This paper addresses the question of the often reported 'something missing', identifies the likely candidates and their modes of action, and approaches to creating a more effective e-liquid, something with enormous potential for impact on health in making e-liquid vaping an even more effective alternative/replacement for smoking.
Beta Carbolines
"β-carboline alkaloids are widespread in plants and animals, and frequently act as monoamine oxidase inhibitors (MAOI). ... Some β-carbolines, notably tryptoline* and pinoline, are formed naturally in the human body. The latter is implicated along with melatonin in the role of the pineal gland in regulating the sleep-wake cycle. The β-carboline can link to cerebral benzodiazepine receptors and induce inverse agonist effect."
beta-Carboline - Wikipedia, the free encyclopedia
( * Associated with the sleep cycle )
That last sentence is very interesting. By action on the GABA neurotransmitter that reduces some neuron excitability, benzodiazepines (Valium is an example) produces a calming, anti-anxiety effect.
( Interesting and simple link re carbolines and coffee and MAOI effect: Human monoamine oxidase enzyme inhibition by coffee and beta-carbolines norharman and harm )
Beta Carbolines, the good guys - Antioxidant properties of ß-carboline alkaloids are related to their antimutagenic and antigenotoxic activities: Antioxidant properties of {beta}-carboline alkaloids are related to their antimutagenic and antigenotoxic activities -- Moura et al., 10.1093/mutage/gem016 -- Mutagenesis
Endorphin Link
Evidence that a benzodiazepine receptor mechanism regulates the secretion of pituitary beta-endorphin in rats. Evidence that a benzodiazepine receptor mechanism ... [Endocrinology. 1985] - PubMed result
Heterocyclic Amines and Alpha Carbolines
In food processing / curing it is the heat mediated reaction of proteins (and dehydrated proteins) and carbohydrates, from which the carbolines arise; most of the products so formed in browning type cooking (over 100C) are toxic heterocyclic amines that are notorious for existing in smoke too.
playing with the curing would be a way to affect carboline levels (and HCAs in general unfortunately; a very blunt instrument); like any other product maker, will alter the product to increase sales.
In fact, alpha carbolines, the bad guys, can be 100s of times higher in cooked meat than in smoke (comparing say 100g meat to 10 cigs); Matsumoto, T. et al, Determination of mutagen amino-alpha-carbolines in grilled foods and cigarette smoke condensate. Cancer Lett. 1981 / 12 (1-2) / 105-110.
( Interesting note for chemists: "The common chemical structure of the alkaloids used in this study comprises one indole nucleus and one six-member pyrrole. According to their oxidation state, these alkaloids can be divided into two groups: dihydro-ß-carbolines (harmaline and harmalol) and ß-carbolines (harmane, harmine and harmol)" )
As I've said before, toxins in food put some perspective on the trace levels that might be found with vaping.
It has also been suggested that withdrawal from smoking can lead to the seeking out of prepared foods causing weight gain (a separate mechanism from keeping busy or loss of appetite suppression).
Indeed, it has also been suggested that food manufacturers deliberately combine sugar and proteins knowing that some beta carbolines will be produced on being cooked; but a lot more alpha carbolines and other toxic HCAs will also be produced, and the body has trouble metabolising these often destructured molecules.
Beta-carbolines and alcohol
"When acetaldehyde [an ethanol metabolite] combines with serotonin [a neurotransmitter not unlike dopamine] it produces beta-carboline. Acetaldehyde plus dopamine produces solsalinol. Solsalinol plus bet-caboline gives tetrahydroisoquinalines; these can activate the same receptors as beta-endorphins."
Alcoholism : the cause and the cure - Google Books
Alkaloids
Not a very well defined term. The -oid just means 'resemble (in shape)'; in the way we say 'cuboid' or 'humanoid'. The alk- root is a contraction of alkaline (or 'basic' as opposed to acidic).
Organic compounds that have a basic nitrogen atom (one with electron lone pairs) are called amines and the term alkaloid is usually reserved for amines found naturally in plants.
Alkaloids, like other inorganic compounds, often involve a 6-carbon ring (compounds that include this benzene ring arrangement are denoted as 'aromatic' as opposed to 'aliphatic').
Nicotine is an alkaloid, and there are many others in tobacco too. Some of these alkaloids can behave as MAOIs.
The biochemistry is complex; there are different types of MAOI that affect, to different degrees, various messengers in the brain. That is, in psychoactive terms, they would produce different effects (some more relaxing, some more stimulating; though more complex than a single axis as in this example).
Basically, the combination of nicorine and MAOI makes the effect more dramatic - faster and stronger - and has been likened to the effect of amphetamines, but milder.
MAOIs are not necessarily dramatic in effect; if i'm not mistaken, catechins are a type of MAOI (have the MAO inhibition effect); these are found in tea, and have a pleasant effect that is both relaxing and stimulating
Carboline MAOI alkaloids in food and tobacco
Relative exposure to beta-carbolines norharman and harman from foods and tobacco smoke.Herraiz T.
