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Am J Public Health. 2007 November; 97(11): 1981–1991.
PMCID: PMC2040350

Pharmacological and Chemical Effects of Cigarette Additives


We investigated tobacco industry documents and other sources for evidence of possible pharmacological and chemical effects of tobacco additives.

Our findings indicated that more than 100 of 599 documented cigarette additives have pharmacological actions that camouflage the odor of environmental tobacco smoke emitted from cigarettes, enhance or maintain nicotine delivery, could increase the addictiveness of cigarettes, and mask symptoms and illnesses associated with smoking behaviors.

Whether such uses were specifically intended for these agents is unknown. Our results provide a clear rationale for regulatory control of tobacco additives.

ACCORDING TO THE WORLD Health Organization, there were approximately 1.3 billion smokers worldwide in 2003, and that number is expected to increase to 1.7 billion by 2020.1 It is estimated that about 1 billion people will die from smoking in the 21st century.2 Research conducted over the past several decades indicates that tobacco companies have engaged in extensive efforts, including developing genetically engineered tobacco to enhance nicotine delivery36 and using reconstituted tobacco and nicotine extracts, to manipulate cigarette nicotine levels and influence people’s smoking behaviors.

Reconstituted tobacco, referred to as “sheet,” is a major ingredient in modern cigarettes; sheet is manufactured from recycled stems, stalks, scraps, collected dust, and floor sweepings.7 Those materials are ground up, nicotine is extracted from them, and chemicals, fillers, glue, and other agents are added to the slurry. The sheet is then pressed out and puffed, with the previously extracted nicotine sprayed onto it, and ground into tiny curls before being incorporated into cigarettes at the desired level.7 Tobacco companies have studied nicotine extracts as a method to augment nicotine levels in cigarettes.814

In addition, tobacco companies have devoted a significant amount of research and development to the use and inclusion of additives in cigarettes, and the industry has acknowledged using 599 different cigarette additives.15,16 According to various tobacco company documents, many of these additives are used to improve taste and decrease harshness.17 We propose that, in contrast, tobacco companies have expended resources to exploit the pharmacological and chemical effects of cigarette additives.

The tobacco industry used few additives in US cigarettes before 1970.18 However, current US-style cigarettes generally contain about a 10% level of additives according to weight, mostly in the form of sugars, humectants, ammonia compounds, cocoa, and licorice.19,20 Most other additives are used in small amounts, less than 0.01% of total weight. There is evidence that the percentage of additives by weight may have increased in the 1990s, especially the use of sweeteners (which many researchers believe were added to entice younger people to smoke).18 Those increases roughly coincided with the controversial Joe Camel cigarette advertising campaign initiated by RJ Reynolds in 1985.

Previous studies have reviewed the use of ammonia technology to increase levels of nicotine and free base nicotine in cigarette smoke18; the use of additives with additional or synergistic addictive potential, anesthetic properties, or bronchodilator effects; and the use of additives that decrease environmental tobacco smoke (ETS) odor, visibility, and irritation without equivalent efforts to decrease the harmful effects of ETS.18,21,22 These tobacco industry practices, motivated by awareness of public concern regarding ETS, may have led to nonsmokers as well as smokers being unaware or less aware of the presence of hazardous substances associated with ETS.2327

In this study, we examined the tobacco industry’s use of additives that inhibit nicotine metabolism and increase the addictive potential of cigarettes, with a particular focus on the neurological techniques used by Philip Morris to assess the effects of additives on smokers’ central nervous system functioning. We also explored the addition of antioxidants and mitigants to cigarettes in an attempt to prevent illness, genetic modifications of tobacco to increase levels of beta-carotene and incorporate molecules intended to decrease carcinogenic tobacco-specific nitrosamines, the use of other “beneficial” additives and specific chemical additives, and the tobacco industry’s objections17 to scientific discussions18 about additives used for cigarette engineering and nicotine addiction.


We used 5 primary sources of information for our review. First, we examined an Indiana University Web site aggregate list of 599 known cigarette additives (the industry does not specify which brands use particular additives).15 In 1984, the US Department of Health and Human Services began requiring tobacco companies to submit annually a confidential, aggregated list of ingredients added to cigarettes manufactured in or imported into the United States. In 1994, National Public Radio reported on a number of these ingredients, which caused a public outcry. Subsequently, in that same year, the 6 major US tobacco companies made the list public. This was the only time the list was made public, and there is no current public list of tobacco additives.

Second, we reviewed documents from 2000 to 2005 housed in the Legacy Tobacco Documents Library (“Legacy Library”) at the University of California, San Francisco.28 The Legacy Library contains 7 million documents related to different practices associated with tobacco products. Visitors can search, view, and download these documents from the library Web site. Included are documents posted on tobacco industry Web sites as of July 1999 in accordance with the Master Settlement Agreement, documents added to those sites since that time, and the document collections from the Tobacco Control Archives maintained by the University of California, San Francisco. New documents are added monthly as they are collected from industry sites.

Initially, we searched for documents about additives on the Indiana University list, as well as keywords such as “additive” and combinations of keywords such as “additive” and “environmental tobacco smoke.” To further our understanding of the use of additives, we employed snowball sampling methods wherein the content of the documents we reviewed (e.g., names, references to other documents, and important concepts) would then be searched in the Legacy Library. We followed these document leads in an effort to better assess industry efforts associated with tobacco additives. In all, we reviewed more than 10000 documents.

