re: Anticholinergics as antidepressants, posted by linkadge on December 29, 2019, at 13:30:50

> >From what I've read, it does bind to the dopamine >transporter, but it is atypical, and does not >bind to the same site as cocaine or >methylphenidate. If it did, we can be pretty sure >it would be even more of a drug of abuse.
>
> Well, if we're going to pick :) It's hard to know whether a drug of abuse would be 'more' abusable under different circumstances.
>

Well, whilst that is true, we can make reasonable predictions. I read there was an opioid (alfentanil IIRC) that is dysphorigenic, but that doesn't change the fact that most (mu) opioids are the opposite. There are individual differences too. I found methoxetamine (MXE, a NMDA-antagonist) the most strongly dysphorigenic drug I ever tried, even though most reports suggest it is a euphoriant. Meanwhile, I enjoyed memantine a *lot*.

> Pure dopamine reuptake inhibitors likely don't have the same abuse potential as cocaine (a triple reuptake inhibitor with monoamine releasing capacity).
>

Well, we can say for sure that they are different, and also that their effects are likely substantially different.

Still, the main difference in my view, is that pure DRIs are free of noradrenergic side effects, which would tend to render them more "likeable". I don't know about the serotonin, but from what I've read it seems the serotonergic action of cocaine attenuates the locomotor response (in rodents).

I believe I experienced a selective (and potent) DRI once, but the circumstances were so improbable that I have to say reason suggests it was a purely psychodynamic experience. Anyway, for what it's worth, based on the effects (of whatever origin), my working memory, self-confidence, and motor functions, were improved in a way that does not take place with methyl- or ethylphenidate. And that was on top of (hypo)mania. For me, that substance (if it was a substance) was more pleasant than mixed noradrenaline- and dopamine reuptake inhibitors. But that's just me; there are indications I have excessive noradrenaline. I agree that some people enjoy the noradrenaline boost from cocaine, and likewise serotonin.

It does seem absolutely clear that the *amount* of dopamine elevation does not explain everything about what makes drugs "likeable". For example, this study claims buprenorphine (low abuse potential) can elevate dopamine by 200%, whereas cocaine (high abuse potential) "only" achieves 180%:
https://www.ncbi.nlm.nih.gov/pubmed/1988653
Part of the reason is of course that cocaine achieves the elevation fast, and with buprenorphine it happens slowly.

As for the monoamine releasing action of cocaine, have you come across any quantifications of that? Ie. how much of 180% elevated dopamine is attributable to the enhanced release as opposed to reuptake inhibition?

> Even in DAT knockout mice, cocaine still exhibits rewarding effects, arguing against the notion that the dopamine transporter is solely responsible for cocaine's actions.
>

I agree, but you have to be careful in interpreting the results of experiments performed on DAT-KO animals. They are different from "wild type" animals in more ways than just lacking the DAT.

> Yes, I head that benztropine acts on the dopamine transporter in a different way from cocaine, but this doesn't mean that it doesn't still increase dopamine levels in the synapse.
>

I agree.

> I found benztropine much 'better' than say dimenhydrinate (which I find pretty discussing to be honest).
>
> I've used the scopolamine patch ... Again, not as 'good' as benztropine.
>

It's my understanding that the differences in effects between individual anticholinergics are usually attributable to the specific affinities for different muscarinic receptors. For example, scopolamine is more euphoriant than atropine. But benztropine may be a special case, in having effects on the DAT.

> >I read that 5-HT2A antagonists acutely increase >dopamine release in the prefrontral cortex, but >with chronic administration, this effect is not >sustained.
>
> Hmm. Any references on that?

No, nothing exact, I read it many years ago. It was on PubMed and I'm pretty sure the drug was olanzapine. I failed to locate it now. While searching, I noticed a few things suggesting that it may be hasty to come to this conclusion from a single study. One article suggested the 5-HT1A receptor, rather than 5-HT2A, is required to increase dopamine.

In my personal experience, I have sometimes noticed a short-lived reduction of apathy upon starting olanzapine. I imagine this is the 5-HT2A antagonism increasing prefrontal dopamine.

> Atypcal antipsychotics can 'normalize' cognition in schizophrenia (in some studies)
>

Some aspects maybe, but there are other aspects that scarcely respond to antipsychotics at all. For example, working memory deficits.

> an effect that is presumably due to 5-ht2a antagonism.

When it comes to psychotic aspects of cognition (thought disorder), it is probably the dopamine antagonism too.

> I haven't heard of this effect 'wearing off' but who knows. 5-ht2a and 5-ht2c antagonists can also produce neurotrophic effects, and increase slow wave sleep / melatonin release.
>

That is interesting.

The 5-HT2C receptor is particularly antidopaminergic.

I seem to recall that most antidepressants suppress REM-sleep, but trimipramine does not, and may even enhance it.

> >It does, acutely, and then there is a rebound >(ie. increased cortisol) effect.
>
> Any references to this? Do you mean a rebound when the drug wears off, or when it is still in the system?
>

The term "rebound" was my interpretation. I meant, that when the drug is taken at night / prior to sleep, the cortisol secretion is suppressed, and then it returns in the morning (rebound), quite possibly because the levels of the drug are lower.

> Ideally you want cortisol to be lower in the evening / night and then increase in the morning.
>

Exactly.