Spanish Council for Scientific Research, Instituto de Fermentaciones Industriales, CSIC, Juan de la Cierva 3, E-28006 Madrid, Spain. therraiz@ifi.csic.es
"Norharman and harman are two heterocyclic beta-carboline (9H-pyrido[3,4-b]indole) alkaloids with biological and potential toxicological activity that appear in foodstuffs and environmental sources. ...
The levels found of beta-carbolines were highly variable. Low processed foodstuffs (i.e. milk, yoghurt, uncooked meats and fish) did not contain norharman and harman above the detection limit. Others, however, contained relatively high concentrations (at the tens of ng g(-1) or microg l(-1) level) depending on the processing conditions as, for example, 'well-done' cooked meat and fish. The highest amounts of norharman and harman were found in brewed coffee (29-207 microg l(-1)), sauces (soy sauce and Tabasco, among others; 4-252 microg l(-1)), 'well done' cooked meat and fish (57-160 ng g(-1)), toasted bread (42-160 ng g(-1)), and fermented alcoholic beverages (n.d.-41 mug l(-1)). beta-Carbolines also occurred in a high amount in the mainstream of cigarette smoke (207-2780 ng/cigarette), which is an important contributor to daily exposure to these compounds.
Based on these results, it is concluded that the daily exposure to beta-carbolines in humans might be from tens to hundreds of micrograms, with cigarette smoke, coffee, certain seasonings, cooked foods and alcoholic beverages, in this order, being the major contributors. Many other foodstuffs might also contribute with minor amounts of norharman and harman. Foods and tobacco smoke might be potential contributors to the reported endogenous presence of beta-carbolines in humans." PMID: 15764332 [PubMed - indexed for MEDLINE]
It is interesting that the high content of carbolines in roasted coffee does not seem to be 'addictive' in to any great extent, certainly dwarfed by the satiation of something else, probably caffeine in this case. As with nicotine, overdosing is unlikely in normal use.
And the conclusion to draw is that carbolines alone, just as nic alone, is not that 'addictive'; it the combination. In layman's terms I'd say it is the ability of this combo to combine alertness with relaxed well-being.
This is not maybe unheard of without psychopharma intervention. What psychologists refer to as 'good stress' (enjoyable) could well elucidate this same combo (physiologically too) - I'm gonna call it 'performers high'. More similarity of effect than similarity biochemically, perhaps.
The MAOI effects of beta carbolines (harman, norharman, anabasine (acetylcholine receptor agonist and close relative of nicotine), anatabine) and nornicotine (a secondary tobacco alkaloid that is produced by the N-demethylation of nicotine) are likely the key cofactor in the physiological effects of smoking and represent the 'something missing' from e-liquid vaping. The calming effect due to higher dosage levels of nicotine (initially stimulating, then relaxing) combined with direct action of the beta carbolines (besides MAO inhibition).
"At higher doses, nicotine enhances the effect of serotonin and opiate activity, producing a calming, pain-killing effect. Nicotine is unique in comparison to most drugs, as its profile changes from stimulant to sedative/pain killer in increasing dosages and use." (Wikipedia)
I propose that the MAOIs are needed to reach the calming stage (carbolines and maybe others).
PET scans do show some activity suggesting activation of other pathways (such as endorphin release), but these are likely secondary in my current estimation.
Patents granted related to MAOIs for improved NRTs
United States Patent 6,350,479
Williams , et al. February 26, 2002
United States Patent 6,569,470
Williams , et al. May 27, 2003
United States Patent 6,929,811
Williams , et al. August 16, 2005
Beta Carboline sources
Carbolines can be synthesised in the lab; there has been a lot of investigation of this due to their potential for a wide variety of pharmaceutical applications.
Synthesized ?-carbolines - Patent 6872830
The chemistry is complex; it's most definetely for a lab.
Actually lots of info on the synthesis of carbolines.
Can be from amides, as in this example: A Versatile Cyclodehydration Reaction for the Synthesis of Isoquinoline and ?-Carboline Derivatives
Beta carbolines can be found in a variety pf plants, with one plant's seeds containing around 3% beta carbolines. This would be a great source for creating an e-liquid based on nicotine and beta-carbolines, rather than all tobacco alkaloids.
Notes on tobacco alkaloids e-liquid
Preparing e-liquid by removing all but the alkaloids will produce an e-liquid that can match smoking for physiological response and thereby be the most effective as a smoking alternative replacement.
It might it be worth removing any alkaloids that are non-volatile in freebase form from the final alkaloid mix, by say slow vaporisation and recondensing in an inert atmosphere. Nicotine is one of few alkaloids that are liquid at room temperature; those that are not are unlikely to vaporise.
