Most of the most solid fish oil results seem to meliorate the effects of age; in my 20s, I’m not sure they are worth the cost. But I would probably resume fish oil in my 30s or 40s when aging really becomes a concern. So the experiment at most will result in discontinuing for a decade. At $X a year, that’s a net present value of sum $ map (\n -> 70 / (1 + 0.05)^n) [1..10] = $540.5.
1. Stough, C., Lloyd, J., Clarke, J., Downey, L. A., Hutchison, C. W., Rodgers, T., & Nathan, P. J. (2001). The chronic effects of an extract of Bacopa monniera (Brahmi) on cognitive function in healthy human subjects. Psychopharmacology (Berl), 156(4), 481-484. 2. Ishaque, S., Shamseer, L., Bukutu, C., & Vohra, S. (2012). Rhodiola rosea for physical and mental fatigue: a systematic review. BMC Complementary and Alternative Medicine, 12(1), 70. doi:10.1186/1472-6882-12-703. Pase, M. P., Kean, J., Sarris, J., Neale, C., Scholey, A. B., & Stough, C. (2012). The cognitive-enhancing effects of Bacopa monnieri: a systematic review of randomized, controlled human clinical trials. J Altern Complement Med, 18(7), 647-652. doi:10.1089/acm.2011.03674. Raghav, S., Singh, H., Dalal, P. K., Srivastava, J. S., & Asthana, O. P. (2006). Randomized controlled trial of standardized Bacopa monniera extract in age-associated memory impairment. 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B., van der Beek, E. J., Orlebeke, J. F., & van den Berg, H. (1992). Vitamin B-6 supplementation in elderly men: effects on mood, memory, performance and mental effort. Psychopharmacology (Berl), 109(4), 489-496.48. Lewerin, C., Matousek, M., Steen, G., Johansson, B., Steen, B., & Nilsson-Ehle, H. (2005). Significant correlations of plasma homocysteine and serum methylmalonic acid with movement and cognitive performance in elderly subjects but no improvement from short-term vitamin therapy: a placebo-controlled randomized study. Am J Clin Nutr, 81(5), 1155-1162. 49. Bryan, J., Calvaresi, E., & Hughes, D. (2002). Short-term folate, vitamin B-12 or vitamin B-6 supplementation slightly affects memory performance but not mood in women of various ages. J Nutr, 132(6), 1345-1356. 50. Schneider, Z., & Stroinski, A. (1987). Comprehensive B12: chemistry, biochemistry, nutrition, ecology, medicine: Walter de Gruyter.51. Polich, J., & Gloria, R. (2001). 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Meta-Analysis: Melatonin for the Treatment of Primary Sleep Disorders. PLoS One, 8(5), e63773. doi:10.1371/journal.pone.006377357. Inagawa, K., Hiraoka, T., Kohda, T., Yamadera, W., & Takahashi, M. (2006). Subjective effects of glycine ingestion before bedtime on sleep quality. Sleep and Biological Rhythms, 4(1), 75-77. doi:10.1111/j.1479-8425.2006.00193.x58. Bannai, M., Kawai, N., Ono, K., Nakahara, K., & Murakami, N. (2012). The Effects of Glycine on Subjective Daytime Performance in Partially Sleep-Restricted Healthy Volunteers. Front Neurol, 3, 61. doi:10.3389/fneur.2012.0006159. Yamadera, W., Inagawa, K., Chiba, S., Bannai, M., Takahashi, M., & Nakayama, K. (2007). Glycine ingestion improves subjective sleep quality in human volunteers, correlating with polysomnographic changes. Sleep and Biological Rhythms, 5(2), 126-131. doi:10.1111/j.1479-8425.2007.00262.x60. Tuli, H. S., Kashyap, D., Sharma, A. K., & Sandhu, S. S. (2015). 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Magnesium supplementation improves indicators of low magnesium status and inflammatory stress in adults older than 51 years with poor quality sleep. Magnes Res, 23(4), 158-168. doi:10.1684/mrh.2010.0220
And when it comes to your brain, it’s full of benefits, too. Coconut oil works as a natural anti-inflammatory, suppressing cells responsible for inflammation. It can help with memory loss as you age and destroy bad bacteria that hangs out in your gut. (5) Get your dose of coconut oil in this Baked Grouper with Coconut Cilantro Sauce or Coconut Crust Pizza.
