203 replies to this topic

[fishinghat]

That is a good point. If my memory serves me correctly I believe I have read studies to that effect. I will see what I can find (hopefully) later today.

[fishinghat]

Per your request...

 

J Biol Chem. 2014 Sep 5; 289(36): 25177–25185. 

 

Synergistic Regulation of Glutamatergic Transmission by Serotonin and Norepinephrine Reuptake Inhibitors in Prefrontal Cortical Neurons*

 

We found that low dose SNRIs, by acting on 5-HT1A and α2-adrenergic receptors, synergistically reduced AMPA receptor (AMPAR)-mediated excitatory postsynaptic currents and AMPAR surface expression in prefrontal cortex pyramidal neurons via a mechanism involving Rab5/dynamin-mediated endocytosis of AMPARs.  Moreover, the depression of AMPAR-mediated excitatory postsynaptic currents by SNRIs required p38 kinase activity, which was increased by 5-HT1A and α2-adrenergic receptor co-activation in an activator of G protein signaling 3-dependent manner. These results have revealed a potential mechanism for the synergy between the serotonin and norepinephrine systems in the regulation of glutamatergic transmission in cortical neurons.

-------------------------------------------------------------------------------------------------------------------------

https://www.ncbi.nlm...les/PMC4713700/

 

Int J Clin Exp Pathol. 2015; 8(11): 15454–15461. 

 

Effects of duloxetine on microRNA expression profile in frontal lobe and hippocampus in a mouse model of depression

 

A significant upregulation of miR-132 and miR-18a in hippocampus in the duloxetine treatment group compared with model group, whereas the levels of miR-134 and miR-124a were significantly downregulated. Furthermore, miR-18a showed significant upregulation in frontal lobe in the duloxetine treatment group relative to model group. Our data showed that miRNA expression profile in frontal lobe and hippocampus was affected by duloxetine in mice model of depression. The effect was especially pronounced in the hippocampus, suggesting that hippocampus might be the action site of duloxetine, which presumably worked by regulating the expression of miRNA levels.

 

-----------------------------------------------------------------------------------------------------------------------------

http://microship.com...ation-syndrome/

 

Phantosmia and SSRI Discontinuation Syndrome A frustrating change of perception

 

There has been research linking phantosmia with a depressed level of the inhibitory GABA in the CNS. In addition, there have been unrelated research projects linking SSRI/SNRI discontinuation with disinhibition of the excitatory glutamatergic system. Discussion of this can get lost in double-negatives, but in essence, from the perspective of many parts of the brain, GABA is a brake and glutamine is an accelerator (a grotesque simplification, but instructive).

-----------------------------------------------------------------------------------------------------------------------------

https://www.ncbi.nlm...pubmed/16522641

 

Chronic antidepressants potentiate via sigma-1 receptors the brain-derived neurotrophic factor-induced signaling for glutamate release.

 

BDNF has been shown by us to reinforce excitatory glutamatergic transmission in cultured cortical neurons 

------------------------------------------------------------------------------------------------------------------------

https://pubmed.ncbi....h.gov/27443158/

 

Mol Neurobiol

2017 Aug;54(6):4683-4695. doi: 10.1007/s12035-016-9992-1. Epub 2016 Jul 21.

 

Duloxetine Reduces Oxidative Stress, Apoptosis, and Ca 2+ Entry Through Modulation of TRPM2 and TRPV1 Channels in the Hippocampus and Dorsal Root Ganglion of Rats

 

Abstract

Overload of Ca2+ entry and excessive oxidative stress in neurons are the two main causes of depression. Activation of transient receptor potential (TRP) vanilloid type 1 (TRPV1) and TRP melastatin 2 (TRPM2) during oxidative stress has been linked to neuronal survival. Duloxetine (DULOX) in neurons reduced the effects of Ca2+ entry and reactive oxygen species (ROS) through glutamate receptors, and this reduction of effects may also occur through TRPM2 and TRPV1 channels. In order to better characterize the actions of DULOX in peripheral pain and hippocampal oxidative injury through modulation of TRPM2 and TRPV1, we tested the effects of DULOX on apoptosis and oxidative stress in the hippocampal and dorsal root ganglion (DRG) neurons of rats. Freshly isolated hippocampal and DRG neurons were incubated for 24 h with DULOX. In whole-cell patch-clamp and intracellular-free calcium ([Ca2+]) concentration (Fura-2) experiments, cumene hydroperoxide and ADP-ribose-induced TRPM2 currents in the neurons were inhibited by N-(p-amylcinnamoyl) anthranilic acid (ACA) and capsaicin-induced TRPV1 currents were inhibited by capsazepine (CPZ) incubations. TRPM2 and TRPV1 channel current densities, [Ca2+] concentration, apoptosis, caspase 3, caspase 9, mitochondrial depolarization, and intracellular ROS production values in the neurons were lower in the DULOX group than in controls. In addition, the above values were further decreased by DULOX + CPZ and DULOX + ACA treatments. In conclusion, TRPM2 and TRPV1 channels are involved in Ca2+ entry-induced neuronal death and modulation of the activity of these channels by DULOX treatment may account for their neuroprotective activity against apoptosis, excessive ROS production, and Ca2+ entry.