> Persistently low cortisol is not a good thing and can make you feel worse.
>

Yes, and there is something called "steroid euphoria" that can be induced by glucocorticoid drugs.

> >I'm afraid not. It did not change the ACTH >(adrenocorticotropic hormone) levels in the >study/ies I read.
>
> Any reference to this?

This one reports that cortisol is normalised but ACTH remains elevated:
https://www.ncbi.nlm.nih.gov/pubmed/1661430

> Here's a study on the d2/d3 receptor upregulation following trimipramine administration. This sets it apart from mirtazapine, which does not induce this upregulation. I found that trimipramine had a much stronger effect than mirtazapine on my core anhedonia. On paper, mirtazapine and trimipramine should induce similar effects, but they apparently don't. Many antidepressants (and ECT) increase the sensitivity of the d2/d3 receptor system.
>
> https://www.ncbi.nlm.nih.gov/pubmed/9660111

I became tolerant to the anti-anhedonic effects of pramipexole (dopamine D3/D2 direct agonist). I wonder if trimipramine could reverse this tolerance.

-undopaminergic

 

Re: Anticholinergics as antidepressants

Posted by phidippus on December 29, 2019, at 21:42:39

In reply to Anticholinergics as antidepressants, posted by undopaminergic on December 27, 2019, at 11:15:45

Scopalomine exerted no antidepressant effect for me.

 

Re: Anticholinergics as antidepressants

Posted by linkadge on December 30, 2019, at 8:28:37

In reply to Re: Anticholinergics as antidepressants, posted by undopaminergic on December 29, 2019, at 20:03:39

>Well, we can say for sure that they are different, >and also that their effects are likely >substantially different.

We can?

>Still, the main difference in my view, is that >pure DRIs are free of noradrenergic side effects, >which would tend to render them more "likeable". >I don't know about the serotonin, but from what >I've read it seems the serotonergic action of >cocaine attenuates the locomotor response (in >rodents).

Norepinephrine reuptake inhibition is involved in some of the cognitive / rewarding process involved in stimulant action / abuse. For example, certain regions of the brain are devoid of dopamine transporters and so dopamine is cleared from the synapse by the norepinephrine transporter. The prefrontal cortex has no dopamine transporters. The ability of Ritalin (for example) to increase prefrontal dopamine does not depend on DAT inhibition (probably a combination of NRI and 5-h1a agonism from d-methylphenidate).

Serotonin reuptake inhibition too enhances the rewarding effects of dopamine reuptake inhibition (via 5-ht1a/b stimulated dopamine release in the NAc). Also, serotonin and dopamine transporters are sometimes promiscuous. For example, in the presence of an SSRI, the dopamine transporter can begin to clear serotonin, and hence combined SERT/DAT inhibition may result in higher levels of serotonin (and possibly dopamine).

In animal models, dopamine is more involved in reward anticipation (and the motivation to achieve a reward) rather than producing reward themselves. In some models, increasing dopamine inhibits opiate release (perhaps creating a sense of dissatisfaction, or increasing goal directed behavior). I remember reading studies on hyperdopaminergic mice. According to the following abstract:

"hyperdopaminergic mutant mice attribute greater incentive salience ("wanting") to a sweet reward in the runway test. But sucrose taste fails to elicit higher orofacial "liking" reactions from mutant mice"

https://www.biopsychiatry.com/hyperdopaminergic.html

"As for the monoamine releasing action of cocaine, have you come across any quantifications of that? Ie. how much of 180% elevated dopamine is attributable to the enhanced release as opposed to reuptake inhibition?"

I have not. However, here is a little blurb on the possible mechanism of dopamine release by cocaine:

https://www.ncbi.nlm.nih.gov/pubmed/16554471

The following study suggests that cocaine increases dopamine release via a cholinergic mechanism (because nicotinergic antagonists were able to block the rewarding effects):

http://grantome.com/grant/NIH/F32-DA040409-01

This also could be one mechanism of tolerance to many drugs (i.e. depletion of cholinergic reserves).

The following study suggests that 5-ht1b receptor expression in the NAc has something to do with the rewarding effects of cocaine. 5-ht1b expression in the NAc is controlled by the P11 protein (which is apparently low in people with depression).

I suppose the firing (and suppression) of the VTA neurons is important in the process of addiction. Dopamine can modulate this firing via inhibition of gaba release in this region. Opiates too block gaba release there and enhance firing. However, overactivity of VTA neurons is also linked to depression. The reward center is meant to help us get through difficult times, but it is not really meant (or even capable) of firing 24/7. There will always be some mechanism (even if its death of the neurons themselves) that limits the ability to experience pleasure constant.

https://www.jneurosci.org/content/22/24/10856

>It's my understanding that the differences in >effects between individual anticholinergics are >usually attributable to the specific affinities >for different muscarinic receptors. For example, >scopolamine is more euphoriant than atropine. But >benztropine may be a special case, in having >effects on the DAT.

Yeah. I think M1 and M2 receptor blockade is important. M1/M2 knockout mice display a depression resistant phenotype.

http://jpet.aspetjournals.org/content/jpet/351/2/448.full.pdf

"These data establish muscarinic M1 and M2 receptors as sufficient to generate behavioral effects consistent with an antidepressant phenotype and therefore as potential targets in the antidepressant effects of scopolamine."

>While searching, I noticed a few things >suggesting that it may be hasty to come to this >conclusion from a single study. One article >suggested the 5-HT1A receptor, rather than 5->HT2A, is required to increase dopamine.

