Whether you started smoking just to look cool or to rebel against your parents, whatever the reason, many of you are still smoking and are unlikely to stop anytime soon. Though, you know it is unhealthy, you still are not going to stop for good. In your heart, you don’t even really want to. It is not just the physical addiction to nicotine that gets you. Smoking is really enjoyable. It is hard to imagine not having a smoke with your coffee or a drink. It is hard to imagine not having one to get you out of bed with a smile in the morning, after a good meal, after sex, or just when you are stressed as hell.
It is not only the chemically produced pleasure, it is the physical act of smoking. It is something to do with your hands, it is something to give your mind a break and re-attain focus. It is the feeling of taking it into your lungs and exhaling it. And, it is not just the smooth, rich taste of tobacco, the coolness of menthol, or some fruity dessert flavor, if that’s your thing. It is essentially your yoga, your meditation.
The massive growth in popularity and innovation of e-cigarettes/vapes attests to this allure. But, as great as they are, even those are still missing something. Namely, the other psychoactive ingredients in tobacco besides nicotine complete the experience. These include cotinine, nornicotine, anabasine, anatabine, myosmine, and beta-carbolines (Nicotine and friends also actually have a number of positive health benefits. Anti-smoking commercials won’t tell you that Truth).
What is needed to make the experience even more real, even more enjoyable, even more perfect is a tobacco extract that contains these complementary ingredients without the laundry list of carcinogenic compounds found in tobacco and tobacco smoke. Almost two years in the making, an optimized WTA — All of the good & none of the bad – is finally here.
You needed a superior tobacco extract in a vapable e-juice, capable of being flavored just the way you like it.
And that is exactly what we are giving you.
You don’t need science to tell you that you like the feeling produced by nicotine, or why, so we won’t exactly bother with that. We will mention that e-cigs/vapes are indeed better for you than conventional cigarettes in a number of ways. The vapors contain much less carcinogenic particulate, present a far lower risk for inflammation and atherosclerosis, and result in much improved indoor air quality vs. second-hand smoke (1).
Nicotine and Weight
You also know that you tend to gain weight when you stop smoking, but you probably do not know exactly why. The most obvious reason is that you start putting food into your mouth instead of a cigarette as something to do. There is much more to it than that, however. Food, especially the fattening delicious kinds, produce a dopaminergic reward response just like nicotine and other psychoactive drugs do (2). Likewise, cellular events that drive appetite and hunger are akin to the craving in drug withdrawal (3). In other words, when smoking, nicotine partially substitutes for the drive and reward response of food — and, when you stop smoking, food partially substitutes for nicotine (4, 5). Comfort foods also reduce stress levels, just as does smoking cigarettes (6, 7). So, this naturally leads to eating more food, with a tendency toward bad foods (8).
Going beyond that, nicotine/smoking have even more effects that reduce hunger and food intake, while increasing metabolism. Nicotine increases tetrahydrobiopterin, an essential co-factor in the rate-limiting pathway of dopamine production (9). It also increases the synthesis of catecholamines epinephrine and norepinephrine (10), which increases lipolysis and fatty acid oxidation, while reducing appetite (11).
Nicotine is further involved in body-weight control via modulation of the body’s adipostat – basically a thermostat for your metabolism and body-fat levels. This is controlled by a number of hormones (12). One of the most important is leptin, an adipokine which suppresses food intake and increases energy expenditure (13). Smokers and users of nicotine gum have significantly higher leptin levels than non-smokers (14, 15). Nicotine also increases the expression of leptin receptors, thus increasing sensitivity (16) – and, leptin sensitivity is more important than leptin levels for all except the very lean (17).
On the other side of the coin, nicotine down-regulates a number of orexigenic signals that increase appetite and hunger, while increasing fat storage. Compared to non-smokers, smokers had reduced Neuropeptide-Y levels, with smoking cessation reversing this, leading to significant weight gain and waist circumferences increases (16, 18). Another orexigenic peptide, Ghrelin, which is produced in the gut in response to calorie restriction and weight loss is increased by smoking cessation (19, 20).
Yet another metabolic benefit of nicotine is to improve insulin sensitivity and glucose tolerance. In addition to being positive for your bodyweight, it is probably the single most important thing for cardiovascular health, given the strong associations between diabetes, metabolic syndrome, and heart disease (21, 22). Chronic exposure to nicotine increases insulin sensitivity and glucose tolerance, independent of weight loss via an anti-inflammatory action. (23). It has also been found to enhance insulin sensitivity independent of inflammation (24). It increases levels of the hormone adiponectin (25), which is maybe the most promising target for pharmacological intervention of insulin resistance (26). Finally, nicotine decreases hepatic gluconeogenesis and glucose output, so your liver isn’t dumping it into your blood (26).
