Clonazepam - an antidepressant

[clubcard]

https://www.ncbi.nlm.nih.gov/pubmed/1723798
https://www.ncbi.nlm.nih.gov/pubmed/8570030
https://www.sciencedirect.com/science/article/pii/009130579190145R
https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1479-8301.2006.00157.x
https://www.researchgate.net/public...f_rats_subchronically_treated_with_clonazepam
http://www.dr-bob.org/babble/20060417/msgs/635570.html


I find this of particular interest since clonazolam produces a much mor prominent effect concerning depression. Anyone who knows that feeling as unipolar depression sets down on you may have noted that clonazepam helps a little. If one sits down and takes clonazolam, that increase in serotonin is VERY pronounced. Anyone who has taken a modest dose of p-TAP or p-Me aminorex or 4,p-dimethylaminorex alone will know exactly what I mean. Increasing serotonin alone is quite subtle. You do feel happier, more contented but more importantly, it does lift that depression. You feel chilled out. Sadly, none of those compounds is safe and they produce their own toxic profile and they display tachyphylaxis. They work for a day or two but soon you are back where you started if not worse.

Now clonazolam IS better but it has it's own set of negative effects mediated by it's α1 affinity. I'm sure we have read the stories from the most mild-mannered members of REM to the most reactionary racists who until recently blighted our screens. What is needed is a nitrobenzodiazepine that doesn't have affinity for the α1 subunit (and ideally not the α5 subunit either). Well a couple of such agents are currently undergoing tests in animal models. They are α2/α3 selective (like pyrazolam) so they don't have much abuse potential (lets be honest, you need about 10 pyrazolam to get any kind of buzz and I haven't seen many cases of people becoming dependent because let's fact it, they aren't much fun). Well, I was visiting The Netherlands and suddenly I was hit by a REALLY bad downer out of nowhere. I mean, I've been looking forward to the visit, we had friends staying looking after the cats, I hadn't seen them in ages - all great stuff.

But after the first night I was feeling just AWEFUL. The tricyclics I am given do help but only in a suicide-prevention manner. I still hate every moment. Well, an old friend arrived who knows me better than I know myself. She was STRAIGHT on the case. 1 hour before a mean she gave me 5mg of her own custom benzo. This has a (S) 3-methyl moiety and a couple of other bits to make it REALLY selective. I sat down and took 2 x 2mg caps. After about 1 hour I could feel it..... all of that badness was slipping away. It was a gos-sent. Now I don't know the exact structure and she's developing it as a medical product but all I can say is that it WORKED.

The dose was limited to 4mg 1 hour before bed-time. I slept and didn't have awful dreams. I could think of others. I bought her flowers, I bought the family we were staying with flowers, I bought my wife flowers.... I bought her sisters flowers. It WORKED. Now I'm just 1 person and this was just 1 occasion but anyone who knows that specific serotonin 'happy place' will know just what I mean. After 10 days I stopped fearing the worst..... and it didn't happen!.



So this is statistically of no value but I'm interested to know if others have benefitted from clonazepam, clonazolam or similar. Was it just a placebo? I didn't dare take a DRI because I associate those serotonin tingles with the before part of me taking a couple of dexis but i didn't WANT stimulating..... all very odd but if the a2 & a3 don't form dependence (and open question) then we MAY have a new fast-acting antidepressant in the works and I for one am excited by this. I've lost too many people and so has she so she was my little sister that night; she loves me and she looked after me.



I am an out and proud philogynist. I don't dislike men but I tend to expect the best of ladies and the worst of men. Every bad thing that someone has done to me has been another man. Every good thing that someone has done for me has been a lady. Maybe I am biased but on reflection, I have NO male friends. I mean, I have about 6 REALLY close friends. My wife is first (obviously) but the other 5 are like the sisters I don't have. I have been VERY lucky.... and I love them all.

