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Classics in Chemical Neuroscience: Amitriptyline

bigjackaal96 said:
Depression Is basically ACH hyperactivity which would explain why TCA's are very potent. Amitriptyline also a potent SNRI which would repair the damage to bowels. I wonder how many cases of Autism from doctors throwing out SRI's like candy since they still affect 5HT2 in the same way as Psychs do.
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how does an SNRI aid in repair of the bowel, what is the mechanism?

are you suggesting that autism is caused by serotonin reuptake inhibitors as well as serotonergic psychedelics?
 
someguyontheinternet said:
how does an SNRI aid in repair of the bowel, what is the mechanism?

are you suggesting that autism is caused by serotonin reuptake inhibitors as well as serotonergic psychedelics?
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It forces the body to keep the excess serotonin as a back up pathway when non-CNS ACH Is very low. Noticed this when I had FAR less IBS episodes with DPH at 25 ~ 125mg. I know It not mild food poisioning or true IBS, Because It happens even on days when I've not ate anything till dinner.
 
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bigjackaal96 said:
It forces the body to keep the excess serotonin as a back up pathway when non-CNS ACH Is very low. Noticed this when I had FAR less IBS episodes with DPH at 25 ~ 125mg. I know It not mild food poisioning or true IBS, Because It happens even on days when I've not ate anything till dinner.
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Wait. You are presenting your own opinions on your own subjective symptoms as evidence backed by no tests whatsoever as evideince?

It has a term and it's not evidence - it's called hearday.
 
4DQSAR said:
Well, I can only speak of the UK. I'm uncertain what the legal position of the stuff IS in the US. Is it prescription only or is it simply so old that nobody sells it any more. I mention that because a couple of quite legal antihistamines such as cyclizine are still in theory available from a pharmacy, none of them stock it. It's not a prescriptiom medicine, it's just died out because nobody was buying.
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It’s prescription only. But rarely used outpatient exception for treatment of hyperemesis gravidarum. If you ask for it specifically, you get the stink eye as it is regarded as suspiciously popular with junkies. Basically you have to be pregnant or allergic to Zofran to get a prescription.
 
4DQSAR said:
I can believe it. No doubt someone had noted that amtohistamines such as promethazine had quite a robust antidepressant action BUT was not optimized for that indication.

I wonder if the competition was for the FIRST synthesis so that one partly holds the patent rights OR was it the fact that their success meant a 'lively' industry in finding cheaper synthetic routes culminated with echical standards even lower than is common to medicinal chemists?
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This is the citation that was provided:
Protiva M. Recent progress in the pharmaco-chemical research on antihistamine drugs and psychotropic agents- derivatives of tricyclic systems having a seven or eight-membered middle ring. Farmaco Sci. 1966 Jan;21(1):76-104. PMID: 5328535.
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File wrapper of US patent application, S.N. 802,298, filed March 27, 1959, now US patent 3,384,663, issued to G. Rey-Bellet and H. Spiegelberg and assigned to Hoffmann-LaRoche. Other applications cited in the file wrapper are: (a) S.N. 855,981, E.L. Engelhard (Merck), filed Nov 30, 1959, now US3428735 (b) S.N. 828,722, F. J. Villani (Schering), filed July 22, 1959; think it's this one US3409640 (c) S.N. 27,267, S. O. Winthrop (Ayerst), filed May 6, 1960; could find this CA717977A (d) J. Mills (Lilly), filing date and serial number not disclosed. corresp. to US3189657
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Well, that's clearly before the class were approved for human use so it would seem that mamy researchers were all trying to patent the same 'novel' compounds.

I wonder if there was an academic paper that noted that something like promethazine had been tested and shown to posess robust antidepressant activity and everyone hurrifly carried out the same research in parallel?

Or industrial espionage took place. A friend worked at a US pharmacutical conglomerate for a while. Their job was instrumental analysis (so pity them) and the lab they worked in paid private investigators to poke through the refuse from the other labs owned by said conglomerate with a view to stealing ideas.

Apparently they were all told 'Other pharmacitical manufacturers are the competition - the other labs within OUR conglometate are the enemy'. And they meant it.

I hve only mentioned a tiny fraction of the things I've seen and the things friends have told me, but there is so much money at stake, there is almost nothing they won't do to get that patent. I've never heard of anyone getting threatened or worse... but it wouldn't surprise me. If they are prepared to use private investigators, they WILL have boxed every single person in each team. So if a threat was made, would we ever hear of it?
 
SeekingOblivion said:
It’s prescription only. But rarely used outpatient exception for treatment of hyperemesis gravidarum. If you ask for it specifically, you get the stink eye as it is regarded as suspiciously popular with junkies. Basically you have to be pregnant or allergic to Zofran to get a prescription.
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To clarify for non-US, codeine (w/ promethazine) cough syrup's legacy in hiphop culture has valued it at extremely high prices. Also notably widely used in rural America, particularly in the same poor, coal-mining Appalachia.
 
Have you heard of the agent where instead of dimethylamine, the last step of the amitriptyline synthesis is performed with norpethidine?

Davis, M. A., Herr, F., Thomas, R. A., Charest, M.-Paule. (July 1967). "New Psychotropic Agents. VIII. 1 Analogs of Amitriptyline Containing the Normeperidine Group". Journal of Medicinal Chemistry. 10 (4): 627–635. doi:10.1021/jm00316a024.

The background patent is for the corresponding benzhydryl compound (lacking the 2C bridge). This agent was discovered to have a duration of above >6 hours and extremely safe therapeutic index:

Gustav Ehrhart, Leopold Ther, Hans-Georg Alpermann, & Heinrich Ott, US3426028 (1969 to Hoechst AG).
 