We’re not quite finished with the beneficial effects of nicotine on bodyweight. Cessation of smoking also results in changes in the microbiome — i.e. the bacteria in your gut that probiotics and prebiotics/fiber address (27). These changes mirror the differences present between lean and obese subjects (28). This microbiomial change results in more efficient energy utilization and contributes to the weight gain when you stop smoking (29).
Nicotine and Cognition
We shall now move to nicotine’s positive effects on the brain. We previously talked about the increase in dopamine production from nicotine. This protects against neural cytotoxicity and cell death. Dopamine is basically a super anti-oxidant of the brain, being even more potent than glutathione (30, 31). Reductions in dopaminergic neurons, oxidative stress, inflammation, and ultimately accumulation of harmful proteins in the brain are widely thought to be the cause of Alzheimer’s, Parkinson’s, ALS, dementia, and other brain wasting diseases (32, 33).
Interestingly, oxidation of dopamine itself is a contributing factor. This seems paradoxical, but in normally functioning cells, dopamine is protected from oxidation (34). We previously mentioned tetrahydrobiopterin, the co-factor in dopamine synthesis which is increased by nicotine. It plays a major role in this process as lack of availability leads to disruptions in the nitric oxide system leading to production of the super radical peroxynitrite, which cannot be scavenged by typical anti-oxidants such as glutathione (35). The cholinergic system has also been more recently implicated strongly in neurodegenerative conditions (36, 37). Nicotine has been found to protect against all of this (38, 39, 40, 41, 42, 43).
Importantly, it is not just in disease states where the above is applicable. The nicotinic cholinergic systems are involved with cognitive deficits that naturally occur with aging (44, 45). Nicotine improves memory and cognition in these healthy populations, as well (46, 47). Not only that, it results in improvements with young subjects with lower baseline performance (48, 49).
Finally, another extremely handy real-world aspect of nicotine is that it prevents alcohol induced neural toxicity (50, 51, 52). This effect is modulated by different receptor subtypes, which could argue for the benefit of the other tobacco components we will soon discuss (51). Given that alcohol increases the amount and rate of smoking (53), as well motivation to smoke, and the extremely high incidence of smoking with alcohol dependence (54), its protective effects play a major role in counteracting the negative cytotoxic effects of alcohol use (51, 52).
Nicotine very likely also protect against amphetamine, cocaine, and MDMA toxicity as well, via its previously mentioned protective effects on dopamine levels and dopaminergic neurons (55-58).
Non-Nicotine Constituents of Tobacco
We will go into the other ingredients of the extract, individually, but first we will take a look at some general studies on their complimentary actions when administered together with nicotine, or as found naturally together in tobacco/tobacco smoke.
We will go ahead and note that the alkaloids to be subsequently discussed, minus the beta-carbolines, share affinity for the nicotinic receptors with nicotine itself, so they will basically do all of the things talked about above regarding nicotine, though generally with lower potency (59). Thus, we will not go into that with each one, unless applicable (namely, differing potency at different receptor subtypes).
Tobacco smoke extract increased striatal dopamine twice as much as pure nicotine (60). Cigarette smoke extract had greater reinforcing effects, leading to both quicker acquisition and prolonged maintenance of self-administration, compared to nicotine, only (61). It also inhibited monoamines oxidases A & B (which break down serotonin and the catecholamines, respectively), whereas nicotine did not (61). Interestingly, roll your own tobacco was more reinforcing and rewarding than commercial cigarettes or nicotine, alone (62). Finally, combining nicotine with the 5 major alkaloids of tobacco (cotinine, nornicotine, anabasine, anatabine, and myosmine) had enhanced neuroactive effects, significantly increasing dopamine levels, self-administration, and locomotor activity versus nicotine by itself (63,64).
Cotinine is the most interesting of the other nicotinic tobacco alkaloids – more so than even nicotine in many ways. While, as noted, nicotine has numerous positive benefits to go with the bad, cotinine could quite reasonably and accurately be called good for you.
Cotinine is contained in tobacco and is also the primary metabolite of nicotine. It has a much longer half-life (15-20 hours vs. 2-3 hours) than nicotine. (65, 66) This explains observations of neurological activity and behavioral responses long after nicotine has cleared the system. It also has differing potency at the various nicotinic subreceptors, which results in differing responses and therapeutic potential (67). Interestingly, menthol cigarettes produce 1.5 times the blood level of cotinine as regular cigarettes (68).
Studies have shown that cotinine does not induce addictive tendencies or withdrawal, even at doses resulting in 10 times higher plasma levels than would be obtained by smoking (66, 68). It did not increase blood pressure at all at levels 13 times higher than clinically used nicotine levels (66, 69). This superior safety profile makes it an extremely fascinating compound for therapeutic applications.
