Humans have been on the search for the perfect nootropic long before the Limitless movie came out. From racetams to other experimental compounds, scientists have been wondering if there’s a pill that can offset cognitive decline and raise our brain’s potential to another level. And although the research is interesting, the dangers of these compounds are too often downplayed. Read on to uncover the truth.
Disclaimer: This post is not a recommendation or endorsement for the use of any of the particular compounds or drugs discussed in this post. The FDA has not approved any of these compounds for “cognitive-enhancement” purposes, and the available research on them is still in a very early stage overall. We have written this post for informational purposes only, and our goal is solely to inform people about what science currently says about these substances’ potential uses and mechanisms.
Drugs Proposed to Improve Memory
INSUFFICIENT EVIDENCE:
Much of the research on the compounds listed below is still in a very early stage, and in most cases, it is not yet possible to come to any firm conclusions about their relative efficacy and safety in human users.
Therefore, the potential effects listed below are still considered to have insufficient evidence, and these findings should be taken with a grain of salt until further research work – including large-scale clinical trials in healthy human users – is performed.
1) Semax
Semax is a drug that has been used in Russia for treating strokes and head injuries, and which has also been claimed to potentially improve learning capacities and memory formation [1].
Semax is not approved by the FDA for use in the United States due to a lack of adequate safety and effectiveness data.
According to some early studies in animals and humans, some of semax’s reported effects include:
- Protecting against low oxygen (hypoxia) by promoting the survival of neurons when the brain is not receiving enough oxygen (in rats) [2]
- Enhancing attention and memory storage [2]
- Influencing the formation of newly-learned information and memories [3]
- Increasing selective attention at the moment of receiving information, as well as strengthening and promoting overall learning abilities [1]
- Improving memory and attention in healthy men under extreme conditions [4]
Some of the potential mechanisms that have been suggested to be behind the effects of Semax include:
- Increasing enkephalins (a natural opiate neurotransmitter), which may be involved in memory formation, consolidation, and reactivation/recall [5, 6]
- Enhancing calcium ion accumulation inside the cells, which may help fight against brain-degenerative processes [7]
- Enhancing the production of key proteins (such as immunoglobulin) that are believed to play a role in protecting the brain from stress and damage [7]
2) Nicotine
Although it is highly addictive and dangerous in most of its common forms, nicotine is one of the most well-documented drugs to have memory-related effects.
However, we are not recommending starting smoking by any means! Since smoking is a major worldwide cause of death, the risks of smoking far outweigh any possible benefit. Therefore, we highly advise against smoking or using tobacco – and if you are already a smoker, seek professional help as soon as possible. Stopping smoking is among the most important things you can do to improve your health and longevity [8].
While nicotine can also be ingested in other forms – such as “e-cigarettes” or “vapes” – the safety of these methods have not been fully proven, and many serious concerns remain about their short-term and long-term effects and safety [8].
Some of the clinical studies on nicotine have relied on other forms, such as nicotine patches or gum. Although these might be “safer”, there is still a high potential for addiction and dependence to nicotine in any form. Therefore, considering how many different – and relatively much safer – options there are, it’s probably best to avoid nicotine altogether, and focus instead on less potentially dangerous options (such as the other ones in this post) [8].
With all that in mind, some of the purported cognitive effects of nicotine include:
- Makes it easier to consolidate memories in perceptual learning [9]
- Improves learning tasks (including contextual conditioning) [10]
- May protect the brain [10]
- Improves attention [11]
- Improves dexterity / fine motor coordination [11]
- Reduces cognitive impairment [11]
- Improves short-term memory [12]
According to one clinical study, nicotine patches reportedly helped alleviate cognitive impairments in Alzheimer’s disease, schizophrenia, and ADD/ADHD patients [13].
Some other researchers have proposed that nicotine may be a promising treatment for Parkinson’s disease, Down’s syndrome, and age-related memory impairment [14, 15].
Some of the potential mechanisms that have been suggested to be behind the effects of nicotine include:
- Increases acetylcholine activity [16, 17]
- Activates the alpha-4 beta-2 nicotinic receptor, which has been implicated in learning [13]
- Activates the alpha-7 nicotinic receptor, which has been implicated in long-term memory [13]
All in all, while some of the existing research on the potential cognitive effects of nicotine might seem promising, the inherent risk of addiction, dependence, and other significant dangers highly suggest against trying to use nicotine for the purposes of “cognitive enhancement”.
