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Clonazepam -- what differentiates it? (re HPPD)

VelocideX

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Clonazepam -- what differentiates it?

Im curious as to what differentiates clonazepam from other benzodiazepines. Does it have a higher affinity / selectivity for a particular receptor than other benzos? Does it have some independent mode of action?

Feel free to suggest moving this thread if you think its in the wrong place... I can always move it :p
 
This is really a case of you needing to do more research before you pop a q. It is both stronger and longer acting than diazepam. Diazepam is the reference to which most benzos are compared. Try cross-examining structures and activity data if you are interested.
 
Your really not a very nice person, are you Smyth? I bet you never got "works and plays well with others" on your report card.

Anyway, what makes you think clonazepam is that different from other benzos? I'll just quote something I said in OD a couple months back, when someone basically asked "why do benzos all feel different".

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That is an epically complicated question. Basically, the differences are going to boil down to different affinities at the different GABA-A receptor subunit make ups.

Now I can't exactly remeber how many different subunit types there are, but I think, there are alpha 1 to 6, beta 1 to 3, gamma 1 to 3, delta, epsilon, theta and pi. Now all of those different benzos, will have different affinities has GABA-A receptors made up with different combination of 5 of those subtypes. So Thats actaully a huge number.

So instead of doing an actual week of research, I'll post this abstract
Doble A.
New insights into the mechanism of action of hypnotics.
J Psychopharmacol. 1999;13(4 Suppl 1):S11-20

Between 1987 and 1989, the different protein subunits that make up the receptor for the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) were identified. These make up the alpha, beta, gamma and delta families, for each of which exist several subtypes. This receptor is the molecular target of modern hypnotic drugs (i.e. benzodiazepines, zopiclone, zolpidem and zaleplon). In the 10 years that have followed this milestone, significant progress has been made in exploring the molecular mechanisms of hypnotic drug action. Receptor subtype specificity of hypnotics has been explained in terms of differential affinity for receptors containing different alpha subunits, which are expressed in different brain regions. Zolpidem and zaleplon bind preferentially to alpha1-containing receptors, whereas benzodiazepines and zopiclone are aspecific. Different sets of subunits are encoded in contiguous 'cassettes' on the genome, and the transcription of each set appears to be regulated coherently. The predominant GABA(A) receptor composition found in the brain is alpha1beta2gamma2, which are all encoded on human chromosome 5. Targeted gene disruption has provided clues to the physiological functions served by GABA(A) receptors containing different subunits. Receptors containing gamma2 appear to have a vital role in maintaining appropriate central inhibition, beta3-containing receptors may also be important determinants of excitability in certain brain regions, whereas a clear role for alpha5-, alpha6- and gamma3-containing receptors has not yet been established by these techniques. Site-directed mutagenesis has indicated that benzodiazepines bind to a cleft on the GABA(A) receptor surface at the interface between the alpha and gamma subunits. Other drugs (flumazenil, zopiclone, zolpidem) also bind to the a subunit, but interact with amino acids in different binding domains to the benzodiazepines. The molecular mechanism of hypnotic dependence has been explored, and seems to involve downregulation of transcription of the normally prevalent alpha1, beta2 and gamma2 subunits, and the reciprocal upregulation of the expression of rarer subunits. Chronic treatment with hypnotic drugs that may have less dependence potential, such as zopiclone and zolpidem, appears to produce more limited change in GABA(A) receptor subunit expression. These ideas will be important both for designing new hypnotic drugs with a better safety/efficacy profile, and for evaluating more appropriate ways of using the drugs available today.


They say the hypnotics are more specific for GABA-A channels that contain the alpha subunit, I'm not sure if thats correct; but the difference in the subjective effect of benzos will be due to their subunit specificity.
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Also, the pharmacokinetics would modulate the effects somewhat, as faster absorbed and distributed benzos would probabyl be more enjoyable.
 
Update on that, instead of just the alpha 1 to 6, beta 1 to 3, gamma 1 to 3, delta, epsilon, theta and pi... there are now theta 1 to 3, and Rho 1 to 3.

