Using nicotine as a cognitive enhancer

For the past few months I’ve been experimenting with nicotine as a nootropic. A nootropic substance is one that improves cognitive function without any harmful effects, and ideally is non addictive and non habit forming. A lot of nootropics do not have hard science backing them up. Nicotine is one of the very few that has scientific literature showing general cognitive benefits.

Is it addictive?

Cigarette smoke contains over 5,000 compounds, but in popular discourse nicotine gets all the attention as the ‘thing that makes cigarettes addictive’. The widespread belief that nicotine alone causes cigarettes to be addictive is due to an influential 640 page report entitled “The Health Consequences of Smoking: Nicotine Addiction” that was released in 1988 by the U.S. Surgeon General. The report leads with the summary statement that “Nicotine is the drug in tobacco that causes addiction”, and goes on to suggest that nicotine is similar in its level of addictiveness to heroin. Today this report is viewed as flawed, because it drew on studies of tobacco use to establish the addictiveness of nicotine, rather than studies on nicotine in isolation. In the intervening years, marketing hype around nicotine replacement products for smoking cessation has kept the focus on nicotine as ‘the solution’ to getting cigarette users to stop smoking. More recently, people have promoted E-cigs as a path to smoking secession, an idea which remains very controversial, [ref, ref] but is promising from a harm reduction perspective.[ref, ref] Because they deliver nicotine quickly to the brain, e-cigs are one of the most addictive methods of nicotine delivery.

A large meta-analysis found that nicotine replacement products (NRP) increased the likelihood of quitting smoking by 50-70%[ref]. However, the base rate for being able to quit cigarettes during any multi-month program remains low (~5 %??), and the number of people who are able to quit after NRP program is likewise low (~10-20%)[ref]. These stubbornly low rates of success have lead some researchers to wonder if something else is making cigarettes addictive. Recent research suggests that the addictiveness of cigarettes may be due to an interaction between MAOIs (which are found in tobacco smoke) and nicotine. Gwern’s writeup contains much more discussion and extensive references on this point.

In response to the focus on nicotine as the cause of smoking’s addictiveness, Frenk and Dar wrote a 241 page monograph, “A Critique of Nicotine Addiction” (2002). As Gwern notes, the authors generally overstate their case by trying to argue that nicotine is not addictive at all. The general consensus is that nicotine is addictive.

Animals, including rats and squirrel monkeys, will self administer nicotine. Nicotine addiction appears to occur through the dopamine system – killing the dopaminergenic neurons in animal models leads to a cessation of self-administration. Interestingly, the dose-response curve of nicotine quickly flattens out in rats — ie. they will quickly self limit how much they are taking. This is in contrast to drugs such as cocaine or amphetamines. Nicotine intake in humans usually lies in a narrow range , between 2-30 mg per day.

The addictiveness of nicotine is modulated by the intensity and duration of nicotine exposure. In general with addictive substances, the more quickly it is delivered, the more dopamine and reward substances are produced. The brain contains mechanisms for for tolerance/habituation, to prevent too many reward compounds from being produced, but when nicotine is delivered quickly, the brain just doesn’t have the time to develop tolerance. Another reason that fast delivery (ie. through vaping / smoking) is more addictive than other methods of intake is that it easier for you brain to associate the reward to the act of smoking / inhaling. Nicotine enters the brain only 10-20 seconds after a person takes a draw from a cigarette. Finally, nicotine receptors sensitize and desensitize fairly quickly.

Optimal dosing and delivery method for nootropic benefit

A cigarette administers about 2 mg of absorbed nicotine. As a nootropic, limiting to 1-2mg a day is recommended.

Delivery methods: risk for addictiveness from highest to lowest:

Vaping
Nasal nasal spray
Nicotine inhaler
Nicotine mouth spray
Chewing gum (when properly taken)
Lozenges (when properly taken, do not chew)
Nicotine patches [these administer nicotine over hours, resulting in significantly lower chance of addiction than all the above, but on the flip side some users report not seeing as much cognitive benefits]

One study of nicotine gum users concluded “Among long-term users (>/=90 days), 20% attributed their use to addiction… Combining the results of Studies 1 and 2 with other data suggests very few gum users develop dependence on the gum.” [ref] Nicotine gum / lozenges should not be consumed quickly, the packaging recommends ‘parking’ the gum/lozenge under your lip and letting it sit there for a while.

My personal observations

I got the idea to take nicotine as a nootropic after reading an interview with Oxford transhumanist philosopher Nick Bostrom. When asked if he has ever taken any cognitive enhancers, he said he experimented with nicotine gum. In his book Superintelligence he also mentions that nicotine gum helped him write the book.

