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

[InterestingFACT]

All I am saying is that the purpose of using drugs to mimic schizophrenia is that if you make a drug, you will be able to know its pharmacology, and if it induces schizophrenesque psychosis without failure, then you can study its pharmacology and therefore learn the pharmacology of schizophrenia. Certain drugs causing psychotic episodes or full blown psychosis is not the same as this.

Hold on here, this is not necessarily--and in fact probably is not--true.

Just because a drug mimics schizophrenia does not mean that something endogenous is mimicking that drug in the schizophrenic brain. Rather, to use an example, if stimulant psychosis can imitate schizophrenia it would be because the excess dopaminergic activity relative to other neuronal activity would be simulating the outcome of a brain that has differing numbers either of dopaminergic neurons, neurons that synapse onto dopaminergic neurons, or neurons that dopaminergic neurons synapse onto.

In other words, it doesn't tell you much of anything about dopamine and schizophrenia, but rather--once you examine the dopamine neuron subtypes most related the the schizoid activity--can tell you what physical portions of the brain are behaving differently in the schizophrenic model.

 

[AlphaMethylPhenyl]

Right, this is useful, but at no point does it actually confirm the set of physiological processes underlying organic psychoses. Even with a properly psychotomimetic drug, we wouldn't gain a firm understanding of such, nor does the pharmacology of prevailing treatments provide a great deal of useful evidence. I hypothesize that the causal processes underlying organic psychosis occur at the ontological and epistemological level of neural circuits, so looking for a receptor or neurotransmitter that "mediates schizophrenia" is wrong-headed in the first place. However, this wouldn't preclude effective treatments rooted in drug-receptor interactions.

ebola

You're essentially stating that there isn't a biological route explaining schizophrenia? That the environment and sense of self determines it, so that we can't find its source? Dualism? Don't understand...

Perhaps you're bridging into the territory of stating that it's merely an illness relative to environment, which is okay, but it seems like a bit of a fallacy given the original statement.

 

[endotropic]

You're essentially stating that there isn't a biological route explaining schizophrenia? That the environment and sense of self determines it, so that we can't find its source? Dualism? Don't understand...

Perhaps you're bridging into the territory of stating that it's merely an illness relative to environment, which is okay, but it seems like a bit of a fallacy given the original statement.

Well, if I may speculate on ebola?'s thoughts for a moment (dangerous proposition, I know), I think he means that schizophrenia is far more complicated than "too much of neurotransmitter A, too little of receptor B" which are the kinds of questions we can answer with neuropharmacological studies. Instead subtle developmental changes in neural organization might explain the true genesis of the disease more accurately - changes brought about by a combination of genetic abnormalities and various life experiences. How'd I do ebola??

I still think psychotomimetic neuropharmacological models are the best way to understand those differences in a preclinical setting though. You can't ask an animal if they're paranoid, or what the voices in their heads are saying, so we need some method to reliably induce "a psychosis-like state". I can't really imagine how you would study psychosis in an animal without some manipulation that causes psychosis in humans, but I'm not very imaginative either. Maybe if we can find a genetic profile that 100% reliably causes psychosis in humans (gosh I hope not) we can use that profile in animals, but we don't have that yet.

 

[crOOk]

I still think psychotomimetic neuropharmacological models are the best way to understand those differences in a preclinical setting though. You can't ask an animal if they're paranoid, or what the voices in their heads are saying, so we need some method to reliably induce "a psychosis-like state".

Exactly. We run into similar issues when it comes to researching affective illness. What we have been doing successfully for quite some time now is mimicking depression in lab animals. Either through genetic knockouts, pharmacological treatment or training. None of these states is ever the same as the specific depressive state of a particular individual, since the pathogenesis and symptoms of depression show a huge variance (the same goes for psychotic states), but they still comes close enough for us to find remedies and to find whatever clues we pick up on the way bit by bit. It's simply all we got and we have to work with it for the time being.

 

[AlphaMethylPhenyl]

So if harmaline isn't responsible for the majorly addictive principles of tobacco relative to nicotine itself, what chemicals might be?

 

[endotropic]

So if harmaline isn't responsible for the majorly addictive principles of tobacco relative to nicotine itself, what chemicals might be?