However, most alkaloids decompose easily on heating (so the loss of the other alkaloids is likely substantial as with nicotine; but post heating the profile would resemble that gained from smoking tobacco; though might be different if switched to ultrasonic misting of the e-liquid); for this reason, this step would lose/waste too much of the useful alkaloids to remove the non-volatile ones. Other than employing evaporation rather than boiling, not sure if another way to do this.
* The 'other alkaloids' in tobacco account for about 10% of the total (nicotine 90%).
Summary
My research into carbolines was the most exciting by far, and will not likely be repeated. It has brought together insights into smoking, and more besides, that ties up so much of what I have researched previously. The importance of these findings and analysis is quite breathtaking. The details may be somewhat fuzzy but the overall scheme is well-defined. So here is a brief summary.
Carbolines are a type of alkaloid with psychoactive, and other, properties that are fairly widespread in nature. Some of the beta carbolines, in particular, have been found to have a bariety of beneficial therapeutic effects. Psychoactively, while some tend to hallucinatory effects, others, and this would include thse in tobacco, have a calming effects similar to opiates (and affecting some of the same receptor sites).
The beta carbolines in tobacco, possibly in conjunction with other alkaloids, particularly those also with MAOI activity, play a role that is both supporting of the activity of nicotine (via MAOI activity), and possibly a secondary more direct role on their own. Together, the synergy of MAOIs plus nicotine, plus additional mild, opiate-like activity, provide the unique features of tobacco smoke on human psychology (mild alertness coupled with mild relaxation).
Previous research, mostly un-noted, suggests that beta carbolines are likely the key alkaloids responsible for the 'something missing' experienced with nicotine alone. Others' extractions of beta carbolines from beta carboline rich sources is a strong indicator that this is indeed on the right lines, given the similarity of color of that extraction with the recent tobacco extraction noted in this thread.
Clues led to the nature of harmful toxins called heterocyclic amines (HCAs) in cooked and processed foods. These are created by the action of heat on micxtures of carbohydrates and proteins/dehydrated proteins. One type of HCA is carbolines. While some of the carbolines will be beta carbolines, others will be toxic alpha carbolines. In general most HCAs are bad news. The levels in cooked foods can be far higher than even those found in cigarette smoke (cigarette smoke contains many other toxins too though).
Nevertheless, the existence of some beta carbolines among the generally toxic HCAs is quite likely a reason why there is an 'addiction' to processed and fast foods beyond ease and sweet taste. From a health perspective, an 'addiction' to food that contains high levels of HCAs (and other similar heat induced toxins), and that are also often devoid of significant nutritional value, is serious matter, whose effects are becoming ever clearer.
Ethanol is primarily a 'downer', with the 'high' attributed to preferential slowing of the frontal cortex creating lowered social inhibitions. But there is likely more to it than that, and once again beta carolines might play a key role.
Indeed, I am proposing that beta carbolines play a key role in a broad range of pharmacologically mediated 'addictictiveness', primarily through a mild stimulation of the opiate mediated reward system, and particularly strongly when combined with nicotine and other MAOIs in smoking, with an endorphin release also involved.
In the context of smoking, the inclusion of beta carbolines - and indeed, the whole family of alkaloids found in tobacco - will ensure the best possible efficacy for smoking replacement products. It is almost impossible to over-stress the importance of this point.
E-liquid that has the other alkaloids prsent is likely to be more effective not only for more people in replacing tobacco smoking, but also reduce consumption of nicotine (and the carrier PG etc) by being more effective at satiation.
I look forward to seeing blind studies comparing the effectiveness and consumption levels of normal e-liquid, full spectrum alkaloid e-liquid and nicotine plus beta carbolines.
The extraction of full spectrum alkaloids from tobacco would be easier than just nicotine as isolation of the alkaloids would likely be a step in isolating just nicotine. However, without some kind of 'harm reduction umbrella' statutory-wise, suppliers might be loathe to market a 'natural extract of mixed alkaloids'. But if the FDA and others wanted to show a real commitment to reducing smoking, they would embrace this, offsetting any possible harm/risks with the far greater harm of not allowing it, as is routinely calculated for drugs.
(A designation of 'tobacco product' would be better than 'drug' in this regard if the opportunity here for running with the 'harm reduction' categorisation is missed.)
Testing can confirm this, but if we take the known ingredients route and add only those alkaloids that are safe and effective to pure nicotine, then the beta-carbolines found in tobacco (or some of) are the likely candidate.
All logic and real concern for health points to the pragmatic solution to an entrenched problem. Will it happen? Maybe, but it will take some bold decision making by regulators. We can simply keep putting forward the facts and in time, with public support, it might come to pass.
Experimental results will go a long way to convince, us as a community first of all, that the 'something missing' is not (just) 'enough nic', but an important co-factor.