Third, we reviewed a Memorial Sloan Kettering Cancer Center Web site that included science-based information on herbs and other supplements.29 Fourth, we searched US Patent and Trademark Office Web site databases30 in an attempt to gain an understanding of patents referenced by numbers and titles in Legacy Library documents. Finally, we used Internet searches and tobacco-related and other reference textbooks2,31 to gain greater insight into previously reviewed material. Internet search engine technology was used to locate information not in the Legacy Library and to verify the information found therein.


Nicotine Metabolism and Addiction Potential

Numerous chemical agents, including gamma-heptalactone, gamma-valerolactone, gamma-decalactone, delta-decalactone, gamma-dodecalactone, delta-undecalactone, and gamma-hexalactone, are mild to weak inhibitors of coumarin-7-hydroxylases (also known as CYP2A5 and CYP2A6; these are enzymes within the P450 enzyme system that metabolize compounds in the body).32 These 7 chemicals are among those found on the additives list. Because CYP2A6 is involved in the metabolism of nicotine, the presence of these chemicals could decrease smokers’ metabolism of nicotine and maintain higher blood levels (thus increasing smokers’ exposure to nicotine by slowing degradation of nicotine in the bloodstream). Furthermore, the inhibitory effect of these chemicals on CYP2A6, although relatively weak in isolation, might be greater when the chemicals act in combination.

If nicotine were the only addictive chemical affecting smoking behavior, then puffing should decrease as the amount of inhaled nicotine increases. However, this hypothesis does not account for the effects of other addictive substances in cigarettes. Acetaldehyde is formed in high concentrations when cigarette constituents, including sugars, are burned. Animal research conducted by Philip Morris demonstrated a synergistic interaction between nicotine and acetaldehyde: rats pressed a bar more for the combination than for either substance alone.33,34 If these data generalize to humans, then smokers would puff more with the combination of nicotine and acetaldehyde. Industry data show that the combination of sugar, sorbitol, and diammonium phosphate (DAP) increases tar and nicotine levels and number of puffs taken.35

Neuropsychological Assessments

Philip Morris developed the science of nicotine delivery and measurement of the effects of nicotine far beyond what was known by the medical community. One goal of the Philip Morris Behavioral Research Lab, described in a 1981 document, was to identify responses of the human brain that change in a predictable and reliable manner as a function of cigarette smoking.36 In research projects conducted by Philip Morris from 1982 to 1995 (e.g., Project 162037), electroencephalography (EEG), pattern reversal evoked potential (PREP), and chemo-sensory event-related potential (CSERP) were used to measure physiological, sensory, and cognitive changes related to nicotine and to cigarette additives.38

Increases in tobacco filler pH increased the “impact” (a tobacco industry term for smokers’ subjective awareness of the drug effects of nicotine) and decreased PREP P1 latencies (an objective electrophysiological measure of brain activity).39 Philip Morris’s research demonstrated “a systematic relationship between increases in filler pH and increases in gas phase (presumably unprotonated) nicotine.”37 Philip Morris researchers noted a significant positive correlation between impact scores and P1-N2 amplitudes (another objective electrophysiological measure of brain activity), both of which were shown to increase with increased nicotine or menthol delivery. However, the effect of the interaction between nicotine and menthol levels on impact and P1-N2 was not a simple linear relationship; rather, it was found to be complex.40 Further research by Philip Morris determined that the addition of other chemicals (e.g., pyrazine, vanillin, and propylene glycol) increased P1-N2 amplitudes.41

Sensory CSERP studies investigated whether given flavorants stimulated the olfactory nerve, the trigeminal nerve, or both.38 Gullotta, one of the Philip Morris researchers, reported that CSERPs provided an objective measure of both impact and odor discrimination, in that different tobacco flavorants (e.g., natural vs synthetic menthol) affected CSERPs differently, even when smokers were unable to discriminate subjectively.38 In effect, Philip Morris developed a putative method of objectively measuring and quantifying “impact.”40

Addition of Antioxidants and Mitigants

RJ Reynolds investigated the addition of beta-carotene to cigarettes, including development of genetically engineered tobacco plants with genes inserted for beta-carotene production. RJ Reynolds’s beta-carotene study group consisted of representatives from 15 different departments within RJ Reynolds.4245 Documents describing this group’s activity were found for 1992 and 1993, but no subsequent documents were found to allow determination of how long the group continued to operate or whether it was disbanded or why.

