[li...] Posted November 28, 2011 Share Posted November 28, 2011 As some people may know, clonazepam has serotonergic properties. How that works is very complicated. Here I'd like to focus on the serotonin transporter. After continuous use clonazepam upregulates the serotonin transporter. It's a bit the opposite of the SSRIs, SSRIs tend to downregulate the serotonin transporter. I think I'm very sensitive to this particular attribute of this drug. Long story. Serotonin affects mood, cognition, perception, metabolism, and lots of basic functions for humans, mammals and lower organisms. Back to the serotonin transporter. If you wanted to target serotonin that would seem to be the most obvious choice. It's both a matter of tapering, undoing what clonazepam has done to the serotonin system and to keep it simple. As far as tapering is concerned, it stands to reason that not all effects of clonazepam (GABA-A, GABA-B, serotonin, glutamate etc.) can be tapered at the same rate ! We're talking about different mechanisms, after all. Benzos act on the benzodiazepine site on the GABA-A receptor, which is an ion channel, GABAB is a GCPR, and the serotonin transporter (SERT) is a monoamine transporter protein. While a slow and gradual 'textbook' taper is preferred, that doesn't always work. A few issues that I have experienced that are at least partly related to 'serotonin', DP/DR, weight gain, perception (taste/color/sound), mood, insomnia (melatonin?), slower/faster metabolism. When I take a dose of clonazepam time appears to speed up, my appetite and metabolism are affected, when the dose wears off time appears to slow down and I experience a lack of energy. When I lower the dose (taper) I seem to experience a lack of energy, which can be counteracted to some extent by eating carbohydrates. For me, clonazepam has both sedating and stimulating properties. Just some of my issues. Obviously, taking an SSRI would work. But I'm not depressed, I don't like the weight gain, insomnia and frankly I just wouldn't want to be 'on' a personality changing drug. What else ? I know alcohol can have serotonergic properties. Alcohol+clonazepam can be very bad, although it may also have positive properties. Frankly, I'm not sure what this combo does. It may have some SERT downregulating-properties. (alcohol acts on both GABAA, GABAB, serotonin and more) t3 (thyroid) acts on serotonin autoreceptors ... I'm sure there is lots more. Any ideas what could be used to downregulate the serotonin transporter, or modulate it in some way ? l-tryptofan seems to do nothing or cause dysphoria, 5-HTP doesn't do anything. Choline/serotonin seem to interact. I hope this makes sense, I have some brain fog. I suppose it doesn't hurt to ask. Approaching this by means of the serotonin transporter is relatively simple, clonazepam causes both upregulation and downregulation of serotonin, (where?), presynaptic vs. postsynaptyc, involvement of GABAB etc. Link to comment Share on other sites More sharing options...
[rs...] Posted November 28, 2011 Share Posted November 28, 2011 As some people may know, clonazepam has serotonergic properties. How that works is very complicated. Here I'd like to focus on the serotonin transporter. After continuous use clonazepam upregulates the serotonin transporter. It's a bit the opposite of the SSRIs, SSRIs tend to downregulate the serotonin transporter. I think I'm very sensitive to this particular attribute of this drug. Long story. Serotonin affects mood, cognition, perception, metabolism, and lots of basic functions for humans, mammals and lower organisms. Back to the serotonin transporter. If you wanted to target serotonin that would seem to be the most obvious choice. It's both a matter of tapering, undoing what clonazepam has done to the serotonin system and to keep it simple. As far as tapering is concerned, it stands to reason that not all effects of clonazepam (GABA-A, GABA-B, serotonin, glutamate etc.) can be tapered at the same rate ! We're talking about different mechanisms, after all. Benzos act on the benzodiazepine site on the GABA-A receptor, which is an ion channel, GABAB is a GCPR, and the serotonin transporter (SERT) is a monoamine transporter protein. While a slow and gradual 'textbook' taper is preferred, that doesn't always work. A few issues that I have experienced that are at least partly related to 'serotonin', DP/DR, weight gain, perception (taste/color/sound), mood, insomnia (melatonin?), slower/faster metabolism. When I take a dose of clonazepam time appears to speed up, my appetite and metabolism are affected, when the dose wears off time appears to slow down and I experience a lack of energy. When I lower the dose (taper) I seem to experience a lack of energy, which can be counteracted to some extent by eating carbohydrates. For me, clonazepam has both sedating and stimulating properties. Just some of my issues. Obviously, taking an SSRI would work. But I'm not depressed, I don't like the weight gain, insomnia and frankly I just wouldn't want to be 'on' a personality changing drug. What else ? I know alcohol can have serotonergic properties. Alcohol+clonazepam can be very bad, although it may also have positive properties. Frankly, I'm not sure what this combo does. It may have some SERT downregulating-properties. (alcohol acts on both GABAA, GABAB, serotonin and more) t3 (thyroid) acts on serotonin autoreceptors ... I'm sure there is lots more. Any ideas what could be used to downregulate the serotonin transporter, or modulate it in some way ? l-tryptofan seems to do nothing or cause dysphoria, 5-HTP doesn't do anything. Choline/serotonin seem to interact. I hope this makes sense, I have some brain fog. I suppose it doesn't hurt to ask. Approaching this by means of the serotonin transporter is relatively simple, clonazepam causes both upregulation and downregulation of serotonin, (where?), presynaptic vs. postsynaptyc, involvement of GABAB etc. liberty, the mechanism of w/d is way over my head. I did read somewhere about the weight gain. It talked about the serotonin uptake and triggers hunger. It also said this "new" finding could open the door for possible drugs to control weight gain in the future. I'll try to find the link,rstud Link to comment Share on other sites More sharing options...