~~~
Earlier paper on MAOIs and comparison of absorption in vaping and smoking :
http://www.e-cigarette-forum.com/fo...-nicotine-absorption-addictiveness-maois.html
~~~
Some notes will integrate later:
Here's what I think is going on (a small part of): the stress relief of having a smoke is two things - the satiation of the craving that builds up as levels dip after being raised, and a 'real' biochemical effect of relaxing nature (I will post shortly what I think that is). The nicotine only has mostly the former in terms of relaxation (though most of the alertness-raising effect of analogs).
First, the worry that overdosing of the other alkaloids could occur: it doesnt happen with smoking, and the presence of the nicotine will ensure people 'cut-off'; in all likelihood, better satiation will lead to less consumption; and DVap has indicated that this can indeed occur. In short, it will more probably work the other way. At the moment, many vape more and more looking for something that isn't there.
TSNAs in e-liquid are some 7000 times less than in malboro cigs; so a lot of leeway here for the possibility (and it is only that) that WTA liquid might have increased TSNA levels.
Btw, few compounds have the same property as alkaloids that allow them to pass through successive acid-alkali phases as used to extract the alkaloids.
Doesn't really matter that e-liquid is 'addictive' - or that not everyone wants to quit nicotine/alkaloids; why should they? The point is to quit smoking; that's where the harm is. And for a smoking alternative to be the most successful, it has to be effective. E-liquid is easily diluted as required, to satisfy all requirements. Some of the anti-smoking people do understand this. To make the biggest impact on reducing smoking requires safer alternatives that are as effective as possible (keep people off smokes). NRT needs to renamed something like SSA (safer smoking alternatives).
But we need to bear in mind one thing: improved efficacy will mean increased addictive potential. It's a trade-off. Something that works well, very well even, to get people off smokes, will be more 'addictive' than something less effective. However, as the addiction is only a problem because of the toxic load of smoking (there's no anti-social behaviour associated with vaping, or mental impairement), this is really a non-issue, but may need to be countered intelligently at some point.
There have been a few voices raising this issue with regard to NRTs over the years, and their fairly dismal success rate at getting people off smokes. Now we have the beginnings of real evidence to back the (pretty obvious) theory and create an alternative that is more effective.
Just as 'lights' are now seen as a mistake, nic-only e-liquid, and indeed nic-only NRTs, are a similar mistake.
A pizza, say, is not much of a pizza if it's only dough, even if that is the main part. E-liquids followed the error of NRT products in just equating smoking with nicotine. The sister alkaloids might be small in quantity, but important for the roundness. Just as seasoning makes the pizza.
The MAOIs are already in the tobacco, no need to add them; just not remove them The (more or less) perfect blend is already right there in the tobacco.
It is important to stress this point: this is not about adding anything to e-liquid. It is still about removing all the unnecessary and bad stuff from tobacco.
Just as nicotine is the predominant alkaloid (perhaps in effect too), MAOI activity is likely the major effect of the other alkaloids; but likely not the only other activity - there could be other activity taking place too, not (directly) related to dopamine but other neurotransmitters.
Alkaloids are naturally occurring chemical compounds containing basic (alkaline) nitrogen atoms. There are a very large number of alkaloids; even caffeine and capsaicin are alkaloids, and (I think) cannabinoids; nearly all the psycoactive chemicals in fact. So we are possibly looking at a dozen or so besides nicotine, acting in a number of different ways.
Extracting all the alkaloids (and nothing else) can be done to a high level of purity. So people don't get the wrong idea, this is not a less pure extraction - it is just as pure, but extracting a range rather than a single element. Can be done just as precisely.
Nicotine constitutes about 90-95% of the alkaloids in tobacco (not completely sure if this figure includes all nicotine-like alkaloids or just nicotine). So if there are others that are important, they would need to be quite powerful given their small quantities. The next three most common ones are nornicotine (~2.5%+?) and anatabine (~0.2%-4% depending who you ask; TRC | Search Results and anabasine; so the remainder would be in (very) small quantities.
http://resources.metapress.com/pdf-p...g&size=largest Image of introduction, with full pdf available.
also: ScienceDirect - Journal of Chromatography B : Enantiomeric analysis of anatabine, nornicotine and anabasine in commercial tobacco by multi-dimensional gas chromatography and mass spectrometry
So anatabine and anabasine might be key 'missing' alkaloids.
Anabasine and anatabine as biomarkers for tobacco use during nicotine replacement therapy
It;s possible that there would be a correlation between smokers of lights / those who inhaled little or only into the mouth and success with e-cigs, because either their intake would have been skewed more to nicotine or the overall amounts being smaller made the other alkaloids / MAOIs unimportant, or that as only a minimal effect was sought, nic alone is sufficient. Hence heavier smokers are, I imagine more dependent on the other alkaloids.