12:18 PM. (There are/were just 2 Adderall left now.) I manage to spend almost the entire afternoon single-mindedly concentrating on transcribing two parts of a 1996 Toshio Okada interview (it was very long, and the formatting more challenging than expected), which is strong evidence for Adderall, although I did feel fairly hungry while doing it. I don’t go to bed until midnight and & sleep very poorly - despite taking triple my usual melatonin! Inasmuch as I’m already fairly sure that Adderall damages my sleep, this makes me even more confident (>80%). When I grumpily crawl out of bed and check: it’s Adderall. (One Adderall left.)
We felt that True Focus offered a good product but the price was slightly high compared to others. Their website doesn’t show a clear money-back guarantee though, which definitely reduced their rating. We found that their customer reviews were mixed and saw that some consumers did not mind paying a little more for a product that is more consumer friendly.
But, thanks to the efforts of a number of remarkable scientists, researchers and plain-old neurohackers, we are beginning to put together a “whole systems” model of how all the different parts of the human brain work together and how they mesh with the complex regulatory structures of the body. It’s going to take a lot more data and collaboration to dial this model in, but already we are empowered to design stacks that can meaningfully deliver on the promise of nootropics “to enhance the quality of subjective experience and promote cognitive health, while having extremely low toxicity and possessing very few side effects.” It’s a type of brain hacking that is intended to produce noticeable cognitive benefits.
A picture is worth a thousand words, particularly in this case where there seems to be temporal effects, different trends for the conditions, and general confusion. So, I drag up 2.5 years of MP data (for context), plot all the data, color by magnesium/non-magnesium, and fit different LOESS lines to each as a sort of smoothed average (since categorical data is hard to interpret as a bunch of dots), which yields:
I’ve spent over a million dollars hacking my own biology. The lion’s share has gone to making my brain produce as much energy as it can. I even wrote a book, Head Strong, about neurofeedback, oxygen deprivation, supplements, deeper sleep, meditation, cold exposure, and about a dozen other brain hacks, and how you can use them to make your brain stronger than you thought possible.
Pop this pill and improve your memory. Swallow that one and reduce your cognitive decline. We see ads for such products all the time and I suspect they will increase as the baby boomers reach senior citizenhood. The most popular brain boosting supplements are fish oil pills and they are also probably the best studied ones. The results are not encouraging. When all the studies are pooled, we are left with the possibility of a barely significant improvement in recalling lists of words soon after they have been learned, but the effect does not last. Extracts of the ginkgo biloba tree are also popular, and here the prospects are even dimmer. There is no impact on memory, despite claims of increased circulation in the brain. And ginkgo can interfere with the action of anticoagulants and has also been shown to be an animal carcinogen.
The benefit of sequential analysis here is being able to stop early, conserving pills, and letting me test another dosage: if I see another pattern of initial benefits followed by decline, I can then try cutting the dose by taking one pill every 3 days; or, if there is a benefit and no decline, then I can try tweaking the dose up a bit (maybe 3 days out of 5?). Since I don’t have a good idea what dose I want and the optimal dose seems like it could be valuable (and the wrong dose harmful!), I can’t afford to spend a lot of time on a single definitive experiment.
Noopept is a Russian stimulant sometimes suggested for nootropics use as it may be more effective than piracetam or other -racetams, and its smaller doses make it more convenient & possibly safer. Following up on a pilot study, I ran a well-powered blind randomized self-experiment between September 2013 and August 2014 using doses of 12-60mg Noopept & pairs of 3-day blocks to investigate the impact of Noopept on self-ratings of daily functioning in addition to my existing supplementation regimen involving small-to-moderate doses of piracetam. A linear regression, which included other concurrent experiments as covariates & used multiple imputation for missing data, indicates a small benefit to the lower dose levels and harm from the highest 60mg dose level, but no dose nor Noopept as a whole was statistically-significant. It seems Noopept’s effects are too subtle to easily notice if they exist, but if one uses it, one should probably avoid 60mg+.
