Additives in tobacco products
3. Enhancing impact -- additives with a pharmacological effect
"The main technical challenge was to decrease the yield of tar in a cigarette while maintaining a level of nicotine acceptable to the smoker."15
(Farone, W.A. 1996 former Philip Morris scientist.)
3.1 Free basing nicotine
Free-basing nicotine
At least as far as its rivals are concerned, the success of Philip Morris's Marlboro brand stems from greater 'free' nicotine resulting from higher alkalinity (pH) induced by the addition of ammonia technology (see section 3.2). Ammonia can speed the delivery of 'free' or unbound nicotine to smokers by raising the pH (alkalinity) of tobacco smoke using additives. This causes the smoker to 'freebase' the drug -- much as a crack-user takes ........ Dr. Jack E Henningfield of the John Hopkins University School of Medicine explains the action of ammonia thus:
"A third thing that ammonia-like compounds can do is increase the pH, increase the amount of free base nicotine, or what Dr Rickert earlier referred to as unprotonated nicotine.... The free-based form of ....... or the free based form of nicotine is more rapidly absorbed, has a more explosive effect on the nervous system. Ammonia is one of the ways that you can provide free-based ....... or free-based nicotine." (1997)16
Nicotine in different forms
Many documents explain the tobacco companies' recognition that nicotine is available in different forms.
"Nicotine may be presented to the smoker in at least three forms: (I) salt form in the particulate phase, (ii) free base form in the particulate phase, (iii) free base form in the vapour phase. It has long been believed that nicotine presented as in (ii)/(iii) is considerably more 'active'."(BAT 1984)17
"Nicotine is in the smoke in two forms as free nicotine base (think of ammonia) and as a nicotine salt (think of ammonium chloride) and it is almost certain that the free nicotine base is absorbed faster into the blood-stream."(BAT 1964)18
More free nicotine means higher 'impact'
Once the relationship between pH, free nicotine and nicotine 'impact' was established, it became a research objective.
"The purpose of this project is to develop a method for increasing the smoke pH of a cigarette. A low smoke solids, low nicotine cigarette with an increased smoke pH would then have relatively more free nicotine in its smoke, and consequently, a higher nicotine impact." (Liggett 1974)19
Changing the chemical form of nicotine increases the 'kick'
In a paper entitled, 'Cigarette concept to assure RJR a larger segment of the youth market' RJR talk about the 'kick' of nicotine:
"Still with an old style filter, any desired additional nicotine 'kick' could be easily obtained through pH regulation."20 (RJR 1973)
The pH also relates to the immediacy of the nicotine impact. As the pH increases, the nicotine changes its chemical form so that it is more rapidly absorbed by the body and more quickly gives a 'kick' to the smoker."21 (RJR 1976)
"When a cigarette is smoked, nicotine is released momentarily in the free-form. In this form, nicotine is more readily absorbed through the body tissue. Hence it is the free nicotine which is associated with IMPACT, i.e. The higher the free nicotine, the higher the IMPACT." (BAT 1988)22
Making nicotine more potent
"Increasing the pH of a medium in which nicotine is delivered increases the physiological effect of the nicotine by increasing the ratio of free base to acid salt form, the free base form being more readily transported across physiological membranes. We are pursuing this project with the eventual goal of lowering the total nicotine present in smoke while increasing the physiological effect of the nicotine which is present, so that no physiological effect is lost on nicotine reduction."23(Liggett 1971)
Free nicotine fraction increases 'physiological strength'
"Since the unbound nicotine is very much more active physiologically and much faster acting than the bound nicotine, the smoke at a high pH seems to be strong nicotine. Therefore, the amount of free nicotine in the smoke may be used for at least a partial measure of the physiological strength of the cigarette."24(RJR 1973)
Nicotine transfer increased as a result of ammonia treatment
According to BAT, the addition of ammonia was a technical option to enhance nicotine transfer:
"The results show that ammonia treatment caused a general increase in the delivery of bases including a 29% increase in nicotine. This result, despite the decrease in nicotine content and a 10% drop in the weight of tobacco burnt in puffing, is only partly due to a small decrease in nicotine filtration. In other words, the nicotine transfer has increased as a result of ammonia treatment..."25 (BAT 1965)
'Judicious' use of additives to increase the free base nicotine