It is unknown whether the 1994 New England Journal of Medicine report46 suggesting that oral beta-carotene supplements might have harmful effects on smokers (e.g., increased frequencies of lung cancer and ischemic heart disease) affected this group’s disposition. Its original vision statement was “to enhance natural tobacco components that may have potential to either reduce or mitigate the biological activity of tobacco-burning cigarettes.”43 This statement was later amended as follows: “to provide smokers with products which contain biological activity mitigants.”42 Biological activities targeted included reducing nitrosamine levels, nitric oxide levels, carbonyl groups, Ames activity (a measure of mutagenic and carcinogenic potential), ciliostatic and cytotoxic response, and possibly free radical concentrations.44

Numerous RJ Reynolds documents showed that the company considered adding mitigants, such as beta-carotene, to cigarettes.42,4756 Mitigants were defined as antioxidants and other compounds for free radical reduction (i.e., reduction of the concentration of free radicals)57,58; compounds “that combat the biological effect of some compounds in cigarette smoke,” such as reducing oxidative stress47; and compounds that “may reduce the risk of developing alleged smoking-related illnesses.”45 RJ Reynolds catalogued and studied mitigants.42,53 Many of these compounds can be found within plant additives or as direct chemical additives to cigarettes. Of 127 chemicals included on one RJ Reynolds list of mitigants,42 12 were direct chemical additives to cigarettes (e.g., beta-carotene, vitamin C, tannic acid, vanillin), and 40 were contained in botanical additives on the tobacco industry additives list15 (Table 1 [triangle]).

Possible Pharmacological Effects of Selected Chemical Additives

Genetic Modification of Tobacco

In addition to Brown and Williamson’s efforts to genetically manipulate nicotine levels of cigarettes sold in the United States (which have been documented in the media6), other companies in the industry also engaged in biotechnology development projects. Two examples were RJ Reynolds’s development projects designed to incorporate the beta-carotene gene, control nicotine levels, and genetically modify the tobacco plant in other ways97100 and Philip Morris’s development of specific molecules (antisense RNA) to decrease carcinogenic tobacco-specific nitrosamines.101

Use of “Beneficial” Additives

A 1981 surgeon general’s report, The Changing Cigarette, expressed concern about cigarette additives causing additional or new health care risks.102(pp6, 8, 51–52, 99–100) After the publication of that report, incorporation of “beneficial” additives into cigarettes was discussed at a pair of Philip Morris meetings in 1981.103 In addition to scientists and other research and development personnel from Philip Morris, Hamish Maxwell, the CEO and president of Philip Morris, attended the meetings.

The Philip Morris document summarizing these meetings defined “beneficial” as follows: (1) “creating more profit (sales) to Philip Morris”; (2) “creating a positive public image”; (3) “being safe, good for you as well as pleasurable”; and (4) “creating a favorable image with government agencies.”103 The document also stated that “rather than deliver a physiological effect directly we might incorporate an additive which causes the body to produce its own physiological agent. Thus, we could alleviate pain, increase sex drive, etc., without adding agents to do this but by adding a naturally occurring promoter.”103 Moreover:

It was noted that one beneficial attribute ascribed to smoking is appetite suppressance [sic]. A thorough study of this effect and publication of the results may have a beneficial impact on the image of smoking. If particular compounds responsible for the effect can be found, it might be possible to enhance the effect in a cigarette aimed at people desiring help with weight control. Care must be taken not to make specific claims or to invoke a “drug additive” image.103

Finally, according to the document:

Other factors were thought of (in addition to appetite suppression) that could be screened for beneficial effects of smoking. The idea again is to ascribe the effect to an additive that is already naturally occurring in tobacco, and then to possibly manipulate that additive: a) dental caries [tooth decay], b) reduction in constipation, c) heart rate regulation, d) effects in colds (i.e., mentholated brands), [and] e) anxiety reduction.103

No information is available on the extent to which Philip Morris engaged in subsequent action to study or incorporate the “beneficial” additives discussed at these meetings.

A separate Philip Morris document titled Nontobacco Biological/Botanical Smoking Materials104 included a long list of patent numbers associated with specific plants (patents listed in reviewed documents were reviewed to gain additional insight into what the tobacco documents were discussing and research that specific tobacco companies were considering or pursuing). Several of those patents discussed direct “beneficial” physiological actions of botanical additives. In one US patent cited,105 it was noted that nicotine in cigarettes has a deleterious vasoconstrictive effect on the cardiovascular system, particularly the blood vessels within and surrounding the heart. It was also noted that vaporized niacin in cigarette smoke has a vasodilating action that helps counteract the vasoconstrictive effect of nicotine. Furthermore, additional “beneficial” effects may be obtained when niacin is combined with rutin (a chemical found in botanicals), “which is considered effective in reducing and preventing capillary fragility.”105

The patent went on to state that “niacin and rutin may also be incorporated in a smoking composition which is made from vegetable materials other than nicotine-containing tobacco and de-nicotinized tobacco.”105 It was noted that both compounds should be in the range of 0.1% to 2.5% by weight of the cigarette.105 It is not known whether cigarettes were ever manipulated to have that concentration range of those chemicals. However, it is known that Philip Morris studied niacin in cigarettes,106,107 investigated commercial production of niacin (i.e., nicotinic acid) and the cost associated with purchasing niacin in lots of 5000 or more kilograms,108 and studied naturally occurring rutin in cigarettes.109