Like nicotine, it has shown beneficial effects against Alzheimer’s and related cognitive diseases and disorders (70, 71). It produces long-acting improvements in working memory and attention (72). It produces improvement in cognitive tasks, executive function, and emotional responses (73). Conitine reduces depressive behavior and preserves synaptic density under conditions of chronic stress (74). It stimulates dopamine release in the striatum, with the accompanying pleasure and reward (75). It facilitates sustained attention, while decreasing impulsive and compulsive behavior (76). Finally, it is anti-inflammatory in the brain, protecting against neuroinflammatory conditions such as bipolar disorder, PTSD, and major depression (77).
Nornicotine is another major component of tobacco, as well as a minor metabolite of nicotine, which displays differential nicotinic subtype signaling (78). This is accompanied by a better pharmokinetic profile and reduced toxicity (79).
It increases dopamine synthesis, with the expected reinforcing, rewarding, and locomotor stimulant effects (80, 81, 82). It partially substitutes for amphetamine in discriminative stimulus test of reinforcement response, though through a different mechanism (83). It also results in inhibition of the dopamine transporter, increasing dopamine in a manner distinct from nicotine (84).
Finally, nornicotine increases analgesia in combination with opiates, allowing for treatment of a broad array pain (neuropathic, nociceptive, and mixed) with a reduction in toxicity (79).
Anatabine, Anabasine, and Myosmine
These are the final major nicotinic alkaloids in tobacco. They don’t have as much data as the previous ones, so we are going to lump them together here and discuss them all at once. At low doses, they increase the reward response to nicotine, while at high doses, they partially substitute for nicotine in reinforcing behaviors (85, 86, 87). This substitution effect seen with most of these tobacco alkaloids could be beneficial, as it allows for lower doses of nicotine to achieve the same reward response with a better safety profile.
As you probably expect by now, they also increase dopamine release in the striatum (88). They share psychomotor stimulant properties with amphetamine (89). Their neuroactive properties include improved attention and memory (90). These compounds improve pathological behavioral deficits in neurodegenerative disorders by inhibiting inflammation (91), while also decreasing formation and accumulation of degenerative proteins like beta-amyloid (92). They reduce levels of inflammatory cytokines such as interleukins and TNF-alpha (93), prevent demyelination of spinal neurons (94), and have been demonstrated to reduce intestinal tissue damage and inflammation in colitis (95)
Beta-carbolines are non-nicotine alkaloids found in tobacco, as well as numerous food and plants regularly encountered such as coffee, chocolate, and cooked proteins like beef, fish, and eggs (96). There are a large number of different ones, with a wide range of pharmacologies ranging from antimicrobial, antifungal, antitumor, antimutagenic, andantigenotoxic to vasorelaxant, antioxidant, thermogenic, stimulatory, and hallucinogenic (97, 98). So, I am going to lump them together and just discuss the aspects relevant to our tobacco extract.
The primary action of beta-carbolines for our purposes is that they inhibit monamineoxididases types A & B (99). Type A breaks down the neurotransmitter serotonin, while type B breaks down dopamine, epinephrine, and norepinephrine. Because they increase these happy chemicals, MAO inhibitors have long been used clinically to treat depression, being particularly useful for atypical and treatment resistant depression (100).
These medicinal qualities make them quite desirable for enhancing the vaping experience, but even more important is that because they are non-nicotinic, they work through different pathways than the alkaloids, making them even more synergistic with nicotine. Indeed, they dramatically increase the reinforcing activity of nicotine and the motivation to smoke (101). Because they are not substituting for nicotine at the receptor, they do so with both low and heavy nicotine intake (102). They not only enhance the response, but also result in neural activity patterns distinct from nicotine by itself (103). Beta-carbolines have also been shown to increase the rewarding and locomotor stimulant response to nicotine (104), as well as to increase the firing of dopaminergic neurons as much as 10 times the rate of nicotine,alone (105). In addition, they inhibit re-uptake of dopamine by its transporter (106). Acetaldehyde, a product of alcohol metabolism, greatly increases beta-carboline levels, thus providing yet another reason why drinking and smoking go so well together (107).
As we have shown, nicotine is not quite the devil you thought you knew, and the other neuroactive tobacco alkaloids are even cooler than the goddamn Marlboro Man.
Smile, be merry, and vape ‘em if you got ‘em.
1. Oh AY, Kacker A. Do electronic cigarettes impart a lower potential disease burden than conventional tobacco cigarettes? Review on E-cigarette vapor versus tobacco smoke. Laryngoscope. 2014;124(12):2702-6.
