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Pharmacology Can someone please explain how trazadone helps combat the effects of stimulants? The pharmacological mechanism.

This thread contains discussion about a Pharmacology-related topic
Juicewrldfan

Juicewrldfan

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I keep hearing about people loving trazadone to combat effects of being overstimulated. I understand it’s often given for sleep but I have difficulty understanding these kind of things sometimes when I try to extrapolate from a paper and having a hard time understanding this one but I’m not very smart so that doesn’t say much.

What is the pharmacological action? All I understand is it antagonizes 5ht2a. Do stims tend to agonize 5ht2a. I wasn’t aware of them acting directly on serotonin.
 
Never heard that on before.

I'm not an expert at all but I'll give it a try. Trazodone has somewhat of a wonky profile, and as such relatively unique. They call it a SARI, serotonin antagonist and reuptake inhibitor. It's a potent 5-HT2a antagonist, like you said. Pure stimulants really don't affect 5-HT too much. Empathogens, kind of like crosses between stimulants and psychedelics, like MDMA and 2C-B, do so. Trazodone also produces these sedative effects by blocking histaminergic and adrenergic receptors. It's a partial 5-HT1a, so maybe it's effective for anxiety, but that effect would in most cases take weeks to manifest. Blocking 5-HT2C might preserve some dopaminergic activity in the prefrontal cortex, the absence of which is key in stimulant comedowns. For most of its mechanisms, it broadly decreases activity at metabotropic receptors and their respective excitatory ligands. Maybe it counters some of the inflammation caused by dopaminergic toxicity, as well. Hope this helps!
 
AlphaMethylPhenyl said:
Never heard that on before.

I'm not an expert at all but I'll give it a try. Trazodone has somewhat of a wonky profile, and as such relatively unique. They call it a SARI, serotonin antagonist and reuptake inhibitor. It's a potent 5-HT2a antagonist, like you said. Pure stimulants really don't affect 5-HT too much. Empathogens, kind of like crosses between stimulants and psychedelics, like MDMA and 2C-B, do so. Trazodone also produces these sedative effects by blocking histaminergic and adrenergic receptors. It's a partial 5-HT1a, so maybe it's effective for anxiety, but that effect would in most cases take weeks to manifest. Blocking 5-HT2C might preserve some dopaminergic activity in the prefrontal cortex, the absence of which is key in stimulant comedowns. For most of its mechanisms, it broadly decreases activity at metabotropic receptors and their respective excitatory ligands. Maybe it counters some of the inflammation caused by dopaminergic toxicity, as well. Hope this helps!
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Damn - doesn’t sound useful enough for me to add an mental illness med
 
The main sedative effects of trazodone are from its histamine receptor antagonism (with a little help from its alpha 1 adrenergic antagonism) as AlphaMethlyPhenyl stated.

The secret sauce of trazodone is that it is probably the lightest 5HT2A antagonist, so it can kill a psychadelic trip without blocking dopamine receptors like most antipsychotics.

It isn't going to be too different from seroquel for stimulant come downs, though it is likely less strong of a sedative, so it's next day effects will be milder.
 
AlphaMethylPhenyl said:
Never heard that on before.

I'm not an expert at all but I'll give it a try. Trazodone has somewhat of a wonky profile, and as such relatively unique. They call it a SARI, serotonin antagonist and reuptake inhibitor. It's a potent 5-HT2a antagonist, like you said. Pure stimulants really don't affect 5-HT too much. Empathogens, kind of like crosses between stimulants and psychedelics, like MDMA and 2C-B, do so. Trazodone also produces these sedative effects by blocking histaminergic and adrenergic receptors. It's a partial 5-HT1a, so maybe it's effective for anxiety, but that effect would in most cases take weeks to manifest. Blocking 5-HT2C might preserve some dopaminergic activity in the prefrontal cortex, the absence of which is key in stimulant comedowns. For most of its mechanisms, it broadly decreases activity at metabotropic receptors and their respective excitatory ligands. Maybe it counters some of the inflammation caused by dopaminergic toxicity, as well. Hope this helps!
Click to expand...
Trazodone reduces levels of glutamate, norepinephrine, dopamine, histamine, and acetylcholine by inhibiting release.

