The Large and Nifty Not-quite-advanced Drug Chemistry, Pharmacology and More Thread

[Sturnam]

Well, some of the flavinoids described mainly inhibit CYP3A4, and some mainly inhibit CYD2D6. I guess it would depend on the ratio of these flavinoids in the grapefruit, as well as how active your CYP2D6 enzymes are in the first place.

Overall, I think that the CYP3A4 inhibition is greater, but the CYP2D6 inhibition basically the rate limiting step. So even if the morphine sticks around longer, the codeine will be processed much slower, and probably will decrease the subjective high. Also, because CYP2D6 is inhibited, it means that more of the codeine will take alternative metabolic pathways, which would result in other, weaker metabolites.

 

[blau1005]

Thanks. I get the feeling that GFJ might be worth a go once or twice, but those who have found success with it are outweighed by those who haven't. I guess there's only so much you can do with codeine.

 

[johanneschimpo]

why not use a (selective) CYP3A4 inhibitor?

 

[acetylcholine]

Quick question that I don't think requires a separate thread.

Psychedelics like LSD and Psilocin are 5-ht2a agonists. They also usually make people feel good, and are sometimes even abused by depressed people for their mood improving effects effects.

Atypical Antidepressants like Mirtazapine and Trazodone are 5-ht2a antagonists. They are prescribed to depressed people to improve mood and are sometimes quite effective.

What gives? I have some inkling that the answer has to do with 5-ht2a receptors being found in different parts of the brain and dopamine release, but I don't have a concrete answer.

Can someone explain this seemingly paradoxical situation?

 

[Hammilton]

It's pretty hard to find evidence regarding real abusive use of psychedelics. They're pretty self limiting, both the physical and mental exhaustion that often results after their use, but even more so, the tachyphylaxis makes it rather impossible. I've seen the occasional trip report documenting a depressed person using the drug to lighten their mood, but not anything that constitutes abuse. It'd be interesting to know how often even this sort of use occurs, though.

Mirtrazepine and Trazodone both have activities that go far beyond 5HT2a antagonism, and these other activities are too relevant to ignore for the sake of discussion. Are there any pure, selective 5HT2a antagonists that produce antidepressant-type effects? I don't know of any off the top of my head.

Despite all of this, I don't think it's neccessary to go much into their actions to explain it.

Psychedelics have their name for a good reason, they "manifest the soul," so to speak. They enable and sometimes force the user to think and address psychological issues and help to resolve them. I think the antidepressant effect they produce can be entirely explained by the cognitive effects they produce.

Mirtrazepine and Trazodone's effects can be explained without even involving their direct action of 5HT2a.

Perhaps this is all wrong. It's getting late and I'm getting tired; I don't feel like going through a bunch of journals right now.

 

[shibireru]

Are there any pure, selective 5HT2a antagonists that produce antidepressant-type effects? I don't know of any off the top of my head.

Ritanserin is, I believe, and appears to have anti-depressant properties. Perhaps also eplivanserin, altanserin, setoperone, and etoperidone. Probably not, but I am feeling much too lazy right now to track down information concerning their receptor affinities.

 

[shibireru]

Quick question that I don't think requires a separate thread.

Psychedelics like LSD and Psilocin are 5-ht2a agonists. They also usually make people feel good, and are sometimes even abused by depressed people for their mood improving effects effects.

Atypical Antidepressants like Mirtazapine and Trazodone are 5-ht2a antagonists. They are prescribed to depressed people to improve mood and are sometimes quite effective.

What gives? I have some inkling that the answer has to do with 5-ht2a receptors being found in different parts of the brain and dopamine release, but I don't have a concrete answer.

Can someone explain this seemingly paradoxical situation?

You should remember that all - or as far as I know anyway - serotonergic psychedelic hallucinogens can cause bad trips and severe anxiety - especially in those who are already feeling depressed and anxious. Perhaps people enjoy themselves while on these drugs despite their capacity for dysphorigenesis (i.e. their basal level of happiness and the pleasure of being thrust into some strange new world are great enough to counteract the dysphoria-encoding neurotransmission that these substances engender.)

Ayuhnoh :shrugs:

 

[blau1005]

why not use a (selective) CYP3A4 inhibitor?

Don't know of any that aren't Rx.

 

[Enkidu]

They are saying that the serotonin hypothesis of depression is BS. Apparently the advertisements/product pushing by drug companies marketing SSRIs have bolstered the hypothesis without enough corresponding scientific data.

For another paradoxical treatment option, look into tianeptine (a selective serotonin reuptake enhancer) vs. all the selective serotonin reuptake inhibitors.

It should be noted that the individual's body chemistry is also important. Slight, preexisting imbalances (i.e., the chemical reason that the individual is depressed, which varies from individual to individual) obviously play a role in dictating the proper therapy.

 

[ebola?]

Psychedelics like LSD and Psilocin are 5-ht2a agonists. They also usually make people feel good, and are sometimes even abused by depressed people for their mood improving effects effects

Yet all of these recreational drugs are 'dirty' in various respects. I cannot think of a pure(ish) 5ht2a agonist in common use. What is more, IIRC, Nichols researched a highly potent 5ht2a agonist that did not yield psychedelic effects. Things are getting weird and complicated, the more we discover (as always).