That could be. However, 5-ht antagonists can increase 5-ht1 mediated neurotransmission by blocking 'alternative' receptors for serotonin to bind to. Mirtazapine also exhibits this 'indirect' 5-ht1a agonism even though the molecule displays no direct 5-ht1 agonism on its own right.

Some research suggests the 5-ht7 receptor may be more involved in the anti-anhedonic effect of certain antipsychotics. 5-ht7 antagonists appear to have rapid acting AD effects.

>I became tolerant to the anti-anhedonic effects >of pramipexole (dopamine D3/D2 direct agonist). I >wonder if trimipramine could reverse this >tolerance.

Possibly. Perhaps worth a try if you have some Mirapex left over.

My only recipe is to keep "changing sh*t up". I know this runs completely contrary to conventional wisdom.

Linkadge

 

Re: Anticholinergics as antidepressants » phidippus

Posted by linkadge on December 30, 2019, at 8:31:11

In reply to Re: Anticholinergics as antidepressants, posted by phidippus on December 29, 2019, at 21:42:39

Just to add...

If the following study is true:

"hyperdopaminergic mutant mice attribute greater incentive salience ("wanting") to a sweet reward in the runway test. But sucrose taste fails to elicit higher orofacial "liking" reactions from mutant mice"

Then enhancing dopamine function SHOULD be at the forefront of research. Think about it. How much money could the economy generate by a fleet of hypermotivated, yet never satisficed customers?

Enhancing dopamine would make us all super eager to achieve things, yet never truly satisfied when we do.

Linkadge

 

Re: Anticholinergics as antidepressants » linkadge

Posted by SLS on December 30, 2019, at 13:00:16

In reply to Re: Anticholinergics as antidepressants » phidippus, posted by linkadge on December 30, 2019, at 8:31:11

> Just to add...
>
> If the following study is true:
>
> "hyperdopaminergic mutant mice attribute greater incentive salience ("wanting") to a sweet reward in the runway test. But sucrose taste fails to elicit higher orofacial "liking" reactions from mutant mice"
>
> Then enhancing dopamine function SHOULD be at the forefront of research. Think about it. How much money could the economy generate by a fleet of hypermotivated, yet never satisficed customers?
>
> Enhancing dopamine would make us all super eager to achieve things, yet never truly satisfied when we do.

That's a brilliant supposition!

BTW, Trintellix (vortioxetine) is a 5-HT7 receptor antagonist.


- Scott

 

Re: Anticholinergics as antidepressants

Posted by undopaminergic on December 30, 2019, at 14:40:32

In reply to Re: Anticholinergics as antidepressants, posted by linkadge on December 30, 2019, at 8:28:37

> >Well, we can say for sure that they are different, >and also that their effects are likely >substantially different.
>
> We can?
>

Say for sure that selective DRIs are different from SNDRIs? Yes. (You yourself seem to be arguing as much.) Nevertheless, I would still insist that the DAT-inhibition is the main thing as far as the "likeability" of mixed monoamine reuptake inhibitors is concerned.

> >Still, the main difference in my view, is that >pure DRIs are free of noradrenergic side effects, >which would tend to render them more "likeable". >I don't know about the serotonin, but from what >I've read it seems the serotonergic action of >cocaine attenuates the locomotor response (in >rodents).
>
> Norepinephrine reuptake inhibition is involved in some of the cognitive / rewarding process involved in stimulant action / abuse.
>

I agree, but I'm inclined to believe the adverse effects (eg. tachycardia and sweating) from NRI outweigh the rewarding aspects. Well, at least I feel that is true for me, but I seem to have too much noradrenaline, so any elevation is aversive to me. Analogously, there are people who don't enjoy the DRI action of stimulants, probably because they have high dopamine already.

> For example, certain regions of the brain are devoid of dopamine transporters
>

Sure, all areas of the brain that don't receive afferent dopamine projections.

> and so dopamine is cleared from the synapse by the norepinephrine transporter.
>

Right. Noradrenergic nerve terminals always take up dopamine, because that is the precursor to noradrenaline.

> The prefrontal cortex has no dopamine transporters.

I don't agree on that. If VTA dopamine projections to the nucleus accumbens have dopamine transporters, why would projections, from the same origin, to the prefrontal cortex lack them? True, they are scarce / low density, but not nonexistent.

I spent a substantial amount of time investigating this, and I found several articles that confirm the existence of DATs in the PFC:

https://www.ncbi.nlm.nih.gov/pubmed/16336224
"A cumulative effect of dopamine and norepinephrine transporter blockade on the output of dopamine in dialysates was also observed in .. the prefrontal cortex."

https://www.ncbi.nlm.nih.gov/pubmed/26056032
"Increased expression of the DA transporter (DAT) is also seen in the adult infralimbic mPFC ..."

https://www.ncbi.nlm.nih.gov/pubmed/8866704
".. [3H]GBR 12935 dopamine transporter (DAT) binding .. in the prefrontal cortex ... intermittent administration of cocaine resulted in a selective alteration of [3H]GBR 12935 binding in the prefrontal cortex .."

https://www.ncbi.nlm.nih.gov/pubmed/1346964
"Moderate levels of [3H]GBR 12935 binding were observed in .. prefrontal and singular cortices."

