Preferring Drugs Based on Their Antagonist Site? (Alpha vs. Beta)

[Ketamania]

So I was just curious as to how much I could learn from this topic, and because it seemed fun. Do our DOC’s come from a biological predisposition?

As far as I know from biology, alpha receptors mostly have to do with blood pressure regulation whereas beta receptors affect the signaling in the sympathetic nervous system.

Upon some research, there’s several types of alpha-receptors which all fall under the general name “adrenic receptors”.

Time for experimental etymology:

Adrenic… adrenal…. adrenal gland? If the adrenal gland is stimulated I’m pretty sure that creates an overall stimulation response in the body. Soooo….
Anti-adrenic = anti=stimulation?

So one time I tried Propanalol (a beta blocker) to help my anxiety. I had a terrible terrible terrible physical reaction to it. Never took it again. This was a beta blocker, so apparently I have bad reactions to beta blockers (anti- sympathetic system messaging drugs?)

So my new GP was helping me wean me off heroin and fent, and I noted to her that Clonidine helped a lot. With anxiety, with WD, with everything. I felt good.

I like clonidine, a lot.

I just took a quick look at a couple of my DOC’s and they seem to also affect the alpha receptors strongly from what I can tell. LSD is a potent 5-HTα2 antagonist (“fills” the receptor so it doesn’t produce a response?) and so is MDMA (not the same exact one, but effects α2’s as well).

AND! Clonidine affects α2’s as well! It stimulates (antiadrenic) aka agonist to alpha-2 receptors in the brain, producing an overall paradoxical effect in the body. It’s “anti”adrenergic (alpha stimulation) effect is thought to decrease overactivity of the sympathetic nervous system.

So, my hypothesis is, maybe people have a chemical predisposition to liking some pharmaceuticals better than others based on site of action?

Idk just thoughts

 

[Ketamania]

So upon more research on antagonists and agonists, they differ based on how the drug binds to the receptor (I remember this now). Without going into that though, antagonists generally tend to cancel the effect of said receptor whereas agonists further stimulate the receptor?

This makes sense for MDMA and Clonidine (since both are alpha agonists) and OMG:

Detomidine is the main ingredient in a horse tranquilizer (Dormosedan). It’s generally not pleasant. However, I found it to be “kinda” nice compared to other reports (or lack of “pleasurable” reports lol).

Maybe if I were able to try just detomidine at a much smaller dose I’d find it much more recreational?

I legit think I am prone to liking alpha agonists!

However, why do I like LSD still then? If it is an antagonist not agonist of the alpha receptors. Maybe just cause it’s neutral?

 

[Mjäll]

The "alpha" in adrenergic receptors has nothing to do with the "a" in 5HT2A. The latter isn't even called "alpha". You've made that up.

LSD is an agonist at 5HT2A, not antagonist.

The connection you imagine does not exist.

 

[Skorpio]

Alpha2 adrenergic receptors are presynaptic receptors. These are located on the same neuron that is releasing norepinephrine, andserve to measure the amount of norepinephrine at a synapse, providing negative feedback on further release.

Clonidine binds to that receptor as an agonist, and makes it think you are flooded with norepinephrine, preventing release.

It has value in opioid withdrawal, because opioid signaling supresses norepinephrine release in the locus coeruleus, which becomes more active as the body tries to regain homeostasis. During withdrawal, the lack of suppression of this region causes quite a bit of norepinephrine signaling, and clonidine helps put the breaks on that.

An alpha2 antagonist like yohimbine will cause fairly massive release of norepinephrine, as the neuron thinks that there is not any in the synapse, due to blockade of the receptor.

The other adrenergic receptors tend to be postsynaptic, where they receive the released norepinephrine from the presynaptic cell and modify the downstream cell's excitability.

As an example beta 2 receptors are located in the heart, and serve to increase heart rate when activated by norepinephrine during sympathetic stimulation. Blocking these receptors tends to decrease heart rate.

Alpha 1 receptors alter blood pressure by constricting smooth muscle in your arteries when activated, increasing blood pressure.

 

[arrall]

There is some genetic basis for drug efficacy due to enzyme production (small subsets of people cannot produce certain enzymes. For example, people completely lacking CYP2D6 (about 7-10% of Caucasians) would find DXM much stronger but also a very different drug due to it not being broken down into DXO, while they would find opiates much weaker due to them not being metabolized into morphine. However, in most cases enzymatic differences will not be this severe and genetics will play far more of a role in medication efficacy and required dosing than in determining how much people actually enjoy recreational drugs. For that, I would suggest that it may be far more attributable to what mental illnesses someone has.

Clonidine helped a lot. With anxiety, with WD, with everything. I felt good.

I like clonidine, a lot.

Clonidine is used to treat ADHD and is often prescribed off-label for PTSD, borderline personality disorder, and anxiety disorders.

I just took a quick look at a couple of my DOC’s and they seem to also affect the alpha receptors strongly from what I can tell. LSD is a potent 5-HTα2 antagonist (“fills” the receptor so it doesn’t produce a response?) and so is MDMA (not the same exact one, but effects α2’s as well).