I have developed a somewhat more nuanced view on addiction. Firstly, if one goes to the level of biochemistry and neurotransmitters, one can draw important distinctions between ‘addiction’, ‘habit’, and ‘dependence’. For instance, SSRIs carry a large dependence but are technically not addictive in the same way that hard drugs are. Technically, addiction can be distinguished from mere habit by the activation of particular reward circuitry in the brain that involves a compound called ‘delta FOS-b’, among other things. But for the purpose of this discussion, we will consider ‘addiction’ to just mean habit and dependence that is really hard to break. An important point when considering nootropics is to understand that addiction, construed in the general sense, is not necessarily a bad thing. For instance, many of us find that the benefits of caffeine outweigh the dependence it entails. The same may hold for more extreme nootropics that are known to be addictive, such as modafinil. As another example, many people find SSRIs and other psychiatric medications useful even though they have a very large dependence. Moving outside the realm of things you ingest, someone might be ‘addicted’ to video games, but video games can provide a good cognitive workout and even facilitate social interaction in some individuals. There are may examples of addictive things that can be net beneficial on one’s health and wellbeing – sex, exercise endorphins, eating healthy, etc. Of course, balance is key, and one must be mindful of the downside – withdrawal symptoms when one does not get their ‘fix’.

Personally, I took nicotine gum at the level of 2 mg / day from January – April, and 1 mg / day from May – June (a single cigarette contains about 2 mg of nicotine). I started noticing dependency after a few weeks of use. I did not take the entire dose at once, I chewed nicotine gum strategically through the day 3-4 times a day, often taking the gum out of my mouth and putting it back in the wrapper. The effects of nicotine are immediately apparent. The withdrawal symptoms are very subtle – there were days where I forgot to take nicotine where I didn’t notice any detrimental effects. The withdrawal became apparent when I tried to do something that requires focus or attention before taking my dose for the day. It was if I had run into a ‘block’ that prevented my mind from functioning at the level I wanted. In my view, the level of dependence feels like a caffeine dependence at the level of 200 mg / day, but more subtle. Additionally, from what I have read, when it comes to quitting, the withdrawal from nicotine can be really protracted (ie a week or longer), while withdrawal effects from caffeine generally only last a few days.

The main problem I’ve had with nicotine is forgetting to bring it with me somewhere, having anxiety about not having it on hand and then having trouble focusing on some cognitively demanding task. It is unclear to me how much of my difficulty came from psychosomatic effects vs actual withdrawal symptoms, however.

While overall taking nicotine on a regular basis has been helpful for me, one should be aware of the dependency downsides and the fact it is harder to ween off than caffeine. However, given that one is dedicated enough, it is possible to ‘taper off’ by simply chewing slightly less each day and for less time.

Some notes on nicotine’s pharmacological effects

Nicotine increases neurotransmitter levels across the board, including catecholamines (dopamine, adrenaline, and nonepinephrine), beta enorphines, seratonin, and even cortisol, the stress hormone, which may not be so good a thing. [ref] See Wikipedia article for detailed refs.
It also increases acetylcholinesterase, the enzyme that breaks down acetylcholine, [ref]
It has a half life of 1-2 hours.
The binding cite with the highest affinity to nicotine is the alpha-4-beta-2-nicotinic receptor. Interestingly, stimulation of this binding site results in increases in human growth hormone secretion.

Nootropic Benefits in the literature

“In 2008, Paul Newhouse, director of the Center for Cognitive Medicine at Vanderbilt University School of Medicine in Nashville, compared performance on a series of cognitive tasks in 15 nonsmoking ADHD patients while wearing either a 7-mg nicotine patch or a placebo patch. After just 45 minutes with the nicotine patch, the young adults were significantly better at inhibiting an impulse, delaying a reward and remembering an image they had seen. Psychologist Jennifer Rusted of the University of Sussex in Britain calls the drug “the most reliable cognitive enhancer that we currently have”. From Discover Magazine, “Nicotine, the wonder drug?”, 2014
Lower incidence of inflammatory and neurodegenerative diseases.[ref]
People show more controlled and fluent handwriting after taking nicotine.
Effects of nicotine chewing gum on a real-life motor task: a kinematic analysis of handwriting movements in smokers and non-smokers.
People can tap their fingers faster without sacrificing accuracy
Effects of nicotine on finger tapping rate in non-smokers, 1986
Participants with a 7mg nicotine patch were able to pay attention to a mentally tiring task longer than controls could.
Nicotine effects on alertness and spatial attention in non-smokers ,2001
Nicotine gum (2mg-4mg) increased vigilance in a visual detection task.
Nicotine chewing gum (2 mg, 4 mg) and cigarette smoking: comparative effects upon vigilance and heart rate., 1989
Both smokers and nonsmokers reacted more quickly to visual cues and did better with word recognition after an injection of 0.3mg – 0.6mg of nicotine.
Cognitive performance effects of subcutaneous nicotine in smokers and never-smokers, 1996.
“People who took nicotine better recalled a list of words they’d just read, and also repeated a story word-for-word, making fewer mistakes than people given placebo made” [ref, ref]