The patent listed 33 botanicals or vegetable materials, or compounds within them, that also appear on the tobacco industry cigarette additive list, including beets, carrots, chamomile, corn, eucalyptus, maple and maple syrup, menthe piperita, oak, patchouli, rose, and vanilla plantifolia. In its discussion of cigarette casing material, the patent listed caramel, licorice root, niacin, rutin, and glycerol as possible additives and noted that the following aromatics, flavoring agents, sweeteners, coloring agents, and humectants could be added or substituted in a vegetable material preparation that would naturally contain niacin and rutin: sage, honey, sucrose, vanillin, coumarin, vanilla bean, fruit flavors, molasses, propylene glycol, apple juice, apple cider, essential oils, anise, angelica, and prune juice. It is noteworthy that so many botanical agents listed in the patent are also mentioned on the tobacco industry’s list of additives.105

Through the years, Philip Morris has maintained listings of patents on vitamins and therapeutic ingredients in cigarettes110 as well as listings of patents on medicated cigarettes111,112 The documents focusing on medicated cigarettes111,112 discussed patents on cigarettes with therapeutic or anticarcinogenic additives and additives that relieve or treat bronchial irritation through means other than cigarette mentholation. Many of the ingredients were derived from pharmacologically active botanicals. However, as noted, it is not known how much effort Philip Morris engaged in to incorporate “beneficial” additives for the uses described in this section.

Other Specific Chemical Additives

Tobacco companies have added many other chemicals with a wide variety of possible effects (Figure 1 [triangle]). Table 1 [triangle] includes a summary of chemical additives that may have pharmacological effects.5996,113

Summary of pharmacological and chemical effects of cigarette additives.

Tobacco Industry Objections

Tobacco industry representatives attempted to refute the conclusions of Bates et al.18 that cigarette additives were added to enhance nicotine addiction and induce other pharmacological effects. A 1999 industry statement denied that use of ammonia compounds increased the amount of ammonia in cigarette smoke, increased smoke pH, increased the amount of nicotine in smoke, or influenced nicotine yield as determined by the Federal Trade Commission/International Organization for Standardization method.17 This refutation ignored tobacco industry documentation of extensive research on ammonia technology and its effect on nicotine form and physiology.18,21

Also, the 1999 industry document just cited17 stated that a synergistic effect of nicotine and acetaldehyde is unlikely.17 However, Philip Morris research has clearly documented a synergistic effect on addictive behavior in rats. The document further stated that plasma levels of theobromine in smokers are far below the dose necessary for a pharmacological effect17 and that glycyrrhizin is not transferred into mainstream smoke and has no bronchodilator effect.17 Furthermore, the industry statement denied that levulinic acid and pyridine are used in the production of cigarettes.17 However, levulinic acid and pyridine are on the list of additives prepared by the tobacco industry.15 This industry statement emphasized that the additives discussed were used in casings or were used to enhance flavor.17


Increased knowledge about cigarette additives makes it clear that modern cigarettes are very different from cigarettes of the past, in that they have been extensively engineered to be delivery devices for nicotine and other ingredients. Evidence from tobacco industry documents indicates that additives have been used to increase free base nicotine and addiction potential and to mask and treat symptoms.

Free Base Nicotine and Addiction Potential

Previous research18,21,114 makes it clear that the industry expended significant resources to develop and use methods to increase free base nicotine via ammonia technology and other methods. Industry research and development programs designed to develop methods to manipulate nicotine levels and forms (i.e., salt particulate, free base particulate, vapor free base) took place over 4 decades, starting in the 1960s. Increases in free base nicotine have been implicated in increasing the addictive potential of cigarettes.18,21,114

The tobacco industry’s scientific efforts were far more advanced compared with public scientific efforts to understand nicotine addiction. Philip Morris’s research into EEG, PREP, and CSERP shows that the tobacco company attempted to quantify “impact” and to monitor the neurological effects of specific additives to maximize “cigarette acceptance” (which encompasses factors such as cigarette “satisfaction” and is influenced by a number of elements, including primary reinforcement [e.g., nicotine addiction] and secondary reinforcement115).

From a public health perspective, increasing the addictive potential of cigarettes with additives (e.g., via formulas including sugar, sorbitol, and DAP) increases the likelihood that new smokers will become addicted and that current smokers will have more difficulty quitting. Consequently, there will be greater levels of morbidity and mortality associated with smoking.

Masking and Treating Symptoms

The tobacco industry has stated that additives are used primarily for flavoring and “smoothing” the smoker’s experience. However, a review of botanical medicine sources103,116 indicates that many botanical and phyto-chemical additives have other properties, including anesthetic, antibacterial, anticancer, anti-inflammatory, antifungal, and antiviral properties. Industry documents65,104,110112 show awareness of and interest in these additional properties.

Unregulated botanical and chemical additives might have “multiple use” purposes, such as enhancing flavor and providing for a “smoother” smoking experience as well as preventing or masking symptoms associated with illnesses induced by smoking. Because inclusion of botanical and chemical additives could reduce, mask, or prevent smokers’ awareness of the adverse symptoms caused by smoking (e.g., cough), smokers might continue to smoke even when they are ill, preventing reductions in cigarette consumption and sales revenues.

RJ Reynolds’s addition of beta-carotene to cigarettes suggests that adverse health effects can occur even when a seemingly benign additive is used and points to the need for regulation by the Food and Drug Administration. Although the actions of beta-carotene and other additives may have decreased the carcinogenicity of cigarettes, their use may have unintentionally increased the risk for and rate of lung cancer in smokers.

