The following is an updated version of notes from 2009. Still not very well written but a reasonable primer, I hope.
Nicotine, addiction and MAOIs
How does smoking affect the brain?
The psychological effects of smoking are surprisingly mild considering that smoking is generally regarded as hard to stop. While there are many behavioual and sensory aspects, nicotine has been regarded as the psychoactive ingredient, providing a mix or relaxation and improvement of focus and concentration (though some of this might be down to relief of the craving that builds up between cigarettes, there is good evidence to suggest that nicotine does have some beneficial effects on brain function).
Nicotine's effect on the brain is primarily through release of dopamine, the 'feel good' neurotransmitter that gives a sense of well-being.
Is nicotine the key psychoactive in smoking?
By itself it is not as addictive as generally believed - as evidenced by quite a few people being able to cut their nicotine use to zero in just days or weeks. The really addictive thing could be the combination of nicotine plus MAOIs (for which biochemistry of this double-whammy makes good sense), with perhaps other factors involved too.
"I question, however, whether nicotine is the active ingredient in tobacco. If it were, nicotine patches should satisfy a smoker's craving for tobacco; they don't! In prisons, where, as a part of the punishment, smoking is sometimes forbidden, the inmates take to smoking corn silk, paper, string, etc., none of which contain any nicotine. ... The authors of the widely respected "Merck Manual" say only that it is "probably" the active ingredient. ... The active ingredient in smoke is smoke."
"In Defence of Smokers", by Lauren A. Colby / Chapter 11
The first point is a very good one. Then, all psychoactive chemicals aside, there are the pleasures of that smoky taste (a mild dose of the harshness of tar can be experienced as pleasurable, lie say a hot chilli or a strong spirit) and of the (blowing out of) smoke ('sensory and behavioural cues'); de-niconised cigarettes can stave off cravings to some extent.
However, probably the point here is that the addiction comes from the whole smoke - at least, not just the nicotine.
What are MAOIs and what is their significance in smoking?
Brain chemistry is a complex of of balanced systems. Nicotine is known to stimulate the release of dopamine - a 'feel good' neurotransmitter. Monoamine oxidase enzymes maintain an equilibrium of monoamine levels by disposing of excess. In the complex system of checks and balances, there are monoamine oxidase inhibitors (MAOIs), whose role is to inhibit the removal of monoamines, of which dopamine is one, prolonging the effects of the monoamines. As such these chemicals are sometimes used as anti-depressant drugs; predictably, some dependence is created (cessation causes withdrawal symptoms). Hence, MAOIs act in synergy with nicotine to enhance its effect by keeping dopamine levels higher for longer.
"Among the different compounds contained in tobacco smoke, monoamine oxidase inhibitors (MAOI) have recently been the focus of a particular interest (Berlin and Anthenelli, 2001). Monoamines are neurotransmitters found in the central nervous system. They are involved in sending signals to the brain which regulate sleep, arousal and pleasure ("Dopamine"). The three main monoamines studied by researchers are dopamine (DA), norepinephrine and serotonin. Monoamine oxidase is one enzyme responsible for the degradation of the monoamines. MAOIs are molecules that inhibit monoamine oxidase, and as a result increase the levels of monoamines found in the brain. According to newly developed research, a synergy between nicotine and MAOIs could be of importance for tobacco addiction to set up (Berlin and Anthenelli, 2001). Then, the association between nicotine and MAOI seems to be an appropriate model to study mechanisms underlying tobacco addiction."
D1 RECEPTORS IN MAOI AND NICOTINE SELF-ADMINISTRATION
There might be other substances that play an active role in the brain chemistry effects of smoking*, though so far MAOIs appear to be the key factor, with a well understood mechanism.
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).
MAOIs can be used to treat depression. One natural source is the plant St John's Wort. Incidentally, it is not clear what the active ingredients are exactly; hypericin has been isolated but is less effective than the whole extract.
SSRIs (Serotonin Specific Reuptake Inhibitors are similar to MAOIs) and can also used to treat depression. MAO metabolizes serotonin, norepinephrine and dopamine. By inhibiting this, MAOIs increase levels of all these monoamine neurotransmitters.