Analgesics Anesthetics General Local Anorectics Anti-ADHD agents Antiaddictives Anticonvulsants Antidementia agents Antidepressants Antimigraine agents Antiparkinson agents Antipsychotics Anxiolytics Depressants Entactogens Entheogens Euphoriants Hallucinogens Psychedelics Dissociatives Deliriants Hypnotics/Sedatives Mood Stabilizers Neuroprotectives Nootropics Neurotoxins Orexigenics Serenics Stimulants Wakefulness-promoting agents
There are a number of smart drugs on the market, the most well-known of which are probably Adderall and Ritalin. Both are technically known as psychostimulants, which means that they stimulate increased activity of the central nervous system: the brain and spinal cord. There are also two other common smart drugs, specifically Modafinil and a class of something called “ampakines”. You’re about to learn how each of them works and the benefits and potential risks therein.
A LessWronger found that it worked well for him as far as motivation and getting things done went, as did another LessWronger who sells it online (terming it a reasonable productivity enhancer) as did one of his customers, a pickup artist oddly enough. The former was curious whether it would work for me too and sent me Speciosa Pro’s Starter Pack: Test Drive (a sampler of 14 packets of powder and a cute little wooden spoon). In SE Asia, kratom’s apparently chewed, but the powders are brewed as a tea.
But according to Professor David Weinshenker of Emory University, most people who take Provigil do not report euphoria or even a level of stimulation close to the effects of caffeine. For Weinshenker, the addiction potential of Provigil is limited, and it’s used in various treatment contexts. Provigil may be an effective medication therapy for depression, ADHD, autism and other disorders.
But what does this all have to do with food? Our gut helps keep our body’s immune responses and inflammation under control. Additionally, gut hormones that enter the brain or are produced in the brain influence cognitive ability, like understanding and processing new information, staying focused on the task at hand and recognizing when we’re full. (3)
Gamma-aminobutyric acid, also known as GABA, naturally produced in the brain from glutamate, is a neurotransmitter that helps in the communication between the nervous system and brain. The main function of this Nootropic is to reduce the unnecessary activity of the nerve cells and helps calm the brain. . Thus it helps improve various conditions, like stress, anxiety and depression by decreasing the beta brain waves and increasing the alpha brain waves. As a result, cognitive abilities like memory power, attention, and alertness also improve. GABA helps drug addicts recover from addiction by normalizing the brain’s GABA receptors which reduce anxiety and craving levels in the absence of addictive substances.
Caffeine keeps you awake, which keeps you coding. It may also be a nootropic, increasing brain-power. Both desirable results. However, it also inhibits vitamin D receptors, and as such decreases the body’s uptake of this-much-needed-vitamin. OK, that’s not so bad, you’re not getting the maximum dose of vitamin D. So what? Well, by itself caffeine may not cause you any problems, but combined with cutting off a major source of the vitamin - the production via sunlight - you’re leaving yourself open to deficiency in double-quick time.
It’s not clear that there is much of an effect at all. This makes it hard to design a self-experiment - how big an effect on, say, dual n-back should I be expecting? Do I need an arduous long trial or an easy short one? This would principally determine the value of information too; chocolate seems like a net benefit even if it does not affect the mind, but it’s also fairly costly, especially if one likes (as I do) dark chocolate. Given the mixed research, I don’t think cocoa powder is worth investigating further as a nootropic.
