Eliminating foggy-headedness seems to be the goal of many users of neuroenhancers. But can today's drugs actually accomplish this? I recently posed this question to Chatterjee's colleague Martha Farah, who is a psychologist at Penn and the director of its Center for Cognitive Neuroscience. She is deeply fascinated by, and mildly critical of, neuroenhancers, but basically in favour - with the important caveat that we need to know much more about how these drugs work. While Farah does not take neuroenhancers, she had just finished a paper in which she reviewed the evidence on prescription stimulants as neuroenhancers from 40 laboratory studies involving healthy subjects. Most of the studies looked at one of three types of cognition: learning, working memory, and cognitive control. A typical learning test asks subjects to memorise a list of paired words; an hour, a few days, or a week later, they are presented with the first words in the pairs and asked to come up with the second. Neuroenhancers did improve retention, especially where subjects had been asked to remember information for several days or longer.
Beans. Beans are "under-recognized" and "economical," says Kulze. They also stabilize glucose (blood sugar) levels. The brain is dependent on glucose for fuel, Kulze explains, and since it can't store the glucose, it relies on a steady stream of energy -- which beans can provide. Any beans will do, says Kulze, but she is especially partial to lentils and black beans and recommends 1/2 cup every day.
To understand further about how food intolerances can impact our mental health, it is important to explain the relationship between our gut microbiome, the immune system and our brain in a little more detail. The walls of our digestive tract provide a barrier between what we eat and the rest of our body and an unhealthy gut microbiome can lead to increased levels of inflammation, leaving the walls vulnerable to structural damage (4). Our intestinal wall is composed of cell junctions that prevent bacteria and large food molecules from entering the bloodstream, however, if these become damaged, proteins from foods that should not be circulating in our bloodstream can enter and an immune response is mounted as a reaction. This response is mediated by IgG, an antibody, that helps to protect against bacterial and viral infections as well as food antigens and is the most abundant immune cell in the body. Whilst food antigens are usually quickly cleared by an intelligent system called the reticuloendothelial system, with structural damage and a poor gut microbiome, this immune response can keep reoccurring. It is suggested that a chronic immune response such as this can have a negative impact on the brain, damaging its own structural barrier, called the Blood Brain Barrier (5).
I met Alex one evening last summer, at an appealingly scruffy bar in the New England city where he lives. Skinny and bearded, and wearing faded hipster jeans, he looked like the lead singer in an indie band. He was ingratiating and articulate, and smoked cigarettes with an ironic air of defiance. Alex was happy enough to talk about his frequent use of Adderall at Harvard, but he didn't want to see his name in print; he's involved with an internet start-up and worried that potential investors might disapprove of his habit.
The BoredAt websites - which allow college students to chat idly while they're ostensibly studying - are filled with messages about Adderall. Posts like these, from the BoredAtPenn site, are typical: "I have some Adderall - I'm sitting by room 101.10 in a grey shirt and headphones"; "I have Adderall for sale 20mg for $15"; "I took Adderall at 8pm, it's 6:30am and I've barely blinked." On the Columbia site one poster complains that her friends take Adderall "like candy", adding: "I don't want to be at a disadvantage to everyone else. Is it really that dangerous? My grades weren't that great this year and I could do with a bump." A Columbia student responds: "It's probably not a good idea if you're not prescribed", but offers practical advice anyway: "Keep the dose normal and don't grind them up or snort them." Occasional dissenters ("I think there should be random drug testing at every exam") are drowned out by testimonials like this one, from the BoredAtHarvard site: "I don't want to be a pusher or start people on something bad, but Adderall is amazing."
Walnuts in particular are excellent brain food. These wrinkly nuts—which kind of resemble the human brain—are rich in vitamin E. Researchers at Chicago’s Rush University Medical Center studied the lifestyle habits of 6,000 people who were unaffected by Alzheimer’s the memory-robbing condition, and found that those who ate the most vitamin E-rich foods had a reduced risk of developing the memory-robbing condition. Vitamin E may trap free radicals that can damage brain cells, according to the Alzheimer’s Research Center. Here’s some more brain food that your noggin will thank you for eating.
“Who doesn’t want to maximize their cognitive ability? Who doesn’t want to maximize their muscle mass?” asks Murali Doraiswamy, who has led several trials of cognitive enhancers at Duke University Health System and has been an adviser to pharmaceutical and supplement manufacturers as well as the Food and Drug Administration. He attributes the demand to an increasingly knowledge-based society that values mental quickness and agility above all else.