It's not?

 

[InterestingFACT]

It's not?

Since when was it ever questioned that nicotine itself was the addictive component?

Or are you referencing the theory that harmaline makes cigarettes more addictive than e-cigarettes?

 

[AlphaMethylPhenyl]

Not according to sekio's research

edit: I think

 

[endotropic]

Since when was it ever questioned that nicotine itself was the addictive component?

Or are you referencing the theory that harmaline makes cigarettes more addictive than e-cigarettes?

My last post was a bit ambiguous, I've always heard that the MAOIs (e.g. harmaline) in tobacco were responsible for turning nicotine into an addictive compound, as nicotine clearly lacks addictive properties on its own. I was questioning why ho-chi thought otherwise.

Not according to sekio's research

edit: I think

Are you referring to something in particular? I don't remember what research sekio did on this topic.

 

[sekio]

From what I understand, pure nicotine doesn't cause self administration in animals the same way cocaine or whatever does. The complex mixture of chemicals emitted from a burning cigarette including the harmala alkaloids and other stuff (menthol, etc) that potentiate and alter nicotine's pharmacological profile, as well as the incredibly fast delivery of the same compounds to the brain - due to smoking being the most rapid drug administration route, are responsible for the wholly different experiences between smoked tobacco, snuff/snus, inhaled nicotine vapors (e-cigs), and pure nicotine either in gum, transdermal patches, etc.

At least this is what I've gathered. I'm not saying that regular nicotine use won't cause dependence, that's obvious. I'm just saying that it could be a reason why cigarette smokers generally prefer cigarettes (with e-cigs coming in a close second) and generally substituting pure nicotine gum or patches for a moderate to heavy tobacco smoking habit is not as effective as it could be. (I've heard that Champix (varenicline) works pretty well.)

Really this is just more proof that route of administration matters a lot, just as much as the actual preparation (pure nicotine vs tobacco). Smoking crack rocks is a pretty different experience from doing cocaine nasally, for instance. (not that I've ever smoked crack.)

 

[pharmakos]

so lab animals get hooked on smoked tobacco but not vaporized nicotine. what happens if you take an animal hooked on smoked tobacco and try switching his smoke out with vaporized nicotine? would he stick with it or would he quit?

 

[endotropic]

so lab animals get hooked on smoked tobacco but not vaporized nicotine. what happens if you take an animal hooked on smoked tobacco and try switching his smoke out with vaporized nicotine? would he stick with it or would he quit?

Forget the rats, let's look at some people. If you gave nicotine to non-smokers to try to make them dependent ethics committee would be none too pleased, but if you give them the nicotine to try to help them in some way maybe you could look at dependence on the side?

Nicotine treatment of mild cognitive impairment - A 6-month double-blind pilot clinical trial

So give non-smokers 15mg of nicotine/day every day for 6 months and what happens?

There was no withdrawal syndrome and no subjects continued to use nicotine products.

That doesn't sound like an addictive drug to me, but would inhaling nicotine vapor lead to a different result? Hopefully someone tricks an ethics committee into approving that one soon!

 

[sekio]

I think with the prevalence of e-cigs nowadays that couldn't be too hard to do.

 

[pharmakos]

Forget the rats, let's look at some people. If you gave nicotine to non-smokers to try to make them dependent...

not what i'm wondering. i'm wondering what happens in animal models if you give vaporized nicotine to animals already hooked on smoked tobacco. we know that the switch to e-cigs works pretty well for many tobacco-dependent humans. i'm wondering how tobacco-dependent animals cope with a switch like that, though. would it fully substitute? i'm guessing not but it would be interesting to see.

 

[endotropic]

not what i'm wondering. i'm wondering what happens in animal models if you give vaporized nicotine to animals already hooked on smoked tobacco. we know that the switch to e-cigs works pretty well for many tobacco-dependent humans. i'm wondering how tobacco-dependent animals cope with a switch like that, though. would it fully substitute? i'm guessing not but it would be interesting to see.

It sounds like the study you want to see would look at how nicotine affects tobacco withdrawal syndrome in a rodent model? I haven't seen much at all in that realm using tobacco smoke or even a tobacco extract. It's really difficult to standardize dosage with an animal inhalation model, which is why you usually see these kinds of studies with IV nicotine instead.