Creatine is a substance that’s produced in the human body. It is initially produced in the kidneys, and the process is completed in the liver. It is then stored in the brain tissues and muscles, to support the energy demands of a human body. Athletes and bodybuilders take creatine supplements for relieving fatigue and increasing the recovery of the muscle tissues that are affected by vigorous physical activities. Apart from helping the tissues to recover faster, creatine also helps in enhancing the mental functions in sleep-deprived adults and it also improves the performance of difficult cognitive tasks.
A protein source linked to a great brain boost is fish -- rich in omega-3 fatty acids that are key for brain health. These healthy fats have amazing brain power: A diet with higher levels of them has been linked to lower dementia and stroke risks and slower mental decline; plus, they may play a vital role in enhancing memory, especially as we get older.
The price is not as good as multivitamins or melatonin. The studies showing effects generally use pretty high dosages, 1-4g daily. I took 4 capsules a day for roughly 4g of omega acids. The jar of 400 is 100 days’ worth, and costs ~$17, or around 17¢ a day. The general health benefits push me over the edge of favoring its indefinite use, but looking to economize. Usually, small amounts of packaged substances are more expensive than bulk unprocessed, so I looked at fish oil fluid products; and unsurprisingly, liquid is more cost-effective than pills (but like with the powders, straight fish oil isn’t very appetizing) in lieu of membership somewhere or some other price-break. I bought 4 bottles (16 fluid ounces each) for $53.31 total (thanks to coupons & sales), and each bottle lasts around a month and a half for perhaps half a year, or ~$100 for a year’s supply. (As it turned out, the 4 bottles lasted from 4 December 2010 to 17 June 2011, or 195 days.) My next batch lasted 19 August 2011-20 February 2012, and cost $58.27. Since I needed to buy empty 00 capsules (for my lithium experiment) and a book (Stanovich 2010, for SIAI work) from Amazon, I bought 4 more bottles of 16fl oz Nature’s Answer (lemon-lime) at $48.44, which I began using 27 February 2012. So call it ~$70 a year.
The fish oil can be considered a free sunk cost: I would take it in the absence of an experiment. The empty pill capsules could be used for something else, so we’ll put the 500 at $5. Filling 500 capsules with fish and olive oil will be messy and take an hour. Taking them regularly can be added to my habitual morning routine for vitamin D and the lithium experiment, so that is close to free but we’ll call it an hour over the 250 days. Recording mood/productivity is also free a sunk cost as it’s necessary for the other experiments; but recording dual n-back scores is more expensive: each round is ~2 minutes and one wants >=5, so each block will cost >10 minutes, so 18 tests will be >180 minutes or >3 hours. So >5 hours. Total: 5 + (>5 \times 7.25) = >41.
10:30 AM; no major effect that I notice throughout the day - it’s neither good nor bad. This smells like placebo (and part of my mind is going how unlikely is it to get placebo 3 times in a row!, which is just the Gambler’s fallacy talking inasmuch as this is sampling with replacement). I give it 60% placebo; I check the next day right before taking, and it is. Man!
The third category was cognitive control - how effectively you can check yourself in circumstances where the most natural response is the wrong one. A classic test is the Stroop Task, in which people are shown the name of a colour (let's say orange) written in a different colour (let's say purple). They're asked to read the word (which is easy, because our habitual response to a word is to read it) or to name the ink colour (which is harder, because our first impulse is to say "orange"). These studies presented a more mixed picture, but overall they showed some benefit "for most normal healthy subjects" - especially for people who had inherently poorer cognitive control.
By blending proven natural cognitive enhancers and naturally occurring smart brain health supporting amino acids like Cordyceps-Sinensis Extract , Coenzyme Q10 , Chlorella (from Green Algae) and Omega-3 Extract to maximize acetylcholine levels with other essential brain health supporting vitamins and amino acids, our powerful and effective brain health supplement assists in elevating serotonin and GABA levels, crucial components to remaining calm, alert, focused and mentally driven while under pressure or stress.
Recent findings also suggest that taking extra vitamins could help preserve memory, especially as we age. Researchers at Australia's University of Sydney tested 117 people in a retirement home by putting them through a battery of mental tests that included remembering a string of words, listing as many words as possible that begin with a certain letter of the alphabet, and doing mental addition and subtraction. Those who regularly took vitamin C, they found, scored higher on the tests.