2. Morris MJ, Beilharz JE, Maniam J, Reichelt AC, Westbrook RF. Why is obesity such a problem in the 21st century? The intersection of palatable food, cues and reward pathways, stress, and cognition. Neurosci Biobehav Rev. 2015;58:36-45.
3. Kalra SP, Kalra PS. Overlapping and interactive pathways regulating appetite and craving.
J Addict Dis. 2004;23(3):5-21.
4. Von der goltz C, Koopmann A, Dinter C, et al.Orexin and leptin are associated with nicotine craving: a link between smoking, appetite and reward. Psychoneuroendocrinology. 2010;35(4):570-7.
5. Mcfadden KL, Cornier MA, Tregellas JR. The role of alpha-7 nicotinic receptors in food intake behaviors. Front Psychol. 2014;5:553.
6. Ulrich-lai YM, Fulton S, Wilson M, Petrovich G, Rinaman L. Stress exposure, food intake and emotional state.
7. Choi D, Ota S, Watanuki S. Does cigarette smoking relieve stress? Evidence from the event-related potential (ERP). Int J Psychophysiol. 2015;98(3 Pt 1):470-6.
8. Gibson EL. The psychobiology of comfort eating: implications for neuropharmacological interventions.
Behav Pharmacol. 2012;23(5-6):442-60.
9. Serova L, Sabban EL. Involvement of alpha 7 nicotinic acetylcholine receptors in gene expression of dopamine biosynthetic enzymes in rat brain. J Pharmacol Exp Ther. 2002;303(3):896-903.
10. Smith KM, Mitchell SN, Joseph MH. Effects of chronic and subchronic nicotine on tyrosine hydroxylase activity in noradrenergic and dopaminergic neurones in the rat brain.
J. Neurochem. 1991; 57:1750-1756
11. Villanueva I, Pinón M, Quevedo-corona L, Martínez-olivares R, Racotta R. Chemical sympathectomy alters food intake and thermogenic responses to catecholamines in rats. Life Sci. 2002;71(7):789-801.
12. Koleva DI, Orbetzova MM, Atanassova PK. Adipose tissue hormones and appetite and body weight regulators in insulin resistance. Folia Med (Plovdiv). 2013;55(1):25-32.
13. Reidy SP, Weber J. Leptin: an essential regulator of lipid metabolism. Comp Biochem Physiol, Part A Mol Integr Physiol. 2000;125(3):285-98.
14. Bai XJ, Fan LH, He Y, et al. Nicotine may affect the secretion of adipokines leptin, resistin, and visfatin through activation of KATP channel. Nutrition. 2016;32(6):645-8.
15. Eliasson B, Smith U. Leptin levels in smokers and long-term users of nicotine gum. Eur J Clin Invest. 1999;29(2):145-52.
16. Jang MH, Shin MC, Kim KH, et al. Nicotine administration decreases neuropeptide Y expression and increases leptin receptor expression in the hypothalamus of food-deprived rats. Brain Res. 2003;964(2):311-5.
17. Unger RH. Leptin physiology: a second look. Regul Pept. 2000;92(1-3):87-95.
18. Hussain T, Al-daghri NM, Al-attas OS, Draz HM, Abd al-rahman SH, Yakout SM. Plasma neuropeptide Y levels relate cigarette smoking and smoking cessation to body weight regulation. Regul Pept. 2012;176(1-3):22-7.
19. Alamri BN, Shin K, Chappe V, Anini Y. The role of ghrelin in the regulation of glucose homeostasis. Horm Mol Biol Clin Investig. 2016;26(1):3-11.
20. Koopmann A, Bez J, Lemenager T, et al. Effects of Cigarette Smoking on Plasma Concentration of the Appetite-Regulating Peptide Ghrelin. Ann Nutr Metab. 2015;66(2-3):155-61.
21. Fonseca VA. The metabolic syndrome, hyperlipidemia, and insulin resistance. Clin Cornerstone. 2005;7(2-3):61-72.
22. Han TS, Lean ME. A clinical perspective of obesity, metabolic syndrome and cardiovascular disease. JRSM Cardiovasc Dis. 2016;5:2048004016633371.
23. Vu CU, Siddiqui JA, Wadensweiler P, et al. Nicotinic acetylcholine receptors in glucose homeostasis: the acute hyperglycemic and chronic insulin-sensitive effects of nicotine suggest dual opposing roles of the receptors in male mice. Endocrinology. 2014;155(10):3793-805.
24. Xu TY, Guo LL, Wang P, et al. Chronic exposure to nicotine enhances insulin sensitivity through ?7 nicotinic acetylcholine receptor-STAT3 pathway. PLoS ONE. 2012;7(12):e51217.