To give you the idea when it comes to behavioural things, alpha1 knock out mice show an increased sensitivity to diazepam, but a decreased sensitivity to flurazepam, midazolam and zolpidem

Gamma 2 (long) subunit knocks outs show increased sensitivity to midazolam and zolpidem

Delta knock outs show now change to midazolam...

This little abstract gives some idea too.
 
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Smyth said:
This is really a case of you needing to do more research before you pop a q. It is both stronger and longer acting than diazepam. Diazepam is the reference to which most benzos are compared. Try cross-examining structures and activity data if you are interested.

Perhaps because no definitive answer to what I'm really getting at exists?

Clonazepam is reported to be the best short-term treatment for HPPD. People with HPPD find their symptoms completely resolve for a time. It appears more successful than any other benzo in this regard.
 
http://www.ncbi.nlm.nih.gov/entrez/...ve&db=pubmed&dopt=Abstract&list_uids=11475916
Isr J Psychiatry Relat Sci. 2001;38(2):133-6. Related Articles,Links

LSD-induced Hallucinogen Persisting Perception Disorder treated with clonazepam: two case reports.

Lerner AG, Skladman I, Kodesh A, Sigal M, Shufman E.

Lev Hasharon Mental Health Medical Center, Pardessya, Israel. [email protected]

Benzodiazepines are recommended for the treatment of Hallucinogen Persisting Perception Disorder (HPPD), although it is unclear which may be more helpful. Two out-patients with LSD-induced HPPD were successfully treated with clonazepam. They had not responded to low potency benzodiazepines or low doses of classic antipsychotics. After clonazepam discontinuation they reported a marked improvement and only mild symptomatology which persisted during a six month follow-up period. High potency benzodiazepines like clonazepam, which has serotonergic properties, may be superior to low-potency benzodiazepines in the treatment of some patients with LSD-induced HPPD.

What exactly are these serotonergic properties?
 
By any chance does the serotonogic properties refer to any activity at the 5HT1A receptor? It's the target for the anxiolytic drug buspirone (it's a 5HT1A partial agonist). I'll have to do a bit of grubbing around in some books, but if anyone has a definitive answer, please say so (then it'll save me the work, and then I can just sit 'round on my arse all day. It's what I'm good at!)
 
Nah, I reckon a) they don't really know what they're talking about (*cough* Israeli Journal of Psychiatry related sciences *cough*) and b) they're talking about the effect of clonazepam to reduce 5-HT turn over (probably by reducing release) (1, 2).

But that action isn't clonazepam specific, other benzos and drugs do it to (clonazepam, diazepam, chlordiazepoxide and diphenylhydantoin) but not Flurazepam, phenobarbitone and carbamazepine; at least according to Pratt et al., 1985.
 
I agree the action isn't clonazepam specific, but this is the sort of info I'm after :)
http://www.ncbi.nlm.nih.gov/entrez/...ve&db=pubmed&dopt=Abstract&list_uids=12227234
Isr J Psychiatry Relat Sci. 2002;39(2):92-9. Related Articles,Links

Flashback and Hallucinogen Persisting Perception Disorder: clinical aspects and pharmacological treatment approach.

Lerner AG, Gelkopf M, Skladman I, Oyffe I, Finkel B, Sigal M, Weizman A.

Lev Hasharon Mental Health Medical Center, Pardessya, POB 90000, Netanya 42100, Israel. [email protected]

One unique characteristic of lysergic acid diethylamide (LSD) and LSD-like substances is the recurrence of some of the symptoms which appeared during the intoxication after the immediate effect of the hallucinogen has worn off. This recurring syndrome, mainly visual, has not been clearly understood, appreciated or distinguished from other clinical entities by clinicians. The terms Flashback and Hallucinogen Persisting Perception Disorder (HPPD) are used interchangeably in the professional literature. Flashback is a usually short-term, non-distressing, spontaneous, recurrent, reversible and benign condition accompanied by a pleasant affect. In contrast, HPPD is a generally long-term, distressing, spontaneous, recurrent, pervasive, either slowly reversible or irreversible, non-benign condition accompanied by an unpleasant dysphoric affect. Flashback and HPPD appear to be part of a vast and broad spectrum of non-psychopathological and psychopathological states reported by hallucinogen users. Pharmacological agents such as clonidine, perphenazine and clonazepan have been shown to ameliorate this syndrome in some of the individuals seeking treatment.