The US tobacco company Lorillard accepts that additives can change the qualitative delivery of nicotine:
"It should be obvious that if the preceding goals of high physiological impact are to be realised, flavour profiles and their effect on physiological impact must be understood, even though measures of such perceived quantities are highly subjective... Hence judicious use of additives may increase the pH of the delivered smoke, thereby the apparent free base nicotine." (Lorillard, 1976)26
Additives to increase nicotine 'kick'
Ammonia can be used to increase the alkalinity of smoke and increase the amount of nicotine in the 'free' form rather than in the 'bound' form of nicotine salts. R J R explains:
"In essence, a cigarette is a system for delivery of nicotine to the smoker in attractive, useful form. At "normal' smoke pH, at or below about 6.0, essentially all of the smoke nicotine is chemically combined with acidic substance hence is non-volatile and relatively slowly absorbed by the smoker. As the smoke pH increases above about 6.0, an increasing proportion of the total smoke nicotine occurs in 'free' form, which is volatile, rapidly absorbed by the smoker, and believed to be instantly perceived as nicotine 'kick'."27 (RJR 1973)
3.2 Ammonia Technology and The Marlboro Story
The Rise of Marlboro - the world's best selling cigarette
The myth is that Marlboro man made the Marlboro cigarette: The square jawed icon of American individualism lassoed a gullible public and herded them into the Marlboro corral. On the face of it Marlboro's success appears to be a tribute to the power of advertising and iconography. However, the chemical history of the brand sheds interesting light on the subject.
In the early sixties Philip Morris was the smallest of America's six leading cigarette companies and RJR's brand Winston had annual sales nearly three times the size of Marlboro's. By 1978 there had been a seismic shift, Marlboro was the world's best selling cigarette accounting for one in five of all cigarettes sold and over fifty percent of smokers aged 17 and below.28
The search begins for the 'soul of Marlboro'
Not surprisingly this dramatic growth in Marlboro cigarettes instigated frenzied research by other tobacco manufacturers. Through analysis and reverse engineering of Marlboro cigarettes, industry competitors came to the conclusion that 'ammonia technology' was essentially the 'soul' of Marlboro.
"Philip Morris began using an ammoniated sheet material in 1965 and increased use of the sheet periodically from 1965 to 1974. This time period corresponds to the dramatic sales increase Philip Morris made from 1965 to 1974."29(RJR)
Ammonia technology is the key to Marlboro
"What product technology, then, makes Marlboro a Marlboro?
Looking at all of the technology employed in Marlboro on a world-wide basis, ammonia technology remains the key factor."30 (B&W 1992)
Brands that are selling well have high levels of free nicotine
The higher pH of Marlboro cigarettes helped to maintain the same level of free nicotine as high-tar cigarettes despite a two third reduction in overall tar and nicotine - and helped develop a 'US standard taste', enhancing the iconography associated with the quintessentially American 'Marlboro Man'.
"If our data, correlations and conclusions are valid, then what has emerged is a rather new type of cigarette, represented by Marlboro and Kool, with high nicotine 'kick', burley flavour, mildness to the mouth, and increased sensation to the throat, all largely the result of higher smoke pH. There is evidence that other brands, which are selling well also, have some of these attributes, particularly increased 'free' nicotine impact.31 (RJR, 1973)
Marlboro's growth follows introduction of ammonia technology
The graph shows how Marlboro's steady rise in sales follows increases in cigarette pH -- which also has led to an increase in free nicotine content.
RJR, 197332
Brown and Williamson seeks to catch up
"It appears that we have sufficient expertise available to 'build' a lowered mg tar cigarette which will deliver as much 'free nicotine' as a Marlboro, Winston or Kent without increasing the total nicotine delivery above that of a 'light' product. There are products already being marketed which deliver high percentage 'free nicotine' levels in smoke, i.e. Merit, Now."33 (B&W 1980)
"It would appear that the increased smoker response is associated with nicotine reaching the brain more quickly... On this basis, it appears reasonable to assume that the increased response of a smoker to the smoke with a higher amount of extractable nicotine (not synonymous with but similar to free base nicotine) may be either because this nicotine reaches the brain in a different chemical form or because it reaches the brain more quickly."34 (BAT 1966)
High smoke pH linked to high sales
Competitors understood the link between Marlboro's sales and its alkalinity.