Atypical Antidepressants like Mirtazapine and Trazodone are 5-ht2a antagonists. They are prescribed to depressed people to improve mood and are sometimes quite effective.

OFF-TOPIC mirtazapine digression:

mmm...mirtazapine (which I take for insomnia) is...perhaps the dirtiest drug evar. I believe that the majority of anti-depressant effects may be attributed to antagonism at a2 adrenergic auto-receptors, which appears to cause increased release of 5ht and NE, in particular enhancing activity at 5ht1a (given the patterns of the drug's 5ht antagonisms). I believe that sedation and anxiolysis may be attributed mainly to H1 agnoism (mostly sedative) and antagonism at 5ht2c (likely quite anxiolytic. Remember that mCPP, a solid 5ht2c agonist, among other things, is commonly referred to as a 'panicogen'), maybe antagonism at 5ht2a, and maybe antagonism at 5ht3 (activity here means that mirtazapine doesn't cause the nausea and sexual side-effects that we see with SSRIs, but it also means that weight gain will be likely).

Weird drug.

Psychedelics have their name for a good reason, they "manifest the soul," so to speak. They enable and sometimes force the user to think and address psychological issues and help to resolve them. I think the antidepressant effect they produce can be entirely explained by the cognitive effects they produce.

Seems parsimonious enough.

They are saying that the serotonin hypothesis of depression is BS. Apparently the advertisements/product pushing by drug companies marketing SSRIs have bolstered the hypothesis without enough corresponding scientific data.

For another paradoxical treatment option, look into tianeptine (a selective serotonin reuptake enhancer) vs. all the selective serotonin reuptake inhibitors.

It should be noted that the individual's body chemistry is also important. Slight, preexisting imbalances (i.e., the chemical reason that the individual is depressed, which varies from individual to individual) obviously play a role in dictating the proper therapy.

I concur, with caveats. Assuming that SSRIs are marginally effective rather than ineffective, given the time-course of their efficacy, there has to be some sort of downstream change in neuroanatomy and/or chemistry that exerts an anti-depressant effect. Whether this is because they correct some prior 'imbalance' in neural circuits involving 5ht transmission is completely unclear.

ebola

 

[acetylcholine]

Shite... I wish I had started a new thread now. This seems to be generating a lot of really interesting discussion. I guess it's too late now.

I want to mention several things in response to what people have said, but I have to run to work.

I do want to mention quickly, though, that at least some SSRI's also block 5-ht2a receptors as Mirtazapine does. Fluoxetine does this, which may explain why people on Prozac require higher doses of, or get very little effect from psychedelics.

 

[Enkidu]

I concur, with caveats. Assuming that SSRIs are marginally effective rather than ineffective, given the time-course of their efficacy, there has to be some sort of downstream change in neuroanatomy and/or chemistry that exerts an anti-depressant effect. Whether this is because they correct some prior 'imbalance' in neural circuits involving 5ht transmission is completely unclear.

There is an article called Biological Markers of Depression that discusses this. (I have the whole book in front of me. ) Yes, downstream changes do cause the persistent mood change, but that is still the result of a correction in a chemical 'imbalance.' There are a variety of chemical hypotheses of depression. So when I said,

It should be noted that the individual's body chemistry is also important. Slight, preexisting imbalances (i.e., the chemical reason that the individual is depressed, which varies from individual to individual) obviously play a role in dictating the proper therapy.

I in no way meant to restrict 'chemical imbalance' to serotonin. It is even true that different chemical imbalances cause different types of depression!

 

[Enkidu]

Yet all of these recreational drugs are 'dirty' in various respects. I cannot think of a pure(ish) 5ht2a agonist in common use. What is more, IIRC, Nichols researched a highly potent 5ht2a agonist that did not yield psychedelic effects. Things are getting weird and complicated, the more we discover (as always).

Oh, I forgot to ask, which one was this?

 

[ebola?]

Hah...I don't know enough to go further in this discussion without looking up journal articles (on which I'm pretty damned burnt, writing a research proposal right now).
...
Another fucking selegiline question:
what do people think of careful use of MDMA + selegiline?
I believe that Nuke posted a study recently suggesting that selegiline will combat neurotoxicity without outright toxic increases in hyptertension and hyperthermia.

So in vivo, in humans, which moderating effect of selegiline will win out:
increased neurotoxicity from increased hypothermia or decreased neurotoxicity from reduced formation of peroxides from the action of MAOB.

Now, given the rife impurities in street ecstasy, I think that this question should remain strictly theoretical. It would be nigh impossible to safely titrate up to a safe but active dose of MDMA that one could repeat when using 'wares' with unclear content and dosage.

ebola

 

[Tsukasa]

^ People shoudn't refer to "ecstacy pills" as MDMA. Theirs only a slight chance it's actually MDMA or even an analogue. It's like russian roullete. Unless you get high grade MD(X)A from a reliable chem vendor, then I wouldn't risk using selegiline with anything you think is molly.