Artichoke + Forskolin: There is plenty of evidence that suggests artichoke extract supplements (made from the leaves of artichokes) offer strong neural antioxidant properties. Additionally, Forskolin (Coleus forskohlii) is one of the few studied compounds known to naturally boost cAMP (Cyclic Adenosine Monophosphate) in your brain and is also important for neural signaling within brain cells (291m 292). I’ve experienced noticeably enhanced memory and word recall when consuming this combo. Tim Ferriss talked about this one a bit in my podcast with him, particularly referencing its presence in the somewhat popular cognition supplement “CILTEP”. Made primarily from artichoke extracts and forskolin, CILTEP is a stack that also contains vitamin B6, L-phenylalanine and acetyl-L-carnitine. It is recommended to take two to three capsules at the beginning of each day and to skip dosage one or two days per week to achieve optimal results.
On 8 April 2011, I purchased from Smart Powders (20g for $8); as before, some light searching seemed to turn up SP as the best seller given shipping overhead; it was on sale and I planned to cap it so I got 80g. This may seem like a lot, but I was highly confident that theanine and I would get along since I already drink so much tea and was a tad annoyed at the edge I got with straight caffeine. So far I’m pretty happy with it. My goal was to eliminate the physical & mental twitchiness of caffeine, which subjectively it seems to do.
Starting from the studies in my meta-analysis, we can try to estimate an upper bound on how big any effect would be, if it actually existed. One of the most promising null results, Southon et al 1994, turns out to be not very informative: if we punch in the number of kids, we find that they needed a large effect size (d=0.81) before they could see anything:
Another promising "smart pill" is phosphatidylserine, or PS, a natural substance that helps cell walls stay pliable and is thought to boost the effectiveness of neurotransmitters, which relay brain signals. In a May 1991 study published in Neurology, neuroscientist Thomas Crook found that patients with age-associated memory impairment improved their scores on key performance tests after 12 weeks on PS. Yet more research is needed before doctors can know that the supplement is safe and effective.
Clinical psychiatrist Emily Deans has a private practice in Massachusetts and teaches at Harvard Medical School. She told me by phone that, in principle, there's "probably nothing dangerous" about the occasional course of nootropics for a hunting trip, finals week, or some big project. Beyond that, she suggests considering that it's possible to build up a tolerance to many neuroactive products if you use them often enough.
The U. S. nootropics industry was valued at more than $1.3 billion in 2015 and is projected to reach $6 billion by 2024. This growth is due in part to slick marketing from biohacking “experts” such as Dave Asprey (founder of Bulletproof) and Josiah Zayner, Ph.D. (CEO of the Odin), who’ve built big social-media and podcast followings as well as customer bases. At the grassroots level, there are meetups across the country like the one at Idea Coffee, plus a vibrant online community.
Past noon, I began to feel better, but since I would be driving to errands around 4 PM, I decided to not risk it and take an hour-long nap, which went well, as did the driving. The evening was normal enough that I forgot I had stayed up the previous night, and indeed, I didn’t much feel like going to bed until past midnight. I then slept well, the Zeo giving me a 108 ZQ (not an all-time record, but still unusual).
But like any other supplement, there are some safety concerns negative studies like Fish oil fails to hold off heart arrhythmia or other reports cast doubt on a protective effect against dementia or Fish Oil Use in Pregnancy Didn’t Make Babies Smart (WSJ) (an early promise but one that faded a bit later) or …Supplementation with DHA compared with placebo did not slow the rate of cognitive and functional decline in patients with mild to moderate Alzheimer disease..
