SNRI's effect on norepinephrine release via Dextroamphetamine

[DepressedADHDHelp]

Hello.

Moderator, please post in Advanced drug discussion because I would like those who are knowledgable about psychopharmacology to address this.

I am on an SNRI (with minimal dopamine reuptake inhibition compared to the 1:9 serotonin:norepinephrine reuptake ratio). I also take .25-.5 mg klonopin as needed (i never take more than 1mg a day though for fear of benzo dependence) but also before bed as a mood stabilizing/pseudoantimanic. The dextroamphetamine is 15mg per dose, up to 3 doses a day (depending on when i wake up/when i want to sleep/what i am doing e.g. work, school, play...)

We all know Dextroamphetamine releases DA,NE, and a little SE, and it is also a reuptake inhibitor of dopamine and NE.

SNRI's, i beleive, eventually downregulate NE levels, which is why they are preferred for anxiety disorders. Klonopin also lowers NE levels through its affect on GABA and consequently the adrenaline system.

The Question: What effect does the SNRI have on the norepinephrine released/and reuptake inhibitied from the Dextroamphetamine?

Some have said that would increase norepinphrine levels in the synapse, but others have said that it limits the amount of NE used in the same way that the serotonergic effects of MDMA are muted by an SSRI.

My feeling, since my anxiety is considerably lower than with dex alone, is that the SNRI actually blocks increase in NE. This results in increased serotonin, correct?

Also, the inhibition of the monoamines SE and NE from the SNRI, make the Dex mostly work on dopamine, which is the desired goal for ADHD.

Finally, the slight dopamine reuptake inhibition may actually keep dopamine longer? And also, SNRI prevents neurotoxicity from reuptake of DA in the SE and NE pumps.

SO......basically: What is the effect on the three monoamines when co-administering Dextroamphetamine and SNRI's (and if you want to mention klonopin, but thats adding a third and more complicated element).

Thank you

 

[Chaos Butterfly]

shifting to advanced drug discussion...

 

[wreckhead]

My opinion is that an SNRI will block the serotonin and noradrenaline release from dextroamphetamine by disabling the SE and NA monoamine transporters. I said this about the combination of reboxetine + PEA, and your experience seems to confirm my hypothesis.

 

[Riemann Zeta]

Well, I am on the same combo as you describe: venlafaxine and dextroamphetamine XR and I have pondered that same question for years. I assume since you mentioned a 1:9 efficacy ratio in inhibiting [3H]5-HT/[3H]NE uptake that you are talking about venlafaxine as opposed to duloxetine.

The Question: What effect does the SNRI have on the norepinephrine released/and reuptake inhibitied from the Dextroamphetamine?

Since dextroamphetamine has no appreciable effect on the SERT at normal therapeutic doses, the big question is, as you point you, what happens with the NET? My take on the situation is that venlafaxine-mediated inhibition of the NET will prevent (d)-amphetamine from causing noradrenaline and/or dopamine release from cells that express the NET as opposed to the DAT. However, one thing to keep in mind about venlafaxine is that its effect on the NET isn't that strong compared to other SNRIs out there: at a dose of 75mg/day, venlafaxine is estimated to occupy around 25% of the NETs in humans, at 150mg this jumps to 40% (Owens et al, 2008). At either dose, the effect on SERT is much greater than the effect on NET. Moreover, unlike other antidepressants, venlafaxine does not appear to significantly downregulate SERT and NET expression in the brain (Zhao et al, 2008), so there are still enough NETs around to be affected by dexamphetamine, unlike with other antidepressants (like duloxetine).

I myself am on 150mg of venlafaxine per day, along with 60mg of dexamphetamine XR. Interestingly, I notice that when I decrease the venlafaxine to 50-75mg, but keep the Dexedrine at the same level, I do experience more of a 'stimulant-like' effect from the amphetamine. I attribute this bump in CNS stimulation to greater release of noradrenaline, as fewer NETs are inhibited by the venlafaxine.

Either way, taking a 5-HT uptake inhibitor with dextroamphetamine is a good thing in my opinion (I don't know why this combo isn't used more often), as the increased 5-HT level helps prevent tolerance to the amphetamine and also help cancel out potential amphetaminergic side effects (like jitteriness). Why do you take the clonazepam, however (if I might ask)? Chances are that it is just counteracting all the wonderful cognition-enhancing effects of the amphetamine. As a less sedating mood stabilizer, you might want to check out low-dose lamotrigine--it doesn't leave one as completely zonked out as a benzo.