While dopamine is involved in the regulation of mood, motivation and pain, serotonin has a broader range of activities, being involved in the regulation of mood, appetite, sleep, movement, memory and learning. Note that these associations are approximate descriptions of influences in complex biochemical systems.
Some people can switch to vaping nicotine only without a problem. However, for some there is 'something missing'. For some of these people, snus provides relief, either alone or with vaping, but without WTA some people will return to analogs.
Any experimental support for the role of MAOIs?
"Nicotine is the major neuroactive compound of tobacco, which has, by itself, weak reinforcing properties. It is known that levels of the enzymes monoamine oxidase A (MAO-A) and MAO-B are reduced in the platelets and brains of smokers and that substances, other than nicotine, present in tobacco smoke have MAO-inhibitory activities. Here, we report that inhibition of MAO dramatically and specifically increases the motivation to self-administer nicotine in rats."
Monoamine Oxidase Inhibition Dramatically Increases the Motivation to Self-Administer Nicotine in Rats -- Guillem et al. 25 (38): 8593 -- Journal of Neuroscience
Do MAOIs have any significance for vaping?
There has been some advocacy for nicotine-free cigarettes, the idea being to make them unappealing. A much better approach might be to increase the nicotine level in cigarettes so that less are smoked (given that the dangers with smoking are not the nicotine but the smoke); this was suggested by Pearson and Shaw; instead 'lights' were created. The best approach of course is to replace the cigarette (tobacco) with a purified nicotine. The e-cigarette does this together with the appearance of smoke (harmless fog) and works well as a smoking alternative for many people.
Whether the addition of a reversible (far safer) MAOI to e-liquid to enhance it's effectiveness further would be acceptable is open to debate.As we cannot be sure of all the mechanisms that might be involved, and which MAOIs most effective and safe, an e-liquid based on all the alkaloids present in tobacco would be the best option (WTA - Whole Tobacco Alkaloids).
If the research continues to hold up, NRTs should also address this issue for improving their effectiveness.
E-liquids followed the error of NRT products in just equating smoking with nicotine. The sister alkaloids (about 6% of the tobacco alkaloids with nicotine being about 94%) might be small in quantity, but important for effectiveness and 'roundness'.
What are 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. As MAOIs generally have a much longer half-life, the effect is also longer.
MAOIs are not necessarily dramatic in effect; catechins are a type of MAOI found in tea that have a pleasant effect that is both relaxing and stimulating.
Any risk of MAOI overdose with WTA?
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. 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.
Only about 10% of the nicotine in tobacco finds its way out of a cigerette when smoked; and only about 3-4% of the 'minor alkaloids'. So WTA could well be much richer in MAOIs and need to be diluted with standard nicotine-only e-liquid.
However, there may be people for whom WTA is unsuitable depending on their medical condition or treatment program.
~~~
* Acetaldehyde (the first metabolite of ethanol, and a major factor responsible for hangovers) is one of a number of other smoke constituents that might help reinforce the psychoactive effects of nicotine.
See for example:
University of California - UC Newsroom | Nicotine's addictive hold increases when combined with other tobacco smoke chemicals, UCI study finds
Other resources :
Monoamine oxidase inhibitor - Wikipedia, the free encyclopedia basics of MAOIs
This is your brain on nicotine - MAO levels in smokers and non-smokers (particularly, MAO-B associated with dopamine and mood)
The Good Drug Guide : new mood-brighteners and antidepressants a very wide ranging look at psych-active drugs (including MAOIs)
Best news online about cigarettes and tobacco.: Nicotine does not cause cigarette addiction on the nicotine/MAOI link
Smoking's reward: nicotine triggers opiate-pleasure response. - Free Online Library - on opiode receptors
Original posts:
http://www.e-cigarette-forum.com/fo...bsorption-addictiveness-maois.html#post683086 October 2009.
http://www.e-cigarette-forum.com/fo...wards-more-effective-e-liquid.html#post732579 November 2009