25. Inoue K, Takeshima F, Kadota K, et al. Early effects of smoking cessation and weight gain on plasma adiponectin levels and insulin resistance. Intern Med. 2011;50(7):707-12.
26. Fisman EZ, Tenenbaum A. Adiponectin: a manifold therapeutic target for metabolic syndrome, diabetes, and coronary disease?. Cardiovasc Diabetol. 2014;13:103.
26. Tsuneki H, Nagata T, Fujita M, et al. Nighttime Administration of Nicotine Improves Hepatic Glucose Metabolism via the Hypothalamic Orexin System in Mice. Endocrinology. 2016;157(1):195-206.
27. Biedermann L, Brülisauer K, Zeitz J, et al. Smoking cessation alters intestinal microbiota: insights from quantitative investigations on human fecal samples using FISH. Inflamm Bowel Dis. 2014;20(9):1496-501.
28. Biedermann L, Zeitz J, Mwinyi J, et al. Smoking cessation induces profound changes in the composition of the intestinal microbiota in humans. PLoS ONE. 2013;8(3):e59260.
29. Begon J, Juillerat P, Cornuz J, Clair C. [Smoking and digestive tract: a complex relationship. Part 2: Intestinal microblota and cigarette smoking]. Rev Med Suisse. 2015;11(478):1304-6.
30. Yen GC, Hsieh CL. Antioxidant effects of dopamine and related compounds. Biosci Biotechnol Biochem. 1997;61(10):1646-9.
31 Kanazawa K, Sakakibara H. High content of dopamine, a strong antioxidant, in Cavendish banana. J Agric Food Chem. 2000;48(3):844-8.
32. Hoozemans JJ, Van haastert ES, Nijholt DA, Rozemuller AJ, Scheper W. Activation of the unfolded protein response is an early event in Alzheimer’s and Parkinson’s disease. Neurodegener Dis. 2012;10(1-4):212-5.
33. Jodko K, Litwinienko G. [Oxidative stress in the neurodegenerative diseases–potential antioxidant activity of catecholamines]. Postepy Biochem. 2010;56(3):248-59.
34. Nakamura K, Bindokas VP, Marks JD, Miller RJ, Kang UJ, Intrinsic antioxidant properties of dopaminergic neurons The role of tetrahydrobiopterin. Society For Neuroscience Abstracts. 1999. 25(1-2): 1595
35. Foxton RH, Land JM, Heales SJ. Tetrahydrobiopterin availability in Parkinson’s and Alzheimer’s disease; potential pathogenic mechanisms. Neurochem Res. 2007;32(4-5):751-6.
36. Bohnen NI, Albin RL. The cholinergic system and Parkinson disease. Behav Brain Res. 2011;221(2):564-73.
37. Takanashi M, Hattori N. [Neurodegenerative diseases]. Nihon Rinsho. 2012 Jan;70(1):94-8.
38. Picciotto MR, Zoli M. Neuroprotection via nAChRs: the role of nAChRs in neurodegenerative disorders such as Alzheimer’s and Parkinson’s disease. Front Biosci. 2008;13:492-504.
39. Levin ED, Hao I, Burke DA, Cauley M, Hall BJ, Rezvani AH. Effects of tobacco smoke constituents, anabasine and anatabine, on memory and attention in female rats. J Psychopharmacol (Oxford). 2014;28(10):915-22.
40. Srinivasan R, Henley BM, Henderson BJ, et al. Smoking-Relevant Nicotine Concentration Attenuates the Unfolded Protein Response in Dopaminergic Neurons. J Neurosci. 2016;36(1):65-79.
41. Wei P, Liu Q, Li D, Zheng Q, Zhou J, Li J. Acute nicotine treatment attenuates lipopolysaccharide-induced cognitive dysfunction by increasing BDNF expression and inhibiting neuroinflammation in the rat hippocampus. Neurosci Lett. 2015;604:161-6.
42. Chen Y, Nie H, Tian L, et al. Nicotine-induced neuroprotection against ischemic injury involves activation of endocannabinoid system in rats. Neurochem Res. 2013;38(2):364-70.
43. Kawamata J, Suzuki S, Shimohama S. Enhancement of nicotinic receptors alleviates cytotoxicity in neurological disease models. Ther Adv Chronic Dis. 2011;2(3):197-208.
44. Wallace TL, Bertrand D. Importance of the nicotinic acetylcholine receptor system in the prefrontal cortex. Biochem Pharmacol. 2013;85(12):1713-20.
45. Hornick A, Lieb A, Vo NP, Rollinger JM, Stuppner H, Prast H. The coumarin scopoletin potentiates acetylcholine release from synaptosomes, amplifies hippocampal long-term potentiation and ameliorates anticholinergic- and age-impaired memory. Neuroscience. 2011;197:280-92.