"The smoke pH for Kool and Marlboro are 7.12 and 6.98 respectively confirming the relationship between high smoke pH and cigarette sales increase."35 (Lorillard 1973)
"As a result of its higher smoke pH, the current Marlboro, despite a two thirds reduction in smoke 'tar' and nicotine over the years, calculates to have essentially the same amount of 'free' nicotine in its smoke as did the early Winston."36 (RJR 1973)
"Our data show that smoke from our brands, and all other significant competitive brands, in recent years has been consistently and significantly lower in pH (less alkaline) than in smoke from Marlboro and to a lesser degree Kool... All evidence indicates that the relatively high smoke pH (high alkalinity) shown by Marlboro (and other Philip Morris brands) and Kool is deliberate and controlled. This has raised questions as to: (1) the effect of higher pH on nicotine impact and smoke quality, hence market performance, and (2) how the higher smoke pH might be accomplished."37 (RJR 1973)
3.3 Concealing the nicotine by increasing the vapour phase
Ammonia helps cheat the federal test for levels of nicotine and tar
The exploitation of 'free' nicotine and its enhanced effects helped cigarette companies cheat the US Federal Trade Commission (FTC) machine measurements of tar and nicotine levels. Using additive technology they were able to build cigarettes which registered low tar readings on the machine but delivered high levels of nicotine to the smoker.
"If the desired goal is defined to be increased nicotine yield in the delivered smoke there appear to be only two alternatives: either increase the absolute yield of delivered nicotine, or increase the pH, which increases the 'apparent' nicotine content without changing the absolute amount."38 (Lorillard, 1976)
Concealing nicotine in the gas phase
The FTC machine measures overall levels of liquid and solid nicotine, but not its concentration in the vapour phase where 'free' nicotine is found. Additives allowed reduced tar and nicotine without compromising the pharmacological effects -- legally required disclosure of tar and nicotine levels on billboards and cigarette packets showed a significant reduction while smokers were still being exposed to high levels of an addictive drug. Changes in the state of nicotine from liquid or solid to gas would have the effect of evading the standard measuring process which records the residues left on the filter in the standard smoking machine.
"The perfect example of that is that if you don't take into account the gas phase, if I do something like increase the pH and the smoke drops so that I can put more of the nicotine from the liquid into the gas and I am not measuring the gas, then in fact, you don't measure that nicotine which gets in the gas phase. This has been known since the late 1960's and early 1970's."39 (Farone, W.A. 6/12/97)
Business as usual while appearing to reduce nicotine
The increase in the free nicotine fraction - a qualitative change in the chemical form of nicotine -- means that the same 'hit' can be obtained from less nicotine. Put another way, there can be the appearance of a reduction in pharmacological impact without there being a real reduction.
"The amount of nicotine in the vapour phase can be modified by changing the acidity (pH) of the smoke. Hence it is readily feasible to have two cigarettes which deliver the same amount of nicotine (as measured on a Cambridge pad - the FTC method) but which are easily differentiated on the sensory basis of impact since the acidity of the smoke (and hence amount of nicotine in the vapour phase) is different."40 (B&W 1984)
3.4 Other additives that may enhance the effect of nicotine
Evidence of other substances with pharmacological effects
Although in the documents surveyed, ammonia emerges as the primary chemical tool used to enhance nicotine effects, other additives with similar functions are currently in use and more are being researched. Of particular note are Acetaldehyde, Levulinic Acid, Theobromine and Glycyrrhizin -- Although described by the tobacco industry as 'smoothers' and 'flavour enhancers', all appear to have some pharmacological effect in controlling nicotine absorption levels and/or delivery.
Synergistic interactions...