https://www.ncbi.nlm.nih.gov/pubmed/2145054
"In the medial prefrontal cortex, cocaine and GBR 12909 could inhibit only about 40% of the [3H]dopamine uptake."

https://www.ncbi.nlm.nih.gov/pubmed/31330230
".. revealed .. decreased DRD2 and DAT mRNA and protein expression in the PFC,"

https://www.ncbi.nlm.nih.gov/pubmed/22119644
".. neonatal ethanol exposure increased the V(max) for DAT in the PFC, suggesting an increase in DAT function in PFC."

https://www.ncbi.nlm.nih.gov/pubmed/19648469
"Furthermore, long-, but not short-access to self-administered methamphetamine resulted in persistent decreases in dopamine transporter (DAT) protein levels in the prefrontal cortex .."

https://www.ncbi.nlm.nih.gov/pubmed/15935059
"In mPFC .., total DAT immunoreactivity was not different .."

https://www.ncbi.nlm.nih.gov/pubmed/12944350
"The lower dopamine transporter density in the orbitofrontal and dorsolateral prefrontal cortex was significantly correlated with the duration of methamphetamine use and the severity of psychiatric symptoms."

https://www.ncbi.nlm.nih.gov/pubmed/9502827
"Dopamine axon varicosities in .. the rat prefrontal cortex exhibit sparse immunoreactivity for the dopamine transporter."

In summary, sparse but not nonexistent.

A couple of articles that suggest you may be right:

https://www.ncbi.nlm.nih.gov/pubmed/11988230
"Infusions of the selective dopamine uptake blocker GBR 12909 failed to alter dopamine efflux in any prefrontocortical subregion."

https://www.ncbi.nlm.nih.gov/pubmed/7796098
".. it appears that [[3H]GBR 12935] in the rat PFC labels mainly 'the piperazine acceptor site' and not the DA transporter."

> The ability of Ritalin (for example) to increase prefrontal dopamine does not depend on DAT inhibition
>

I agree. The dopamine transporters of the PFC are very sparse, and to inhibit them takes a very high affinity and potent antagonist. Some of the GBR-xxx series of selective DRIs are potent enough to do so. The dose-effect curve of methylphenidate with respect to DAT inhibition flattens long before reaching 100% inhibition. Some of the radio-tracers used in PET to visualise the distribution of DATs do not sufficiently bind to these transporters in the PFC (at the concentrations used), and so it may appear from the images that the transporters are entirely absent.

> (probably a combination of NRI and 5-h1a agonism from d-methylphenidate).
>

Are you saying d-methylphenidate is a 5-HT1A agonist?

> Serotonin reuptake inhibition too enhances the rewarding effects of dopamine reuptake inhibition (via 5-ht1a/b stimulated dopamine release in the NAc).
>

I'm inclined to agree, albeit with the qualification that it probably varies between individuals. Some people feel worse rather than better from SSRIs.

Also, some actions of serotonin antagonise dopamine, whereas some some of them synergise. The question is which of them predominates.

> Also, serotonin and dopamine transporters are sometimes promiscuous. For example, in the presence of an SSRI, the dopamine transporter can begin to clear serotonin, and hence combined SERT/DAT inhibition may result in higher levels of serotonin (and possibly dopamine).
>

Seems to me that the extracellular serotonin would be reduced if the DAT contributes to its clearance?

I think one of the mechanisms behind the serotonergic neurotoxicity of MDMA is that the SERT begins to take up dopamine into serotonergic nerve terminals, and I propose that the latter are ill-equipped to "deal" with dopamine, resulting in oxidative stress.

> In animal models, dopamine is more involved in reward anticipation (and the motivation to achieve a reward) rather than producing reward themselves.
>

Absolutely.

> In some models, increasing dopamine inhibits opiate release (perhaps creating a sense of dissatisfaction, or increasing goal directed behavior). I remember reading studies on hyperdopaminergic mice. According to the following abstract:
>
> "hyperdopaminergic mutant mice attribute greater incentive salience ("wanting") to a sweet reward in the runway test. But sucrose taste fails to elicit higher orofacial "liking" reactions from mutant mice"
>

That is consistent with what I've read. Nevertheless, I did experience more "liking" when I first took pramipexole. For example, music sounded better, and I *liked* it more. Likewise (pun not intended) food and movies.

I also experienced enhanced taste of foods in one of my (hypo)manic episodes.

> "As for the monoamine releasing action of cocaine, have you come across any quantifications of that? Ie. how much of 180% elevated dopamine is attributable to the enhanced release as opposed to reuptake inhibition?"
>
> I have not. However, here is a little blurb on the possible mechanism of dopamine release by cocaine:
>
> https://www.ncbi.nlm.nih.gov/pubmed/16554471

Alternatively, this article suggests that sigma-agonism may be a mechanism through which cocaine could enhance DA release:

https://www.ncbi.nlm.nih.gov/pubmed/8608783
"sigma receptor ligands appear to facilitate dopamine release from nigrostriatal, and presumably mesocorticolimbic, neurons through a non-transporter-mediated mechanism."

> The following study suggests that cocaine increases dopamine release via a cholinergic mechanism (because nicotinergic antagonists were able to block the rewarding effects):
>
> http://grantome.com/grant/NIH/F32-DA040409-01

Interesting.

> This also could be one mechanism of tolerance to many drugs (i.e. depletion of cholinergic reserves).
>

Seems this could be tested with acetylcholinesterase inhibitors.