 

[toastmann]

Does anybody know an explaination of why I only seem to get tachycardia and some minor arrhytmia near the tail end of an mixed levo/dextro amphetamine experience? Whilst the experience lastst minor tachycardia (80->90 bpm) but near the and a few double/ empty beats and more tachycardia (ranging from 95 to 130bpm) I cant seem to find an explaination.


I mean with methamphetamine you could blame it on the conversion from methamphetamine to amphetamine but thats bit the case here.

I wonder why I have these things at the end of the experience.

 

[crOOk]

Does anybody know an explaination of why I only seem to get tachycardia and some minor arrhytmia near the tail end of an mixed levo/dextro amphetamine experience? Whilst the experience lastst minor tachycardia (80->90 bpm) but near the and a few double/ empty beats and more tachycardia (ranging from 95 to 130bpm) I cant seem to find an explaination.


I mean with methamphetamine you could blame it on the conversion from methamphetamine to amphetamine but thats bit the case here.

I wonder why I have these things at the end of the experience.

Same for me and this goes for some of the psychological effects as well. For 6h or so I'd be alert, but with minor tachycardia and relatively calm to the outside. Afterwards I'll get really hypomanic and my heart would be beating a lot faster. I've personally always attributed this to having bipolar I disorder since I've seen it in other bipolars as well, while most other people just crash and come down.

 

[crOOk]

not what i'm wondering. i'm wondering what happens in animal models if you give vaporized nicotine to animals already hooked on smoked tobacco. we know that the switch to e-cigs works pretty well for many tobacco-dependent humans. i'm wondering how tobacco-dependent animals cope with a switch like that, though. would it fully substitute? i'm guessing not but it would be interesting to see.

I did at least find the following studies and have also seen a lot of studies expose test animals to tobacco smoke, eventhough I can't recall if these were studies looking at addictive properties of tobacco.

Nicotine-like behavioral effects of the minor tobacco alkaloids nornicotine, anabasine, and anatabine in male rodents.

Accordingly, we systematically evaluated the minor tobacco alkaloids nornicotine, anabasine, and anatabine using assays of behavioral tolerability, nicotine withdrawal, nicotine discrimination, and nicotine self-administration in male rodents. At doses that were well tolerated, all 3 minor alkaloids dose-dependently engendered robust substitution for a nicotine discriminative stimulus in mice (0.32 mg/kg, IP), and anabasine attenuated nicotine withdrawal. When the ED50 dose of each alkaloid was administered in combination with nicotine, the discriminative stimulus effects of nicotine were not enhanced by any of the alkaloids, and anatabine blunted nicotine's effects. In drug self-administration studies, only nornicotine was self-administered by rats that self-administered nicotine intravenously; anabasine and anatabine had no reinforcing effects. Moreover, prior administration of each of the minor tobacco alkaloids dose-dependently decreased nicotine self-administration. Collectively these results suggest that the minor tobacco alkaloids may substitute for the subjective effects of nicotine and attenuate withdrawal and craving without the abuse liability of nicotine.

And even better:

The monoamine oxidase inhibitor phenelzine enhances the discriminative stimulus effect of nicotine in rats.

In addition to delivering nicotine, tobacco smoke also inhibits monoamine oxidase (MAO). Although MAO inhibitors (MAOIs) can increase nicotine self-administration in rodents, the effects of MAOIs on the discriminative stimulus effect of nicotine are not known. This study examined the effects of three MAOIs (phenelzine, clorgyline and pargyline) with varying selectivity for MAOA and MAOB in the nicotine drug discrimination procedure in rats. Adult male Sprague-Dawley rats were trained to discriminate nicotine (0.3 mg/kg, subcutaneously) from saline in a standard, two-lever food-reinforced operant task. Once the discrimination was acquired, the ability of each MAOI to substitute for or alter the discriminative stimulus effect of nicotine was determined. In substitution tests, nicotine (0.03-0.3 mg/kg) produced full, dose-dependent substitution. Although the selective MAOA inhibitor clorgyline (3-56 mg/kg) and the selective MAOB inhibitor pargyline (3-56 mg/kg) did not elicit any nicotine-appropriate responding, partial substitution was obtained with the nonselective MAO inhibitor phenelzine (1-17 mg/kg). Phenelzine (10 mg/kg) also enhanced the discriminative stimulus effect of a low dose of nicotine (0.056 mg/kg) and prolonged the time course effect of the nicotine-training dose. These findings indicate that concomitant inhibition of MAOA and MAOB can enhance the discriminative stimulus effect of nicotine in rats.