A 1994 study concluded that there was no reduction in the incidence of lung cancer among male smokers after 5 to 8 years of oral supplementation with alpha-tocopherol or beta-carotene. That study raised the possibility that oral beta-carotene supplements might actually have harmful effects in smokers and might increase lung cancer rates.46 A newer study117 also has documented the possible adverse effects of oral beta-carotene on lung cancer. This is an example of the potential occurrence of unwanted and unanticipated dangerous effects if appropriate regulatory agencies do not monitor the use of additives.

Unresolved Issues

The actual composition of extracts used, the parts of plants used, and the physiological and pathological effects of these additives are unknown. It is not clear whether sufficient amounts of pharmacologically active chemicals derived from these additives remain after pyrolysis; no information is available on the effects of combustion of these compounds in cigarettes at the concentrations used, let alone whether the combustion products actually have any of the listed properties in vivo when smoked. For example, only scientific experimentation will be able to reveal whether theobromine, glycyrrhizin, and other cigarette additives induce a bronchodilator effect.


Modern cigarettes have been extensively engineered and optimized as nicotine delivery devices developed through major national and international research and development programs. The average smoker has been unaware of these efforts by the tobacco industry and of the extensive manipulation of cigarette chemistry.

Our results indicate that more than 100 of 599 documented cigarette additives have pharmacological actions. Previous research18,21,22 has documented extensive efforts by the tobacco industry to use additives to mask the presence of ETS by reducing the visibility, odor, and irritability of tobacco smoke. Similar to the findings of previous studies, our results show that the tobacco industry used additives (1) that enhance or maintain nicotine delivery and could increase the addictiveness of cigarettes and (2) that mask symptoms and illnesses associated with smoking behavior.

To our knowledge, there has been no systematic evaluation of the public health effects of cigarette additives or their combustion products. The tobacco industry has actively manipulated cigarette content by using potentially hazardous chemical and phytochemical additives that should be regulated. Unregulated use of additives in tobacco products subjects billions of smokers and nonsmokers alike to an uncontrolled experiment with potentially devastating health effects.


This project was supported by a pilot grant from the National Institute of Mental Health (NRSA training grant MH 14585).

We acknowledge Keith Nuechterlein, director of the Aftercare Program in the Department of Psychiatry, University of California, Los Angeles, and Sandra Malik, administrative assistant for the Aftercare Program, for providing facilities and administrative support for the project.

Human Participant Protection
No protocol approval was needed for this study.


Peer Reviewed

M. Rabinoff was involved with all aspects of research, writing, and editing of the article. N. Caskey was involved in all aspects of editing and helped with research on many of the issues brought up during the review process. A. Rissling helped with most areas of research and did some writing for the initial version of the article. C. Park helped with research on numerous issues, especially on the topic of additives affecting environmental tobacco smoke.