Taking these drugs without a doctor’s supervision can be dangerous. There are interactions and contraindications that can cause serious problems. These drugs should not be used if you drink alcohol or take an antidepressant. (50) The possibility of adverse drug reactions should not be taken lightly. By some calculations, adverse drug reactions are now the fourth leading cause of death in the US. (51)
The easiest way to use 2mg was to use half a gum; I tried not chewing it but just holding it in my cheek. The first night I tried, this seemed to work well for motivation; I knocked off a few long-standing to-do items. Subsequently, I began using it for writing, where it has been similarly useful. One difficult night, I wound up using the other half (for a total of 4mg over ~5 hours), and it worked but gave me a fairly mild headache and a faint sensation of nausea; these may have been due to forgetting to eat dinner, but this still indicates 3mg should probably be my personal ceiling until and unless tolerance to lower doses sets in.
These are the most highly studied ingredients and must be combined together to achieve effective results. If any one ingredient is missing in the formula, you may not get the full cognitive benefits of the pill. It is important to go with a company that has these critical ingredients as well as a complete array of supporting ingredients to improve their absorption and effectiveness. Anything less than the correct mix will not work effectively.
A cup of coffee before a big exam can help your brain perform at its best. That’s because caffeine improves short-term memory and speeds up reaction times, according to New Scientist. Researchers from the National Institute on Aging found that individuals who drank more caffeine had better scores on memory tests, which explains why has been linked to a lowered risk of Alzheimer’s disease. It can also help prevent Parkinson’s disease and relieve headache pain. But don’t overdo it—too much caffeine can make you jumpy or irritable. Look out for the signs that you’re drinking too much coffee.
Potassium citrate powder is neither expensive nor cheap: I purchased 453g for $21. The powder is crystalline white, dissolves instantly in water, and largely tasteless (sort of saline & slightly unpleasant). The powder is 37% potassium by weight (the formula is C6H5K3O7) so 453g is actually 167g of potassium, so 80-160 days’ worth depending on dose.
Avocados. Avocados are almost as good as blueberries in promoting brain health, says Pratt. "I don't think the avocado gets its due," agrees Kulze. True, the avocado is a fatty fruit, but, says Kulze, it's a monounsaturated fat, which contributes to healthy blood flow. "And healthy blood flow means a healthy brain," she says. Avocados also lower blood pressure, says Pratt, and as hypertension is a risk factor for the decline in cognitive abilities, a lower blood pressure should promote brain health. Avocados are high in calories, however, so Kulze suggests adding just 1/4 to 1/2 of an avocado to one daily meal as a side dish.
Regardless, while in the absence of piracetam, I did notice some stimulant effects (somewhat negative - more aggressive than usual while driving) and similar effects to piracetam, I did not notice any mental performance beyond piracetam when using them both. The most I can say is that on some nights, I seemed to be less easily tired when writing or editing or n-backing (and I felt less tired than ICON 2011 than ICON 2010), but those were also often nights I was also trying out all the other things I had gotten in that order from Smart Powders, and I am still dis-entangling what was responsible. (Probably the l-theanine or sulbutiamine.)
Took pill 1:27 PM. At 2 my hunger gets the best of me (despite my usual tea drinking and caffeine+piracetam pills) and I eat a large lunch. This makes me suspicious it was placebo - on the previous days I had noted a considerable appetite-suppressant effect. 5:25 PM: I don’t feel unusually tired, but nothing special about my productivity. 8 PM; no longer so sure. Read and excerpted a fair bit of research I had been putting off since the morning. After putting away all the laundry at 10, still feeling active, I check. It was Adderall. I can’t claim this one either way. By 9 or 10 I had begun to wonder whether it was really Adderall, but I didn’t feel confident saying it was; my feeling could be fairly described as 50%.
Alpha GPC + AC-11 + Bacopa Monniera + Huperzine: This combination is found in the supplement Alpha Brain, created by the company Onnit. According to a clinical trial that was conducted by the Boston Center for Memory, this combination has demonstrated a notable increase in cognitive performance for healthy individuals and shows particular potential to boost the memory and learning capacity of users. AC-11 is derived from a rainforest herb, and studies have found that it may be able to help people in a variety of ways such as slowing the growth of cancer due to its DNA repairing antioxidant properties. This stack seems to work best if you take it daily for at about two weeks. After that, effects become more pronounced over time, so, similar to the Gingko, Bacopa, Lion’s Mane stack above you need to allow this blend to build up in your system before you judge its overall effectiveness.