 

[hugo24]

A 9:1 binding ratio SERT/NET I know of Duloxetin and Venlafaxine in my book is extremely weak (30:1) in vitro,altough in vivo the reuptake inhibition ratio appears more balanced.Can you confirm you take Venlafaxine and not Duloxetin?

Interestingly,amphetamine (and Methcathinon) works quite well with Duloxetin,from my personal experience.

 

[DepressedADHDHelp]

RE: SNRI + Dexamphetamine Norepinephrine follow up post

Hello. This is the OP.

Actually, it isn't venlafaxine, it is DESvenlafaxine. Interestingly, it has the same ratio as cymbalta of SE:NE::1:9.... You are correct in saying effexor is 1:30 as well as duloxetine's 1:9 ratio.

DESvenlafaxine also has SLIGHT dopamine reuptake inhibition, which I don't think should be disreguarded. Finding the actual figure of the reuptake is nearly impossible as desvenlafaxine is fairly new and most studies done on this family's dopamine reuptake involve high doses of effexor.

However, I think it has more dopamine affinity than effexor does at high doses. I beleive if SE:NE is 1:9, then the DA is probably 30 parts to serotonin, but that is simply a deduction based on effexor being 1:30 for SE:NE. It could be less, and its obvoiusly not as potent as wellbutrin, though interestingly enough, when I combined my 50mg dose of pristiq (xr) with 150mg WEllbutrin SR (done twice with father's wellbutrin to see if I could use wellbutrin instead of amphetamines for ADHD, so it was for therapuetic experimentation not recreational as i obviouly didnt wanna take amp), i did not notice any difference in mood or concentration (dopamine), but i did have very slurred speech as if i drank or took too many benzos.

Desvenlafaxine is has potent NRI reuptake, especially in comparison to low dose effexor. I can tell you that before I even took any Dex. NE reuptake inhibition causes two things: dopamine to be increased in the prefrontal cortex and a slight elevation of serotonin.

I am beginning to think, based on my anxiety level and reactions to these meds (almost 6 months on desvenlafaxine), NRI's lower NE levels, and keep them regulated. Dr Jones says NRI's increase NE initially and as months go on, they downregulate them for their anxiolytic effect while also not sedating the patient.

Anyway, if anymore info is needed, i will post

PS Does anyone wanna theorize what happens to NE when low does of klonopin (.25-.5mg) are added to this environment? I would only suppose it lowers the NE as well, but thats kinda obvious...any input?

 

[DepressedADHDHelp]

sorry moderator, OP again.... forgot to reply to the other question re: klonopin that someone asked.

I am technically "bipolar", though i insistently disagree with my therapist and psych about this all the time and insist its more of mood instablility/impusilivness/hyperness attributed to ADHD and high NE levels that change (maybe thyroid related because I tested positive for mercury toxicity/heavy metal poisoning which i have been chelating from).....

Ive tried the typical antipsychotic/mood stabiliznig approach before. they are too much for whatever problem I have. Im not off the wall, I control my symptoms very well through behavioral adjustments (which mostly involves stayin away from certain people at certain times when necessary lol... in any case, i requested that we try a non-toxic alternative for my depression and anxiety (SNRI). with that, klonopin was added because it has slight anti-manic properties for when i get really, lets just say, worked up. its enough to stop my episodes if i take my maximum allowed daily dosage,which is 2mg, but that has rarely occured during my whole treatment. at 2mg, my episode is silenced.

i didnt want the toxicity of antipsychotics, plus i have adhd, so im not gonna be takin a liver destroying cockatil of stimulant, antipsych (which is the most toxic), and an antidepressent. the klonopin works very well for me, some days i dont take any, though im supposed to keep .5mg in my blood everyday for the agressive/mood swing stuff. like i said, i havent needed it that much, and in light of the dex, i can attribute most of my psyhiatric stuff to INCREASED norepinephrine/adrenaline, and low levels of serotonin and dopamine. at least thats how i see my issue.

the klonopin doesnt mute my dex effect. i also dont really get a high from dex at 10-15mg, if i go up to 20mg it starts to get speedy, but at 15mg its like my therapuetic dosage so im just working, not like "yay, i gota do some more stuff and have fun"...30mg+is a different story lol but i dont go there (experimenting with my scrips ended a long time ago, now i just want to be as functional as i can be)

THANK YOU

 

[spork]

^Replies from OP

 

[Lupus]

The way i understand it.