46. Zanardi A, Leo G, Biagini G, Zoli M. Nicotine and neurodegeneration in ageing. Toxicol Lett. 2002;127(1-3):207-15.
47. Carrasco C, Vicens P, Redolat R. Neuroprotective effects of behavioural training and nicotine on age-related deficits in spatial learning. Behav Pharmacol. 2006;17(5-6):441-52.
48. Niemegeers P, Dumont GJ, Quisenaerts C, et al. The effects of nicotine on cognition are dependent on baseline performance. Eur Neuropsychopharmacol. 2014;24(7):1015-23.
49. Potter AS, Newhouse PA. Acute nicotine improves cognitive deficits in young adults with attention-deficit/
50. Tizabi Y, Al-namaeh M, Manaye KF, Taylor RE. Protective effects of nicotine on ethanol-induced toxicity in cultured cerebellar granule cells. Neurotox Res. 2003;5(5):315-21.
51. Tizabi Y, Manaye KF, Smoot DT, Taylor RE. Nicotine inhibits ethanol-induced toxicity in cultured cerebral cortical cells. Neurotox Res. 2004;6(4):311-6.
52. Tizabi Y, Manaye KF, Taylor RE. Nicotine blocks ethanol-induced apoptosis in primary cultures of rat cerebral cortical and cerebellar granule cells. Neurotox Res. 2005;7(4):319-22.
53. Mintz J, Boyd G, Rose JE, Charuvastra VC, Jarvik ME. Alcohol increases cigarette smoking: a laboratory demonstration. Addict Behav. 1985;10(3):203-7.
54. Field M, Mogg K, Bradley BP. Alcohol increases cognitive biases for smoking cues in smokers. Psychopharmacology (Berl). 2005;180(1):63-72.
55. Vieira-brock PL, Mcfadden LM, Nielsen SM, et al. Chronic Nicotine Exposure Attenuates Methamphetamine-Induced Dopaminergic Deficits. J Pharmacol Exp Ther. 2015;355(3):463-72.
56. Gould RW, Garg PK, Garg S, Nader MA. Effects of nicotinic acetylcholine receptor agonists on cognition in rhesus monkeys with a chronic cocaine self-administration history. Neuropharmacology. 2013;64:479-88.
57. Gould RW, Garg PK, Garg S, Nader MA. Effects of nicotinic acetylcholine receptor agonists on cognition in rhesus monkeys with a chronic cocaine self-administration history. Neuropharmacology. 2013;64:479-88.
58. Huang LZ, Parameswaran N, Bordia T, Michael mcintosh J, Quik M. Nicotine is neuroprotective when administered before but not after nigrostriatal damage in rats and monkeys. J Neurochem. 2009;109(3):826-37.
59. Harris AC, Tally L, Muelken P, et al. Effects of nicotine and minor tobacco alkaloids on intracranial-self-stimulation in rats. Drug Alcohol Depend. 2015;153:330-4.
60. Khalki H, Navailles S, Piron CL, De deurwaerdere P. A tobacco extract containing alkaloids induces distinct effects compared to pure nicotine on dopamine release in the rat. Neurosci Lett. 2013;544:85-8.
61. Costello MR, Reynaga DD, Mojica CY, Zaveri NT, Belluzzi JD, Leslie FM. Comparison of the reinforcing properties of nicotine and cigarette smoke extract in rats. Neuropsychopharmacology. 2014;39(8):1843-51.
62. Brennan KA, Crowther A, Putt F, Roper V, Waterhouse U, Truman P. Tobacco particulate matter self-administration in rats: differential effects of tobacco type. Addict Biol. 2015;20(2):227-35.
63. Clemens KJ, Caillé S, Stinus L, Cador M. The addition of five minor tobacco alkaloids increases nicotine-induced hyperactivity, sensitization and intravenous self-administration in rats. Int J Neuropsychopharmacol. 2009;12(10):1355-66.
64. Hoffman AC, Evans SE. Abuse potential of non-nicotine tobacco smoke components: acetaldehyde, nornicotine, cotinine, and anabasine. Nicotine Tob Res. 2013;15(3):622-32.
65. Buccafusco JJ, Terry AV. The potential role of cotinine in the cognitive and neuroprotective actions of nicotine. Life Sci. 2003;72(26):2931-42.
66. Moran VE. Cotinine: Beyond that Expected, More than a Biomarker of Tobacco Consumption. Front Pharmacol. 2012;3:173.
67. Buccafusco JJ, Shuster LC, Terry AV. Disconnection between activation and desensitization of autonomic nicotinic receptors by nicotine and cotinine. Neurosci Lett. 2007;413(1):
68-71. 68. Ha MA, Smith GJ, Cichocki JA, et al. Menthol attenuates respiratory irritation and elevates blood cotinine in cigarette smoke exposed mice. PLoS ONE. 2015;10(2):e0117128.