 

[Limpet_Chicken]

Fuck, clubcard, I read the edit, you have my most sincere condolences on the loss of your sister. Stay strong mate, I know it isn't easy, throw yourself into your work if you must, it might help at least take your mind a little further from the pain of your loss. I hope this doesn't sound trite, it isn't meant to, I'm just that straight to the meat and bones of things sort of person in what I say, autie thing I guess. But I mean it. If you want someone to talk to about it, feel free to PM me, if you think it might do any good, at any rate, the offer is open to you should you wish to make use of it. I am not trying to pry, simply, placing the offer upon the table, for you to take or leave as you should wish, just so you know that it is there. I won't hide the fact I am a guy, but again, I have neither reason to, or wish to do you ill. I'm kinda the same way, most of my true friends, are XX or XXX karyotype, and if not ladies in some cases, certainly female (and in my case either aspie, autie, or Rett's girls too, not that there are very many living males with Rett's, I certainly know none).

Hang in there clubcard. I know what it is like to lose somebody you love dearly. She isn't dead, but I lost my fiancee, the younger of the two (one was 14, just about, while the other was 16-17) and even a bit less than a decade and a half later, it still eats me inside; for, never mind her age, that was important to neither of us, I loved that woman more than I value my own life itself, and even now, I still do, with not one single day passing by, in which I do not feel hollowed out, and empty. For in losing that stunningly beautiful, warm, bubbly, funny, smart Kanner's autie girl. When I lost her, I lost not only the woman I loved more than anything in the world, but half of my own, for lack of a better word, soul. We were not simply man and wife to be, but two halves of one greater being. You have my well wishes and empathy, for the loss of your sister.

I hope I've caused no offense in bringing it up, but I'll keep you in my mind mate, for whatever that might be worth.

 

[d1nach]

Idk i took alprazolam and at first it seemed to work but in the long term i end up becoming worse and worse until i attempted suicide.

 

[Coolwhip]

Well there's no doubt about it, women are mean to each other, but men are just plain evil. probably has something to do with mirror neurons.

As far as rapid anti-depressant effect from benzo's. This is something I DEFINITELY noticed when first taking them, and it would be too far after dosing and a much different feeling to be contributed to a benzo buzz. I kind of thought it was just because of acquiring a much needed good nights sleep. But I would wake up the next day absolutely GLOWING and full of energy, and I am talking about something equivalent to 12 hours after dosing 1mg of alprazolam. Really there were times I pursued this next day feeling more than any benzo buzz, I couldn't figure it out when it stopped, I would try taking larger doses and going straight to sleep just so I could wake up feeling so GOOD, not high, good. But the effect actually fades with higher doses, now that I rarely take benzos anymore I can still acquire a similiar feeling from taking a fairly low dose with no recreational value a few solid hours before even attempting to sleep, and then waking up early in the morning(like 8am, not before dawn) and it doesn't resemble anything I could achieve from benzos alone.

It obviously couldn't be harnessed long term, and I think you'd have a hard time getting any such treatment protocol widely accepted, but if one is suicidal I could see great utility.

 

[Limpet_Chicken]

Mirror neurons? why?

I'm probably not in a position to just intuit the 'usual' in that respect, because I'm an autie and as a spazz, my mirror neurons are probably of a nonstandard wiring configuration. The rest of me is certainly running a different OS to the NT majority (thankfully getting ever smaller as we short-bus riding lot breed more and more auties/aspies [and perhaps Rett's girls, since I kinda have eyes for one in particular, a real stunning cutie with a HILARIOUS sense of snark)

 

[Coolwhip]

Sorry, that was kind of an inside joke which would be too hard to explain in detail(at least this early) which goes back to a research project my wife was part of concerning the differences in the mirror neuron system between the sexes; in short women have a higher functioning mirror neuron system. I should have just said empathy; which you seem to posses in spades(or at least compassion, describing complex ideas like this is a semantic minefield) regardless of how your mirror neurons function.

 

[Limpet_Chicken]

No, not at all. I am interested in learning more about how mirror neurons function.

And yes, I can be empathic, contrary to popular belief, the idea that auties, aspies etc. wouldn't know empathy or compassion if it jumped on them from a great height and kicked them in the balls, that actually holds about as much water as the 'refrigirator mother' theory, or the kind of quackery promoted by heaps of festering dung like Autism squea..ahem..Speaks, such as chelation (which has killed too many of our kind and certainly won't cure anything affecting anybody, unless one happens to be suffering from poisoning by arsenic, lead, cadmium, mercury etc. (and I mean actual clinical Hg poisoning there, not the garbage slobbered out from the backsides of slack-jawed soldiers in the mercury militia, the kind that puts people in hospital, rather than adds a nanogram or two over the official average detectable levels in a hair sample test. Rotten, I know, but that is AutSqueaks and their howling mercury militia fanatics for you; a bunch of cretinous, bigoted curebie zealots, with the collective IQ of a small cucumber, but unfortunately they are as dangerous as they are stupid.