> The following study suggests that 5-ht1b receptor expression in the NAc has something to do with the rewarding effects of cocaine. 5-ht1b expression in the NAc is controlled by the P11 protein (which is apparently low in people with depression).
>

That's very interesting. As far as I've seen, the 5-HT1B receptor is largely neglected by researchers, because you rarely come across it.

> I suppose the firing (and suppression) of the VTA neurons is important in the process of addiction.
>

Absolutely. Especially as far as opies go.

> Dopamine can modulate this firing via inhibition of gaba release in this region.
>

You mean dopamine in the NAc inhibits GABAergic neurons projecting to the VTA?

> Opiates too block gaba release there and enhance firing.

Right. I also read that kappa-opioid receptor antagonism enhances dopamine release in the prefrontal cortex, but I don't have any references at hand -- other than personal experience with buprenorphine.

> However, overactivity of VTA neurons is also linked to depression.

I wasn't aware of that. It's counterintuitive, but I suppose there can be dysregulations of this circuitry, so that it doesn't function normally.

> The reward center is meant to help us get through difficult times,

Amongst other things. It seems particularly important in establishing rewarding habits, some of which can be dysfunctional (eg. taking certain drugs), and may be at odds with helping us through difficult times (such as lack of the drug of choice).

> but it is not really meant (or even capable) of firing 24/7. There will always be some mechanism (even if its death of the neurons themselves) that limits the ability to experience pleasure constant.
>

Well, that is the conventional wisdom. But I do know consistent pleasure can be sustained for days, if not weeks, on end. It does lose its novelty after some days, and you begin to take it for granted, but you still feel good. More modest (or "normal") well-being can be sustained for even longer.

> https://www.jneurosci.org/content/22/24/10856

That's cool.

> Yeah. I think M1 and M2 receptor blockade is important. M1/M2 knockout mice display a depression resistant phenotype.
>
> http://jpet.aspetjournals.org/content/jpet/351/2/448.full.pdf
>
> "These data establish muscarinic M1 and M2 receptors as sufficient to generate behavioral effects consistent with an antidepressant phenotype and therefore as potential targets in the antidepressant effects of scopolamine."
>

I'm a bit confused. You say M1/M2 knockouts are resistant to depression, but it seems the article is saying that these receptors, and not their absence, are sufficient *for* an antidepressant phenotype?

> That could be. However, 5-ht antagonists can increase 5-ht1 mediated neurotransmission by blocking 'alternative' receptors for serotonin to bind to.
>

Oh, yes, that makes sense. Ie. 5-HT2A blockade would enhance the relative "dominance" of the 5-HT1A or -1B receptors, shifting the balance.

> Mirtazapine also exhibits this 'indirect' 5-ht1a agonism even though the molecule displays no direct 5-ht1 agonism on its own right.
>

Right.

> Some research suggests the 5-ht7 receptor may be more involved in the anti-anhedonic effect of certain antipsychotics. 5-ht7 antagonists appear to have rapid acting AD effects.
>

Very interesting. It's not only antipsychotics:
https://en.wikipedia.org/wiki/5-HT7_receptor#Antagonists

I'm taking one of them, clozapine, and I wonder if sulpiride and/or trimipramine may share this action too.

> >I became tolerant to the anti-anhedonic effects >of pramipexole (dopamine D3/D2 direct agonist). I >wonder if trimipramine could reverse this >tolerance.
>
> Possibly. Perhaps worth a try if you have some Mirapex left over.

Sifrol in my case, but alas, I have none left, and at this point it seems my doctor(s) would be unlikely to prescribe it.

> My only recipe is to keep "changing sh*t up". I know this runs completely contrary to conventional wisdom.
>

Not really. It makes a lot of sense. By changing things, ie. experimenting, you can learn things, and gradually figure out what works or not.

-undopaminergic

 

Re: Anticholinergics as antidepressants » SLS

Posted by linkadge on December 30, 2019, at 17:14:35

In reply to Re: Anticholinergics as antidepressants » linkadge, posted by SLS on December 30, 2019, at 13:00:16

>Trintellix (vortioxetine) is a 5-HT7 receptor >antagonist.

Interesting.

Linkadge

 

Re: Anticholinergics as antidepressants

Posted by linkadge on December 30, 2019, at 18:34:00

In reply to Re: Anticholinergics as antidepressants, posted by undopaminergic on December 30, 2019, at 14:40:32

>I would still insist that the DAT-inhibition is the >main thing as far as the "likeability" of mixed >monoamine reuptake inhibitors is concerned.

Possibly. However, I've never taken a selective dopamine reuptake inhibitor, so I can't say. I believe modafinil has some ability to inhibit DAT (again perhaps at an alternative binding site) yet it has nowhere near the abuse potential of cocaine. Many of the studies you reference (which suggest some function of DAT in the prefrontal cortex) still seem to reinforce my real point - that additional NET blockade can significantly augment the ability of DAT inhibitor to increase dopamine levels.

Your first link suggests:

"Administration of reboxetine, a selective blocker of the norepinephrine transporter, 20 min after the administration of GBR 12909, a selective blocker of the dopamine transporter, produced an increase of dopamine output in the nucleus accumbes shell (+408% above basal) greater than that obtained by GBR 12909 alone (+308% above basal)."

