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The Big and Bangin' Pseudo-Advanced Drug Chemistry, Pharmacology and More Thread, V.2

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Yeah, heroin immediately came to mind. The metaphor I always used is that it is an "arrow" to better "pierce" the BBB.
 
aced126 said:
Why don't dopamine receptor agonists have the same effect as dopamine releasing agents or reuptake inhibitors?


Not recommending this at all, but hypothetically if one were to take a MAOb inhibitor along with phenethylamine, what would happen?
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Old post, but this may be of interest to someone.

Ironically, while selegiline can't be mixed with cheese or Prozac, it can be mixed with methamphetamine and cocaine. A small placebo controlled study found that concomittant administration of methamphetamine (15 or 30mg) with selegiline (oral) caused no EKG, lab, or vital sign changes. The clearance and half-life of methamphetamine was also unchanged. Similarly, 10mg PO can be safely mixed with up to 40mg cocaine, should you be into that. An earlier study found that 10mg/d could reduce the high of cocaine and reduced the activity of the amygdala (as defined as glucose utilization on PET scan) and not cause any negative interactions.
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http://www.filedropper.com/gatley1996

Anybody know what is meant by "Hill slope" as per:

e.g. pg. 4 @
temperature on the IC50s values for o-bromomethylphenidate binding to the dopamine transporter. However, methylphenidate at 37 degrees had a higher IC50 value and a lower Hill slope than at 0 or 22 degrees. A possible explanation is a significant degree of hydrolysis of the methyl ester during incubations at the higher temperature.
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The above link to the article.
 
A few pages ago, Shulgin's method of trialing drugs was discussed. Here is an excerpt from the 2,5-dimethoxy-4-methylthioamphetamine entry in Pihkal:

This specific compound is probably the first sulfur-containing phenethylamine to have been evaluated as apotentially active CNS stimulant or psychedelic. It was a complete, total, absolute unknown. The first trials were made at the sub-microgram level,specifically at 0.25 micrograms, at 11:30 AM on September 3, 1975. Part of this extreme precaution was due to the uniqueness of a new heteroatom ina phenethylamine system. But part was due to the strange manic excitement that occurred at the time of the isolation and characterizing of the finalproduct in the laboratory. Although it was certainly all placebo response, I was jumpy and unable to stay in the lab for more than a few minutes at atime. Maybe dust in the air? Maybe some skin contact with the free base? Now, I know there was nothing, but the possibility of extraordinary potencywas real, and I did indeed wash everything down anyway. In fact, it took a total of 18 trials to work the experimental dosage up to as much as a singlemilligram. In retrospect, overly cautious. But retrospection, as they say, is cheap.
 
The power of Sasha's mind's belief that ALEPH-1 (DOT) would be phenomenal likely produced a placebo like effect. It was later found to be "boring."
 
PiHKAL said:
This specific compound is probably the first sulfur-containing phenethylamine to have been evaluated as a potentially active CNS stimulant or psychedelic. It was a complete, total, absolute unknown. The first trials were made at the sub-microgram level,specifically at 0.25 micrograms, at 11:30 AM on September 3, 1975. Part of this extreme precaution was due to the uniqueness of a new heteroatom in a phenethylamine system. But part was due to the strange manic excitement that occurred at the time of the isolation and characterizing of the final product in the laboratory. Although it was certainly all placebo response, I was jumpy and unable to stay in the lab for more than a few minutes at a time. Maybe dust in the air? Maybe some skin contact with the free base? Now, I know there was nothing, but the possibility of extraordinary potency was real, and I did indeed wash everything down anyway. In fact, it took a total of 18 trials to work the experimental dosage up to as much as a single milligram.
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Shulgin was an expert. Years of experience and education resulted in these procedures. They are effective. Utilizing this procedure with newly received chemicals has saved my life. If you're interested, PiHKAL and TiHKAL have more.
 
Hey aced, you should check out some of this person's writings http://biopsychiatry.com

engineering pharmacological utopia isn't necessarily a bad thing but if it caused apathy/contentment to stare at a wall all day it could be bad, I mean maybe there are benefits to having pain/sadness and being able to understand other people's suffering. Maybe a permanent state of an MDMA type experience would at least have enough empathy to it that hyperthymic people wouldn't disregard normal people's troubles.
 