There will be some who are outside of this relationship of course, because also likely is individual differences in need for nic versus the others alkaloids, and this can hold regardless of actual dose required.
Beta Carbolines
"β-carboline alkaloids are widespread in plants and animals, and frequently act as monoamine oxidase inhibitors (MAOI). ... Some β-carbolines, notably tryptoline* and pinoline, are formed naturally in the human body. The latter is implicated along with melatonin in the role of the pineal gland in regulating the sleep-wake cycle. The β-carboline can link to cerebral benzodiazepine receptors and induce inverse agonist effect."
beta-Carboline - Wikipedia, the free encyclopedia
( * Associated with the sleep cycle )
That last sentence is very interesting. By action on the GABA neurotransmitter that reduces some neuron excitability, benzodiazepines (Valium is an example) produces a calming, anti-anxiety effect.
( Interesting and simple link re carbolines and coffee and MAOI effect: Human monoamine oxidase enzyme inhibition by coffee and beta-carbolines norharman and harm )
Beta Carbolines, the good guys - Antioxidant properties of ß-carboline alkaloids are related to their antimutagenic and antigenotoxic activities: Antioxidant properties of {beta}-carboline alkaloids are related to their antimutagenic and antigenotoxic activities -- Moura et al., 10.1093/mutage/gem016 -- Mutagenesis
Endorphin Link
Evidence that a benzodiazepine receptor mechanism regulates the secretion of pituitary beta-endorphin in rats. Evidence that a benzodiazepine receptor mechanism ... [Endocrinology. 1985] - PubMed result
Heterocyclic Amines and Alpha Carbolines
In food processing / curing it is the heat mediated reaction of proteins (and dehydrated proteins) and carbohydrates, from which the carbolines arise; most of the products so formed in browning type cooking (over 100C) are toxic heterocyclic amines that are notorious for existing in smoke too.
playing with the curing would be a way to affect carboline levels (and HCAs in general unfortunately; a very blunt instrument); like any other product maker, will alter the product to increase sales.
In fact, alpha carbolines, the bad guys, can be 100s of times higher in cooked meat than in smoke (comparing say 100g meat to 10 cigs); Matsumoto, T. et al, Determination of mutagen amino-alpha-carbolines in grilled foods and cigarette smoke condensate. Cancer Lett. 1981 / 12 (1-2) / 105-110.
( Interesting note for chemists: "The common chemical structure of the alkaloids used in this study comprises one indole nucleus and one six-member pyrrole. According to their oxidation state, these alkaloids can be divided into two groups: dihydro-ß-carbolines (harmaline and harmalol) and ß-carbolines (harmane, harmine and harmol)" )
As I've said before, toxins in food put some perspective on the trace levels that might be found with vaping.
It has also been suggested that withdrawal from smoking can lead to the seeking out of prepared foods causing weight gain (a separate mechanism from keeping busy or loss of appetite suppression).
Indeed, it has also been suggested that food manufacturers deliberately combine sugar and proteins knowing that some beta carbolines will be produced on being cooked; but a lot more alpha carbolines and other toxic HCAs will also be produced, and the body has trouble metabolising these often destructured molecules.
Beta-carbolines and alcohol
"When acetaldehyde [an ethanol metabolite] combines with serotonin [a neurotransmitter not unlike dopamine] it produces beta-carboline. Acetaldehyde plus dopamine produces solsalinol. Solsalinol plus bet-caboline gives tetrahydroisoquinalines; these can activate the same receptors as beta-endorphins."
Alcoholism : the cause and the cure - Google Books
Alkaloids
Not a very well defined term. The -oid just means 'resemble (in shape)'; in the way we say 'cuboid' or 'humanoid'. The alk- root is a contraction of alkaline (or 'basic' as opposed to acidic).
Organic compounds that have a basic nitrogen atom (one with electron lone pairs) are called amines and the term alkaloid is usually reserved for amines found naturally in plants.
Alkaloids, like other inorganic compounds, often involve a 6-carbon ring (compounds that include this benzene ring arrangement are denoted as 'aromatic' as opposed to 'aliphatic').
Nicotine is an alkaloid, and there are many others in tobacco too. Some of these alkaloids can behave as MAOIs.
The biochemistry is complex; there are different types of MAOI that affect, to different degrees, various messengers in the brain. That is, in psychoactive terms, they would produce different effects (some more relaxing, some more stimulating; though more complex than a single axis as in this example).
Basically, the combination of nicorine and MAOI makes the effect more dramatic - faster and stronger - and has been likened to the effect of amphetamines, but milder.
MAOIs are not necessarily dramatic in effect; if i'm not mistaken, catechins are a type of MAOI (have the MAO inhibition effect); these are found in tea, and have a pleasant effect that is both relaxing and stimulating
Carboline MAOI alkaloids in food and tobacco
Relative exposure to beta-carbolines norharman and harman from foods and tobacco smoke.Herraiz T.