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40. Gullotta F, Hayes C, Martin B. The effects of nicotine and menthol on electrophysiological and subjective responses. June 27, 1991. Philip Morris. Bates no. 2028817734/7740. Available at: http://legacy.library.ucsf.edu/tid/rfp12e00. Accessed August 2, 2004.
41. P1-N2 amplitude change. Philip Morris. Bates no. 2062170324/0330. Available at: http://legacy.library.ucsf.edu/tid/oxg33e00. Accessed July 5, 2004.
42. Beta-Carotene Study Group graphics: safer cigarette. April 27, 1993. RJ Reynolds. Bates no. 512228142/8146. Available at: http://legacy.library.ucsf.edu/tid/eeb43d00. Accessed June 21, 2004.
43. Beta-Carotene Study Group vision. September 9, 1992. RJ Reynolds. Bates no. 508303718/3718. Available at: http://legacy.library.ucsf.edu/tid/mmw93d00. Accessed August 2, 2004.
44. Beta carotene AT XB-tar modification. May 18, 1993. RJ Reynolds. Bates no. 510354645/4757. Available at: http://legacy.library.ucsf.edu/tid/fof63d00. Accessed December 20, 2003.
45. Beta-Carotene Study Group opportunity. October 23, 1992. RJ Reynolds. Bates no. 508698033/8033. Available at: http://legacy.library.ucsf.edu/tid/abb93d00. Accessed August 2, 2004.
46. Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group. The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. N Engl J Med. 1994;330:1029–1035. [PubMed]
47. Mitigant enriched cigarette–reduced oxidative stress cigarette. RJ Reynolds. Bates no. 512290169/0169. Available at: http://legacy.library.ucsf.edu/tid/gww33d00. Accessed June 16, 2004.
48. Mitigant technical review. RJ Reynolds. Bates no. 512278126/8144. Available at: http://legacy.library.ucsf.edu/tid/gzl38c00. Accessed June 16, 2004.
49. McGee CD. Monthly highlights: mitigant research program. March 18, 1994. RJ Reynolds. Bates no. 512231181/1181. Available at: http://legacy.library.ucsf.edu/tid/dua43d00. Accessed June 18, 2004.
50. Mitigant article summaries. May 6, 1994. RJ Reynolds. Bates no. 510663988/4019. Available at: http://legacy.library.ucsf.edu/tid/kou87c00. Accessed June 18, 2004.
51. Simmons WS. The “mitigant” approach to modifying biological activity of tobacco smoke. June 20, 1992. RJ Reynolds. Bates no. 510812596/2597. Available at: http://legacy.library.ucsf.edu/tid/pbt53d00. Accessed June 15, 2004.
52. Biological testing of mitigant efficacy. RJ Reynolds. Bates no. 511111742/1742. Available at: http://legacy.library.ucsf.edu/tid/aah38c00. Accessed June 15, 2004.
53. Mitigant Steering Committee. Meeting announcement. July 28, 1993. RJ Reynolds. Bates no. 508695980/ 5981. Available at: http://legacy.library.ucsf.edu/tid/bmb93d00. Accessed June 15, 2004.
54. Biological testing/oxidative mitigant project. September 22, 1993. RJ Reynolds. Bates no. 510067221/7230. Available at: http://legacy.library.ucsf.edu/tid/uxm63d00. Accessed June 16, 2004.
55. McGee CD. Monthly highlights: mitigant research program. October 18, 1993. RJ Reynolds. Bates no. 512231185/1185. Available at: http://legacy.library.ucsf.edu/tid/hua43d00. Accessed June 16, 2004.
56. Dube M. Mitigant research: protocept development projects. December 15, 1993. RJ Reynolds. Bates no. 512396717/6724. Available at: http://legacy.library.ucsf.edu/tid/ddr33d00. Accessed June 17, 2004.
57. Mitigant team objective. January 26, 1994. RJ Reynolds. Bates no. 512076415/6418. Available at: http://legacy.library.ucsf.edu/tid/pnf43d00. Accessed June 16, 2004.
58. Status of mitigant team activities and recommendations. February 17, 1994. RJ Reynolds. Bates no. 508698026/8027. Available at: http://legacy.library.ucsf.edu/tid/yab93d00. Accessed June 17, 2004.
59. Wrona MZ, Waskiewicz J, Han QP, Han J, Li H, Dryhurst G. Putative oxidative metabolites of 1-methyl-6-hydroxy-1,2,3,4-tetrahydro-beta-carboline of potential relevance to the addictive and neurodegenerative consequences of ethanol abuse. Alcohol. 1997;14:213–223. [PubMed]
60. Fowles J, Dybing E. Application of toxicological risk assessment principles to the chemical constituents of cigarette smoke. Tob Control. 2003;12:424–430. [PMC free article] [PubMed]
61. Bates M, Fowles J, Noiton D. The chemical constituents in cigarettes and cigarette smoke: priorities for harm reduction. Philip Morris. Bates no. 2505913406/3471. Available at: http://legacy.library.ucsf.edu/tid/nsn81c00. Accessed June 21, 2004.
62. Food Extract Manufacturers’ Association. Scientific literature review of salicylates and salicylaldehyde in flavor usage. Lorillard. Bates no. 89403838/ 3968. Available at: http://legacy.library.ucsf.edu/tid/fom64c00. Accessed June 15, 2004.
63. Hurt R, Robertson C. Prying open the door to the tobacco industry’s secrets about nicotine: the Minnesota tobacco trial. JAMA. 1998;280: 1173–1181. [PubMed]
64. Sokmen A, Vardar-Unlu G, Polissiou M, Daferera D, Sokmen M, Donmez E. Antimicrobial activity of essential oil and methanol extracts of Achillea sintenisii hub. Mor. (Asteraceae). Phytother Res. 2003;17:1005–1010. [PubMed]