This would seem to suggest that NET inhibition contributes to the rewarding effects of these drugs (if elevated dopamine is, in fact, the key mechanism).

Keep in mind too, that the infralimbic prefrontal cortex is a sub-region of the prefrontal cortex.

"This study shows that dopamine extracellular concentration can be elevated by norepinephrine transporter blockade, even in areas where the dopamine transporter is predominant, when the latter is pharmacologically blocked."

Again, there is the possibility that monoamine transporters are promiscuous and can replace each other's roles in deficiency states. For example, this study suggests that after long term SSRI administration, the dopamine transporter begins to take up serotonin as well. The authors postulate depression is relived by when presynaptic neurons start to co-release dopamine and serotonin at the same time.

https://www.eurekalert.org/pub_releases/2005-04/cp-sai040105.php

Some evidence of the (relative) lack of dopamine transporters in the prefrontal cortex:

"have tested this hypothesis by comparing the effects of inhibitors selective for the three monoamine transporters with those of a nonspecific inhibitor, cocaine, on uptake of 3H-dopamine into synaptosomes from frontal cortex, caudate nucleus, and nucleus accumbens from wild-type, NET, and dopamine transporter (DAT) knock-out mice. Dopamine uptake was inhibited by cocaine and nisoxetine, but not by GBR12909, in frontal cortex synaptosomes from wild-type or DAT knock-out mice."

https://pdfs.semanticscholar.org/e32b/b1abc682dc7490aea0d6039136bf1edd0139.pdf

(again, not really my main point).

>Are you saying d-methylphenidate is a 5-HT1A >agonist?

Yes (see link below). My hunch is that (if one is targeting increased dopamine in the prefrontal cortex) then a combination of 5-ht1a agonism and NET inhibition would be (likely) synergistic.

https://www.ncbi.nlm.nih.gov/pubmed/19322953

Of course too, one needs to ensure they have adequate levels of omega-3 polyunsaturated fats in their diet which increase both dopamine content and cellular responsiveness to dopamine.

There are some studies that buspirone (5-ht1 agonist) can be effective for ADHD and can augment atomoxetine for ADHD.

https://www.ncbi.nlm.nih.gov/pubmed/20517641

There is a serotonergic theory for ADHD that many of the stimulants are working via 5-ht mechanisms (or some other unknown mechanism) to calm hyperactive individuals. For example, DAT knockout mice are hyperactive! Yet, DAT inhibitors like Ritalin calm DAT knockout mice down. Interestingly cocaine also calms down hyperactive DAT knockout mice.

https://science.sciencemag.org/content/288/5463/11

Interestingly, in the study they were perplexed by the fact that Ritalin calmed the mice only after a lag of 30 minutes (whereas serotonin enhancing drugs calmed the mice much faster). Perhaps this is the lag required for d-methylphenidate to kick in (with 5-t1a receptor agonism)??

>I'm inclined to agree, albeit with the >qualification that it probably varies between >individuals. Some people feel worse rather than >better from SSRIs.

Again, SSRIs alone have other issues (i.e. dopamine suppression via 5-ht2c receptors). By themselves they are not rewarding (actually in DAT knockout mice they are!). However (not sure if you've taken an SSRI + Ritalin), it is substantially more 'reinforcing' than Ritalin alone. Some studies suggest a very similar pattern of NAc cfos activity following SSRI + Ritalin to cocaine.

>Alternatively, this article suggests that sigma->agonism may be a mechanism through which cocaine >could enhance DA release:

Right. I was going to mention that, but wasn't sure how significant the effect was. I think the effect is due to sigma-2 more so than sigma-1 (or vice versa). I think sig-1 receptor agonists display more antipsychotic effects (i.e. fluvoxamine in psychotic depression). Interestinly, the sensitization of cocaine appears to be due to sigma receptor mechanisms. Sigma receptor modulation can reduce the addictive and sensitizing effects of cocaine.

Here's a study suggesting that sigma receptors themselves can alter (perhaps enhance) the way that cocaine inhibits DAT (and as you mention also increase dopamine release). Sigma receptors also modulate glutamate and gaba release, which again could enhance the rewarding effects of cocaine.

https://www.ncbi.nlm.nih.gov/pubmed/28495886

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4830437/

In fact, the study suggests that agents which inhibit DAT AND block sigma receptors appears to have much lower abuse potential (if any) (and may even aid in cocaine withdrawal).

https://www.ncbi.nlm.nih.gov/pubmed/12801223

Sigma receptors may be some of the link between stimulant abuse and schizophrenia (or stimulant induced psychosis). I believe quetiapine has actions on sigma receptors, which may explain its antipsychotic effects at doses too low to achieve significant d2 antagonism.

Ok. Enough for tonight. Take care!

Linkadge

 

Re: Anticholinergics as antidepressants

Posted by undopaminergic on January 1, 2020, at 14:10:29

In reply to Re: Anticholinergics as antidepressants, posted by linkadge on December 30, 2019, at 18:34:00

> >I would still insist that the DAT-inhibition is the >main thing as far as the "likeability" of mixed >monoamine reuptake inhibitors is concerned.
>
> Possibly. However, I've never taken a selective dopamine reuptake inhibitor, so I can't say. I believe modafinil has some ability to inhibit DAT (again perhaps at an alternative binding site) yet it has nowhere near the abuse potential of cocaine.
>

I agree. But this abstract suggests only "moderate" selectivity for the DAT:
https://www.ncbi.nlm.nih.gov/pubmed/29091428

Corroborated by:
https://www.ncbi.nlm.nih.gov/pubmed/16885432
"Modafinil (i.v.) occupied striatal DAT sites (5 mg/kg: 35 +/- 12% .. 8 mg/kg: 54 +/- 3% ..). In thalamus, modafinil occupied NET sites (5 mg/kg: 16 +/- 7.8% .. 8 mg/kg: 44 +/- 12% ..)."