The dopamine action (DAT cells expelling DA)/MAOI action is really the important part that kicks in the rest of the drugs effects. Dopamine transferase breaks the influx of DA slowly into NE which inadvertently causes higher 5ht levels. DA is really the only thing getting pushed into your neuronal cleft and everything else is sort of a waterfall of side effects.

Thats the simplest way i can explain it.

Taking NRIs and dex at the same time was uncomfortable for me personally.

 

[ebola?]

as the increased 5-HT level helps prevent tolerance to the amphetamine

Interesting. What is the mechanism?

Why do you take the clonazepam, however (if I might ask)? Chances are that it is just counteracting all the wonderful cognition-enhancing effects of the amphetamine.

The doses he pointed to were pretty low. I would expect impairment to be minimal, although the formation of long-term memories in clear detail might be mildly hindered. I've found (along with others) that stims partially inhibit LTM formation in a different way, so there might be some unfortunate synergy...or at least an additive effect.

 

[DepressedADHDHelp]

re: SNRI on NE + dex

Id also like to know what ebola asked regaurding tolerance prevention thru snri's

also, ebola?, can you explain the affect on LTM (?) and the additive effect of small doses of clonazepam. honestly, the most ive taken in one day was .75mg, that was .25 (or a half of a .5mg pill) 3 times during the day, so there is no effect at all really on the dex effect.

 

[Chaos Butterfly]

^^

anon reply merged in.

 

[JustABump]

RIEMANN ZETA:

Because of your experience with almost identical meds (dex+venlafaxine), i would like to know about the neuroprotection and tolerance reduction, if you can expand on it or even maybe link us up with some of the scientific journal/medical articles that point to these benefits of the combination.

i admit, i have heard people on selective reuptake inhibitors sometimes have a problem with dex because of serotonin syndrome/toxicity. on addforums a few people have reported that they had to stop taking dex because of the ssri and switch to methylphenidate


EBOLA?:

I would like to know what you mean by "I've found (along with others) that stims partially inhibit LTM formation in a different way, so there might be some unfortunate synergy...or at least an additive effect. " I do not know what LTM stands for, and can you explain this synergy between stims and klonopin


FINALLY...for anyone at all:

Does anyone know Duloxetine or Desvenlafaxine's effect on DRI (dopamine reuptake inhibition). If SE:NE reuptake is 1:9, what would the dopamine be? also do you think there is strong affinity for DA receptors?

Last question is about DRI +Dexamphetamine. I've read this is a potential seizure risk if wellbutrin is too high, but at low/minimal/baseline/threshold doses of wellbutrin (lets say 150mg) what would the interaction produce. would the amphetamine be enhanced, less effective, or would this simply be neuroprotective on DA/NE sites?

Thank you Riemann Zeta, Ebola, and whoever has any idea about the last DRI+DEX question. Have a nice day.

 

[LabRatNW]

I am technically "bipolar", though i insistently disagree with my therapist and psych about this all the time and insist its more of mood instablility/impusilivness/hyperness attributed to ADHD and high NE levels that change (maybe thyroid related because I tested positive for mercury toxicity/heavy metal poisoning which i have been chelating from).....

My GF was told she was bipolar, but now we both know better. She has MAJOR PTSD issues from childhood physical abuse and bad relationships. They can exhibit similar symptoms, but in the end, antipsychotics just don't seem to work or over load PTSD patients. Thats why she's on an SSRI for some symptoms, and Adderall for her ADD. It seems Bipolar is the new catch-all for when they know there's something chemically awry, and figure they can throw meds at you to make it better.

 

[Lupus]

RIEMANN ZETA:Because of your experience with almost identical meds (dex+venlafaxine), i would like to know about the neuroprotection and tolerance reduction,

Neuroprotection from what? Its been established that there is no neurotoxicity with oral D-AMP despite whatever nonsense people say on this board. Ricarte was the only one to ever come to that conclusion and it turned out of course to be bunk just like all the other studies he did for the war on drugs.

 

[ebola?]

]
I would like to know what you mean by "I've found (along with others) that stims partially inhibit LTM formation in a different way, so there might be some unfortunate synergy...or at least an additive effect. " I do not know what LTM stands for, and can you explain this synergy between stims and klonopin

Sorry for the delay. What I mean is that I've found psychomotor stimulants to hinder mildly the formation of new long term memories (LTM), presumably through a mechanism other than benzodiazapines. I have a feeling that this effect is somehow tied to the subjective experience of time-constriction. This is nothing obvious, but it does mean that I'm usually better off 'hitting the books' sober, unless I take extensive notes to what I'm reading.