NeuroFuse was almost there with a top quality product but we felt that there were several key elements missing. It does contain a lot of the top natural ingredients for cognitive energy enhancement. However, the fact that their money-back guarantee is not apparent and that they are baiting customers in using a 14-day free trial offer, made us slightly wary. If they addressed these issues, we felt that this could have been a winner!
I largely ignored this since the discussions were of sub-RDA doses, and my experience has usually been that RDAs are a poor benchmark and frequently far too low (consider the RDA for vitamin D). This time, I checked the actual RDA - and was immediately shocked and sure I was looking at a bad reference: there was no way the RDA for potassium was seriously 3700-4700mg or 4-5 grams daily, was there? Just as an American, that implied that I was getting less than half my RDA. (How would I get 4g of potassium in the first place? Eat a dozen bananas a day⸮) I am not a vegetarian, nor is my diet that fantastic: I figured I was getting some potassium from the ~2 fresh tomatoes I was eating daily, but otherwise my diet was not rich in potassium sources. I have no blood tests demonstrating deficiency, but given the figures, I cannot see how I could not be deficient.
Compared with those reporting no use, subjects drinking >4 cups/day of decaffeinated coffee were at increased risk of RA [rheumatoid arthritis] (RR 2.58, 95% CI 1.63-4.06). In contrast, women consuming >3 cups/day of tea displayed a decreased risk of RA (RR 0.39, 95% CI 0.16-0.97) compared with women who never drank tea. Caffeinated coffee and daily caffeine intake were not associated with the development of RA.
The Lynches said that Provigil was a classic example of a related phenomenon: mission creep. In 1998, Cephalon, the pharmaceutical company that manufactures it, received US government approval to market the drug but only for "excessive daytime sleepiness" due to narcolepsy; by 2004, Cephalon had obtained permission to expand the labelling so that it included sleep apnoea and "shift-work sleep disorder". Net sales of Provigil climbed from $196m in 2002 to $988m in 2008.
The above are all reasons to expect that even if I do excellent single-subject design self-experiments, there will still be the old problem of internal validity versus external validity: an experiment may be wrong or erroneous or unlucky in some way (lack of internal validity) or be right but not matter to anyone else (lack of external validity). For example, alcohol makes me sad & depressed; I could run the perfect blind randomized experiment for hundreds of trials and be extremely sure that alcohol makes me less happy, but would that prove that alcohol makes everyone sad or unhappy? Of course not, and as far as I know, for a lot of people alcohol has the opposite effect. So my hypothetical alcohol experiment might have tremendous internal validity (it does prove that I am sadder after inebriating), and zero external validity (someone who has never tried alcohol learns nothing about whether they will be depressed after imbibing). Keep this in mind if you are minded to take the experiments too seriously.
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.)
Difficulty concentrating. As mentioned previously, this may not be a direct result of age—though it can be a common side-effect of struggling with fatigue and brain fog. When it takes more mental energy to think, it is harder to stay with it for a long time. Many of us also are surrounded by distractions clambering for our limited attention. Modern life is fast-paced, stressful, and overcrowded.
2ml is supposed to translate to 24mg, which is a big dose. I do not believe any of the commercial patches go much past that. I asked Wedrifid, whose notes inspired my initial interest, and he was taking perhaps 2-4mg, and expressed astonishment that I might be taking 24mg. (2mg is in line with what I am told by another person - that 2mg was so much that they actually felt a little sick. On the other hand, in one study, the subjects could not reliably distinguish between 1mg and placebo25.) 24mg is particularly troubling in that I weigh ~68kg, and nicotine poisoning and the nicotine LD50 start, for me, at around 68mg of nicotine. (I reflected that the entire jar could be a useful murder weapon, although nicotine presumably would be caught in an autopsy’s toxicology screen; I later learned nicotine was an infamous weapon in the 1800s before any test was developed. It doesn’t seem used anymore, but there are still fatal accidents due to dissolved nicotine.) The upper end of the range, 10mg/kg or 680mg for me, is calculated based on experienced smokers. Something is wrong here - I can’t see why I would have nicotine tolerance comparable to a hardened smoker, inasmuch as my maximum prior exposure was second-hand smoke once in a blue moon. More likely is that either the syringe is misleading me or the seller NicVape sold me something more dilute than 12mg/ml. (I am sure that it’s not simply plain water; when I mix the drops with regular water, I can feel the propylene glycol burning as it goes down.) I would rather not accuse an established and apparently well-liked supplier of fraud, nor would I like to simply shrug and say I have a mysterious tolerance and must experiment with doses closer to the LD50, so the most likely problem is a problem with the syringe. The next day I altered the procedure to sucking up 8ml, squirting out enough fluid to move the meniscus down to 7ml, and then ejecting the rest back into the container. The result was another mild clean stimulation comparable to the previous 1ml days. The next step is to try a completely different measuring device, which doesn’t change either.