But in contrast:
https://www.ncbi.nlm.nih.gov/pubmed/26347626
"Modafinil was binding to the DAT but insignificantly to SERT or NET and dopamine reuptake was blocked .."

Furthermore:
https://www.ncbi.nlm.nih.gov/pubmed/23933217
"These results demonstrate that modafinil potentiates brain dopaminergic signals via DAT inhibition by acting at the same binding site of cocaine."

But:
https://www.ncbi.nlm.nih.gov/pubmed/22043293
"The atypical stimulant and nootropic modafinil interacts with the dopamine transporter in a different manner than classical cocaine-like inhibitors."

However, DAT inhibiton does not seem to be the only action of modafinil:
https://www.ncbi.nlm.nih.gov/pubmed/1359924
"These results suggest that the arousal effect of modafinil does not depend on the availability of the endogenous catecholamines but results from an enhancement of alpha 1- and beta-receptor activity .."

And:
https://www.ncbi.nlm.nih.gov/pubmed/1973114
"These effects could be linked to modulation (stimulation) of central alpha 1-adrenoceptors unaccompanied by peripheral sympathetic effects .."

And, with respect to amphetamines:
https://www.ncbi.nlm.nih.gov/pubmed/8998404
".. it is concluded that the mechanism underlying the modafinil induced stimulant locomotor effect differs completely from that of (+)amphetamine."

> Many of the studies you reference (which suggest some function of DAT in the prefrontal cortex) still seem to reinforce my real point - that additional NET blockade can significantly augment the ability of DAT inhibitor to increase dopamine levels.
>

Oh, but I agree on that. However, see below.

> Your first link suggests:
>
> "Administration of reboxetine, a selective blocker of the norepinephrine transporter, 20 min after the administration of GBR 12909, a selective blocker of the dopamine transporter, produced an increase of dopamine output in the nucleus accumbes shell (+408% above basal) greater than that obtained by GBR 12909 alone (+308% above basal)."
>
> This would seem to suggest that NET inhibition contributes to the rewarding effects of these drugs (if elevated dopamine is, in fact, the key mechanism).
>

Yes. However, I am wondering about the significance of elevated dopamine in noradrenergic synapses. This dopamine does not necessarily reach dopamine receptors, except where DA and NA receptors are closely co-localised.

> Keep in mind too, that the infralimbic prefrontal cortex is a sub-region of the prefrontal cortex.
>

Sub-region? You mean analogous to medial or ventrolateral PFC (ie. "subsections")? Or do you mean it is located below/under the PFC without actually being part of the PFC?

> Again, there is the possibility that monoamine transporters are promiscuous and can replace each other's roles in deficiency states. For example, this study suggests that after long term SSRI administration, the dopamine transporter begins to take up serotonin as well. The authors postulate depression is relived by when presynaptic neurons start to co-release dopamine and serotonin at the same time.
>
> https://www.eurekalert.org/pub_releases/2005-04/cp-sai040105.php
>

Interesting. I'm thinking of L-dopa induced dyskinesias in Parkinson's disease. Maybe this happens because L-dopa elevates the extracellular concentrations of dopamine to the point that SERT begins to take up -- and release -- dopamine.

> Some evidence of the (relative) lack of dopamine transporters in the prefrontal cortex:
>
[..]
> (again, not really my main point).

Right. I have already acknowledged that the DAT is sparse in the PFC, but argued that it is not nonexistent. I am still confused as to whether the DAT is sparse because DA terminals are sparse, or whether DA terminals actually express the NAT protein in place of the DAT.

> >Are you saying d-methylphenidate is a 5-HT1A >agonist?
>
> Yes (see link below).
>
> https://www.ncbi.nlm.nih.gov/pubmed/19322953

My intuition suggests that this action of d-MPH takes very high doses. The abstract speaks of 5 to 100 micromol... whereas at the DAT and NAT, d-MPH is active at *nano*molar concentrations.

Indeed, Wikipedia confirms my suspicions -- look at the receptor binding table:
https://en.wikipedia.org/wiki/Methylphenidate#Pharmacodynamics
According to that table, the IC50 concentration of d-MPH at the DAT is only 23 nM, whereas the EC50 at 5-HT1A is 6800!

> My hunch is that (if one is targeting increased dopamine in the prefrontal cortex) then a combination of 5-ht1a agonism and NET inhibition would be (likely) synergistic.
>

I agree on that. Seems methylphenidate and buspirone might be an interesting combination.

> Of course too, one needs to ensure they have adequate levels of omega-3 polyunsaturated fats in their diet which increase both dopamine content and cellular responsiveness to dopamine.
>

How common is omega-3 deficiency? I've tried this supplement with no effect.

> There are some studies that buspirone (5-ht1 agonist) can be effective for ADHD and can augment atomoxetine for ADHD.
>

Pretty much what I suggested above.