[li...] Posted December 1, 2011 Author Share Posted December 1, 2011 Bump. Nobody ? I know it's complicated and I didn't expect a 'real' response. Well, I can try once. Link to comment Share on other sites More sharing options...
[li...] Posted July 8, 2012 Author Share Posted July 8, 2012 http://www.ncbi.nlm.nih.gov/pubmed/2418652 Link to comment Share on other sites More sharing options...
[sp...] Posted July 8, 2012 Share Posted July 8, 2012 Is there any reason to think Clonazepam exerts stronger 5-HT action than other benzos? It looks to me like they probably all affect that system: http://www.ncbi.nlm.nih.gov/pubmed/2844552 Link to comment Share on other sites More sharing options...
[li...] Posted July 8, 2012 Author Share Posted July 8, 2012 Yes, lots, too much to get into right now. And maybe more 'different' rather than 'stronger'. Maybe the statement that clonazepam upregulates the serotonin transporter is incorrect or misleading. Long story. I'm not sure why I posted the previous link. It was part of something I was researching. Link to comment Share on other sites More sharing options...
[li...] Posted July 8, 2012 Author Share Posted July 8, 2012 The wikipedia article may be quite misleading. Initially, SSRIs cause an excess of available extracellular serotonin. Over time, this results in a downregulation of SERT (serotonin transporter). Initially, clonazepam causes an 'availability' of extra serotonin. Different mechanisms. Over time, adaptations follow. 'upregulation' of SERT suggests the opposite of downregulation. Perhaps clonazepam and SSRIs are more similar than dissimilar. After the initial 'extra' serotonin, compensatory mechanisms follow. 'upregulation' may be a misnomer. I had a complicated article somewhere, but I cannot seem to find it. Link to comment Share on other sites More sharing options...
[sp...] Posted July 9, 2012 Share Posted July 9, 2012 I'm still confused why clonazepam is mentioned specifically. I can't actually find any PET / fMRI imaging studies which confirm what mechanism benzos affect serotonin release; what I've found is a lot of possible mechanisms tossed around based on behavioral effects in animal studies. Why would clonazepam exert more 5-HT action than other benzos? I don't quite follow you when you say "clonazepam and SSRIs are more similar than dissimilar"; SSRIs act directly on serotonin receptors, whereas benzos seem to affect serotonin levels indirectly: The concept that benzodiazepines may exert a primary action on GABA-containing neurons, which in turn regulate serotonergic transmission, was supported by preliminary psychopharmacological evidence. The list of things that indirectly regulate serotonergic transmission is very long, and includes THC which seems to be 'similar' to benzos insofar as it also leads to reduced serotonin levels over time because of tertiary action, but it doesn't have any of the long-term withdrawal issues associated with it which benzos do. Link to comment Share on other sites More sharing options...
[li...] Posted July 10, 2012 Author Share Posted July 10, 2012 It's complicated ! I no longer have my original research. Clonazepam's anti-absence and antimyoclonic actions seem to be related to serotonin. The effects on serotonin may be mediated through GABAB, possibly other pathways. It seems to have something to do with GABAB, thalamic reticular nuclearis/thalamic reticular nucleus http://www.ncbi.nlm.nih.gov/pubmed/7931539 www.jneurosci.org/content/18/21/9099.full.pdf Google books, GABAb Receptor Pharmacology: A Tribute to Norman Bowery, by Thomas Blackburn. Page 220 and 221 If you want to, try digging through google scholar for clonazepam and serotonin transporter/SERT ? The statement in wikipedia that clonazepam upregulates the serotonin transporter may be misleading. Link to comment Share on other sites More sharing options...
[li...] Posted July 13, 2012 Author Share Posted July 13, 2012 Some technical stuff. huguenardlab.stanford.edu/reprints/czp.pdf edoc.unibas.ch/212/1/DissB_7136.pdf http://en.wikipedia.org/wiki/Thalamic_reticular_nucleus Also, nucleus reticularis thalami = nuclearis reticularis thalami http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1783475/ A bit too much for me: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3342575/ Link to comment Share on other sites More sharing options...
[sp...] Posted July 13, 2012 Share Posted July 13, 2012 what's your background, anyway? Do you have a professional interest in this stuff? Link to comment Share on other sites More sharing options...
[li...] Posted July 13, 2012 Author Share Posted July 13, 2012 what's your background, anyway? Do you have a professional interest in this stuff? None whatsoever ! Previous post is work in progress. Trying to make sense of stuff. Link to comment Share on other sites More sharing options...
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