16 replies to this topic

[metabrain]

N-Acetylcysteine (NAC) worked really well for me for my Bipolar 2 however I noticed I didn't seem to enjoy anything, music, T.V. the movies. Not that it made me depressed but it was like I no longer had any emotional response. Has anyone else experienced this and could I add something else to even it all out?

[Duchykins]

NAC indirectly increases histamine. Anhedonia is one symptom that can be caused by elevated histamine. Increases in histamine doesn't necessarily mean sinus/eye troulble or itching

Perhaps try an antihistamine like Zrytec or Claritin? You'd have to give them 24 hours before expecting results, though.

If nothing after two days, then you know histamine isn't the problem

[metabrain]

Very Interesting. I think I have some anti histamine somewhere around here, I will give that a go.

[Flex]

I experience this also when using it.

I really dont like it and it increases the long lasting side effects of Cannabis anhedonia.

Its Mglu1 activating effects can be also perhaps be blamed for.

Mglu1 is implicated in endocannabinoid transmission, however I dont know if this is the cause for the anhedonia.

 

 

[Duchykins]

Ill-informed my ass.

http://clinicaltrial...how/NCT01209455

N-acetylcysteine (NAC) has been the antidote of choice for over 30 years but its use is associated with adverse effects in 40% of cases. Patients characteristically experience nausea, vomiting and an anaphylactoid ('pseudo-allergic') syndrome. This reaction is clinically similar to true anaphylaxis (allergic reaction) including flushing, rash, constriction of airways, and a fall in blood pressure, but occurs via a different mechanism. Although treatable, these reactions lead to patient distress, commonly cause confusion among treating physicians, and lead to significant delays in antidote administration. The aetiology of these adverse reactions to NAC remains unclear. We hypothesise: i) these reactions result from a dose-dependent release of the chemical histamine, causing dilatation of blood vessels (vasodilatation) and the anaphylactoid syndrome; ii) paracetamol conversely exerts a protective effect on the reaction, with a less severe reaction observed in the presence of higher paracetamol concentrations. We will investigate the mechanisms underlying adverse reactions to NAC in the human forearm model, examining the role of histamine and other markers involved in the inflammatory process.

ClinicalTrials.gov processed this record on July 31, 2014




http://www.ncbi.nlm..../pubmed/2409763

Histamine secretion induced by N-acetyl cysteine



Abstract
The mucolytic drug N-acetyl cysteine has been shown to release histamine from cultured mouse mast cells and from human basophils. At neutral pH the release was moderate and non-cytotoxic. If the acidity of the drug was not neutralized, this histamine release was markedly potentiated, but was then associated with a reduction in the viability of the cells. However, the high level of release could not be reproduced by simply exposing the cells to an acidic medium. The results are discussed in terms of a possible mechanism for the adverse reactions sometimes observed during N-acetyl cysteine therapy





http://www.ncbi.nlm....pubmed/20136478


Paracetamol (acetaminophen) attenuates in vitro mast cell and peripheral blood mononucleocyte cell histamine release induced by N-acetylcysteine.
Coulson J1, Thompson JP.
Author information

Abstract
INTRODUCTION:
The treatment of acute paracetamol (acetaminophen) poisoning with N-acetylcysteine (NAC) is frequently complicated by an anaphylactoid reaction to the antidote. The mechanism that underlies this reaction is unclear. We used the human mast cell line 1 (HMC-1) and human peripheral blood mononucleocytes (PBMCs) to investigate the effects of NAC and paracetamol on histamine secretion in vitro.

METHOD:
HMC-1 and human PBMCs were incubated in the presence of increasing concentrations of NAC +/- paracetamol. Cell viability was determined by the Trypan Blue Assay, and histamine secretion was measured by ELISA.

RESULTS:
NAC was toxic to HMC-1 cells at 100 mg/mL and to PBMCs at 67 mg/mL. NAC increased HMC-1 and PBMC histamine secretion at concentrations of NAC from 20 to 50 mg/mL and 2.5 to 100 mg/mL, respectively. NAC-induced histamine secretion by both cell types was reduced by co-incubation with 2.5 mg/mL of paracetamol.

CONCLUSION:
Paracetamol (acetaminophen) is capable of modifying histamine secretion in vitro. This may explain the clinical observation of a lower incidence of adverse reactions to NAC in vivo when higher concentrations of paracetamol are present than when paracetamol concentrations are low. Paracetamol (acetaminophen) attenuates in vitro mast cell and PBMC cell histamine release induced by NAC.



Morons. NAC does and WILL bother some people.

I had to look all this crap up months ago because NAC did the same thing to me. $30 down the drain.

[Duchykins]

Anyways OP if you get no result from the antihistamine, perhaps try Tylenol. Haha

[hmahal]

Keep in mind that if you're using antihistamines, you'll want to use 1st generation ones (modern antihistamines either minimally or don't cross the blood-brain-barrier ("non-drowsy"))

Edited by hmahal, 01 August 2014 - 09:59 AM.

[metabrain]

It's strange though that you mention it releases histamine, I have Bipolar and problems wit hhistamine binding is implicated, for me NAC worked really well for my depression but of course I experienced a lack of pleasure in things. I was hoping there was a way to have my cake and eat it so to speak. 

[lourdaud]

This is probably not because of histamine. Cysteine modulates glutamatergic transmission and glutamate release in the brain's reward system. I believe this is why it can be useful for bipolar, addictions etc.

[Duchykins]

It's strange though that you mention it releases histamine, I have Bipolar and problems wit hhistamine binding is implicated, for me NAC worked really well for my depression but of course I experienced a lack of pleasure in things. I was hoping there was a way to have my cake and eat it so to speak.