------------------------------------------------------------------------------------------------------------------------

https://pubmed.ncbi....h.gov/24145093/

 

Pharmacol Rep

. 2013;65(4):991-7. doi: 10.1016/s1734-1140(13)71080-6.

 

Involvement of NMDA and AMPA receptors in the antidepressant-like activity of antidepressant drugs in the forced swim test

 

Abstract

Background: The involvement of glutamate system (particularly the NMDA and AMPA receptors) in the mechanism of antidepressant activity was demonstrated in preclinical and clinical studies.

Methods: In the present study, we investigated the effect of NMDA and AMPA receptors' ligands (agonists and antagonists) on the antidepressant-like activity of escitalopram, milnacipran, imipramine and reboxetine in the forced swim test in mice.

Results: Antidepressant activity (reduction in immobility time) of escitalopram and milnacipran but not of imipramine and reboxetine was antagonized by N-methyl-D-aspartate acid. CGP37849 (antagonist of the NMDA receptor) enhanced the antidepressant activity of all examined antidepressants. On the other hand, CX614 (a potentiator/positive allosteric modulator of the AMPA receptor) enhanced the antidepressant activity of imipramine and reboxetine but not of escitalopram and milnacipran in this test. NBQX (the AMPA receptor antagonist) did not influence the antidepressant activity of all tested agents.

Conclusions: The data indicate the complex interactions following the activation or blockade of the NMDA and AMPA receptors with antidepressant drugs. The general phenomenon is the enhancing effect of the NMDA receptor antagonism on the antidepressant activity. Moreover, is can be concluded that the activity of antidepressants with a serotonergic mechanism of action can be inhibited by NMDA activation, while antidepressants with a noradrenergic mechanism of action are dependent on AMPA receptor transmission.

----------------------------------------------------------------------------------------------------------------------

https://pubmed.ncbi....h.gov/23895555/

 

BMC Neurosci

. 2013 Jul 29;14:75. doi: 10.1186/1471-2202-14-75.

 

Chronic treatment with agomelatine or venlafaxine reduces depolarization-evoked glutamate release from hippocampal synaptosomes

 

Abstract

Background: Growing compelling evidence from clinical and preclinical studies has demonstrated the primary role of alterations of glutamatergic transmission in cortical and limbic areas in the pathophysiology of mood disorders. Chronic antidepressants have been shown to dampen endogenous glutamate release from rat hippocampal synaptic terminals and to prevent the marked increase of glutamate overflow induced by acute behavioral stress in frontal/prefrontal cortex. Agomelatine, a new antidepressant endowed with MT1/MT2 agonist and 5-HT2C serotonergic antagonist properties, has shown efficacy at both preclinical and clinical levels.

Results: Chronic treatment with agomelatine, or with the reference drug venlafaxine, induced a marked decrease of depolarization-evoked endogenous glutamate release from purified hippocampal synaptic terminals in superfusion. No changes were observed in GABA release. This effect was accompanied by reduced accumulation of SNARE protein complexes, the key molecular effector of vesicle docking, priming and fusion at presynaptic membranes.

Conclusions: Our data suggest that the novel antidepressant agomelatine share with other classes of antidepressants the ability to modulate glutamatergic transmission in hippocampus. Its action seems to be mediated by molecular mechanisms located on the presynaptic membrane and related with the size of the vesicle pool ready for release.

------------------------------------------------------------------------------------------------------------------------

https://pubmed.ncbi....h.gov/22840611/

 

J Affect Disord

. 2013 Apr 5;146(2):262-5. doi: 10.1016/j.jad.2012.06.037. Epub 2012 Jul 25.

 

Cerebrospinal fluid levels of glutamate and corticotropin releasing hormone in major depression before and after treatment

 

Abstract

Background: Glutamate and corticotropin releasing hormone (CRH) are pro-stress neurotransmitters and may be altered in the plasma and cerebrospinal fluid (CSF) of persons with major depressive disorder (MDD). The goal of this study was to compare the CSF levels of glutamate, glutamine and CRH between patients with depression and healthy controls.