3) Selegiline
In small doses, selegiline (L–deprenyl) has been reported to inhibit the enzyme MAO-B. Similarly, in relatively larger doses, some evidence suggests that it may inhibit both MAO-B as well as MAO-A.
Because these MAO (monoamine oxidase) enzymes are involved in the breakdown of several major types of neurotransmitter in the brain (monoamines), inhibiting them can lead to increased levels of several different important neurotransmitters throughout the brain:
- MAO-A: dopamine, serotonin, melatonin, epinephrine, norepinephrine, and tyramine
- MAO-B: phenylethylamine, dopamine, and other amines
These altered neurotransmitter levels, in turn, could theoretically have a number of effects on the brain and certain cognitive processes.
For example, some early studies in both animals and humans have reported that selegiline may:
- Help memory impairments associated with Alzheimer’s [18]
- Improve memory and overall cognitive functioning in Parkinson’s patients (vs. placebo) [19]
- Improve memory impairments via the cholinergic system, a major brain system that has been associated with dementia [20]
- Improve long-term memory (in aged mice; 0.25 mg/kg, 3 times per week) [21]
- Protect against memory impairments from iron (in mice) [22]
Some of the potential mechanisms that have been suggested to be behind the effects of selegiline include:
- Enhancing the activity of the “P300” signal (a brain response associated with vigilance, attention, and decision-making) [19, 23, 24]
- Increasing dopamine (through inhibiting MAO-B) [25, 26]
- Acting as an antioxidant, and protecting against glutamate toxicity (excitotoxicity) in neurons [27]
- Inhibiting acetylcholinesterase (AChE) – the enzyme that breaks down the neurotransmitter acetylcholine – thereby potentially increasing acetylcholine levels throughout the brain [27, 28]
4) Modafinil
Modafinil is a medical drug that is FDA-approved for treating certain health conditions, such as narcolepsy and other fatigue-related disorders.
As such, it can only be obtained legally via a doctor’s prescription, and should only be used under the ongoing supervision of a qualified medical professional.
While this drug is not approved for any applications related to cognition (or cognitive enhancement), some findings from early clinical studies in human patients suggest that this prescription medication may nonetheless have some secondary effects on brain function and cognitive processing.
For example, one study in depressed patients reported that those who used modafinil showed better episodic and working memory [29].
According to another study, adult ADHD patients who were administered modafinil (200 mg/day) were reported to show significant improvements in short-term memory, visual memory, and spatial planning. However, although they responded more accurately on tests, they had slower responses overall – which may suggest that there are some important trade-offs involved in some of modafinil’s potential cognitive effects [30].
Similarly, modafinil has been reported to improve working memory in individuals with cognitive impairments related to chronic methamphetamine abuse [31].
While some of these early results seem somewhat promising, it is important to note that all of these studies involved human patients with very specific medical conditions or disorders, and so there is no direct evidence as yet that this drug would have similar effects in healthy human users.
Some of the potential mechanisms that have been suggested to be behind the effects of modafinil include:
- Increases glutamate in the thalamus [32]
- Prevents glutamate toxicity (excitotoxicity), which damages and kills neurons [32]
- Increases dopamine, norepinephrine (inhibits dopamine/norepinephrine transporter) and serotonin [32]
- Increases histamine neurons in multiple parts of the brain [32]
However, while it is possible to find and order this drug online, it is not advised to experiment with it casually, as it may not be legal to possess where you live. It also has some serious potential side-effects and other risks, which is why it is typically only available by a doctor’s prescription. Taking all of this into account, if you are interested in using supplements to potentially enhance your cognitive abilities, you are better off sticking to many of the safer and legal options discussed elsewhere in this post!
Racetams and Other Research Chemicals
INSUFFICIENT EVIDENCE:
Similar to some of the supplements discussed in the preceding sections, the following “nootropic” (“cognitive-enhancing”) drugs and compounds are still in a very early stage of research, and are considered to have “insufficient evidence” to come to any firm conclusions about their efficacy in healthy human users.
Note that this doesn’t mean that they’re not effective – just that there isn’t enough hard data on them (such as from large-scale clinical trials in humans) to say for sure.
Nonetheless, this means that you should take the scientific claims discussed below with a healthy grain of salt until appropriate large-scale follow-up studies in humans are performed.
5) Piracetam
Piracetam is the oldest member of the “racetam” family of nootropic drugs. It is also one of the most “popular” nootropic compounds, and as such there have been many claims made about its potential effects. But what does the current science really say?
