One thing that has annoyed me more than anything since starting Nootropics Expert. The ignorant bloggers, so-called professional journalists and “science writers” who equate nootropics with smart drugs.
I see headlines like this every week:
“Not So Smart: The Dangers behind Nootropics, aka ‘Smart Drugs’”
“Potential Dangers Of Nootropics: What To Consider Before Using Smart Drugs”
“The Dark Side of Smart Drugs – The dangers, risks, and side effects of nootropics.”
Let’s be clear.
Smart drugs can kill you. And
nootropics can heal your brain.
Smart drugs and nootropics are completely different compounds used to optimize the brain. In this post we’re going to briefly explore the difference between the two.
We’ll dig into the pros and cons of smart drugs. The negative effects of smart drugs. And why they can be so dangerous for the young and aging brain.
We’ll also briefly look at some safe and natural nootropic alternatives to smart drugs that can achieve similar brain optimization goals for most people.
And if you need to use smart drugs to manage ADHD, we’ll look at some nootropics that can help mitigate the damage caused by these drugs.
Table of Contents
Cognitive Enhancement by Any Means Necessary
In 2013, Alan Schwarz of the New York Times wrote an article entitled, “Drowned in a Stream of Prescriptions”.[i] It’s a story about a young college class president named Richard Fee.
Richard did not have ADHD. This 24-year old college graduate lied to doctor after doctor. And for years, received a quick diagnosis and got a prescription for Adderall.
Young Mr. Fee became violently delusional and spent a week in a psychiatric hospital in 2011. He met with his doctor and got a prescription for another 90 days of Adderall. Two weeks after the prescription ran out, young Richard hanged himself in his bedroom closet.
Richard Fee is just one of an estimated one in four American teens who has misused or abused a prescription drug at least once their short lifetime.[ii]
The same study found that one in eight teens have taken a stimulant like Ritalin or Adderall. Without a prescription.
The researchers also pointed out the lax attitude of parents regarding the misuse of prescription stimulants by their kids.
If you are using or considering using prescription stimulants to help with your school work. Or to get ahead in business. It is certainly not my intention to insult your intelligence. Or to dismiss your desire to optimize your brain for whatever reason.
It is my intention however, to explore the danger involved in using prescription medications for cognitive enhancement. And to suggest safer alternatives using nootropic supplements to achieve the same goals.
The Dark Side of Smart Drugs
In January 2008, the science journal Nature conducted an informal poll of 1,400 readers from 60 countries. The journal specifically asked about three drugs: methylphenidate (Ritalin), modafinil (Provigil) and beta blockers.
One in five respondents said they had used drugs for non-medical reasons to stimulate their focus, concentration or memory. For those who did use, 62% reported using methylphenidate, 44% reported taking modafinil, and 15% said they had taken beta blockers like propranolol. A few survey respondents said they were using Adderall.[iii]
We’re going to dig into each of these smart drugs. What they are, how they work in your brain, and potential problems caused by these drugs.
Let’s start with…
MPH is a stimulant that blocks the transporters that reuptake dopamine and norepinephrine into the presynaptic neuron following their release. This action prolongs the availability of these neurotransmitters in synapses to exert effects on postsynaptic neurons.[v]
MPH also affects glutamate transmission which we’ll deal with in a minute.
Studies found that reduced hyperactivity and impulsivity in MPH-treated ADHD patients also occurred in healthy people given the same dose.[vi] And this is the reason that methylphenidate is considered a cognitive enhancer.
But MPH is dose dependent. For example, doses higher than what is used to treat ADHD increases hyperactivity. And impairs attention and performance on cognition that is dependent on the prefrontal cortex.
But lower doses reduce hyperactivity and improve cognition even in healthy people.[vii]
Lower methylphenidate doses result in slight increases in dopamine and norepinephrine in the prefrontal cortex. While not affecting other brain regions. Allowing for improvements in executive function and working memory. Without increasing hyperactivity.
The Dark Side of Methylphenidate
The problem with cognitive enhancers like methylphenidate is directly related to their effects on regulation of dopamine and norepinephrine in your brain.
At optimal doses, dopamine binds to D1 receptors. And norepinephrine binds to α2 receptors. This action leads to an increase in prefrontal cortex signal-to-noise ratio. Which enhances the flow of information and strengthens communication between neurons.[viii] Helping executive function and working memory.
When dopamine and norepinephrine go beyond optimal levels, you have a problem. They activate dopamine D2 receptors and noradrenergic α1 and β receptors. This weakens the signal-to-noise ratio by activating neurons that are not supposed to be involved in the current task.
This activation of neurons that are not supposed to be involved results in hyperactivity, distractibility and poor impulse control.
But to further complicate things. Levels of dopamine and norepinephrine in a normal, healthy brain are not constant. They vary slightly even within the same person based on seasons, time of day, or the activity you are involved in.