Trazodone further blocks the effects of norepinephrine by antagonizing alpha adrenergic receptors. Antagonism of histamine may also reduce stimulation as rats require histamine release to induce effects of methamphetamine.

There is literature from the 1960s that compounds that act as alpha/beta blockers (called catecholamine inhibitors in the paper) can completely prevent/ameliorate subjective and locomotor effects of amp/meth.

Recent papers also indicate that "unopposed alpha stimulation" caused by administration of alpha/beta blockers in stimulant overdose is actually unsupported in the literature, and ER physicians have seen complete amelioration of sympathomimetic symptoms of stimulant OD when such are administered.

 
snmfmy said:
Trazodone reduces levels of glutamate, norepinephrine, dopamine, histamine, and acetylcholine by inhibiting release.

Trazodone further blocks the effects of norepinephrine by antagonizing alpha adrenergic receptors. Antagonism of histamine may also reduce stimulation as rats require histamine release to induce effects of methamphetamine.

There is literature from the 1960s that compounds that act as alpha/beta blockers (called catecholamine inhibitors in the paper) can completely prevent/ameliorate subjective and locomotor effects of amp/meth.

Recent papers also indicate that "unopposed alpha stimulation" caused by administration of alpha/beta blockers in stimulant overdose is actually unsupported in the literature, and ER physicians have seen complete amelioration of sympathomimetic symptoms of stimulant OD when such are administered.

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So if its antagonism of 5ht2a is weak then would its risk of SS be low? @Skorpio
 
Juicewrldfan said:
So if its antagonism of 5ht2a is weak then would its risk of SS be low? @Skorpio
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Just because antagonism of a certain sub-receptor is low doesn't mean re-uptake inhibition isn't high, leading to high levels of serotonin in the synaptic cleft, coupled with inhibition of MAO, and inhibited retro-transport and antagonism or not enough serotonin is going to be toxic
 
Trazodone is an SSRI, so indirect serotonin subtype binding, but sedative effects tend to be more potent than SRI capability. I think it was introduced as an antidepressant, then the hypnotic effects became more obvious, and they switched it to mainly for insomnia. I would be interested to know the aggregate behavioral effects of it's main active metabolite, I think it was mCPP, which I think is a piperazine, binding to a whole slew of serotonin receptor types and releasing it as well. Anxiogenic and dysphoric in some cases, hmm. Funny how it technically is S-I by the analogue act, but trazodone isn't scheduled.
 
Skorpio said:
The main sedative effects of trazodone are from its histamine receptor antagonism (with a little help from its alpha 1 adrenergic antagonism) as AlphaMethlyPhenyl stated.

The secret sauce of trazodone is that it is probably the lightest 5HT2A antagonist, so it can kill a psychadelic trip without blocking dopamine receptors like most antipsychotics.

It isn't going to be too different from seroquel for stimulant come downs, though it is likely less strong of a sedative, so it's next day effects will be milder.
Click to expand...

Not a scientist so I only get part of this discussion even after looking up the terminology. But I've long suspected that my nightly 25mg trazodone hit was what was inhibiting the effects of the psychedelics I've tried, viz. DMT, shrooms, LSD. Ditto for MDMA but that just made me anxious. I'd also wondered if my long-time use of kratom might have played a part. Stopped that 6 weeks ago.

I'd love anthing further on this. Specifically, is the opinion of those in the know that in order to fully experience those other substances I would need to discontinue the traz entirely? Any guesses as to how long to wait?

Very grateful!
 
Canberra Slim said:
Not a scientist so I only get part of this discussion even after looking up the terminology. But I've long suspected that my nightly 25mg trazodone hit was what was inhibiting the effects of the psychedelics I've tried, viz. DMT, shrooms, LSD. Ditto for MDMA but that just made me anxious. I'd also wondered if my long-time use of kratom might have played a part. Stopped that 6 weeks ago.