Methods: Eighteen patients with MDD and 25 healthy controls underwent a lumbar puncture (LP); CSF samples were withdrawn and assays were done for glutamine, glutamate, and CRH. Patients with MDD underwent 8 weeks of treatment with the antidepressant venlafaxine and then had a repeat LP post treatment.

Results: Patients had higher baseline scores on depression and suicide rating scales and those scales improved significantly post-treatment. Higher suicidal ratings at baseline were correlated with higher glutamate levels (p=0.016). There were no significant differences between the control and patient group in any baseline CSF measures of glutamate (p=0.761), glutamine (p=0.226) or CRH (p=0.675). Despite no significant change in glutamate (p=0.358) and CRH (p=0.331) in the treatment group, there was a post-treatment decrease in glutamine (p=0.045) in patients.

Limitations: There was a small sample size, age discordance between patients and controls, lack of a follow-up LP in controls, absence of dexamethasone suppression testing, and fluctuating sample sizes among various measures.

Conclusion: Although no significant differences were noted between patients and controls at baseline there was an association of high CSF glutamate and suicidal ideation and lower glutamine post-treatment which may be correlated with attenuation of dysfunction in the glutamatergic system after antidepressant treatment.

---------------------------------------------------------------------------------------------------------------------------https://pubmed.ncbi....h.gov/19447293/

 

Neurosci Res

. 2009 Jul;64(3):251-8. doi: 10.1016/j.neures.2009.03.009. Epub 2009 Mar 25.

 

Effects of antidepressants on GluR2 Q/R site-RNA editing in modified HeLa cell line

 

Abstract

Marked reduction of RNA editing at the glutamine (Q)/arginine ® site of the glutamate receptor subunit type 2 (GluR2) in motor neurons may be a contributory cause of neuronal death specifically in sporadic ALS. It has been shown that deregulation of RNA editing of several mRNAs plays a causative role in diseases of the central nervous system such as depression. We analyzed the effects of eight antidepressants on GluR2 Q/R site-RNA editing in a modified HeLa cell line that stably expresses half-edited GluR2 pre-mRNA. We also measured changes in RNA expression levels of adenosine deaminase acting on RNA type 2 (ADAR2), the specific RNA editing enzyme of the GluR2 Q/R site, and GluR2, in order to assess the molecular mechanism causing alteration of this site-editing. The editing efficiency at the GluR2 Q/R site was significantly increased after treatment with seven out of eight antidepressants at a concentration of no more than 10 microM for 24h. The relative abundance of ADAR2 mRNA to GluR2 pre-mRNA or to beta-actin mRNA was increased after treatment with six of the effective antidepressants, whereas it was unchanged after treatment with milnacipran. Our results suggest that antidepressants have the potency to enhance GluR2 Q/R site-editing by either upregulating the ADAR2 mRNA expression level or other unidentified mechanisms. It may be worth investigating the in vivo efficacy of antidepressants with a specific therapeutic strategy for sporadic ALS in view.

-------------------------------------------------------------------------------------------------------------------------------

https://pubmed.ncbi....h.gov/18208909/

 

Randomized Controlled Trial J Psychopharmacol

. 2008 Jul;22(5):473-6. doi: 10.1177/0269881107081510. Epub 2008 Jan 21.

 

Differential effects of citalopram and reboxetine on cortical Glx measured with proton MR spectroscopy

 

Abstract

The pharmacological effects of monoamine potentiating antidepressants are likely to be expressed ultimately on cortical pyramidal neurones that use glutamate as a neurotransmitter. However, there are few data on the effects of antidepressant treatment on cortical glutamate levels in humans. The aim of the present study was to use proton magnetic resonance spectroscopy (MRS) to assess the effects of short-term administration of the selective serotonin re-uptake inhibitor, citalopram and the selective noradrenaline re-uptake inhibitor, reboxetine, on a composite measure of glutamate and glutamine (Glx) in occipital cortex in healthy volunteers using a parallel group, placebo-controlled design. We found that relative both to placebo and reboxetine, seven days treatment with citalopram significantly increased cortical Glx. Our data suggest that short-term treatment with citalopram, but not reboxetine, increases occipital Glx in healthy subjects. Further studies are needed to find out if similar effects occur in anterior brain regions and whether they reflect changes in glutamate or glutamine or both.

--------------------------------------------------------------------------------------------------------------------------

And many more similar articles. I you decide you want to see more articles let me know.

[invalidusername]

Well there is another few pages for the next eBook update

[Troypants]

Also, do you guys still recommend ashwaghanda? No bad withdrawal? Dosages?