Spanish Council for Scientific Research, Instituto de Fermentaciones Industriales, CSIC, Juan de la Cierva 3, E-28006 Madrid, Spain. therraiz@ifi.csic.es
"Norharman and harman are two heterocyclic beta-carboline (9H-pyrido[3,4-b]indole) alkaloids with biological and potential toxicological activity that appear in foodstuffs and environmental sources. ...
The levels found of beta-carbolines were highly variable. Low processed foodstuffs (i.e. milk, yoghurt, uncooked meats and fish) did not contain norharman and harman above the detection limit. Others, however, contained relatively high concentrations (at the tens of ng g(-1) or microg l(-1) level) depending on the processing conditions as, for example, 'well-done' cooked meat and fish. The highest amounts of norharman and harman were found in brewed coffee (29-207 microg l(-1)), sauces (soy sauce and Tabasco, among others; 4-252 microg l(-1)), 'well done' cooked meat and fish (57-160 ng g(-1)), toasted bread (42-160 ng g(-1)), and fermented alcoholic beverages (n.d.-41 mug l(-1)). beta-Carbolines also occurred in a high amount in the mainstream of cigarette smoke (207-2780 ng/cigarette), which is an important contributor to daily exposure to these compounds.
Based on these results, it is concluded that the daily exposure to beta-carbolines in humans might be from tens to hundreds of micrograms, with cigarette smoke, coffee, certain seasonings, cooked foods and alcoholic beverages, in this order, being the major contributors. Many other foodstuffs might also contribute with minor amounts of norharman and harman. Foods and tobacco smoke might be potential contributors to the reported endogenous presence of beta-carbolines in humans." PMID: 15764332 [PubMed - indexed for MEDLINE]
It is interesting that the high content of carbolines in roasted coffee does not seem to be 'addictive' in to any great extent, certainly dwarfed by the satiation of something else, probably caffeine in this case. As with nicotine, overdosing is unlikely in normal use.
And the conclusion to draw is that carbolines alone, just as nic alone, is not that 'addictive'; it the combination. In layman's terms I'd say it is the ability of this combo to combine alertness with relaxed well-being.
This is not maybe unheard of without psychopharma intervention. What psychologists refer to as 'good stress' (enjoyable) could well elucidate this same combo (physiologically too) - I'm gonna call it 'performers high'. More similarity of effect than similarity biochemically, perhaps.
The MAOI effects of beta carbolines (harman, norharman, anabasine (acetylcholine receptor agonist and close relative of nicotine), anatabine) and nornicotine (a secondary tobacco alkaloid that is produced by the N-demethylation of nicotine) are likely the key cofactor in the physiological effects of smoking and represent the 'something missing' from e-liquid vaping. The calming effect due to higher dosage levels of nicotine (initially stimulating, then relaxing) combined with direct action of the beta carbolines (besides MAO inhibition).
"At higher doses, nicotine enhances the effect of serotonin and opiate activity, producing a calming, pain-killing effect. Nicotine is unique in comparison to most drugs, as its profile changes from stimulant to sedative/pain killer in increasing dosages and use." (Wikipedia)
I propose that the MAOIs are needed to reach the calming stage (carbolines and maybe others).
PET scans do show some activity suggesting activation of other pathways (such as endorphin release), but these are likely secondary in my current estimation.
Patents granted related to MAOIs for improved NRTs
United States Patent 6,350,479
Williams , et al. February 26, 2002
United States Patent 6,569,470
Williams , et al. May 27, 2003
United States Patent 6,929,811
Williams , et al. August 16, 2005
Beta Carboline sources
Carbolines can be synthesised in the lab; there has been a lot of investigation of this due to their potential for a wide variety of pharmaceutical applications.
Synthesized ?-carbolines - Patent 6872830
The chemistry is complex; it's most definetely for a lab.
Actually lots of info on the synthesis of carbolines.
Can be from amides, as in this example: A Versatile Cyclodehydration Reaction for the Synthesis of Isoquinoline and ?-Carboline Derivatives
Beta carbolines can be found in a variety pf plants, with one plant's seeds containing around 3% beta carbolines. This would be a great source for creating an e-liquid based on nicotine and beta-carbolines, rather than all tobacco alkaloids.
Notes on tobacco alkaloids e-liquid
Preparing e-liquid by removing all but the alkaloids will produce an e-liquid that can match smoking for physiological response and thereby be the most effective as a smoking alternative replacement.
It might it be worth removing any alkaloids that are non-volatile in freebase form from the final alkaloid mix, by say slow vaporisation and recondensing in an inert atmosphere. Nicotine is one of few alkaloids that are liquid at room temperature; those that are not are unlikely to vaporise.