I'd love anthing further on this. Specifically, is the opinion of those in the know that in order to fully experience those other substances I would need to discontinue the traz entirely? Any guesses as to how long to wait?

Very grateful!
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For looking at how long a drug takes to wash out, a decent rule of thumb is to multiply the half life of the drug by 5.
Trazodone has a half life range between 4 and 15 hours, so the washout period is between 1 and 3 days.

Of course, don't discontinue meds if you will lose stability without them.
 
Many thanks indeed. Would you opine that in the case of trazodone - that is, in my case long-term (4-5 years) use - there would be no, or little, residual effects after the 1-3 day washout? I realize this is likely a question with a lot of leeway, in the YMMV department if nothing else. Guess I'm overly dotting the i's, etc. here.

I also very much appreciate your last caution.
 
I'm just curious why this specifically can stop trips. No other antidepressant can, but this can. Why exactly? I'm pretty sure in House, you know, that show that used to be on Fox, he'd taken LSD to stop a migraine he'd purposely induced to see if some former colleague's new "cure" actually worked, and then admitted he took Trazodone to stop it because hours later he was fully functional.

I've heard of it stopping 300microgram+ acid trips in their tracks and have a supply of it, maybe one day I'll take 7g of shrooms, with a trip sitter, and then if I get out of control, which I probably would, drop 4 of them down the hatch for me.
 
BourbonMac said:
I'm just curious why this specifically can stop trips. No other antidepressant can, but this can. Why exactly? I'm pretty sure in House, you know, that show that used to be on Fox, he'd taken LSD to stop a migraine he'd purposely induced to see if some former colleague's new "cure" actually worked, and then admitted he took Trazodone to stop it because hours later he was fully functional.

I've heard of it stopping 300microgram+ acid trips in their tracks and have a supply of it, maybe one day I'll take 7g of shrooms, with a trip sitter, and then if I get out of control, which I probably would, drop 4 of them down the hatch for me.
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5HT2a antagonism
 
Canberra Slim said:
Many thanks indeed. Would you opine that in the case of trazodone - that is, in my case long-term (4-5 years) use - there would be no, or little, residual effects after the 1-3 day washout? I realize this is likely a question with a lot of leeway, in the YMMV department if nothing else. Guess I'm overly dotting the i's, etc. here.

I also very much appreciate your last caution.
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Honestly I've got no clue. How many times per day do you take it? I honestly worry that the ssri effects will cause withdrawal after that amount of time but am unsure.
 
Canberra Slim said:
Thanks, friend. I only take 25mg before bed, but I appreciate your concern about withdrawal after so long.
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That's quite a small amount, and it's not known for discontinuation issues like others. But four or five years is quite a while. I got off of trazodone pretty fast and I don't remember any ill effects, but I was on it for probably six months or so, taking 100mg or 200mg, I forgot. Ask your doc. But this isn't really the place for this kind of question. I'd ask you to reflect why you want to get off of it, too, and make sure the doc is on board.
 
AlphaMethylPhenyl said:
Trazodone is an SSRI, so indirect serotonin subtype binding, but sedative effects tend to be more potent than SRI capability. I think it was introduced as an antidepressant, then the hypnotic effects became more obvious, and they switched it to mainly for insomnia. I would be interested to know the aggregate behavioral effects of it's main active metabolite, I think it was mCPP, which I think is a piperazine, binding to a whole slew of serotonin receptor types and releasing it as well. Anxiogenic and dysphoric in some cases, hmm. Funny how it technically is S-I by the analogue act, but trazodone isn't scheduled.
Click to expand...
It's antihistamine action and anti-adrenergic Action is what causes the sedation.
 
It has an antihistaminerg action feom H1 to H5? Not sure H1 an H3 counts but doubt me. There is anatoginst action from it and has angonism on the adrenergic receptors aswell. Other action is non selective serotonin reuptak inhibition which is really weak compared to newer antidepressants. I have never heard it would counteract stimulants.
 
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