LSD is a 5HT2A agonist. A meaning the first group of 5HT2 receptors and having absolutely nothing to do with alpha receptors. MDMA is also a 5HT2A agonist, but quite a weak one.

AND! Clonidine affects α2’s as well! It stimulates (antiadrenic) aka agonist to alpha-2 receptors in the brain, producing an overall paradoxical effect in the body. It’s “anti”adrenergic (alpha stimulation) effect is thought to decrease overactivity of the sympathetic nervous system.

Correct.

So, my hypothesis is, maybe people have a chemical predisposition to liking some pharmaceuticals better than others based on site of action?

In theory certain genes may affect this, but I suspect that it is FAR more to due with the person's personality and mental illnesses (or lack thereof) than a random biological/chemical predisposition.

 

[Ballz_Trippington]

Hmmmmmm
This is extremely interesting!
I've never thought about choosing a drug based on its antagonistic effects except for trazadone ot ketenserin for its 5h2a antagonistism to end a psychedelic trip.
Since most dissociatives are DRI's which I assume is responsible for most the stimulating activity, then would that mean that if a dopamine antagonist like seroquel would block the stimulating effects of O-PCE or other Arylcychlohexelamines ????
I love dissociative but I hate the lingering stimulation that only seems to be absent from legit Ketamine.
Very curious about this!!
If anyone could give some educational info regarding this I would be most grateful

 

[Ballz_Trippington]

Hmmmmmm
This is extremely interesting!
I've never thought about choosing a drug based on its antagonistic effects except for trazadone ot ketenserin for its 5h2a antagonistism to end a psychedelic trip.
Since most dissociatives are DRI's which I assume is responsible for most the stimulating activity, then would that mean that if a dopamine antagonist like seroquel would block the stimulating effects of O-PCE or other Arylcychlohexelamines ????
I love dissociative but I hate the lingering stimulation that only seems to be absent from legit Ketamine.
Very curious about this!!
If anyone could give some educational info regarding this I would be most grateful

Anyone out there versed in neuropharmacology able to shed any light on this at all???
I'm sorry to ask again ...it seems like a simple yes or no question but I don't want to be the guinea pig taking MXE or O-PCE with something like rispiderone and risking a seriously bad interaction....
I love dissos but I hate the stimulation part of the experience....it would awesome if there was a way to counter the stimulation while still being able to "hole" from dissos.
Anyhoo, sorry again fir asking twice but if anyone out there with more knowledge than I could share some knowledge I would be in your debt!!!❤

 

[plumbus-nine]

For me clonidine has only value as a last resort (when no benzo's available) med for anxiety/panic attacks; even in withdrawal it has only limited positive effects (notably easing restlessness). I took it for some months, long ago, hoping for positive effects on my character as I associated norepinephrine with anxiety, fear, fight or flight and thus aggression, but what I got was depression. I learned that one needs some norepinephrine for a healthy state of mind. Cold turkey (was hospitalized and got a shitty doc as usual) from 150mcg clonidine + 30mg memantine per day gave me the first and so far only manic episode, Idk which med was more relevant for this or if it was kind of a bad synergy.

The body seems to be able to work better without beta than alpha receptors, alpha blockers as well as clonidine induce stuff like orthostatic hypotension which beta blockers in usual dosages don't. I overdosed propranolol just for fucks sake and got.. nothing. Independently if I take the usual 200mg or 400mg or 600mg, I get the same result, maybe a BIT more orthostatic stuff but nowhere near what clonidine gives me. Other than that just a reduction of tachycardia, from 90-110bpm it will sink to 70 bpm and a healthy blood pressure of 120/70. As said, even in overdose. Initially it (propranolol) made me tired, so I took the whole dose at night, but after a few weeks this stopped and now I just get a slight depression of drive (not general depression, just less drive and energy) independent of the dosage. Weird.

I use propranolol because of hoped anxiolytic effects, there are some but nothing special and I guess I'll switch to one of the non brain penetrating, newer gen beta blockers. Or do a combination, 40mg propranolol and some biso/metoprolol.
Clonidine was effective in reversing the increase in blood pressure from the RIMA moclobemide + a challenge dose of ~2mg d-amphetamine.
But for withdrawal I'd prefer a benzo, as I do against panic attacks.

In my teens I tried yohimbine, knew little about drugs and they sold it as 'stimulant' which it is but the most uncomfortable one BY FAR. Only naloxone comes close to the hell it gave me, just yohimbine was a body thing while naloxone was in mind. I got this from naloxone even without a opioid tolerance - maybe my genetics are weird but it's interesting how different people react to drugs!
Once before I had clonidine I got carisoprodol but don't remember whether I tested it. Possibly just a low dose without much effects.

Yeah I know that clonidine is used against ADHD but probably only works for the hyperactive type, I have diagnosed inattentive ADD and for me it doesn't help at all. Stimulants do but have limited dosages as cardiac side effects are strong for me. Didn't test beta blocker + amphetamine yet though.