It's still possible that histamine isn't the culprit, or at least has only a small role to play. Histamine actually does have a role in the pleasure-reward system, it's been studied in relation to alcohol addiction, and we also know there is a relationship between glutamate and histamine, though not as well understood as glutamate and GABA.

But it could be that neither histamine nor glutamate is the problem here, but dopamine. Or serotonin and norepinphrine, since NAC affects all three of those. Think of it like any other anti-depressant; good for some, meh for others, and bad for others still.


How much NAC were you taking and how long? How long before you noticed the anhedonia? And were you taking any prescriptions at the same time?

[metabrain]

I was taking 800 mg of NAC by Temmler pharma in effervescent form. It was maybe a day or two but it calmed me within an hour of taking it. Very relaxing. I could sleep really well on it too.

[Flex]

I experience this also when using it.

I really dont like it and it increases the long lasting side effects of Cannabis anhedonia.

Its Mglu1 activating effects can be also perhaps be blamed for.

Mglu1 is implicated in endocannabinoid transmission, however I dont know if this is the cause for the anhedonia.

 

Sry have to revise this.

Seems that my memory is somehow bad and I will try to post allways references to my statements.

 

The only related thing to my statement is:

http://www.plosone.o...al.pone.0032503

 

Moreover it seems that it activates mGlu2/3

http://www.ncbi.nlm....pubmed/24987341

http://www.pubfacts....-Behavioral-mol

 

and mGlu5

http://www.pubfacts....apse-to-cocaine.

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

Comming back to the topic, I think that mGlu2 could be responsible for its dulling effects.

http://en.wikipedia.org/wiki/MGS-0039

 

But I´m not sure whether mGlu5 could be also be implicated

http://www.future-sc...4155/fmc.13.137

It is likely that PAMs specific for mGluR5 still have some indirect impact on the
dopaminergic system, due the reported associations between mGluR5 and dopamine.

For example, the mGluR5 PAM CDPPB has been shown to reduce amphetamine-induced hyperlocomotion and

prepulse inhibition deficits, presumably mediated through the dopaminergic system[18]
Furthermore, the dopamine D2 receptor and mGluR5 reportedly form heterodimers in the striatum, particularly at the

corticostriatal glutamate synapse, suggesting a possible avenue for indirect effects of mGluR5 PAMs on striatal dopaminergic signaling[19]

 

[19]

An integrated view on the role of receptor mosaics at perisynaptic level: focus on adenosine A(2A), dopamine D(2), cannabinoid CB(1), and metabotropic glutamate mGlu(5) receptors.

http://www.ncbi.nlm....pubmed/20524778

Edited by Flex, 01 August 2014 - 09:02 PM.

[metabrain]

That is some really interesting information Flex, it seems every thing that works great for my Bipolar has really bizarre side effect profiles. I guess it's a matter of finding the right combination of items though. 

[Blackkzeus]

It's definitely something with glutamate. i think lowering glutamate levels may decrease emotional range. My comment means nothing , I have no evidence to back this up. But whenever I take supplements that negatively modulate nmda receptors my emotions become duller. I Experienced the same thing with NAC as the OP

[deeptrance]

General NAC question --- I've been taking 700 mg twice a day, once when I first wake up and then about a half hour before bedtime with glycine, magnesium, taurine, and tryptophan. Is 1400 a day too much? I haven't noticed any problems associated with it, but that doesn't mean there aren't any. I'm hyper-sensitive to excess glutamate activity, so I'm encouraged to read that NAC can counteract that to some extent. Am wondering if maybe I should skip the morning dose and just take it at night, although I take spirulina and nutritional yeast in the AM and those are both very high in glutamic acid, and I even get tingles and jitters from those sometimes.

[Daniel Cooper]

If anyone is still experiencing a dulling of their emotions on NAC, try Glycine. I respond positively to NAC, helps my thoughts flow more freely and naturally and I enjoy things better. For the longest time I thought NAC reduced glutamate overload by creating more glutathione and using up glutamate, however I'm starting to lean in the direction that NAC positively modulates glutamate firing. Please check out my thread if you would like more knowledge on this, or if you can contribute anything.

 

http://www.longecity...an/#entry746719

 

This was posted in my thread by Nootist:

"It has been postulated that cysteine may cross the BBB via a sodium-dependent transport system where it is converted into cystine, the di-sulfide derivative of cysteine. High levels of cystine stimulate the exchange of intracellular glutamate for cystine through the cystine-glutamate antiporter, thereby elevating non-synaptic glutamate. This process activates the metabotropic glutamate receptors (mGluR2/3) on presynaptic neurons, responsible for inhibiting the synaptic release of glutamate and thereby restoring extracellular glutamate levels in the nucleus accumbens. Regulating this exchange system has been shown to improve impulse control and reduce addictive behaviour both pre-clinically and clinically. Intracellular cystine can then be reduced back to cysteine and used for GSH production, the potent and most abundant endogenous antioxidant in the body."

http://www.ncbi.nlm....les/PMC4423164/

 

I have an idea that anhedonia from NAC is caused by one of two things:

1. Excessive acetyl- groups contribute to acetylcholine overload (emotional dulling, brain fog, neck pain, irritability). I dont have evidence to back this up but I know this is how ALCAR increases acetylcholine by donating an acetyl- group.
2. Reducing the amount of Glycine that is active in the CNS. If more glutamate is available in the extracellular space, then more Glycine will be used up to agonize the NMDA receptor. Since the NMDA needs both co-agonists, glutamate and glycine (or D-serine), then maybe NAC should be paired with Glycine.

I'm not convinced by my own hypothesis but I hope someone will try this and get back to me! Glycine is relatively cheap and this would be an easy experiment.

 

I'm curious about item 1.  What is the mechanism for acetylcholine increasing neck pain?  What is the evidence for this?

 

Would you expect the same effect from ALCAR?