In his testimony during recent litigation, W.A. Farone noted that,
"the interactions (between additives and nicotine) may be the basis for the difference between the difficulty in giving up pipe or cigars compared to giving up cigarettes."41 (Farone WA 1997)
3.4.1 Acetaldehyde
Acetaldehyde is produced by the burning of sugars (the most common tobacco additives42). Industry scientists suspected that acetaldehyde could enhance the addictive effects of nicotine. Senior Philip Morris scientist Victor J. DeNoble began research in the early eighties, into the behavioural effects of nicotine and acetaldehyde in rats. He discovered that the two drugs worked synergistically to enhance the addictive nature of nicotine. DeNoble's research papers for Philip Morris reveal the potential for acetaldehyde to act in this way:
"The results can be summarized as follows: 1 acetaldehyde does function as a positive reinforcer for rats. 2 acetaldehyde at equal doses (mg) to(-) nicotine is more effective at maintaining self-administration behaviour, 3 the endogenous opioid system is not involved in the maintenance of acetaldehyde self administration, and 4) combinations of nicotine and acetaldehyde produce supra-additive effects when self administered."43 (PM)
"Acetaldehyde alone maintained lever pressing at a greater rate than nicotine at equal mg/kg doses. This is consistent with other findings at this laboratory." (Philip Morris, 1983)44
"Overall, the effects of acetaldehyde on EEGs were similar to those of nicotine."45 (PM 1983)
"DeNoble detected a synergistic or "additive" effect with acetaldehyde-nicotine combinations. This experiment was extended, with a slightly different but acceptable protocol, with one rat again using doses less than one cigarette (8 ug/kg / dose) and again DeNoble detected a synergistic effect between acetaldehyde - nicotine."46 (PM 1982)
Following this discovery DeNoble and his team were ordered to find the optimal ratio of the two compounds. According to DeNoble's testimony, once the company had discovered the optimal ratio for addiction they increased the levels of sugar in Marlboro cigarettes to achieve the required increase in levels of acetaldehyde.
"How did they do it? Simple, they added sugar, because if you burn sugar you form acetaldehyde. Now I ask you this. If tobacco companies are reducing acetaldehyde as Philip Morris says why has Marlboro increased acetaldehyde by 40% in ten years and has maintained that increase today?"47 (DeNoble, Verbal Testimony 1997)
3.4.2 Levulinic acid
Adding straight nicotine to tobacco has two unwanted effects. Firstly it makes the smoke harsh and difficult to smoke, and secondly it increases the FTC reading of nicotine. RJR patented a way round this by using a nicotine salt of an organic acid, (e.g., nicotine levulinate) which increases the impact of nicotine whilst keeping a low tar to nicotine ratio on the FTC reading:
The use of organic acid salts to mask the harshness of nicotine.
It would be desirable to provide a cigarette such as an 'ultra low tar' cigarette, which is capable of delivering a good tobacco taste, strength and smoking satisfaction characteristic of a 'full flavour low tar' cigarette while not being perceived as being overly harsh or irritating. In addition, it would be desirable to provide a cigarette such as a ' full flavour low tar' cigarette, which is capable of delivering a good tobacco taste, strength and smoking satisfaction characteristic of a 'full flavour' cigarette while not being perceived as being overly harsh or irritating. Cigarettes having incorporated therein a salt such as nicotine levulinate exhibit low FTC 'tar' to nicotine ratios while (i) having a smooth palatable, flavourful taste, and (ii) providing smoking satisfaction to the user. The cigarettes do not exhibit a harsh or irritating character; and do not exhibit a non-tobacco or off taste.
Patent No 4,830,028. Salts provided from nicotine and organic acids as cigarette additives, RJR, May 16 1989.
RJR researches techniques for enhanced binding
Titled 'Enhancement of nicotine binding to nicotinic receptors by nicotine levulinate and levulinic acid', the following document shows how levulinic acid enhances the effects of nicotine.
"Nicotine levulinate and levulinic acid significantly increased the amount of L (3H) nicotine bound to nicotinic receptors in rat brain tissue. The observed increase ranged from 20 - 50 %, with a mean value of around 30 %. The total amount of radiolabeled nicotine bound to receptors was more than could be accounted for by binding to high affinity receptors alone. The maximal effect which was observed at concentrations of nicotine levulinate and levulinic acid in the low nanomolar range, was reversed at higher concentrations. A computer model consistent with the results was developed and tested. According to the model, levulinic acid binds to an allosteric site on a class of low-affinity receptors and increases the affinity of these receptors for nicotine. At higher concentrations, this effect is reversed by the levulinic acid itself, assuming that it also has a reasonable affinity for the nicotine binding sites."48 (RJR 1989)
"Levulinic acid (4-oxopentanoic acid) is primarily a breakdown product of starch, cane sugar and other cellulosic materials."49 (RJR 1989)
Are there other compounds which help nicotine bind to receptors?
The same document possibly describing other research.