> There is a serotonergic theory for ADHD that many of the stimulants are working via 5-ht mechanisms (or some other unknown mechanism) to calm hyperactive individuals. For example, DAT knockout mice are hyperactive! Yet, DAT inhibitors like Ritalin calm DAT knockout mice down. Interestingly cocaine also calms down hyperactive DAT knockout mice.
>

I'm still trying to figure this out. Methylphenidate stimulates me to be more active, even "hyper"-active, eg. staying up the whole night (or longer) and being less apathetic. Meanwhile, the first doses of PEA that I took, calmed me down to the point that I could have slept, had I not been focussing on watching the news and weather forecast. Perhaps PEA and amphetamines can calm you down through actions at the trace amine-receptors? Or do these drugs simply release so much DA that it hits the autoreceptors strongly enough to calm the presynaptic neuron enough to in turn calm the postsynaptic neuron through absence of DA-agonism?

> https://science.sciencemag.org/content/288/5463/11

I agree with the criticism by Volkow et al.

> Interestingly, in the study they were perplexed by the fact that Ritalin calmed the mice only after a lag of 30 minutes (whereas serotonin enhancing drugs calmed the mice much faster). Perhaps this is the lag required for d-methylphenidate to kick in (with 5-t1a receptor agonism)??
>

I don't know. It would seem to be a process that starts slowly and then progresses until reaching some kind of "critical mass".

> >I'm inclined to agree, albeit with the >qualification that it probably varies between >individuals. Some people feel worse rather than >better from SSRIs.
>
> Again, SSRIs alone have other issues (i.e. dopamine suppression via 5-ht2c receptors). By themselves they are not rewarding (actually in DAT knockout mice they are!).
>

Interesting, regarding the DAT-KO mice. As I said before, they are different in more ways than just lacking the DAT.

Here's another abstract in that context:
https://www.ncbi.nlm.nih.gov/pubmed/11222668
"DAT knock-out mice were also unresponsive to the normally robust wake-promoting action of modafinil, methamphetamine, and the selective DAT blocker GBR12909 but were hypersensitive to the wake-promoting effects of caffeine."

> However (not sure if you've taken an SSRI + Ritalin),

I think I've neglected to try that combination.

> it is substantially more 'reinforcing' than Ritalin alone. Some studies suggest a very similar pattern of NAc cfos activity following SSRI + Ritalin to cocaine.
>

Seems intuitive, but this article suggests that modafinil+escitalopram is not nearly as "good" as cocaine:

https://www.ncbi.nlm.nih.gov/pubmed/24928479
".. no treatment significantly reduced choices for cocaine infusions. ... Modafinil attenuated many positive subjective effects produced by cocaine; however, escitalopram combined with modafinil did not enhance the efficacy of modafinil to reduce cocaine effects."

One would intuitively expect the combination -- as a "simulation" of cocaine pharmacodynamics -- to better (than modafinil alone) substitute for cocaine, and thereby reducing interest in cocaine infusions.

Anyway, modafinil differs substantially from Ritalin, so this article may not be entirely relevant to the combination of MPH+SSRI.

> >Alternatively, this article suggests that sigma->agonism may be a mechanism through which cocaine >could enhance DA release:
>
> Right. I was going to mention that, but wasn't sure how significant the effect was. I think the effect is due to sigma-2 more so than sigma-1 (or vice versa). I think sig-1 receptor agonists display more antipsychotic effects (i.e. fluvoxamine in psychotic depression).
>

I thought it was sigma-*ant*agonism that produced antipsychotic-like effects?

> Interestinly, the sensitization of cocaine appears to be due to sigma receptor mechanisms. Sigma receptor modulation can reduce the addictive and sensitizing effects of cocaine.
>

Do you have any references at hand? I'm very interested in this, and other cocaine trivia. Walking in the footsteps of Freud...

> Here's a study suggesting that sigma receptors themselves can alter (perhaps enhance) the way that cocaine inhibits DAT (and as you mention also increase dopamine release). Sigma receptors also modulate glutamate and gaba release, which again could enhance the rewarding effects of cocaine.
>

I don't have a clear understanding of "conformations" of the DAT. Also, I definitely need to read more about sigma.

> https://www.ncbi.nlm.nih.gov/pubmed/28495886
>
> https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4830437/
>
> In fact, the study suggests that agents which inhibit DAT AND block sigma receptors appears to have much lower abuse potential (if any) (and may even aid in cocaine withdrawal).
>

And by extension, maybe agents that potently a) block the DAT and b) stimulate sigma, would be "particularly" abusable. Especially if they have a fast onset of action -- compare oral methylphenidate with crack cocaine.

> Sigma receptors may be some of the link between stimulant abuse and schizophrenia (or stimulant induced psychosis). I believe quetiapine has actions on sigma receptors, which may explain its antipsychotic effects at doses too low to achieve significant d2 antagonism.
>

Interesting speculation. If quetiapine (QTP) is a sigma-ligand, maybe that is the reason why it is the only(?) antipsychotic drug associated with drug-seeking. I don't know if it has been said before here, but there are even people who are into "Q-balls" -- that is a recreational combination of QTP and cocaine, and which is commonly injected. It strikes me now, that the recently popular practice of "augmenting" antidepressive (including stimulants) treatment with antipsychotics is really analogous to Q-balling. Could Abilify+Dexedrine be a recrational combo that is subjectively superior to Dexedrine alone?

-undopaminergic


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