So far, the available data and hard evidence from legitimate clinical studies of this drug are a bit modest – at least compared to a lot of the hype that you can find about piracetam online. This isn’t to say that there isn’t any evidence, though; just that the full picture is still complex, with many mixed and inconclusive results so far.
We’ll briefly discuss some of the more promising findings behind it below: but if you want to get a more complete picture of the current science behind this drug – as well as some of its potential side-effects and other risks – we would encourage you to check out our other, more detailed SelfHacked posts on it here and here.
According to one early human study, piracetam was reported to improve long-term/short-term memory retrieval in 60 dyslexic boys [33].
Piracetam was also associated with a significant improvement in verbal and nonverbal short-term memory and attention in patients undergoing bypass surgery [34]. However, this was a small study, and only dealt with patients with a specific underlying medical condition – so we can’t assume that similar effects would necessarily apply to healthy human users without appropriate follow-up studies to confirm this.
Additionally, a couple of early animal studies have reported that chronic treatment (250 mg/kg) with piracetam significantly improved working memory in mice with drug-induced amnesia. However, in one of these studies, piracetam was combined with citicoline, so it’s not possible to determine which specific compound was responsible for these effects [35, 36].
Some of the potential mechanisms that have been suggested to be behind the effects of piracetam include:
- Increasing the function of muscarinic choline receptors [37]
- Stimulating NMDA receptors [38]
- Improving cell membrane permeability [38]
- Enhancing the brain’s ability to use glucose
6) Phenylpiracetam (“Phenotropil”)
Phenylpiracetam is a Russian drug developed in 1983 to combat the prolonged stress of working in space. Today it is a prescription medication typically sold under the name “Phenotropil” in Russia.
It is not approved elsewhere (such as by the FDA in the USA) for any specific use.
According to one preliminary study, phenotropil was reported to improve daily functioning and brain function in stroke patients [39].
In another study on patients with brain damage (encephalopathy), phenotropil was reported to improve brain functions, memory, and counting ability [40].
In animals that lack blood flow to the brain, phenotropil was reported to improve their memory functions and vitality [41].
However, it is important to notice that all of the above studies were done in subjects with various underlying forms of brain damage, and so it cannot be concluded that phenotropil would have similar effects in healthy users on the basis of any of these findings.
The mechanisms of phenylpiracetam/phenotropil are not clinically clear but should – in theory – be similar to other drugs in the racetam family.
7) Oxiracetam
Oxiracetam is another racetam drug with some early results showing potential effects on cognitive function.
For example, in a study of patients with Alzheimer’s or multi-infarct dementia, 800 mg oxiracetam twice daily was reported to improve memory, with no signs of tolerance developed. However, performances on some cognitive tests were statistically worse than baseline after late-stage follow-up, indicating very mixed results [42].
One study in humans reported that oxiracetam’s effects on memory may be greater compared to piracetam [43].
In a study on rats and mice, oxiracetam was reported to improved memory as well as piracetam. In addition, it also reported improved these animals’ learning abilities [44].
According to one rat study, oxiracetam reportedly reduced brain injury, and increased learning, memory, and spatial cognition in rats with traumatic brain injuries [45].
Some of the potential mechanisms that have been suggested to be behind the effects of oxiracetam include:
- Prevents decreases in the brain’s levels of acetylcholine, a neurotransmitter that is believed to be critical in overall memory function [46].
8) Pramiracetam
Pramiracetam is marketed as a potential treatment for memory and attention deficits in aging people with neurodegenerative diseases and vascular dementia. However, its evidence for efficacy in healthy human subjects remains somewhat limited.
In one study of males with brain injuries, pramiracetam (400 mg) was reported to improve memory (with no build-up of tolerance) over an 18-month period. The effect was reported to be consistent up to 1 month after discontinuing treatment [47].
Pramiracetam has also been reported to partially counteract experimentally-induced amnesia (caused by scopolamine) in one study of both young and old (18-42 and 55-65-year-old) human participants [48].
According to one other human study, pramiracetam was reported to have a statistically significant effect on improving the memory of patients suffering from lack of oxygen in the brain (chronic cerebral blood insufficiency) [49].
However, all of these human studies were done on people with brain injuries or experimentally-induced cognitive deficits, and so cannot be translated over into healthy human users without much additional research.
In one animal study on rats, pramiracetam (7.5 mg/kg and 15 mg/kg) was reported to improve long-term memory, but did not significantly improve working memory [50].