SeekingOblivion said:
“hiphop culture” 🤣
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are you disputing this or just a racial jab? promethazine+codeine syrup- "Texas Tea" - and its effects were a huge influence/inspiration to the sounds of texas 90s rap, and its use/abuse grew to become commonplace in hiphop/rap culture as a whole. its demand and popularity led to the eventual discontinuation of Actavis Prometh+codeine syrup a decade ago. I could elaborate on its popularity in bluegrass culture, but its relative significance/impact on popular culture is far lesser.

Hence why someone asking about promethazine might be given a dirty look- it's asking about a commonly known drug of abuse.

Apologies for getting off topic.
 
pcplease said:
are you disputing this or just a racial jab? promethazine+codeine syrup- "Texas Tea" - and its effects were a huge influence/inspiration to the sounds of texas 90s rap, and its use/abuse grew to become commonplace in hiphop/rap culture as a whole. its demand and popularity led to the eventual discontinuation of Actavis Prometh+codeine syrup a decade ago. I could elaborate on its popularity in bluegrass culture, but its relative significance/impact on popular culture is far lesser.

Hence why someone asking about promethazine might be given a dirty look- it's asking about a commonly known drug of abuse.

Apologies for getting off topic.
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It’s just a racial jab.
 
4DQSAR said:
I would be extremely careful in asscribing a specific action in the brain as the cause of clinical depression. I'm old enough to have seen dozens of mechanisms proposed. It may well be the case that like schizophrnaia, it's actually more than one illness that presents with the same set of symptoms.

Often we don't know if a given action is the cause OR is the result of something further upstream.

Certainly if animal models agree one one thing, it's that depression in man cannot be modelled in animals very well. Hence so many candidates that showed robust antidepressent action in animal models proved to be of little or no value in man.
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Scoplamine Is a full anticholinergic yet displays very potent antidepressant effects.
 
I have treatment resistant depression, I have tried TMS 2 times the second time was a waste of time. No benefits.
Nowadays I take Vyvanse and 20mg Dexamphetimine with Vraylar that acts as an antidepressant. Surprisingly stimulants work well with antidepressants especially if you are adhd
 
Smyth2 said:
Maura L. Furey & Wayne C. Drevets, WO2006127418 (to US Department of Health and Human Services (HHS)).
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...a study that has to ignore over 100+ US army cases where anticholinergic's more potent than what in Datura had to save people who got caught by ACH-E gases. Ignores the nootropic community having to state on having Benadryl at 50 ~ 125mg If you consume too much, Same with seafood. Why in psychosis ACH levels drop to levels only seen in people with severe AD yet without the severe IQ issues.
 
M1sterEd said:
I have treatment resistant depression, I have tried TMS 2 times the second time was a waste of time. No benefits.
Nowadays I take Vyvanse and 20mg Dexamphetimine with Vraylar that acts as an antidepressant. Surprisingly stimulants work well with antidepressants especially if you are adhd
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Yeah - ECT DOES work... but has significant side-effects.

I'm subject to tonic-clonic seizures which do exactly the same thing and after one depression and anxiety disapper for a couple of weeks. But that's all you get and I for one would not with 20 TC seizures per annum on anyone.

But it's still out there and if one is suicidal, I would suggest at least tying it can't hurt at that point. It works anf you recover... or you do what you were planning to do anyway.
 
Please consider taking a break/few days at the psyche ward, getting a stronger antipsychotic and block that extra dopamine that may be floating around up there. Suicidal thoughts come easy when manic from dopamine It is pretty hard to think rationally when levels are high. Reevaluate, reconsider.

Vraylar is not a typical antidepressant in the slightest- at all. I have a schizophrenic friend it works pretty well, but he still hates taking it.

The traditional SSRI, SNRIS, (S)NDRI's, are reuptake inhibitors. Classics like amitriptyline might be a likely balance to your daytime depressions. till providing the serotonin antagonist effects. Depression itself can be symptoms of untreated ADHD. I know the feeling. Mere a1 blockers (of which amitriptyline also acts as) help me a LOT with focus. Racing thoughts, sweaty palms, etc.

Maybe also consider trying the other side of ADHD treatment, i.e. Ritalin, as a dopamine and norepinephrine inhibitor, and I assume petter results especially if continuing on Vraylar.

I guess my main point is there are plenty of other combinations of medicine that may help you, and if they aren't, you can stop. You can't "un-shock" yourself.
 
4DQSAR said:
But 64 years after it's introduction, new antidepressants are compared with amitryptaline but often in a VERY dubious manner. For example, studies on paroxetine stated that it had 'similar effacacy to amitryptaline' BUT they were prescribing the control group tiny doses of amitryptaline and the test group the highest prescribabde dose of paroxetine... because medicinal chemistry isn't particularly ethical.
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"Three years before Prozac received approval by the US Food and Drug Administration in late 1987, the German BGA, that country's FDA equivalent, had such serious reservations about Prozac's safety that it refused to approve the antidepressant based on Lilly's studies showing that previously nonsuicidal patients who took the drug had a fivefold higher rate of suicides and suicide attempts than those on older antidepressants, and a threefold higher rate than those taking placebos.

Using figures on Prozac both from Lilly and independent research, however, Dr. David Healy, an expert on the brain's serotonin system and director of the North Wales Department of Psychological Medicine at the University of Wales, estimated that "probably 50,000 people have committed suicide on Prozac since its launch, over and above the number who would have done so if left untreated."

The Boston Globe, 2000
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Serotonin, depression, and aggression - The problem of brain energy.

Serotonin research is relatively new, but it rivals estrogen research for the level of incompetence and apparent fraudulent intent that can be found in professional publications. This is partly because of the involvement of the drug industry, but the U.S. government also played a role in setting...
raypeat.com
 
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