I know, its Israeli :p

Perhaps what I'm getting at is this: HPPD clearly has some sort of serotonergic origin (LSD, or any of the other hallucinogens).

IF it is reversible by some pharmacological means, and its not the result of irreversible structural modifications or damage, then surely the serotonin system has to be involved at some point.

Many HPPDers report that SSRIs increase their symptoms over time. Some people have been known to develop HPPD-like symptoms (palinopsia) etc after treatment with SSRIs or things like mirtazapine (I think, or one of its related drugs). Could some sort of serotonergic excess be at fault?

I'm going to rename the topic to be a little more specific
 
My problem isn't that it is Israeli, its that its from some highly obscure journal. I was going to look up its impact factor, guessing it was going to be like 0.005 (vs natures 31)... but they don't even rate it!

ANYWAY, I suspect HPPD is caused by excessive glutamate, leading to aberrant synaptic plasticity. HMMMMMM clonidine also should decrease serotonin...

Ahh, this is complicated systems neuroscience.... we don't know enough to comment. If we either new the mechanism of the cause, or the mechanism of the cure, then we could look for some correlations, but if we don't know how it's caused, or how it's cured, then we're really talking out our asses.

Also this:
IF it is reversible by some pharmacological means, and its not the result of irreversible structural modifications or damage, then surely the serotonin system has to be involved at some point.
The only way the serotonin system has to be involved is through the 5-HT receptors that LSD bound to at the begining... and we don't even know it is 5-HT2A receptors... it could be 5-HT1A... do we even know if phenetylamines can induce HPPD (if we did we could narrow it down to 5-HT2A/B/C).
 
Here's a study with clonidine, though its another israeli study

http://www.ncbi.nlm.nih.gov/entrez/...ve&db=pubmed&dopt=Abstract&list_uids=10836284
Int Clin Psychopharmacol. 2000 Jan;15(1):35-7. Related Articles,Links

LSD-induced hallucinogen persisting perception disorder treatment with clonidine: an open pilot study.

Lerner AG, Gelkopf M, Oyffe I, Finkel B, Katz S, Sigal M, Weizman A.

Lev Hasharon Mental Health Medical Center, Pardessya, Israel. [email protected]

A pilot open study was conducted in order to evaluate the efficacy of clonidine in the treatment of LSD-induced hallucinogen persisting perception disorder (HPPD). Eight patients fulfilled entrance criteria. All complained of HPPD for at least 3 months and were drug free at least 3 months. They received fixed low doses of clonidine, 0.025 mg, three times a day for 2 months. They were evaluated by the Clinical Global Impression Scale (CGI) and a self-report scale on the severity of symptoms (graded 0-5). Patients scored an average of 5.25 (SD = 0.46) on the CGI and 4 on the self-report scale at baseline, indicating marked psychopathology. One patient dropped out at week 3 and a second patient dropped out at week 5. Of the six patients remaining at the end of 2 months, the average CGI score was 2.5 (SD = 0.55) and the self-report scale score was 2, indicating mild symptomatology. LSD-related flashbacks associated with excessive sympathetic nervous activity may be alleviated with clonidine in some patients.
 
bilz0r -- their studies appear to have made it to Int Clin Psychopharmacol.

Here's that first one again:
http://www.ncbi.nlm.nih.gov/entrez/...ve&db=pubmed&dopt=Abstract&list_uids=12598822
Int Clin Psychopharmacol. 2003 Mar;18(2):101-5. Related Articles,Links

Clonazepam treatment of lysergic acid diethylamide-induced hallucinogen persisting perception disorder with anxiety features.