However, most alkaloids decompose easily on heating (so the loss of the other alkaloids is likely substantial as with nicotine; but post heating the profile would resemble that gained from smoking tobacco; though might be different if switched to ultrasonic misting of the e-liquid); for this reason, this step would lose/waste too much of the useful alkaloids to remove the non-volatile ones. Other than employing evaporation rather than boiling, not sure if another way to do this.
* The 'other alkaloids' in tobacco account for about 10% of the total (nicotine 90%).
Summary
My research into carbolines was the most exciting by far, and will not likely be repeated. It has brought together insights into smoking, and more besides, that ties up so much of what I have researched previously. The importance of these findings and analysis is quite breathtaking. The details may be somewhat fuzzy but the overall scheme is well-defined. So here is a brief summary.
Carbolines are a type of alkaloid with psychoactive, and other, properties that are fairly widespread in nature. Some of the beta carbolines, in particular, have been found to have a bariety of beneficial therapeutic effects. Psychoactively, while some tend to hallucinatory effects, others, and this would include thse in tobacco, have a calming effects similar to opiates (and affecting some of the same receptor sites).
The beta carbolines in tobacco, possibly in conjunction with other alkaloids, particularly those also with MAOI activity, play a role that is both supporting of the activity of nicotine (via MAOI activity), and possibly a secondary more direct role on their own. Together, the synergy of MAOIs plus nicotine, plus additional mild, opiate-like activity, provide the unique features of tobacco smoke on human psychology (mild alertness coupled with mild relaxation).
Previous research, mostly un-noted, suggests that beta carbolines are likely the key alkaloids responsible for the 'something missing' experienced with nicotine alone. Others' extractions of beta carbolines from beta carboline rich sources is a strong indicator that this is indeed on the right lines, given the similarity of color of that extraction with the recent tobacco extraction noted in this thread.
Clues led to the nature of harmful toxins called heterocyclic amines (HCAs) in cooked and processed foods. These are created by the action of heat on micxtures of carbohydrates and proteins/dehydrated proteins. One type of HCA is carbolines. While some of the carbolines will be beta carbolines, others will be toxic alpha carbolines. In general most HCAs are bad news. The levels in cooked foods can be far higher than even those found in cigarette smoke (cigarette smoke contains many other toxins too though).
Nevertheless, the existence of some beta carbolines among the generally toxic HCAs is quite likely a reason why there is an 'addiction' to processed and fast foods beyond ease and sweet taste. From a health perspective, an 'addiction' to food that contains high levels of HCAs (and other similar heat induced toxins), and that are also often devoid of significant nutritional value, is serious matter, whose effects are becoming ever clearer.
Ethanol is primarily a 'downer', with the 'high' attributed to preferential slowing of the frontal cortex creating lowered social inhibitions. But there is likely more to it than that, and once again beta carolines might play a key role.
Indeed, I am proposing that beta carbolines play a key role in a broad range of pharmacologically mediated 'addictictiveness', primarily through a mild stimulation of the opiate mediated reward system, and particularly strongly when combined with nicotine and other MAOIs in smoking, with an endorphin release also involved.
In the context of smoking, the inclusion of beta carbolines - and indeed, the whole family of alkaloids found in tobacco - will ensure the best possible efficacy for smoking replacement products. It is almost impossible to over-stress the importance of this point.
E-liquid that has the other alkaloids prsent is likely to be more effective not only for more people in replacing tobacco smoking, but also reduce consumption of nicotine (and the carrier PG etc) by being more effective at satiation.
I look forward to seeing blind studies comparing the effectiveness and consumption levels of normal e-liquid, full spectrum alkaloid e-liquid and nicotine plus beta carbolines.
The extraction of full spectrum alkaloids from tobacco would be easier than just nicotine as isolation of the alkaloids would likely be a step in isolating just nicotine. However, without some kind of 'harm reduction umbrella' statutory-wise, suppliers might be loathe to market a 'natural extract of mixed alkaloids'. But if the FDA and others wanted to show a real commitment to reducing smoking, they would embrace this, offsetting any possible harm/risks with the far greater harm of not allowing it, as is routinely calculated for drugs.
(A designation of 'tobacco product' would be better than 'drug' in this regard if the opportunity here for running with the 'harm reduction' categorisation is missed.)
Testing can confirm this, but if we take the known ingredients route and add only those alkaloids that are safe and effective to pure nicotine, then the beta-carbolines found in tobacco (or some of) are the likely candidate.
All logic and real concern for health points to the pragmatic solution to an entrenched problem. Will it happen? Maybe, but it will take some bold decision making by regulators. We can simply keep putting forward the facts and in time, with public support, it might come to pass.
Experimental results will go a long way to convince, us as a community first of all, that the 'something missing' is not (just) 'enough nic', but an important co-factor.