 

[Coolwhip]

I'm sorry to take this thread further off topic, but it made me think of an Atwood quote which I've been told was found in The Handmaid's Tale(which I have been watching but didn't notice it) and again was just used in Dietland(did notice it this time) "Men are afraid that women will laugh at them. Women are afraid that men will kill them."

But for benzo's used for rapid anti-depressant effect, perhaps you should check out JB Hester's work, I know he did some research concerning the anti-depressant effect benzo's, although it may be a little dated by now.

As far as mirror neurons go, I am by means no an expert and couldn't tell you any more than you can find on wikipedia, my wife could tell you more about but even then her forte is child psychology, not neuroscience. But from what I know I imagine they are more important for reading a persons emotions or recognizing emotional pain and have less to do with actually feeling empathy, especially not when it comes to complex situations like having compassion for someone whose in a situation you can can only struggle to relate to miles and miles away. But its hard to be empathetic when you can't recognize emotional pain in another, and I could easily see how not being able to recognize others pain could over years pose an obstacle to developing empathy or even stunt development of neural networks that are responsible for feeling compassion.

 

[adder]

This unique effect of clonazepam among benzodiazepines on serotonin has been brought up a few times on Bluelight throughout the years that I've spent here and of course saying nothing about the effect itself, I'm very skeptical about any benzodiazepine being a potential antidepressant. I took clonazepam for 6 years straight and if it did anything to my depression, it made it worse or at best steadied it so that I got trapped in a zombie-like state of mind in which I had no urge to do something with my life to get it back. I somehow doubt that you can separate addictive properties of benzodiazepines by simply making them a2/a3-selective. I have not taken pyrazolam, but I had a chance to take the 7-nitro analogue on several occasions and to me it had the typical triazolobenzodiazepine anxiolytic kick that I know very well from alprazolam and estazolam which is very characteristic and not present with any classic benzodiazepine that I've taken. Granted my opinion is subjective and I was dependent on clonazepam when I took pynazolam on several occasions, so I can't say much if it has any hypnotic properties although I could still identify extra hypnotic effect from nifoxipam over clonazepam which was not present with pynazolam.

But now, 5 years after quitting benzodiazepines after a 9-year long dependence, I've been on alprazolam for 6 months and I can report its effects more objectively. The way it differs for me at 0.5-0.75mg and >0.75mg is prominent, above 0.75mg the sedative and amnesic effects suddenly become noticeable while at the lower dose it is an anxiolytic which while lowering anxiety effectively leaves me productive as well, actually makes me more productive than I would be if I was feeling anxious, it makes everything seem brighter, it's kind of an effect you could call antidepressant, but it fades faster than the last perceivable effects of the drug. This effect of alprazolam itself, anxiolysis without hypnotic effect, this relaxing, calming effect that makes people less hostile, disinhibited and more open to socialize is addictive itself IME, much more so than the hypnotic effect that may leave you wandering mindless and then on the following day remembering nothing of it. Throughout all the years I spent taking benzos I took way too much only once and it happened before I even ended up physically dependent on them, it was definitely the relaxed feeling they gave me that made me addicted to them. If a2- and/or a3-selective benzodiazepines are anxiolytics like alprazolam but almost completely devoid of hypnotic and muscle relaxant effects, I would still find them addictive and I imagine if one took them for an extended period of time, abrupt discontinuation would result in rebound anxiety and withdrawal too. Perhaps a2/a3-selective benzodiazepines could substitute unselective anxiolytic ones we have now, maybe a2/a3 partial agonists could be safer with potential dependence, but still, I can't picture them being antidepressants. Benzodiazepines are great drugs, at first they seem too good to be true, but it's for limited time only and it's extremely easy to fall in their trap if you're prone to suffer from too much stress and anxiety.