Now, there might be some sort of additive effect in terms of impairment when stimulants are combined with GABAnergics, perhaps boosting otherwise behaviorally nonexistent impairment to a level that matters.

ebola

 

[Idontknowbutiask]

Lupus:

Im not sure aside from the fact that Riemann Zeta has said it, and a few other people have said it as well. I really dont know to be honest. Maybe its neurotoxic against methamphetamine?

actually, im curious. could you combine snri's like pristiq effexor and cymbalta with methamphetamine? would it be a good comibation as with dex/adderall/ritalin,etc...? would it be protective from meth neurotoxicity (like how SSRIs protect from MDMA toxicity)? or would you be doing the opposite, like maybe serotonin toxicity or syndrome?

I dont mean to sidetrack or go off topic, but instead of starting another thread i thought it just ask since its really kinda related in a way (antidepressants with adhd stimulant meds)

So...anyone wanna guess or actually know (journal aarticles) about combing SNRI's (or even SSRI's) with methamphetamine. (im sure theres some info on ssris+meth on the site probly)

THANKS

 

[taylorbb]

I have been on bupropion (a NE/DA reuptake inhibitor) and Vyvanse (prodrug that metabolizes to dextroamphetamine) for about a month now. I am a third year pharmacy student and I have scoured the medical literature and clinical trials and studies for HOURS looking for some kind of interaction/connection with these two. It doesn't make sense to me that they both release and prevent reuptake of NE and dopamine at the alpha-2 adrenergic receptors in the CNS. I swear that I think bupropion somehow can block or blunt the effects of the amphetamine. I am taking Vyvanse for clinically-diagnosed hypersomnolence, which pretty much is borderline narcolepsy without all the paralysis and crazy hallucinations. I have been increased from 30mg (equal to 20 mg Adderall XR) to 70mg (equal to 30 mg Adderall XR) in a period of 3 weeks with 2 titrations from 30 to 60 to 70mg. I STILL cannot stay awake to save my life. I notice that when I stop taking the Wellbutrin, the next day, my dose of Vyvanse feels more potent, but not in a good way. I am extremely fatigued, mainly because I am lightheaded and burning up from the cardiovascular effects of the amphetamine.

My question is if anyone else has experienced this. The day after I didn't take my Wellbutrin (I'm on 150mg XL, so it took a day or so to be eliminated from my body) my blood pressure shot up to 152/116 (normal for me is around 120s/mid-80s) and my pulse was 140 (normal of 100). I had to take a beta-blocker to bring it back in check because it stayed high for at least 3 hours.

I truly believe there is some inhibition going on with these two, and it probably holds true for any other antidepressant that affects NE or DA, like Pristiq, Effexor, Cymbalta...maybe not so much for SSRIs but who knows? Still trying to locate actual literature preferably related more to hypersomnia/narcolepsy instead of ADHD. If anyone has any info, please pass it on.

 

[seep]

Taylor, seeing as how bupropion acts as an NE releaser and a NAchR antagonist, and its side effect profile includes vasodilation and postural hypotension...

Personally, the combo has triggered panic attack on more than one occasion, and the old immediate-release bupes gave me profoundly grandiose and sometimes even messianic delusions.

Out of curiosity what's the cause of the hypersomnia do you know?

 

[taylorbb]

They never determined why I have hypersomnia. The technical term for it is primary idiopathic hypersomnolence. I had an overnight polysomnogram done to rule out sleep apnea and RLS, and then I had a multple sleep latency test (MSLT) done to determine how fast I could fall asleep at 2 hour time intervals. I wish I knew why, cause this Vyvanse is awesome for about 6 hours, then it wears off. I'm thinking I may have hyperactive hepatic enzymes that are breaking it down too quickly instead of it lasting 10-12 hours like it's supposed to. I am afraid to tell my sleep practitioner that I think I may need an extra Adderall IR perhaps around noon just to pull through the rest of my school day. I have to study at night, and it's exhausting to try and stay awake and stay focused. I usually break down and take a nap, which just makes it worse. I don't want the MD thinking I'm a drug seeker if I suggest Vyvanse 70mg plus adderall 10-20 mg on top of it. I'm already maxed out on Vyvanse, but I don't want to switch to other med. I dont know what else to do. If Vyvanse 70mg and bupropion 150 XL won't keep me awake, I don't know what will. And trying not to send my heart into overdrive.