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Earlier paper on MAOIs and comparison of absorption in vaping and smoking :
http://www.e-cigarette-forum.com/fo...-nicotine-absorption-addictiveness-maois.html
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Some notes will integrate later:
Here's what I think is going on (a small part of): the stress relief of having a smoke is two things - the satiation of the craving that builds up as levels dip after being raised, and a 'real' biochemical effect of relaxing nature (I will post shortly what I think that is). The nicotine only has mostly the former in terms of relaxation (though most of the alertness-raising effect of analogs).
First, the worry that overdosing of the other alkaloids could occur: it doesnt happen with smoking, and the presence of the nicotine will ensure people 'cut-off'; in all likelihood, better satiation will lead to less consumption; and DVap has indicated that this can indeed occur. In short, it will more probably work the other way. At the moment, many vape more and more looking for something that isn't there.
TSNAs in e-liquid are some 7000 times less than in malboro cigs; so a lot of leeway here for the possibility (and it is only that) that WTA liquid might have increased TSNA levels.
Btw, few compounds have the same property as alkaloids that allow them to pass through successive acid-alkali phases as used to extract the alkaloids.
Doesn't really matter that e-liquid is 'addictive' - or that not everyone wants to quit nicotine/alkaloids; why should they? The point is to quit smoking; that's where the harm is. And for a smoking alternative to be the most successful, it has to be effective. E-liquid is easily diluted as required, to satisfy all requirements. Some of the anti-smoking people do understand this. To make the biggest impact on reducing smoking requires safer alternatives that are as effective as possible (keep people off smokes). NRT needs to renamed something like SSA (safer smoking alternatives).
But we need to bear in mind one thing: improved efficacy will mean increased addictive potential. It's a trade-off. Something that works well, very well even, to get people off smokes, will be more 'addictive' than something less effective. However, as the addiction is only a problem because of the toxic load of smoking (there's no anti-social behaviour associated with vaping, or mental impairement), this is really a non-issue, but may need to be countered intelligently at some point.
There have been a few voices raising this issue with regard to NRTs over the years, and their fairly dismal success rate at getting people off smokes. Now we have the beginnings of real evidence to back the (pretty obvious) theory and create an alternative that is more effective.
Just as 'lights' are now seen as a mistake, nic-only e-liquid, and indeed nic-only NRTs, are a similar mistake.
A pizza, say, is not much of a pizza if it's only dough, even if that is the main part. E-liquids followed the error of NRT products in just equating smoking with nicotine. The sister alkaloids might be small in quantity, but important for the roundness. Just as seasoning makes the pizza.
The MAOIs are already in the tobacco, no need to add them; just not remove them The (more or less) perfect blend is already right there in the tobacco.
It is important to stress this point: this is not about adding anything to e-liquid. It is still about removing all the unnecessary and bad stuff from tobacco.
Just as nicotine is the predominant alkaloid (perhaps in effect too), MAOI activity is likely the major effect of the other alkaloids; but likely not the only other activity - there could be other activity taking place too, not (directly) related to dopamine but other neurotransmitters.
Alkaloids are naturally occurring chemical compounds containing basic (alkaline) nitrogen atoms. There are a very large number of alkaloids; even caffeine and capsaicin are alkaloids, and (I think) cannabinoids; nearly all the psycoactive chemicals in fact. So we are possibly looking at a dozen or so besides nicotine, acting in a number of different ways.
Extracting all the alkaloids (and nothing else) can be done to a high level of purity. So people don't get the wrong idea, this is not a less pure extraction - it is just as pure, but extracting a range rather than a single element. Can be done just as precisely.
Nicotine constitutes about 90-95% of the alkaloids in tobacco (not completely sure if this figure includes all nicotine-like alkaloids or just nicotine). So if there are others that are important, they would need to be quite powerful given their small quantities. The next three most common ones are nornicotine (~2.5%+?) and anatabine (~0.2%-4% depending who you ask; TRC | Search Results and anabasine; so the remainder would be in (very) small quantities.
http://resources.metapress.com/pdf-p...g&size=largest Image of introduction, with full pdf available.
also: ScienceDirect - Journal of Chromatography B : Enantiomeric analysis of anatabine, nornicotine and anabasine in commercial tobacco by multi-dimensional gas chromatography and mass spectrometry
So anatabine and anabasine might be key 'missing' alkaloids.
Anabasine and anatabine as biomarkers for tobacco use during nicotine replacement therapy
It;s possible that there would be a correlation between smokers of lights / those who inhaled little or only into the mouth and success with e-cigs, because either their intake would have been skewed more to nicotine or the overall amounts being smaller made the other alkaloids / MAOIs unimportant, or that as only a minimal effect was sought, nic alone is sufficient. Hence heavier smokers are, I imagine more dependent on the other alkaloids.
There will be some who are outside of this relationship of course, because also likely is individual differences in need for nic versus the others alkaloids, and this can hold regardless of actual dose required.
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