[Troypants]

Yeh there ya go! Thanks for those articles, they would be a good addition to the book!

So, instead of the usual GABA desensitisation which happens in benzo withdrawal, with SSRIs we are talking about a sensitisation of glutamate activity, and particularly the AMPAR is affected by SNRIs.

[Troypants]

In effect, it is a similar result I guess?

[Troypants]

https://www.scienced...006322312009900

Another good study on glutamate and antidepressants

[invalidusername]

Also, do you guys still recommend ashwaghanda? No bad withdrawal? Dosages?

 

Covered somewhere in the eBook, but no withdrawals at all. Always better to opt for the finest which is KSM-66 variant. 

 

Much like anything else, dose varies from person to person. I found around 1000mg was my sweet spot. One thing to remember with Ashwagandha is that you need to take a tolerance break as the system gets used to it quite quickly. Again, it varies, but as a guide, it is recommended to take 2-3 days off every couple of weeks to maintain potency. 

[Troypants]

Thanks IUN, I might buy some powder.

I have been using 50mg l-theanine 2ce a night along with 300-400 NAC, seems to cut the edge off the horribleness of the evening anxiety. I take my doses during the day and by the end of the day I get worse anxiety and other crappy sensations.

I have had my hormones checked, my e2 is normal but my testosterone is below the lowest level.... 120 when it should be 150-600.

Do any of you have experience supplementing testosterone?

[fishinghat]

Cymbalta shut down my testosterone production and I have been on testosterone replacement therapy since 2013. Do you have some questions I can help with?

[Troypants]

Hey hat, yeah I was just wondering if testosterone replacement made your withdrawal easier or harder?

I wasn't sure whether the low test was from previous AAS use or from the cymbalta, but it looks more like its from the cymbalta.

[invalidusername]

Quite likely the cymbalta, but it will be difficult to know the true culprit.

 

Best just to keep check of it. I found that Maca root helped me a lot before opting for the allopathic route.

[fishinghat]

It definitely made it harder Troy. Low testosterone causes depression and too high causes a stimulation effect, higher energy, which can aggravate anxiety. It can take testosterone levels 6 weeks to stabilize after a dose change so definitely makes things harder to control.

[Troypants]

So you recommend just waiting till I'm off the cymbalta and see how I go? Still holding at 16 beads until I feel normal.

Might be quite a while

[fishinghat]

Then data my drs gave me was that testosterone usually rebounded to near normal levels within 3 months after the last dose. I emphasize "usually". Obviously that didn't happen in my case. I am sure age can play an important part as well as to whether or not you recover testosterone production or not. In addition, if the depression it may cause gets too bad you might have no choice but to go ahead with replacement therapy. If you can, I would wait until Cymbalta withdrawal was over and keep measuring your testosterone levels every 6 months. Something else you may want to do is try some supplements to increase production. I looked at that when my levels collapsed and will see if I have any research saved on my computer. I will let you know.

[fishinghat]

Unluckily I did not save any of my research on what supplements to use. Sorry.

[Troypants]

All good thanks for having a look, I just hope the lowered test isn't going to cause me to be more withdrawn. I don't want to be around people at the moment, I get foreign ideas and feelings and anxious and I hate the hypersensitivity which makes me put off signals to people that aren't me.

It took me a long time to get social, motivated, and comfortable after recreational drug rehabilitation and now I'm going through it all over again, and its not from rec drug use, its from the shit my "trusted doctor" put me on.

Isolation and lack of motivation causes depression which causes isolation and lack of motivation and on and on the cycle goes until you can't go outside... Its a scary prospect.

[Troypants]

Hey IUN, I just got my ashwaghanda, it's 3-4% withanolides(I think that's what they are), its not ksm-66 but I'll see how I go.

How much would you suggest to take and how often? I saw another member take 800mg twice a day?

[invalidusername]

The withanolides are the active parts of the ashwagandha and the fact that it is estimated at 3-4% is not always a good sign. But all the same, you have it now and hopefully it will give you a good indication if it is going to work. For the record, pure KSM-66 will be a minimum of 5% withanolides, otherwise it is not KSM-66. 

 

I would suggest you try 800mg when you feel you need it. It acts fairly quickly. If it works, any stress or anxiety will dissipate within 20-45 minutes. The effect is simply "not caring" about what is going on. It is sort of a drunk type of feeling is you have hit the sweet spot. But not to the point that you feel out of control and there will of course be no hangover!

 

The issue with non-KSM is that they get the plant - the whole plant - and grind it up and put the result in the capsules - hence the estimation. You get leaf, stem, root - the lot. Whereas KSM is the thickest part of the root, which is the most potent. But all the same, try with what you have. 

