TECHNICAL WRITEUP

E-quilibrium

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.

 

The Extract

Nicotine

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

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

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

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.

 

References

 

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