Microdosing with Ketamine: Ketamine is a general anesthetic that is most commonly used on animals but ironically was originally devised for and tested on humans. Users of ketamine have claimed increased compassion and sensitivity to others, an increase in joy of life, and a reduced fear around death. Finding your ideal microdose of ketamine can be tricky, so it is important to start just a bit below the recommended doses. Taking ketamine sublingually (under the tongue) is the most effective and direct route of administration, and a sublingual microdose is about .75 milligrams per kilogram of body weight, although you can get a significant mood enhancement with as little as 0.2 milligrams per kilogram of body weight. I’d recommend that you never mix ketamine with any drugs that depress breathing such as alcohol, opioids, and tramadol, as it is an extremely calming agent that can produce a heavy sedative effect if you’re not careful or if you combine it with other sedative-like compounds. I’ve found a microdose of ketamine to be best combined with a trip to a float tank, or any other environment that involves sensory deprivation and introspection.
Back home, I contacted Aubrey Marcus, whose company Onnit Labs produces Alpha Brain. He attributed my lucid dreaming to increased levels of the neurotransmitter acetylcholine, which enhances REM dreaming. Alpha Brain has two ingredients that boost acetylcholine levels: GPC choline, which the body converts to acetylcholine, and Huperzine A, an alkaloid derived from Chinese club moss, also known as Huperzia serrata. "Huperzine A disarms the enzyme that naturally breaks down acetylcholine," Marcus said. "So while the GPC choline is being converted to acetylcholine, the Huperzine A is keeping it from disappearing. It's like plugging the drain and turning on the faucet."
Mosconi gets the anthropology right. Her foundation is based on two empirical findings. The first one is her studying of the “Blue Zones” or the five areas in the World associated with the greatest proportion of centenarians. And, her second one is her experience as a neuroscientist. She has seen thousands of brain MRIs while knowing what diet her patients ate. She uncovered a link between brain health and diet. The ones who ate a Mediterranean diet had far healthier brains (per MRIs) than the ones on an American diet. She also observed that 2 out of the 5 Blue Zones eat a Mediterranean diets. And, the three other ones have major overlapping components with a Mediterranean diet including complex carbohydrates (fresh produce) that have a lot of fiber, starches (sweet potatoes), nuts, fish, and not much meat and animal protein.
The soft gels are very small; one needs to be a bit careful - Vitamin D is fat-soluble and overdose starts in the range of 70,000 IU36, so it would take at least 14 pills, and it’s unclear where problems start with chronic use. Vitamin D, like many supplements, follows a U-shaped response curve (see also Melamed et al 2008 and Durup et al 2012) - too much can be quite as bad as too little. Too little, though, is likely very bad. The previously cited studies with high acute doses worked out to <1,000 IU a day, so they may reassure us about the risks of a large acute dose but not tell us much about smaller chronic doses; the mortality increases due to too-high blood levels begin at ~140nmol/l and reading anecdotes online suggest that 5k IU daily doses tend to put people well below that (around 70-100nmol/l). I probably should get a blood test to be sure, but I have something of a needle phobia.
Alex remains enthusiastic about Adderall, but he also has a slightly jaundiced critique of it. "It only works as a cognitive enhancer insofar as you are dedicated to accomplishing the task at hand," he said. "The number of times I've taken Adderall late at night and decided that, rather than starting my paper, hey, I'll organise my entire music library! I've seen people obsessively cleaning their rooms on it." Alex thought that generally the drug helped him to bear down on his work, but it also tended to produce writing with a characteristic flaw. "Often I've looked back at papers I've written on Adderall, and they're verbose. They're labouring a point, trying to create this airtight argument. I'd produce two pages on something that could be said in a couple of sentences." Nevertheless, his Adderall-assisted papers usually earned him at least a B. They got the job done. As Alex put it: "Productivity is a good thing."
“Most people assume that because it’s a supplement, it can’t be bad for you because it’s natural,” says Louis Kraus, M.D., a psychiatrist with Rush University Medical Center in Chicago. In 2016, he chaired a committee that investigated nootropics for the American Medical Association. After reviewing the science, the committee found little to no evidence to support the efficacy or safety of nootropics.