Lerner AG, Gelkopf M, Skladman I, Rudinski D, Nachshon H, Bleich A.

Lev Hasharon Mental Medical Center, Pardessya and Sackler Faculty of Medicine, Tel-Aviv University, Israel. [email protected]

blah blah blah.
 
There's a study which shows people who smoke peyote don't get it --- Halpern et al 2001

There's no report of full-blown HPPD but some of flashbacks from MDMA -- Creighton et al 1991, McGuire et al 1994, Worarz et al 1993

I think there's a major problem in that there seems to be gradations in the syndrome that people don't quite recognise. Very few people develop full blown HPPD, but many people report increasing visual static and garbage after 2C-I or MDMA use.
 
In terms of cures... there's some reports of antipsychotics effecting a cure, but most people report that it makes their symptoms worse.

reboxetine has no effect

SSRIs either have no effect or make it worse.

benzos seems to be the only thing that work, and even then clonidine and clonazepam seem to be the two best ones for that. clonazepam is also an antiepileptic.

--
in regards to impact factors: Physiological reviews (PHYSIOL REV) is on 36 :p
 
So they might work in some way via the 5HT1A receptor, considering it's one of the two important receptors when it comes to the activity of LSD, 5HT1A is concerned with anxiety (hence the target of buspirone), and it seems to be best controlled by drugs used to treat anxiety (benzos, clonidine - used in opiate withdrawl).

I know it's a lot of ifs and buts...


VelocideX: who the hell smokes peyote? (damn weirdos I'll bet!)
 
Well annual review of immunology is 54 or something... (why do I care?) Int Clin Psychpharmacol is a 3, so it's hardly astounding, but I suppose its better than Life Sciences or something... :p

Anyway, enough stupid elietism.

I don't think proper, honest to god, HPPD is common enough to look for induction in a clinical setting, so I don't trust that mescaline paper at all... oh I see, you're second referencing, what a naughty boy...

Meanwhile, that review by Halpern says that pretty much everything cures HPPD, from haloperidol to naltrexone. Yeah and those native americans who don't report HPPD, there usage is very different to normal usage... so it's a hard comparison.
 
yeah i read that review. ah well... its just interesting that so many people even on bluelight report grainy vision after excessive MDMA use. would be nice to think that some research is happening, but it really doesn't seem to be.
 
i get HPPD quite a bit, i think it's induced from the massive amounts of dxm i went through, a dxm overdose, and a lot of experiences with 2c-e, 2c-i, and 5-meo-dmt and salvia. i've also done 2c-t7, dpt and 2c-e with dpt, dipt, and your basic mushrooms, etc etc. i see crazy shit all the time when im sober for weeks even, clonazepam helps a lot too, i know that for sure (not that hppd bothers me). its mostly dxm flashbacks though we're things look like they did when i took over a gram (way over). that could probably kill a lot of people so dont do that, im surprised i survived. basically im just saying i know klonopin helps real well with this for me, living proof anyway, later.
 
over 1g dxm, what the hell did you do that 4? That is unbelievable!
 
When I hear that benzo's help reduce hppd symptoms, it makes more inclined to believe my original theory that hppd works psychologically in the same way as generalised anxiety. People who suffer from generalised anxiety are highly sensitised to their bodies, and feel fear or panic towards normal sensations, and in time sensations which are formed as a result of this fear/panic. It really is a vicious circle.

I think that sufferers of hppd turn so much attention to some initial visual distortion, that they actually end up prolonging it - and in fact even creating it.

I don't believe for a second that hppd is a result of a chemical imbalance or 'damage' to the brain. If this were the case then we would be seeing cases of hppd in a far higher percentage of hallucinogenic drug users.

I have read stories from people with hppd who have gotten over their symptoms to varying degrees, and from those who have had them get worse with time. There is no coincidence that those who manage to free themselves of their problems are the ones who chose accept their visual distortions, depersonalization, derealisation etc.. and get on with their life anyway. Just with anxiety, if you can ignore the bully, it will eventually lose interest in tormenting you.
 
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