Another prescription stimulant medication, modafinil (known by the brand name Provigil), is usually prescribed to patients suffering from narcolepsy and shift-work sleep disorder, but it might turn out to have broader applications. “We have conducted at the University of Cambridge double-blind, placebo-controlled studies in healthy people using modafinil and have found improvements in cognition, including in working memory,” Sahakian says. However, she doesn’t think everyone should start using the drug off-label. “There are no long-term safety and efficacy studies of modafinil in healthy people, and so it is unclear what the risks might be.”
As expected since most of the data overlaps with the previous LLLT analysis, the LLLT variable correlates strongly; the individual magnesium variables may look a little more questionable but were justified in the magnesium citrate analysis. The Noopept result looks a little surprising - almost zero effect? Let’s split by dose (which was the point of the whole rigmarole of changing dose levels):
Absorption of nicotine across biological membranes depends on pH. Nicotine is a weak base with a pKa of 8.0 (Fowler, 1954). In its ionized state, such as in acidic environments, nicotine does not rapidly cross membranes…About 80 to 90% of inhaled nicotine is absorbed during smoking as assessed using C14-nicotine (Armitage et al., 1975). The efficacy of absorption of nicotine from environmental smoke in nonsmoking women has been measured to be 60 to 80% (Iwase et al., 1991)…The various formulations of nicotine replacement therapy (NRT), such as nicotine gum, transdermal patch, nasal spray, inhaler, sublingual tablets, and lozenges, are buffered to alkaline pH to facilitate the absorption of nicotine through cell membranes. Absorption of nicotine from all NRTs is slower and the increase in nicotine blood levels more gradual than from smoking (Table 1). This slow increase in blood and especially brain levels results in low abuse liability of NRTs (Henningfield and Keenan, 1993; West et al., 2000). Only nasal spray provides a rapid delivery of nicotine that is closer to the rate of nicotine delivery achieved with smoking (Sutherland et al., 1992; Gourlay and Benowitz, 1997; Guthrie et al., 1999). The absolute dose of nicotine absorbed systemically from nicotine gum is much less than the nicotine content of the gum, in part, because considerable nicotine is swallowed with subsequent first-pass metabolism (Benowitz et al., 1987). Some nicotine is also retained in chewed gum. A portion of the nicotine dose is swallowed and subjected to first-pass metabolism when using other NRTs, inhaler, sublingual tablets, nasal spray, and lozenges (Johansson et al., 1991; Bergstrom et al., 1995; Lunell et al., 1996; Molander and Lunell, 2001; Choi et al., 2003). Bioavailability for these products with absorption mainly through the mucosa of the oral cavity and a considerable swallowed portion is about 50 to 80% (Table 1)…Nicotine is poorly absorbed from the stomach because it is protonated (ionized) in the acidic gastric fluid, but is well absorbed in the small intestine, which has a more alkaline pH and a large surface area. Following the administration of nicotine capsules or nicotine in solution, peak concentrations are reached in about 1 h (Benowitz et al., 1991; Zins et al., 1997; Dempsey et al., 2004). The oral bioavailability of nicotine is about 20 to 45% (Benowitz et al., 1991; Compton et al., 1997; Zins et al., 1997). Oral bioavailability is incomplete because of the hepatic first-pass metabolism. Also the bioavailability after colonic (enema) administration of nicotine (examined as a potential therapy for ulcerative colitis) is low, around 15 to 25%, presumably due to hepatic first-pass metabolism (Zins et al., 1997). Cotinine is much more polar than nicotine, is metabolized more slowly, and undergoes little, if any, first-pass metabolism after oral dosing (Benowitz et al., 1983b; De Schepper et al., 1987; Zevin et al., 1997).