"Similarly, it has been shown that there are some compounds which enhance the binding of nicotine to its receptors in brain tissue"50 (RJR 1989)
The above quotes illustrate the extent to which cigarette manufacturers can manipulate the chemistry of smoke and nicotine addiction. Levulinate and levulinic acid change the chemistry of the brain itself so it becomes more receptive to nicotine.
3.4.3 Cocoa and theobromine
Widely used as an additive, cocoa contains alkaloids, which may modify the effects of nicotine and have a pharmacological effect in themselves. Cocoa also contains about 1% theobromine, a 'bronchodilator' - encouraging expansion of the airways and facilitating increased smoke and nicotine intake.
The following quotes are from scientific and medical papers held by Philip Morris:
"Theobromine: The principal alkaloid of the cocoa bean which contains 1.5-3% of the base... bronchodilation effect in asthma."51
"The bronchodilator effect of a 10mg dose of theobromine was compared with that of 5mg of theophylline in young patients with asthma.... In this single dose study the bronchodilatory effect produced by theobromine was clinically and statistically significant.... improvement in all pulmonary function tests was noted after the ingestion of theobromine or theophylline."52
It should be noted that 'improvement' refers to a significant expansion of the airways within the smoker's lungs.
3.4.4 Glycyrrhizin
An ingredient of liquorice - another commonly used additive, glycyrrhizin also acts as a bronchodilator.
"What does a bronchodilator do? The bronchodilator makes it easier for you to inhale, so obviously if you are having difficulty putting smoke in your lungs, it's good to have a bronchodilator in there. Now I was asked recently whether I knew whether the glycerizon being delivered is delivered in adequate concentration to cause that to happen. I do not know the answer to that question. It would be interesting to know whether that has been studied by the industry. If they have studied it, it would seem that that is the kind of information that should be shared with regard to ingredients. The point is, however, that we know it can happen, it is a bronchodilator. The probability that it happens is very high, but that would be related to studies that should be done."53 (Farone WA 1997)
3.4.5 Pyridine
A testimony from WA Farone, a former Philip Morris employee, speculates on the impact of adding alkaloids other than nicotine to cigarettes:
"We normally think only of nicotine, but we have to remember there are other alkaloids in tobacco. As an example of that I have here a very old book on pharmacy and therapeutics. It was written in 1894, published in 1895, and I'd like to just read you one little thing. This is on the section under tobacco and it says, 'It contains a very powerful and poisonous food alkaloid named nicotine'. It goes on to say, "It's combustion gives rise to several products of which pyridine and its compounds of the sheath having the same action as nicotine but of less severity." So here we are back in 1894 knowing full well that pyridine acts like nicotine at least in some regard, and if you go to a modern book.... you are going to find out that it is a central nervous system depressant, much the same as nicotine. So if I now add pyridine, either in the form of pyridine itself or in the form of some chemical, which when I combust it or pyrolyse it , it converts to pyridine, then I have increased the pyridine that the smoker gets if I put pyridine in with nicotine I increase the total central nervous system effect, and it becomes very, very important for us to understand the interactions between the additives the ingredients, and what is happening with the pharmacological effects of nicotine."54 (Farone WA 1997)
The following BAT report explores the absorption of pyridine and its synergy with nicotine. While the report says that the levels of pyridine found in tobacco smoke are 'unlikely' to be high enough to cause any effect, due to lack of disclosure it is difficult to ascertain weather current level of pyridine are high enough to be pharmacologically active.
"Peripherally, i.e. the tissue of the body excluding the brain, whether acting similarly, by nicotine receptor stimulation, or by different mechanisms pyridine and nicotine act synergistically."55 (BAT)
"Centrally, pyridine and nicotine produce opposite antagonistic effects, nicotine being stimulant, pyridine depressant."56 (BAT)
"...This is indicative that pyridine is producing this effect by stimulating a nicotinic receptor at this site."57 (BAT)
"Discussion of the Interaction of Pyridine with Nicotine.
It would appear that in the majority of cases there is a degree of addition between the effects of nicotine and pyridine. It does not really matter if the two agents are producing their effects by different mechanisms, as with their effects on heart rate.
This conclusion seems to be true for the peripheral effects, but as can be seen from the results of the section concerned with the CNS effects of pyridine, and from the results of the mouse and rat toxicities in: the absorption section of the report, pyridine and nicotine have directly opposite effects on the brain, and thus will antagonise each others effects."58 (BAT)