Some of the potential mechanisms that have been suggested to be behind the effects of pramiracetam include:
- Increases nicotinic acetylcholine receptor activity [51].
- Increases choline uptake (in rat hippocampus) [51].
9) PRL-8-53
PRL-8-53 is an experimental nootropic research drug. As such it is extremely new, and very little is known about what its potential effects or mechanisms might be.
In one double-blind study, PRL-8-53 was reported to enhance learning and memory retention in humans (at very low doses) [52].
The Mechanisms of PRL-8-53 have not been studied yet, and currently, remain unclear.
Animal And Cell Research (LACKING EVIDENCE):
For the compounds listed below, what we currently know about their potential effects is based solely on animal- or cell-based studies, and are lacking evidence from any appropriate human trials so far. Therefore, these are only potential “launching-points” for future clinical studies in humans, and no solid conclusions can be made about these effects in human users until much more additional research is done.
10) Fasoracetam (“NS-105”)
Fasoracetam – also sometimes referred to as “NS-105” – is another member of the racetam family of drugs. It is currently undergoing clinical trials for the treatment of vascular dementia and ADHD, although it is most likely still a long ways off from possibly becoming FDA-approved for any particular official use.
The mechanisms of fasoracetam are not clinically clear, but are theoretically similar to those of other drugs in the racetam family, due to the chemical and molecular similarities they appear to share.
Apart from one preliminary animal study (below), large-scale clinical studies on this drug are generally lacking, and so not much is known for sure about how effective or safe it may be in healthy human users – especially over the long term.
According to one early animal study, fasoracetam was reported to partially reverse memory impairments caused by baclofen (a potent GABA B agonist drug) [53].
However, this is only one study, in rats, and so a lot more research will clearly be needed to understand more about this drug’s potential effects in humans. As such, it’s not recommended to experiment with this drug, since its efficacy and safety remain unknown.
>>> To learn more about fasoracetam, check out our detailed SelfHacked post on it here.
11) Coluracetam (“BCI-540” / “Mkc-231”)
Coluracetam is yet another drug variant in the racetam family with a couple of animal studies on its potential effects. However, no human studies have been performed yet.
In one animal study in rats with brain damage from chemicals, coluracetam was reported to reduce the toxically-induced memory impairments, with no apparent adverse side-effects [54].
In one other animal study, coluracetam was also reported to induce long-lasting (72-hour) effects on cognitive function after repeated administration (rat study) [55].
Some of the potential mechanisms that have been suggested to be behind the effects of coluracetam include:
- Increasing choline uptake [54].
- Reversing hippocampal acetylcholine depletion [56].
12) Selank
Selank is another compound that was originally developed in Russia, and which has been reported to be a nootropic and anxiety-reducing peptide. It is a synthetic analog of a component of immunoglobulin G (tuftsin).
However, the evidence in support of its effects, while somewhat promising, has only been shown in animals so far.
For example, according to some early findings, selank reportedly improved memory and brain function in rats with lowered learning abilities. The studied rats were also reported to have enhanced memory abilities under conditions of high emotional stress [57].
In another study in rats, injecting 300 μg/kg of selank was reported to increase the stability of memory traces (newly-formed memories) for up to one month [58].
Finally, selank (300 μg/kg) was reported to help restore certain cognitive functions (such as memory, learning, and attention to sensory stimuli) in rats with chronic artificial inhibition of the brain (specifically, the cerebral catecholaminergic system) [59].
Some of the potential mechanisms that have been suggested to be behind the effects of Selank include:
- Activates the dopamine D5 receptor (DRD5), which plays a key role in the formation of memory and learning processes [3].
- Increases BDNF in the hippocampus of rats [60].
- Increases enkephalins, which play a role in memory formation, consolidation, and reactivation/recall [5, 6].
However, all of these preliminary findings will have to be followed up on by large-scale human studies in order to fully confirm these potential effects.
Takeaway
Only a handful of drugs have been properly researched for their alleged nootropic effects, while all others lack scientific ground.
On top of that, the existing research suffers major flaws. For example, some drugs that are claimed to be nootropics in Russia (like Semax and Phenylpiracetam) never underwent proper trials in healthy humans. For this reason, they have not been approved by the FDA.
Other purported nootropics are downright dangerous, such as nicotine. A handful of prescription drugs like selegiline and modafinil are also claimed to enhance cognition in healthy people, but in reality, they’ve only been researched in patients with certain neurodegenerative disorders.
In other words, there is no limitless pill that we know of in the real world.