 

[Coolwhip]

I don't think clubcard is necessarily looking for something one could take as continuously as SSRI or tricyclics, just something that acts quickly that isn't abuse-able, to get one over any humps one might encounter while already medicated, or while waiting for another medication which takes longer to work to become effective.

Honestly my condition sounds like it could be similiar to clubcards, I was diagnosed as being "double dysthymic", and my description of said disorder has changed throughout my life depending on my treatment and lifestyle, but before I obtained any diagnosis or treated it aggressively(don't necessarily mean an aggressive drug protocol) I had learned to, I won't say live happily, but function with my dysthmia but when that second dip occured it was a real struggle to keep going and if there weren't people who depended on me I wouldn't be here today. And even when I sought treatment for the dysthmia, the depressive episodes would re-occur, and there was nothing I could really do to treat them as they popped up, and even now I don't take anything for dysthmia or depression specifically anymore, I didn't like being on anti-depressants, each class came with their own set of side effects such as killing my libido, weight gain, feeling apathetic, whatever it was they weren't very effective for dysthmia in the first place and I found living a structured lifestyle with a regimented diet, excercise, and ESPECIALLY sleep hygiene to be just as effective and come with their own set of positive "side effects". So thats what I do, and as long as I stay on top of everything, I wouldn't say I am necessarily happy, but I am not constantly suicidal and can feel joy, sometimes, and don't feel blunted or constantly suicidal, but sometimes that second dip hits, and sometimes I take medication for it, but the weeks waiting for any medication to kick in are rough to say the least and if I didn't have the proper support network around me(both a talk therapist and friends/family) my life would fall apart before the medication kicked in.

Adder, the analog you took also had a pyridine ring? How would this differ from nitrazolam in effects? I have always been really interested in benzo SAR and could never find a solid answer on how the pyridine ring fits in, same question with a cyclohenyl substitution. I do find benzos extremely useful and take them more often than I should, but not everyday, I generally try to stay away from triazolo derivatives, but love the nitro's.

anxiolysis without hypnotic effect, this relaxing, calming effect that makes people less hostile, disinhibited and more open to socialize is addictive itself IME, much more so than the hypnotic effect that may leave you wandering mindless and then on the following day remembering nothing of it. Throughout all the years I spent taking benzos I took way too much only once and it happened before I even ended up physically dependent on them, it was definitely the relaxed feeling they gave me that made me addicted to them..

QFT, at least to me, getting "fucked up" on benzos is fun, as a novelty, but the affects that always kept me coming back to them were the subtle ones. I don't know if it holds true for the general population, but unfortunately once you build a tolerance to benzo's even obtaining said effect becomes quite difficult, and if you abuse them in order to "wander mindlessly"(I like that), you lose said effect almost instantly, so its very careful to take the minimum amount required.

 

[AlphaMethylPhenyl]

Sorry if it's been stated, but foremost you're confusing clonazepam with clonazolam. Also, you cited one study twice, used a case study, and cited a discussion about a study that itself you had listed.

"[R]eduction in the synaptic availability of serotonin during clonazepam treatment" means less serotonin. Also, less 5-HT1a action usually means more anxiety.

 

[Limpet_Chicken]

Wouldn't less action at 5HT1a, if via a global reduction in 5HT, essentially even itself out, given the difference in action between a presynaptic and a post-synaptic agonist, one is anxiolytic, the other anxiogenic. Although given one is an autoreceptor, that might tend to increase levels of 5HT again at least somewhat.

 

[AlphaMethylPhenyl]

No. For one 5-HT3 works with channel proteins and the rest of the 5-HT receptors work via signal proteins. It's my understanding that signal proteins (via 2nd messenger and so on) affect a cell much more particularly than LGIC's, and that subtypes of the 5-HT receptor can cause a myriad of different effects based on subtype as a result of this. Signal proteins affect cell transcription, which is part of what makes serotonergics useful for mood, I'd think. But no, they can't "even" things out like LGIC's might, I guesstimate.

So a 5-HT1a partial like buspirone causes a much different phenomenal effect than a 5-HT2a partial like psilocybin, for example.

That said, I've only heard of partial 5-HT1a agonists as anxiolytic, not full agonists or antagonists.

I don't know when/what receptor effects a 2nd messenger vs a channel protein further along the membrane (when speaking of GPCR's). I have incomplete understanding, in essence.