 

[leungkachong]

Yet all of these recreational drugs are 'dirty' in various respects. I cannot think of a pure(ish) 5ht2a agonist in common use. What is more, IIRC, Nichols researched a highly potent 5ht2a agonist that did not yield psychedelic effects. Things are getting weird and complicated, the more we discover (as always).

It appears that the differential activation of catalytic activity (or of the G protein subunits) is what underlies whether a 5-HT2A agonist is psychedelic or not. Which also means that F&B's SAR can only bring us so far, as we don't yet understand the microdomain interactions which decide whether we get more/any PLC vs PLA2 activity. Yah, it's the phospholipase C doing the PIP2 --> IP3 + DAG that seems to be necessary+sufficient.

I guess it'd be pretty damn cruel to constituitively activate the PLC-mediating subunit... but it's not weird and complicated, just selective/picky. And this signal-directed trafficking stuff REALLY expands our repertoire and pharmacologists!

 

[acetylcholine]

Ritanserin is, I believe, and appears to have anti-depressant properties. Perhaps also eplivanserin, altanserin, setoperone, and etoperidone. Probably not, but I am feeling much too lazy right now to track down information concerning their receptor affinities.

Ritanserin and its analogues are pretty close. They have no affinity for Histamine receptors or a2 receptors like tetracyclic AD's, so someone who takes it should really be able to "feel" only the 5-HT effect. I say 5-HT and not 5-HT2a because, according to IUPHAR, it has affinity for just about every serotonin receptor as well as a1. Still, its effect is strongest on 5-HT2a, and if it is indeed a relatively efficacious antidepressant according to clinical studies, then there you go.

Considering the fact that Yohimbine has undeniably imo, antidepressant effects, and it is a relatively selective a2 blocker, I would wager to say that a2 antagonism is likely a stronger, and certainly faster antidepressant route than 5-HT antagonism. However, from my experience, tetracyclics' a2 is effect is hardly noticeable compared to Yohimbine. I never stayed on a tetracyclic for long, but it never felt anything like Yohimbine, or any stimulant for that matter. Any Remeron users here care to differ?

According to this abstract posted on biopsychiatry.com:
http://biopsychiatry.com/schizoserotonin.htm

In the prefrontal cortex, 5-HT(2A)-receptors stimulation increases the release of glutamate

Considering the evidence for NMDA antagonists as potential antidepressants, it seems reasonable to me say that 5-HT2a antagonists may work through this route. I say this because, if I remember correctly, Ketamine functions as an antidepressant by increasing glutamate receptor subtype activation.

Your thoughts?

 

[ebola?]

I never stayed on a tetracyclic for long, but it never felt anything like Yohimbine, or any stimulant for that matter. Any Remeron users here care to differ?

I'm yohimbine naive and plan to stay that way.
I have a working hypothesis that adrenergic activation in isolation of alternate 'euphorogenesis' feels fucking bad, man.

ebola

 

[acetylcholine]

I'm yohimbine naive and plan to stay that way.
I have a working hypothesis that adrenergic activation in isolation of alternate 'euphorogenesis' feels fucking bad, man.

ebola

Funny you say that. When I first tried Yohimbe, I fucking hated it too. I felt nauseous, feverish, and dizzy, a feeling akin to smoking too many cigarettes. I stayed away for years because of that bad experience. I now know that my bad experience was very likely due to my ingesting GNC Yohimbe bark extract, rather than pure alkaloid. There are many active chemicals in the bark other than Yohimbine and it's spatial isomers. Some of these impurities are possibly MAOIs, and I believe that is what made me feel sick.

Years later, I decided to try Yohimbine HCl, and I was surprised how effective of an atypical stimulant it was. There was no nausea or other nasty peripheral side effects at up to 7.5 mg. It is not euphoric, but there is a definite positive CNS effect. I find it's an effective appetite suppresant and all around mood brightener. It's also great for treating dry mouth due to medication. Yohimbine would never pass as a desirable illicit "drug," but it is a terrific nutritional "supplement."

Too much will cause side effects even without nausea; I get tremors, racing thoughts, and muscle stiffness from too much Yohimbine, but it's no big deal to me.

 

[shibireru]

Considering the fact that Yohimbine has undeniably imo, antidepressant effects, and it is a relatively selective a2 blocker, I would wager to say that a2 antagonism is likely a stronger, and certainly faster antidepressant route than 5-HT antagonism.

Yohimbine is a 5-HT1A, 5-HT1D, and 5-HT2A agonist and a 5-HT1B, 5-HT2B, and alpha 2 adrenergic receptor antagonist.

When I take yohimbine, I feel excruciatingly bored, aboulic, and anhedonic (or more so than usual anyways), but when it wears off, I feel quite blissful and sociable. It seems to be that its anti-depressant effect lies within its rebound effects - at least for me.

The other day I conducted a little, fairly risky experiment wherein I took 50 micrograms of clonidine with 500 or 1000mg of Yohimbe bark powder every half an hour for two hours and threw in a few hundred milligrams of 5-hydroxytryptophan for good measure. I felt better the next day than I had in years. (5-HTP alone makes me feel worse, so it probably wasn't that.)