In summary on cotinine and niacin - cotinine might be the main benefit giving constituent, and minus the negatives of nicotine (e.g increaded heart rate), with niacin as the MAOI component.
Steeped e-liquid more like WTA (though not it's equal, maybe not too far off?)
That some nicotine will be oxidised at vape time might be why vaping is more suucessful than traditional NRT - it gives more than just nicotine (the behavioural mimic aspect is also important).
I think I've made a good case for oxidation of nicotine not being 'an unavoidable 'loss'', but actually beneficial (and why vaping beats other NRTs). Cotinine and niacin being two oxidation producta that can be reasonably argued to fit the bill (there may be others but I've not had much time to look into it further).
So, steeping is not just about improving flavor. High power vaping is not just about quantity, but also quality. In fact, by creating (more) other alkaloids, in both cases.
If correct, it's a big step in our understanding.
"Nicotinamide, a form of the B vitamin niacin, is known to exert similar effects on the brain as benzodiazapenes.13 Nicotinamide stimulates the GABA-benzodiazapene receptor complex, an inhibitory neuron grouping. By activating these neurons, a calming effect is the end result.14 Other investigations designed to test the efficacy of nicotinamide and brain function revealed that GABA nerve receptors were under less control (meaning that because they are inhibitory in nature, when they are not activated the brain is more excitable-which in theory may lead to more anxiety) when nicotinamide was found at suboptimal levels in the subject, and reintroduction of nicotinamide led to a calming effect on the GABA receptors.
Approaches to Anxiety (Oct. 2004)
No time right now but will look into possible pathways related to this. Is the amide group necessary even? For this to be important it would seem necessae=ry that the oxidation product itself by psychoactive (not reliant on metabolism - slow).
A little later ...
Niacin itself passes the blood-brain barrier easily (while the amide much less so) and is also psychoactive in a way that fits (calming; a MAOI, via histamine release).
"The most promising theoretical base at this point in time appears to lie in the metabolism of 5-OHtryptamine, or the monoamine oxidase reaction, The cerebral catecholamines have already been implicated in previous work with schizophrenics. An adrenochrome or serotonin-chrome has been postulated. Although some of the phenomena observed in our study could be related to a DNA mechanism, the observed effects were much more global and occurred too quickly in many cases to be confined only to this theoretical base. The breakdown of 5-OH-tryptamine into serotonin, dopamine, noradrenalin, and nicotinic acid explains all of the presently observed phenomena far better. These psychoactive substances have now been shown to be responsible for sensory perception, sleep, appetite, mood, and alertness among other important and vital functions. Levels of these biogenic amines are regulated both at the site of production and through controlled degradation to inactive metabolites through the monoamine oxidase reaction. It should again be emphasized that nicotinic acid is a normal byproduct of this important body reaction.
In theory we find the 5-OH-tryptamine mechanism most compatible with observed and reported phenomena regarding nicotinic acid in alcoholics. Nicotinic acid is a simple molecule capable of passing the blood-brain barrier. This fact alone could explain the failure of nicotinamide to significantly benefit alcoholics. The saturation of the CNS nicotinic acid mechanism could inhibit 5-OHtryptamine metabolism reducing levels of serotonin, dopamine, and noradrenalin. Nicotinic acid is a proved histamine stimulant. High levels of histamine tend to inhibit the monoamine oxidase reaction causing reaccumulation of the biogenic amines. Nicotinic acid could well be a biochemical governor regulating in a very significant way the metabolic levels of the cerebral catecholamines."
Obviously read between the lines, so to speak, given that the paper is primarily about alcoholics.
The thing is - I have niacin in my cupboard in something like 50mg tablets (with histamine flush in ~10 minutes), so how does niacin achieve its effect in smoke (if it does) at tiny doses? A similar but more potent variant? Or it's simply the combined effect with the other alkaloids (synergy) ? (likely)
Thinking about the relative nature of smoke and vapor. Smoke will contain other alkaloids beside nicotine, but what nicotine is released is more likely to be oxidised than the nicotine in vapor (because largely the 'vapor' is mostly actually a mist of tiny droplets of PG/VG with the nicotine less susceptible to oxidation as it is mostly dissolved in the PG/VG carrier; there will still be some oxidation given the small droplet size (large surface to air ratio). Some 25-35% of the nicotine in vaping will be oxidised (best guess) before it enters the blood stream whereas in smoke it is probably a lot higher (say 60-70%, best guess, maybe more).
So, nicotine may be less important than generally thought (other than as a precursor).
And 'steeping' creates a 'vapor' that is more like smoke in alkaloid profile (primarily, less nicotine, more cotinine; at the point of absorption into the bloodstream).
One wonders about the anecdotal evidence regarding the advantages of: 1) 'steeping' and 2) high power vaping - and whether there might be psychopharmacological advantages to oxidation / heat induced changes (beyond improvements in taste).
This paper is interesting : http://legacy.library.ucsf.edu/docum.../Sjgh39c00.pdf
For example (there are other oxidation products), although nicotine oxide (cotinine) is the primary metalolite of nicotine, perhaps it enhances the psychopharmacological effects when absorebed together with nicotine (i.e. quickly; or a different / mixed isonomer?). Just maybe, oxidation / degradation can partially 'restore' a pure nicotine effect to a more WTA like effect by the production of other alkaloids that just might be more active than we thought (rather than, say, anatabine, anabasine). With WTA, there are probably a number of elements that are important. But one might be cotinine (in the leaf); and cotinine can also be produced from pure nicotine by oxidation / heat.
An interesting experiment would be to quickly oxidise some e-liquid with, say, a drop of hydrogen peroxide, and subjectively evaluate how it compares when vaped.
22 Dec 2013
Much of the beneficial (to smokers) effects ascribed to nicotine are more correctly attributable to cotinine, including protection from brain degeneration with age as well as a calming effect (research, what little there is, such as Cotinine: Beyond that Expected, More than a Biomarker of Tobacco Consumption focuses on psychological illnesses (as drug money is the driver in medicine) and the mechanisms are not all clear (neurotransmitters such as dopamine and serotonin being part of the picture).
Although cotinine has a long plasma half-life of some 10 hours (much longer than nicotine), there could be a 'boost' effect from the initial inhalation.
Cotinine does not boost heart-rate like nicotine; it doesn't have those classic physiological stimulant effects, and I'd say it is not one.
On a partial tangent, I'd also like to note something I have been thinking about - that the boost in mental abilities that is thought to be a stimulant effect could well be an effect of increased calm. In terms of attention, it is focused by reducing the amount diverted by anxiety, negative thoughts, ...
One has to laugth at the paper cited above - 'beyond that expected' - 'beyond our stupidly myopic assumptions' would be more honest. While not necessarily (inherently) an imperfection of science, the focus on bit A does B and bit C does D over-simplification is a major flaw in the way that science is commonly practiced.
In summary, what part might cotinine play in WTA - best guess: somewhere between 20 and 80%. In 'steeping', it is likely to play a bigger role.
(some hours later)
Something of an a-ha moment : why is vaping more successful than traditional NRT? - because it converts some (~30% ?) of the nicotine to cotinine (see initial headline image of this blog entry).
The existing literature lists cotinine as more minor in effects but I am leaning to this being wrong - it is more than minor, and somehow it is important that the initial inhalation contain significant cotinine (rather than cotine produced by metalism of nicotine); why, I don't know atm. Likely either the form of the cotinine or the rate of change of concentration. Will research in future show cotinine to be a MAOI ?
Oxidised e-liquid (it will happen at vape time anyway) DOES matter - but in a POSITIVE way
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