65. Hasani A, Pavia D, Toms N, Dilworth P, Agnew JE. Effect of aromatics on lung mucociliary clearance in patients with chronic airways obstruction. J Altern Complement Med. 2003;9: 243–249. [PubMed]
66. Juergens UR, Dethlefsen U, Steinkamp G, Gillissen A, Repges R, Vetter H. Anti-inflammatory activity of 1.8-cineol (eucalyptol) in bronchial asthma: a double-blind placebo-controlled trial. Respir Med. 2003;97: 250–256. [PubMed]
67. Moteki H, Hibasami H, Yamada Y, Katsuzaki H, Imai K, Komiya T. Specific induction of apoptosis by 1,8-cineole in two human leukemia cell lines, but not in a human stomach cancer cell line. Oncol Rep. 2002;9:757–760. [PubMed]
68. Santos FA, Rao VS. Antiinflammatory and antinociceptive effects of 1,8-cineole, a terpenoid oxide present in many plant essential oils. Phytother Res. 2000;14:240–244. [PubMed]
69. Steele RH. Clove oil, eugenol, isoeugenol, and methyl eugenol. July 17, 1985. RJ Reynolds. Bates no. 504239346/9361. Available at: http://legacy.library.ucsf.edu/tid/aen58d00. Accessed June 18, 2004.
70. Carcinogenesis studies of eugenol in F344/N rats and B6C3F1 mice (feed studies). RJ Reynolds. Bates no. 521764618/4618. Available at: http://legacy.library.ucsf.edu/tid/mrd50d00. Accessed June 18, 2004.
71. Eugenol. June 9, 2000. RJ Reynolds. Bates no. 521764619/4619. Available at: http://legacy.library.ucsf.edu/tid/ymh20d00. Accessed June 18, 2004.
72. Suber R. Re: pulegone and eugenol. June 14, 2000. RJ Reynolds. Bates no. 521533572/3572. Available at: http://legacy.library.ucsf.edu/tid/qoy20d00. Accessed June 18, 2004.
73. Grundschober F, Techn S. Information letter 1265—USA: methyl eugenol. RJ Reynolds. Bates no. 524434480/ 4480. Available at: http://legacy.library.ucsf.edu/tid/ayu03c00. Accessed June 18, 2004.
74. NTP technical report on the carcinogenesis bioassay of eugenol. January 12, 1981. Brown and Williamson. Bates no. 504001029/1051. Available at: http://legacy.library.ucsf.edu/tid/mqt24f00. Accessed June 18, 2004.
75. Yazlovitskaya EM, Melnykovych G. Selective farnesol toxicity and translocation of protein kinase C in neoplastic HeLa-S3K and non-neoplastic CF-3 cells. Cancer Lett. 1995;88:179–183. [PubMed]
76. Kai K, Komine K, Asai K, et al. Anti-inflammatory effects of intramammary infusions of glycyrrhizin in lactating cows with mastitis caused by coagulase-negative staphylococci. Am J Vet Res. 2003;64:1213–1220. [PubMed]
77. Shibata S. A drug over the millennia: pharmacognosy, chemistry, and pharmacology of licorice. Yakugaku Zasshi. 2000;120:849–862. [PubMed]
78. Ohtsuki K, Iahida N. Inhibitory effect of glycyrrhizin on polypeptide phosphorylation by polypeptide-dependent protein kinase (kinase P) in vitro. Biochem Biophys Res Commun. 1988; 157:597–604. [PubMed]
79. van Rossum TG, Vulto AG, de Man RA, Brouwer JT, Schalm SW. Glycyrrhizin as a potential treatment for chronic hepatitis C. Aliment Pharmacol Ther. 1998;12:199–205. [PubMed]
80. Hsiang CY, Lai IL, Chao DC, Ho TY. Differential regulation of activator protein 1 activity by glycyrrhizin. Life Sci. 2002;70:1643–1656. [PubMed]
81. Lawrence BM. Eugenol (eugenyl) glucoside. August 26, 1991. RJ Reynolds. Bates no. 509734218/4218. Available at: http://legacy.library.ucsf.edu/tid/ajz63d00. Accessed June 18, 2004.
82. Tuttleolm D, Reynolds JH, Rees DC. Eugenol glucoside as an aroma precursor. April 2, 1992. RJ Reynolds. Bates no. 509010630/0631. Available at: http://legacy.library.ucsf.edu/tid/gal83d00. Accessed June 18, 2004.
83. Opdyke DLJ. Isovaleric acid. Lorillard. Bates no. 87500751/0753. Available at: http://legacy.library.ucsf.edu/tid/zuh98c00. Accessed July 10, 2004.
84. Nicotine levulinic enhancement of (3H)-nicotine binding to nicotinic receptors in rat brain. RJ Reynolds. Bates no. 507863526/3535. Available at: http://legacy.library.ucsf.edu/tid/epk14d00. Accessed June 20, 2004.
85. Gullotta F, Hayes C, Martin B. The effects of nicotine and menthol on electrophysiological and subjective responses. June 27, 1991. Philip Morris. Bates no. 2028817734/7740. Available at: http://legacy.library.ucsf.edu/tid/rfp12e00. Accessed August 2, 2004.
86. Phytochemical and ethnobotanical database. Available at: http://www.ars-grin.gov/duke/. Accessed July 1, 2004.
87. Farone W. Pyridine studies. April 11, 1996. Philip Morris. Bates no. 2064791028. Available at: http://legacy.library.ucsf.edu/tid/kgn93c00. Accessed June 25, 2004.
88. Salicylaldehyde. September 8, 1994. RJ Reynolds. Bates no. 515165144/5147. Available at: http://legacy.library.ucsf.edu/tid/kli01d00. Accessed August 2, 2004.
89. Written statement of Victor John DeNoble. April 27, 1994. Philip Morris. Bates no. 511407704/7710. Available at: http://legacy.library.ucsf.edu/tid/fxp31d00. Accessed August 2, 2004.
90. Baker R, Carling WR, Leeson PD, Smith JD. US patent 5,231,102: tetra-hydroquinoline derivatives useful for neurodegenerative disorders. July 27, 1993. RJ Reynolds. Bates no. 515822483/2483. Available at: http://legacy.library.ucsf.edu/tid/bvg92d00. Accessed August 8, 2004.