I read that a while ago actually. I don't think complete utopia would be ideal for reasons you discussed. But it seems to me that hyperthymic temperament is considered not really a disorder, but more of a bad thing than a good thing by the psychiatric community and I'm not sure why.
 
Well my theory would be that hyperthymia is usually associated with hypomanic/bipolar and my theory on the cycling between depression and mania is that it's really receptor homeostasis - during a state of hypomania or hyperthymia the receptors down regulate and this eventually leads into depression/dysthymia. Then the receptors up regulate and lead back into hyperthymia.

To avoid the depression which is clearly pathological you might have to avoid the hyperthymia, which at first glance doesn't appear pathological.

Of course this does not apply if there are people out there who are 100% hyperthymic and don't actually cycle.
 
Cotcha Yankinov said:
Well my theory would be that hyperthymia is usually associated with hypomanic/bipolar and my theory on the cycling between depression and mania is that it's really receptor homeostasis - during a state of hypomania or hyperthymia the receptors down regulate and this eventually leads into depression/dysthymia. Then the receptors up regulate and lead back into hyperthymia.

To avoid the depression which is clearly pathological you might have to avoid the hyperthymia, which at first glance doesn't appear pathological.

Of course this does not apply if there are people out there who are 100% hyperthymic and don't actually cycle.
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Do you think many people like this exist? Could one live a long period of their life (say, the first 25 years of their life) as a hyperthymic and then finally cycle into the dysthymic phase? If your theory about receptor up & down-regulation is true, then if someone was hyperthymic for a long period of their life, they would very slowly transition into a dysthymic phase?

I feel as though I have been hyperthymic all my life (and still am, although I have admittedly not lived very long) but I sometimes fear if I will eventually transition phases.
 
Hi, it's my first post. Do you know something about 3-diethylamine-carbazole (don't know how to attach a pic)? It is active? does anybody tried?
 
aced126 said:
Do you think many people like this exist? Could one live a long period of their life (say, the first 25 years of their life) as a hyperthymic and then finally cycle into the dysthymic phase? If your theory about receptor up & down-regulation is true, then if someone was hyperthymic for a long period of their life, they would very slowly transition into a dysthymic phase?

I feel as though I have been hyperthymic all my life (and still am, although I have admittedly not lived very long) but I sometimes fear if I will eventually transition phases.
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Well many people are indeed happy people, though whether that's related to them being in a good situation or having a good temperament is hard to say. Some people are happy with very little - Sam Harris talks of how some people in history have found profound happiness by isolating themselves and meditating, which sounds like hell to some people. I can only assume if you remove stimulation (by isolation) that receptors up regulate and such. But maybe there's more to it, such as maybe with meditation and shutting off the thoughts comes a weakening of the glutamatergic inputs that inhibit the nucleus accumbens.

So I'll start this off by highlighting two concepts that might be good to differentiate between later on - intense short term euphoria (you could think methamphetamine or intense mania/bipolar I) and long term mild euphoria (hyperthymia).

I think my theory of receptor homeostasis leading to mood swings makes most sense in the context of "rapid cycling" bipolar with a consciousness (or "thought patterns") that lead to activation of brain regions important for euphoria like the nucleus accumbens, whereby after a lot of stimulation in a short period of time the receptors are down regulated, but if we ponder how sustainable a constant state of hyperthymia is I'd say a lot of it probably has to do with DeltaFosB and neurotrophic factors like BDNF, also essentially long term potentiation / long term depression.

Even though all drugs of abuse induce DeltaFosB and will create a sensitization with that genetic expression through various routes (wiki has a good page on what DeltaFosB does), I think drugs like meth will cause receptor downregulation that will outpace the induction of DeltaFosB and from this you will get less and less euphoria from it. I theorize the same happens with intense mania - the receptor downregulation outpaces the expression of DeltaFosB's ability to sensitize the "euphoria brain regions" and so depression ensues.