69. Hatsukami DK, Grillo M, Pentel PR, Oncken C, Bliss R. Safety of cotinine in humans: physiologic, subjective, and cognitive effects. Pharmacol Biochem Behav. 1997;57(4):643-50.
70. Echeverria V, Zeitlin R. Cotinine: a potential new therapeutic agent against Alzheimer’s disease. CNS Neurosci Ther. 2012;18(7):517-23.
71. Li P, Beck WD, Callahan PM, Terry AV, Bartlett MG. Pharmacokinetics of cotinine in rats: a potential therapeutic agent for disorders of cognitive function. Pharmacol Rep. 2015;67(3):494-500.
72. Terry AV, Hernandez CM, Hohnadel EJ, Bouchard KP, Buccafusco JJ. Cotinine, a neuroactive metabolite of nicotine: potential for treating disorders of impaired cognition. CNS Drug Rev. 2005;11(3):229-52.
73. Grizzell JA, Echeverria V. New Insights into the Mechanisms of Action of Cotinine and its Distinctive Effects from Nicotine. Neurochem Res. 2015;40(10):2032-46.
74. Grizzell JA, Iarkov A, Holmes R, Mori T, Echeverria V. Cotinine reduces depressive-like behavior, working memory deficits, and synaptic loss associated with chronic stress in mice. Behav Brain Res. 2014;268:55-65.
75. Dwoskin LP, Teng L, Buxton ST, Crooks PA. (S)-(-)-Cotinine, the major brain metabolite of nicotine, stimulates nicotinic receptors to evoke [3H]dopamine release from rat striatal slices in a calcium-dependent manner. J Pharmacol Exp Ther. 1999;288(3):905-11.
76. Terry AV, Buccafusco JJ, Schade RF, et al. The nicotine metabolite, cotinine, attenuates glutamate (NMDA) antagonist-related effects on the performance of the five choice serial reaction time task (5C-SRTT) in rats. Biochem Pharmacol. 2012;83(7):941-51.
77. Echeverria V, Alex grizzell J, Barreto GE. Neuroinflammation: A Therapeutic Target of Cotinine for the Treatment of Psychiatric Disorders?. Curr Pharm Des. 2016;22(10):1324-33.
78. Papke RL, Dwoskin LP, Crooks PA. The pharmacological activity of nicotine and nornicotine on nAChRs subtypes: relevance to nicotine dependence and drug discovery. J Neurochem. 2007;101(1):160-7.
79. Holtman JR, Crooks PA, Johnson-hardy JK, Wala EP. The analgesic and toxic effects of nornicotine enantiomers alone and in interaction with morphine in rodent models of acute and persistent pain. Pharmacol Biochem Behav. 2010;94(3):352-62.
80. Green TA, Brown RW, Phillips SB, Dwoskin LP, Bardo MT. Locomotor stimulant effects of nornicotine: role of dopamine. Pharmacol Biochem Behav. 2002;74(1):87-94.
81. Green TA, Crooks PA, Bardo MT, Dwoskin LP. Contributory role for nornicotine in nicotine neuropharmacology: nornicotine-evoked [3H]dopamine overflow from rat nucleus accumbens slices. BiochemPharmacol. 2001 Dec 15;62(12):1597-603.
82. Dwoskin LP, Teng L, Buxton ST, Crooks PA. (S)-(-)-Cotinine, the major brain metabolite of nicotine, stimulates nicotinic receptors to evoke [3H]dopamine release from rat striatal slices in a calcium-dependent manner. J Pharmacol Exp Ther. 1999;288(3):905-11.
83. BardoMT, Bevins RA, Klebaur JE, Crooks PA, Dwoskin LP. (-)-Nornicotine partially substitutes for (+)-amphetamine in a drug discrimination paradigm in rats. PharmacolBiochemBehav. 1997 Dec;58(4):1083-7.
84. Middleton LS, Crooks PA, Wedlund PJ, Cass WA, Dwoskin LP. Nornicotine inhibition of dopamine transporter function in striatum via nicotinic receptor activation. Synapse. 2007;61(3):157-65.
85. Hall BJ, Wells C, Allenby C, et al. Differential effects of non-nicotine tobacco constituent compounds on nicotine self-administration in rats. Pharmacol Biochem Behav. 2014;120:103-8.
86. Desai RI, Doyle MR, Withey SL, Bergman J. Nicotinic effects of tobacco smoke constituents in nonhuman primates. Psychopharmacology (Berl). 2016;233(10):1779-89.