 

[Jabberwocky]

So if harmaline isn't responsible for the majorly addictive principles of tobacco relative to nicotine itself, what chemicals might be?

My last post was a bit ambiguous, I've always heard that the MAOIs (e.g. harmaline) in tobacco were responsible for turning nicotine into an addictive compound, as nicotine clearly lacks addictive properties on its own.

harmaline is one of (if not the) alkaloids that are responsible for the massive dependence that tobacco has over raw nicotine. Nicotine is reinforcing, but not much more than caffeine; nicotine + a low-level MAOi(MAO-a, if i recall correctly; pretty sure nicotine + deprenyl[an MAOb-i] doesn't do this), which is a pretty central theme in nicotine addiction/recovery.
Anecdote: much over a yr ago, i swapped from cigs to a vaporizer (ie., from tobacco, to pure nicotine), and it wasn't working for me. I even tried the 21mg patches w/ a vaporizer, and it didn't cut it. Fast-forward a while, and I was at the point of using zero cigarettes, and only using my vaporizer (at a 1.2% potency, cuz i tended to vape w/o noticing... g'damn delicious flavours!), BUT i had gotten into another tobacco-habit: smoking tobacco several times a day, errr... probably 2 or 3x during the day and another 2 at night... out of a tobacco pipe. I'm still there now, although i've 'kicked'* the vaporizer, and haven't used a patch in forever, but i still smoke 2-5 hits of tobacco a day through my(boss-ass)tobacco pipe. I get lightheaded and a rush everytime i do it; i do not think i intend to stop at this point, i'm very happy that my overall nico intake** is down but, the only thing of importance: burnt tobacco consumption, is at incredibly low levels, even compared to 1 or 2 cigarettes daily.
*vaporizer was kicked cuz, after a while using it while doing a handful of tobacco hits out of my old-man-style, wooden tobacco pipe daily, the vaporizer ended up unappealing to me; i intended to use it for a while, but right now i have cartridges and liquid that've sat for months and i doubt i'll ever touch them.
**my nico intake right now is only a good handful of hits daily from a pipe, w/ regular/generic rolling tobaccos. I switch them up routinely, but notice no difference. I take a good puff of tobacco, i get a headrush for half a minute, and i do this a handful of times a day. I'm early 30's and smoked since i was mid-teens. I stopped using cigarettes about a year ago, when i got into vaporizers, and i got off vaporizers&patches when i got into my 'pipe-smoking phase'. I don't intend to stop this phase, cuz i smoke so little that it's not worrying me. When i get a chance to smoke bud, i choke on it like a virgin. I love my hits of tobacco, they're much more rewarding than any cigarette ever was, and i NEVER crave them, i just tend to do them at nighttime, they're a night-cap thing for me.

It blows my mind to think that i spent over a decade trying, w/o any success whatsoever, to get off tobacco, and after finding the right products i was able to kick it to the point that cigarettes have abso-fucking-lutely zero appeal to me now, and haven't for a long time. Sometimes i'm in a social setting (not terribly often for me right now), and am drinking and just really.want.to.hit.my.tobaccy.pipe, but cannot; my mind immediately goes to 'a puff from someone's cigarette?', and then my subconscious counters it, and i realize once again that cigarettes suck for me now- which is the ultimate triumph for someone who was cigarette/tobacco dependent.

I do love my nico+maoBi hits, and the handful i take daily are so much more rewarding than when i smoked cigarettes; i got here by doing a long-ish, nicotine-only regimen (vaporizers) but in the end i can 100% say that the tobacco blend is what's addictive, not the nicotine. I could also link a million pubmeds to prove that nicotine is hardly reinforcing while tobacco is heavily reinforcing, but ya'll can google so figure my lil op-ed is all that's relevant to type out

 

[Puzzled]

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