Other misc benefits

Lower risk for Parkinson’s disease. Decades ago researchers noticed a strong correlation between smoking and a lower risk for Parkinson’s disease. Since then a large body of research has demonstrated nicotine is responsible for this. Some research suggests it may be useful for treating Parkinsons as well.
Barreto, GE; Iarkov, A; Moran, VE (Jan 2015). “Beneficial effects of nicotine, cotinine and its metabolites as potential agents for Parkinson’s disease”. Front Aging Neuroscience. 9 (6): 340.
For Alzheimer’s treatment Alzheimers results in a loss of nicotinic cholinergenic receptors (which nicotine binds to an activates) and impairs cognitive function, thus nicotine can help counteract some of the symptoms of Alzheimers. This becomes less true in patients with later-stage Alzheimers, as there are then very few nicotininc receptors left for nicotine to work on.
For treatment of depression There are at least two preliminary research studies [N=11 and N=12] suggesting that nicotine administration, through a nicotine patch, may be useful for treating depression. [Science Daily, 2006] [ref]
People with depression are much more likely to smoke than those without, and it is widely believed that they are self-medicating with nicotine. As a side note, one of the main metabolites of nicotine, cotinine, was developed as an antidepressant but never marketed.
Mineur YS, Picciotto MR (December 2010). “Nicotine receptors and depression: revisiting and revising th s e cholinergic hypothesi”. Trends Pharmacol. Sci. 31 (12): 580–6.
For treatment of ADD/ ADHD [ref]

Risks / things to be aware of

A 2016 Royal College of Physicians report found “nicotine alone in the doses used by smokers represents little if any hazard to the user”
Wilder, Natalie; Daley, Claire; Sugarman, Jane; Partridge, James (April 2016). “Nicotine without smoke: Tobacco harm reduction”. UK: Royal College of Physicians. p. 125.
Nicotine suppresses appetite.[ref]
Decreased bone mass – has been showin rat models. The mechanism is unknown.
Broulik, et al. The effect of chronic nicotine administration on bone mineral content in mice., Horm. Metab. Res. 25(4) 1993
Broulik, et al. The Effect of Chronic Nicotine Administration on Bone Mineral Content and Bone Strength in Normal and Castrated Male Rats, Horm. Metab. Res., 2007
Increased anxiety during withdrawal period.[ref]
Pregnant women should definitely not take nicotine!
Holbrook, Bradley D. (2016). “The effects of nicotine on human fetal development”. Birth Defects Research Part C: Embryo Today: Reviews. 108 (2): 181–92. doi:10.1002/bdrc.21128.
Cardiovascular risk – at one point it was assumed that nicotine probably conveyed a greater risk for cardiovascular disease, but that based on studies of tobacco consumption. Studies on nicotine itself do not show a significant effect on cardiovascular disease although there may be some low risks.
Benowitz, Neal L.; Burbank, Andrea D. (2016). “Cardiovascular toxicity of nicotine: Implications for electronic cigarette use”. Trends in Cardiovascular Medicine. 26 (6): 515–523.
One study suggests nicotine reduces HDL-C, a type of bad cholesterol [ref]. It may also decrease the good type of cholesterol, LDL.[ref]
Cancer risk Some in-vitro experiments suggest nicotine increase carcinogenesis. No strong in-vivo correlation between nicotine and cancer has been reported so far , though. A 2013 study, which received a lot of press attention, found that nicotine upregulated 2 particular genes in endiothelial cells which are linked to cancer. The main caveat to this study is that they used the LD50 (lethal) concentration of nicotine, which is orders of magnitude higher than the concentration obtained from nootropic use of nicotine. [ref][for more refs see https://en.wikipedia.org/wiki/Nicotine#Cancer]
Lowered sexual arousal A 2007 N=28 study showed that nicotine use in non-smoking males lead to 23% lower sexual arousal, as measured by girth of erection while viewing erotic material. This study showed that nicotine leads to an acute reduction in libido which is not necessary a bad thing for those taking nicotine for nootropic reasons. The long term effects of nicotine on sexual potency are unknown, but there is a correlation between smoking an impotence.
Toxicity – nicotine is toxic at high levels. It is extremely toxic to insects, which is why many plants produce it. The exact LD50 concentration of nicotine in humans is controversial, but lies somewhere between 0.5-10 mg/kg. More important to bear in mind is the range for a fatal single dose, which is 30-60 mg in adults and 10 mg in children. This is import ant to bear in mind with e-cigarettes, as a single vial of e-liquid can easily contain 20 mg of nicotine – so they should be kept away from children! Death from nicotine overdose is extremely rare though, Between 2010-2012 only one death from e-liquids was reported, which was a suicide.[wikipedia]