87. Mello NK, Fivel PA, Kohut SJ, Caine SB. Anatabine significantly decreases nicotine self-administration. Exp Clin Psychopharmacol. 2014;22(1):1-8.
88. Dwoskin LP, Teng L, Buxton ST, Ravard A, Deo N, Crooks PA. Minor alkaloids of tobacco release [3H]dopamine from superfused rat striatal slices. Eur J Pharmacol. 1995;276(1-2):195-9.
89. Desai RI, Bergman J. Methamphetamine-like discriminative-stimulus effects of nicotinic agonists. J Pharmacol Exp Ther. 2014;348(3):478-88.
90. Levin ED, Hao I, Burke DA, Cauley M, Hall BJ, Rezvani AH. Effects of tobacco smoke constituents, anabasine and anatabine, on memory and attention in female rats. J Psychopharmacol (Oxford). 2014;28(10):915-22.
91. Verma M, Beaulieu-abdelahad D, Ait-ghezala G, et al. Correction: Chronic Anatabine Treatment Reduces Alzheimer’s Disease (AD)-Like Pathology and Improves Socio-Behavioral Deficits in a Transgenic Mouse Model of AD. PLoS ONE. 2015;10(7):e0134776.
92. Paris D, Beaulieu-abdelahad D, Bachmeier C, et al. Anatabine lowers Alzheimer’s Aß production in vitro and in vivo. Eur J Pharmacol. 2011;670(2-3):384-91.
93. Paris D, Beaulieu-abdelahad D, Abdullah L, et al. Anti-inflammatory activity of anatabine via inhibition of STAT3 phosphorylation. Eur J Pharmacol. 2013;698(1-3):145-53.
94. Paris D, Beaulieu-abdelahad D, Mullan M, et al. Amelioration of experimental autoimmune encephalomyelitis by anatabine. PLoS ONE. 2013;8(1):e55392.
95. Bai A, Guo Y, Lu N. The effect of the cholinergic anti-inflammatory pathway on experimental colitis. Scand J Immunol. 2007;66(5):538-45.
96. Herraiz T. Relative exposure to beta-carbolines norharman and harman from foods and tobacco smoke. Food Addit Contam. 2004;21(11):1041-50.
97. Khan FA, Maalik A, Iqbal Z, Malik I. Recent pharmacological developments in ß-carboline alkaloid “harmaline”. Eur J Pharmacol. 2013;721(1-3):391-4.
98. Patel K, Gadewar M, Tripathi R, Prasad SK, Patel DK. A review on medicinal importance, pharmacological activity and bioanalytical aspects of beta-carboline alkaloid ”Harmine”. Asian Pac J Trop Biomed. 2012;2(8):660-4.
99. Herraiz T, Chaparro C. Human monoamine oxidase is inhibited by tobacco smoke: beta-carboline alkaloids act as potent and reversible inhibitors. Biochem Biophys Res Commun. 2005;326(2):378-86.
100. Shulman KI, Herrmann N, Walker SE. Current place of monoamine oxidase inhibitors in the treatment of depression. CNS Drugs. 2013;27(10):789-97.
101. Guillem K, Vouillac C, Azar MR, et al. Monoamine oxidase inhibition dramatically increases the motivation to self-administer nicotine in rats. J Neurosci. 2005;25(38):8593-600.
102. Smith TT, Rupprecht LE, Cwalina SN, et al. Effects of Monoamine Oxidase Inhibition on the Reinforcing Properties of Low-Dose Nicotine. Neuropsychopharmacology. 2016.
103. Arnold MM, Loughlin SE, Belluzzi JD, Leslie FM. Reinforcing and neural activating effects of norharmane, a non-nicotine tobacco constituent, alone and in combination with nicotine. Neuropharmacology. 2014;85:293-304.
104. Villégier AS, Salomon L, Granon S, et al. Monoamine oxidase inhibitors allow locomotor and rewarding responses to nicotine. Neuropsychopharmacology. 2006;31(8):1704-13.
105. Arib O, Rat P, Molimard R, Chait A, Faure P, De beaurepaire R. Electrophysiological characterization of harmane-induced activation of mesolimbic dopamine neurons. Eur J Pharmacol. 2010;629(1-3):47-52.
106. Drucker G, Raikoff K, Neafsey EJ, Collins MA. Dopamine uptake inhibitory capacities of beta-carboline and 3,4-dihydro-beta-carboline analogs of N-methyl-4-phenyl-1,2,3,6-
107. Talhout R, Opperhuizen A, Van amsterdam JG. Role of acetaldehyde in tobacco smoke addiction. Eur Neuropsychopharmacol. 2007;17(10):627-36.