So with these 8 results in hand, what do I think? Roughly, I was right 5 of the days and wrong 3 of them. If not for the sleep effect on #4, which is - in a way - cheating (one hopes to detect modafinil due to good effects), the ratio would be 5:4 which is awfully close to a coin-flip. Indeed, a scoring rule ranks my performance at almost identical to a coin flip: -5.49 vs -5.5420. (The bright side is that I didn’t do worse than a coin flip: I was at least calibrated.)
Although research linking diet and dementia is still in its infancy, there are a few important relationships between nutrients and brain health that are worth exploring. Having a nourishing, well rounded diet gives our brain the best chance of avoiding disease. If your diet is unbalanced for whatever reason, you may want to consider a multivitamin and mineral complex and an omega-3 fatty acid supplement to help make up a few of the essentials. If you are considering taking a supplement it is best to discuss this with your GP or qualified healthcare professional.
Looking at the prices, the overwhelming expense is for modafinil. It’s a powerful stimulant - possibly the single most effective ingredient in the list - but dang expensive. Worse, there’s anecdotal evidence that one can develop tolerance to modafinil, so we might be wasting a great deal of money on it. (And for me, modafinil isn’t even very useful in the daytime: I can’t even notice it.) If we drop it, the cost drops by a full $800 from $1761 to $961 (almost halving) and to $0.96 per day. A remarkable difference, and if one were genetically insensitive to modafinil, one would definitely want to remove it.
Broccoli is great source of vitamin K, which is known to enhance cognitive function and improve brainpower. Researchers have reported that because broccoli is high in compounds called glucosinolates, it can slow the breakdown of the neurotransmitter, acetylcholine, which we need for the central nervous system to perform properly and to keep our brains and our memories sharp. Low levels of acetylcholine are associated with Alzheimer's.
Some suggested that the lithium would turn me into a zombie, recalling the complaints of psychiatric patients. But at 5mg elemental lithium x 200 pills, I’d have to eat 20 to get up to a single clinical dose (a psychiatric dose might be 500mg of lithium carbonate, which translates to ~100mg elemental), so I’m not worried about overdosing. To test this, I took on day 1 & 2 no less than 4 pills/20mg as an attack dose; I didn’t notice any large change in emotional affect or energy levels. And it may’ve helped my motivation (though I am also trying out the tyrosine).
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.
The abuse liability of caffeine has been evaluated.147,148 Tolerance development to the subjective effects of caffeine was shown in a study in which caffeine was administered at 300 mg twice each day for 18 days.148 Tolerance to the daytime alerting effects of caffeine, as measured by the MSLT, was shown over 2 days on which 250 g of caffeine was given twice each day48 and to the sleep-disruptive effects (but not REM percentage) over 7 days of 400 mg of caffeine given 3 times each day.7 In humans, placebo-controlled caffeine-discontinuation studies have shown physical dependence on caffeine, as evidenced by a withdrawal syndrome.147 The most frequently observed withdrawal symptom is headache, but daytime sleepiness and fatigue are also often reported. The withdrawal-syndrome severity is a function of the dose and duration of prior caffeine use…At higher doses, negative effects such as dysphoria, anxiety, and nervousness are experienced. The subjective-effect profile of caffeine is similar to that of amphetamine,147 with the exception that dysphoria/anxiety is more likely to occur with higher caffeine doses than with higher amphetamine doses. Caffeine can be discriminated from placebo by the majority of participants, and correct caffeine identification increases with dose.147 Caffeine is self-administered by about 50% of normal subjects who report moderate to heavy caffeine use. In post-hoc analyses of the subjective effects reported by caffeine choosers versus nonchoosers, the choosers report positive effects and the nonchoosers report negative effects. Interestingly, choosers also report negative effects such as headache and fatigue with placebo, and this suggests that caffeine-withdrawal syndrome, secondary to placebo choice, contributes to the likelihood of caffeine self-administration. This implies that physical dependence potentiates behavioral dependence to caffeine.
Systematic reviews and meta-analyses of clinical human research using low doses of certain central nervous system stimulants found enhanced cognition in healthy people. In particular, the classes of stimulants that demonstrate cognition-enhancing effects in humans act as direct agonists or indirect agonists of dopamine receptor D1, adrenoceptor A2, or both types of receptor in the prefrontal cortex. Relatively high doses of stimulants cause cognitive deficits.