Long term mild euphoria is probably much more sustainable in the sense that there might be a better DeltaFosB to receptor downregulation ratio, or maybe even that the receptors always have enough time to up regulate during sleep to be able to sustain a daily mild euphoria. Sort of like bipolar but the "depression/upregulation" phase is always during sleep.

The other thing to take into account is the specific mechanics of the nucleus accumbens - I'll use NMDA antagonists (known to induce DeltaFosB) as an example. The reason why NMDA antagonists cause dopamine release / euphoria / hallucinations is because NMDA provides a lot of input to inhibitory interneurons. So when you block that NMDA input you get release of monoamines downstream because you're inhibiting the inhibitors essentially. And apparently the reason why opoids cause euphoria is because there are opoid receptors on the GABA interneurons in the nucleus accumbens, and when opoids bind there they inhibit the GABA neurons and let the dopamine flow downstream.

So knowing what we know about those mechanics, you might make a prediction - too much long term potentiation (that strengthens the NMDA/glutamate signal that inhibits the GABA interneurons) is bad, and too much GABA is bad. Now I'd have to dig up my textbook, but I recall very specifically it said that BDNF over expression in the nucleus accumbens is implicated in depression - which at first makes no sense (and the authors noted this) because normally BDNF is a great thing that strengthens neurons, but in light of the nucleus accumbens mechanics I think it makes sense how BDNF over expression might lead to depression.

In my mind, assuming there isn't too much BDNF or LTP strengthening the inhibition of the nucleus accumbens, and you have enough long term depression to keep those glutamatergic inhibitory inputs weak, your hyperthymia could definitely be sustainable. With the exception that there are more hormonal reasons for your sense of well being (that might decline with age). Sorry for the wall of text lol
 
Which receptors do you refer to when talking about downregulation and, is up & down-regulation a process which can really take place over the time frame of hours? I thought it was a much longer process. Which textbook are you using?
 
Dopamine is mostly implicated when talking about feelings of wellbeing, serotonin is important as well but some of dopamine release is via serotonin. Regarding the time frame, from what I understand there are pathways downstream of the receptor like beta arrestin (if I recall correctly) that signal receptor internalization (serotonin can signal through either G proteins or beta arrestin, and it sounds like inverse agonists are really agonists that are selective for beta arrestin) so I would assume that down regulation can occur rapidly. At least I would assume that you can signal through beta arrestin at the same speed that you would signal through G proteins... I don't know how immediate the receptor internalization is. Not too sure about upregulation - I imagine that there are factors that influence the rate of upregulation but it might be genetically predetermined to some extent. I suppose hyperthymia could be explained by having a high basal rate of up regulation.

I liked molecular neuropharmacology by Nestler, got it for cheap used on Amazon. Introduction to neuropsychopharmacology by Iversen has been good too.

I was thinking about making a thread about receptor homeostasis and hoping serotonin2A would chime in - my textbooks didn't go very into detail at all on the subject and I bet you serotonin knows a bunch. Cus I mean I could be horribly wrong on all of this lol
 
The significance of Brain-Derived Neurotrophic Factor and other similar chemicals have piqued my interest. I recently noticed Brain-Derived Neurotrophic Factor was mentioned on William Leonard Pickard's Twitter page.

William Leonard Pickard said:
Researchers determine that "Dihexa" is more active than Brain-Derived Neurotrophic Factor (BDNF) in enhancing cognitive function
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https://twitter.com/scalable_mind
 
I was hoping that someone could give an elaborate explanation of how opiates are so addictive. Sorry a lot of this is noob knowledge. I know that they inhibit Substance P and further cause depolarization of the cell so that it's less likely to fire. They also seem to inhibit GABA efflux, but I'm assuming in parts of the brain where such would somehow be more pleasurable than not...somehow. Is mu stimulation a better indicator of euphoria/abuse potential than D2 activation in the striatum and associated regions? Are there delta opiate agonists in clinical trials for depression (heard buprenorphine is making some headway but as I remember it's not a delta agonist)? I'm assuming that part of the allure of opiates has to do with volume/non-direct transmission so that they essentially have very far reach wherever they're released. Are beta-endorphin and friends also hormones? If so, and this is a long-shot, but might the opiate user be more liked by others by virtue of this? Just spitballing here.
 
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