 

[Captain.Heroin]

I find benzodiazepines work really well for depression and anxiety.

 

[AlphaMethylPhenyl]

Yeah it seems that a lot of the time, depression results as a side effect of an untreated, more primary illness.

 

[adder]

That is true, depression can be a symptom of an anxiety disorder, then benzodiazepines work rapidly and are very effective, one does gain a boost when suddenly the stress is taken away. I know this feeling of relief very well and often it gives you a sense of feeling normal again. Still, this is short-term. Every time I started taking benzodiazepines regularly, be it lorazepam, clonazepam or alprazolam, after some time side effects such as low mood, lack of motivation, drowsiness, and memory problems kicked in. I have no idea if this is related to an action at GABA receptors composed of specific alpha subunits, but somehow I think this is basically due to long-term inhibitory action, likely also due to changes in the functioning of glutamate system overall. After all the basis for SSRI's working as antidepressants is causing new connections between neurons to form in the brain and this ability is impaired in depressed people. Depressants like benzodiazepines will not promote new connections between neurons, just the opposite, I bet.

I'd still like to see some more research into selective a2/a3-containing GABA receptor ligands. I'm far from a hobbyist expert on pharmacology, but it could be a game changer. After all buprenorphine, although also used as an analgesic just like morphine in doses starting at 0.2 mg, at higher doses presents a completely different pharmacodynamical profile which makes it unique among opioids and have other applications as well. It is a drug that gave me a lot of time to think about my opioid addiction, when I still occasionally felt cravings even though I'd already associated opioids with extreme pain, rather than peace and serenity that could last forever, having gone through long-lasting methadone withdrawal. However, it seems that the introduction of any benzodiazepine onto the market is particularly difficult now due to the stigma. I'm wondering why partial agonists like bretazenil have been dropped, even if it'd been found out that it caused dependence and tolerance, being a partial agonist it might have been a good addition to benzodiazepines available on the market, and there's a lot of them many of which have overlapping purpose, yet there's no place for a benzodiazepine which differs substantially from those currently available.

Adder, the analog you took also had a pyridine ring? How would this differ from nitrazolam in effects? I have always been really interested in benzo SAR and could never find a solid answer on how the pyridine ring fits in, same question with a cyclohenyl substitution. I do find benzos extremely useful and take them more often than I should, but not everyday, I generally try to stay away from triazolo derivatives, but love the nitro's.

Yes, it was the 7-nitro analogue of pyrazolam so it shared the 2-pyridyl ring. I have no experience with nitrazolam though, so I can't compare these two. Is nitrazolam more hypnotic than alprazolam? Apparently, pynazolam was supposed to be pyrazolam-like but with more recreational value, but I can't really say, I haven't taken pyrazolam either. The SAR among classic benzodiazepines doesn't always translate well for triazolobenzodiazepines with the same substitution pattern at C7 and C2', but the 7-nitro group in both classes seems to always produce compounds with superior potency and could be associated with increased affinity at alpha-1 containing receptors (flunitrazepam, a hypnotic, nitrazepam, also marketed as a hypnotic, clonazolam and flunitrazolam - both RC's with very high potency and amnesic properties from reports). Nevertheless, anecdotal reports are not enough to draw conclusions IMO, although if there is a large number of reports, then they clearly do present the effects of a compound, but it'd be nice if there was a study comparing the influence of various substituents and their combinations at C7 and C2' with respect to affinity at GABA receptors possessing specific alpha subunits.

 

[clubcard]

It turns out that nitro benzodiazepines are serotonergic. The reason they are used as hypnotics is because increased levels of serotonin are sedating... and relieve depression as a side-effect. I've just worked it out from notes taken in 2012. If you can use a scaffold that precludes α1 affinity, you end up with a very potent and fast-acting antidepressant. I don't know if clonazolam has α1 affinity but it isn't hard to search patents to find a useful example.

The problem I am now left with is designing something that has a long duration as well as excluding α1 affinity. Many thanks for the input. I have actually experienced the ASC from an agent that had such activity so I know (as do others) that once it's pointed out, it's obvious. Obviously I'm not going to go through the design until it's got a patent application... but I guess I SHOULD reference this site....