 

Remember that KSM is at least 3 times more potent than the non-standardised version. I took around 1gm of KSM, so that would be the equivalent of 3gm (3000gm) of what you have. So don't be disappointed if 800gm does nothing. It is perfectly safe to try 3gm (3000mg) in one sitting, but the quality is the factor here, not the quantity.

 

Have a go and let us know what you find.

 

I am always here for questions...

 

IUN

[Troypants]

Hey IUN, I have been taking 3g in the morning and 3g at night, it was nice the first couple of days, not so much of an effect now but apparently it can lower cortisol and raise testosterone over time? Also supposedly has long term effects on anxiety?
Do you recommend using like this or just using PRN?

Its a pretty torturous process this withdrawal, seems like it goes in waves, you start to feel good for a few days, followed by brain zaps, palpitations and physical symptoms, followed by stupid anxiety and mental symptoms, then back to feeling good again... I've written this down to see if its a recurring pattern.

[fishinghat]

That is a standard pattern for sure. Hang in there sir. It will get there.

[invalidusername]

Hey Troy - apologies for delay. I got hit pretty bad with "man flu" and was laid up for a few days...

 

"I have been taking 3g in the morning and 3g at night, it was nice the first couple of days, not so much of an effect now."

That is a big dose to start with but a non-standardised dose will vary in potency and some people do need to get the dose right, so even 5g might be right, but that would be about 1.5g of KSM at most.

 

"but apparently it can lower cortisol"

Absolutely... that's the idea! We don't want stress in our lives!!

 

and raise testosterone over time?

Yes, this has been the result of some studies in larger doses

 

Also supposedly has long term effects on anxiety?
In what respect? Bad effects? Good effects obviously, which is why we take it!

 

Do you recommend using like this or just using PRN?

I would suggest taking it as it is needed - there is no problem taking it PRN at all as the potency will be better, but some people can get hooked on the effect and end up taking more and more, but that won't work as you will hit a tolerance wall. It is a supplement remember. So I would take it when needed - if that is daily, so be it, but it shouldn't be taken routinely if not needed to build up a "store" and it doesn't work like that. If you are having a good day, don't take it.

[Troypants]

Hey IUN, all good mate, I just got back from a camping(glamping) trip.

Miserable last couple of days, anxiety makes me want to do nothing, and doing nothing makes me feel depressed and hopeless.

I think the problem with social anxiety is that every time I go out I get punished rather than rewarded for social interaction. Its like being punched in the face every time I see people, just makes me want to stay home. I wonder how good it is for me?

OK, so today I had no ashwaghanda, felt what seemed like a high cortisol day, went spastic over a computer game and punched the couch, I haven't done that since I was a kid.

I was hoping taking it every day could raise my testosterone a bit because I work out, and losing muscle is another thing which makes me miserable. But if you reckon just take it PRN, then I'll just take it 4-5 days if needed per week.

I have Christmas coming up and I don't feel like going, do you think benzodiazepines would help with the day or will they go paradoxical? I have some research benzos, flualprazolam and etizolam which I could take if needed but I am afraid of having a paradoxical reaction and making my day realllllly unmanageable.

The worst thing is, being around people and being so damned skittish and hyperfocused my thoughts get all bent up and my body language betrays me, then people get uncomfortable because I put off vibes, and then I just want to hide under the floorboards. I think I have given myself a phobia or something..


I've been here before though, when withdrawing from phenibut. And I did get better, it was a slow process over years similarly, its only looking back that I noticed how far I had come.

[fishinghat]

Years, yes indeed. z test of patience and endurance.

[Troypants]

What do you think hat? Is it safe to take a benzo on Christmas? Is there any significant risk of paradoxical effect?

[fishinghat]

Unless you have adhd it is possible but unlikely.

[Troypants]

Thanks hat, I'll prepare a solution and just have it there in case.

I may not even feel like I need it, it may alleviate the phobia I've given myself around having panic attacks in company though....

[fishinghat]

The best medicine I have found for panic attacks is Clonidine. It is not addictive and has no withdrawal. You might consider talking to your dr about it.

[Troypants]

I don't think I could use it, I am taking a beta2 blocker (bisoprolol) and an ace inhibitor(perindopril).

I will be stopping the beta blocker after this because my blood pressure has dropped quite a bit since basically stopping the cymbalta (2.5mg left)

[fishinghat]

You are correct. A no-go for clonidine or probably any other panic attack medication as they will surely reduce blood pressure as well. 

 

You do know to wean off the bisoprolol over a two or three week period, right? Not a true withdrawal but stopping it suddenly can cause a large spike in blood pressure which can be avoided by a short taper.