91. DeNoble J. Written statement of Victor DeNoble, PhD. Congressional testimony. American Tobacco. Bates no. 980232257/226. Available at: http://legacy.library.ucsf.edu/tid/ysn84f00. Accessed June 6, 2007.
92. Hadley S, Petry J. Valerian. Am Fam Physician. 2003;67:1755–1758. [PubMed]
93. Houghton PJ. The scientific basis for the reputed activity of Valerian. J Pharm Pharmacol. 1999;51:505–512. [PubMed]
94. Teychenne PF, Walters I, Claveria LE, et al. The encephalopathic action of five-carbon-atom fatty acids in the rabbit. Clin Sci Mol Med. 1976;50: 463–472. [PubMed]
95. Hendriks H, Bos R, Allersma DP, Malingre TM, Koster AS. Pharmacological screening of valerenal and some other components of essential oil of Valeriana officinalis. Planta Med. 1981;42: 62–68. [PubMed]
96. Ortiz JG, Nieves-Natal J, Chavez P. Effects of Valeriana officinalis extracts on [3H] flunitrazepam binding, synaptosomal [3H] GABA uptake, and hippocampal [3H] GABA release. Neurochem Res. 1999;24:1373–1378. [PubMed]
97. Biosource project review. RJ Reynolds. Bates no. 508303793/3808. Available at: http://legacy.library.ucsf.edu/tid/xmw93d00. Accessed August 2, 2004.
98. RJR/Biosource joint venture agreement. April 3, 1992. RJ Reynolds. Bates no. 508303810/3826. Available at: http://legacy.library.ucsf.edu/tid/ymw93d00. Accessed August 2, 2004.
99. Biotechnology research program: update and review. RJ Reynolds. Bates no. 508303728/3742. Available at: http://legacy.library.ucsf.edu/tid/smw93d00. Accessed August 2, 2004.
100. Beta carotene. RJ Reynolds. Bates no. 522541730/1752. Available at: http://legacy.library.ucsf.edu/tid/xgc92a00. Accessed August 2, 2004.
101. Banzhaf JF. Secret cigarette industry tape recordings filed today with FDA describe nicotine delivery, and removal of carcinogens. Bates no. 2061693331/3337. Available at: http://legacy.library.ucsf.edu/tid/uyk32d00. Accessed August 2, 2004.
102. The Health Consequences of Smoking—The Changing Cigarette: A Report of the Surgeon General. Washington, DC: US Department of Health and Human Services; 1981.
103. Farone WA. Idea session on beneficial additives. February 16, 1981. Philip Morris. Bates no. 1003395096/ 5101. Available at: http://legacy.library.ucsf.edu/tid/kta28e00. Accessed May 17, 2005.
104. McDonald CE, Rosenberg MD. Technical Information Section non-tobacco biological/botanical smoking materials. October 19, 1983. Philip Morris. Bates no. 1000082599/2616. Available at: http://legacy.library.ucsf.edu/tid/kpx64e00. Accessed May 17, 2005.
105. Finberg J. Smoking composition. Available at: http://www.uspto.gov. Accessed April 10, 2006.
106. Rodriguez BK, Bellin SA, Snyder GA. Niacin and nicacinamide in fluecured cigarette smoke condensate. August 10, 1960. Philip Morris. Bates no. 500600367/0381. Available at: http://legacy.library.ucsf.edu/tid/pnx69d00. Accessed May 29, 2005.
107. Falk KG. The absorption of niacin in the smoking of cigarettes. December 19, 1944. Philip Morris. Bates no. 1003072792/2796. Available at: http://legacy.library.ucsf.edu/tid/sqm25e00. Accessed May 29, 2005.
108. Debardeleben MZ. Commercial production of niacin (nicotinic acid). July 24, 1989. Philip Morris. Bates no. 2022203224/3225. Available at: http://legacy.library.ucsf.edu/tid/jys58e00. Accessed May 29, 2005.
109. Job procedure: chlorogenic acid and rutin by high pressure liquid chromatography E 54. Philip Morris. Bates no. 2074114452/4454. Available at: http://legacy.library.ucsf.edu/tid/bpn45c00. Accessed May 29, 2005.
110. Inskeep GE. Patents on vitamins and therapeutic ingredients in cigarettes. December 12, 1966. Philip Morris. Bates no. 2028665601. Available at: http://legacy.library.ucsf.edu/tid/sqm25e00. Accessed May 29, 2005.
111. Monroe B. Medicated cigarettes. January 6, 1988. Philip Morris. Bates no. 2023132355/2401. Available at: http://legacy.library.ucsf.edu/tid/awy18d00. Accessed May 29, 2005.
112. Patent list: medicated cigarettes. January 6, 1988. Philip Morris. Bates no. 500600367/0381. Available at: http://legacy.library.ucsf.edu/tid/btp04e00. Accessed May 29, 2005.
113. Chung H, Aldridge JC. Pyrolytic study of eugenol glucoside. August 21, 1981. RJ Reynolds. Bates no. 508009154/9157.Available at: http://legacy.library.ucsf.edu/tid/nwx04d00. Accessed June 18, 2004.
114. Pankow JF, Tavakoli AD, Luo W, Isabelle LM. Percent free base nicotine in the tobacco smoke particulate matter of selected commercial and reference cigarettes. Chem Res Toxicol. 2003;16: 1014–1018. [PubMed]
115. Brauer LH, Behm FM, Lane JD, Westman EC, Perkins C, Rose JE. Individual differences in smoking reward from de-nicotinized cigarettes. Nicotine Tob Res. 2001;3:101–109. [PubMed]
116. Fleming T. PDR for Herbal Medicines. 2nd ed. Montvale, NJ: Medical Economics Co; 2000.
117. Virtamo J, Pietinen P, Huttunen JK, et al. Incidence of cancer and mortality following alpha-tocopherol and beta-carotene supplementation. JAMA. 2003;290:476–485. [PubMed]

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