And to be honest, there’s no way to measure optimal levels of these neurotransmitters. So dosing methylphenidate (or any other stimulant) is mostly guess work.
Methylphenidate and the Developing Brain
And continues to develop through to your late 20’s and early 30’s.[x]
Dopamine and norepinephrine levels rise and fall to allow for the maturation of executive control and reward pathways in your brain. And using MPH during this maturation process can disrupt this natural ebb and flow. Resulting in lasting behavior problems.
Methylphenidate and Ion Channels
Methylphenidate works differently in young brains compared to adult brains.
Researchers have recently found that methylphenidate depresses neuron activity and synaptic transmission in the prefrontal cortex of young brains. But the same dose in adult brains produces the opposite effect.[xii]
The researchers then discovered why neuronal activity was depressed in young brains. Because of activation of a channel called the hyperpolarization-activated non-specific cation channel (HCN).
The HCN channel allows for flow of positively-charged ions (like potassium), out of a neuron. Lowering its voltage potential and making it harder for the neuron to fire action potentials.
This HCN channel is activated by a hyper-dopaminergic state (too much dopamine). Which suggests that in the young brain, excess dopamine and norepinephrine caused by MPH depresses neuron activity and synaptic transmission.
But wait. There’s more…
Methylphenidate and Neuroplasticity
One important and unique property of the prefrontal cortex is its high level of neuroplasticity. Allowing for executive functions like working memory and decision-making. Neuroscientists believe this neuroplasticity may be due to the slow maturation of this part of the brain.[xiii]
NMDA receptors contain two NR1 subunits with a combination of either NR2A or NR2B subunits. NR2B conveys a slower biochemical reaction to the channel. Allowing it to remain partially open during multiple stimulations.[xiv]
This property results in continuation of neuron activity briefly after input has stopped. Which is thought by neuroscientists to be part of how working memory works.
I’ll not go into detail with the molecular biology here. Except to say that the ratio of NR2A to NR2B receptors is hypersensitive to dopamine levels.
Your prefrontal cortex has high levels of this NR2B subunit throughout life. And it’s involved in working memory formation. When this ratio is knocked out of whack from dopamine boosted by methylphenidate, you have problems with working memory.
And this could by why young people using methylphenidate who are not ADHD, seem to pay more attention in the classroom, and are less hyperactive. Which means learning might improve.
But what does this mean out in the ‘real world’? Take someone out of a classroom setting and put them behind the wheel of a car. And you’ve got problems.
Behavioral flexibility is needed for driving a car. You need to be able to quickly shift attention from the road, to road signs, other vehicles, and back to the road.
Rigid attention and lack of flexibility could potentially lead to inattentive or distracted driving. I’m Adult ADD and use Ritalin daily. And my wife can certainly verify her level of anxiety when I’m behind the wheel. Now I know why.
Behavioral flexibility is also part of interpersonal skills. We must be able to adapt to different people. And when at work, be able to shift plans and roles within a group to meet team goals.
A change or reduction in this behavioral flexibility caused by methylphenidate can lead to problems at work. Resulting in lower wages, unemployment or even disciplinary action.
Methylphenidate in Summary
Methylphenidate has been around for a long time. It’s safety has been proven through countless clinical trials.[xv] And treatment by 10’s of thousands with ADD, ADHD and narcolepsy has been a life-changer for many.
But recent research shows that methylphenidate is bad news for the developing brain. Anyone aged 5 – 35 years ago should take pause before dosing with this drug. Because it negatively affects the developing brain. The results of using methylphenidate could stay with you for life. Long after you stop using it.
Modafinil (Provigil®) was originally developed in France in the 1970’s for the treatment of narcolepsy. It is currently approved by the US FDA for the treatment of narcolepsy, shift-work disorder and obstructive sleep apnea.
Modafinil also binds to the dopamine transporter. And acts as a dopamine reuptake inhibitor (similar to methylphenidate).[xviii] Which increases dopamine, norepinephrine, and serotonin in the prefrontal cortex.
Modafinil produces a unique response in the brain compared to other stimulant drugs. It enhances the efficiency of prefrontal cortex information processing which affects executive function and working memory. While reducing reactivity to fear stimuli in the amygdala (the brain region involved in anxiety).[xix]
Modafinil and the Developing Brain
If this is true, then it’s a cause for concern when used as a cognitive enhancer in adolescent and developing young adult brains.
As I mentioned earlier in this post, the prefrontal cortex is the center for attention and executive function. And this brain area does not finish development until the late 20’s and early 30’s.
So use of modafinil by healthy young adults under 30 years old are at risk of disruptions in brain development. Similar to young adult use of methylphenidate.[xxii]
This means that modafinil could cause changes in neuroplasticity and behavioral problems. Affecting working memory and decision making.
Modafinil and IQ
Some research shows that modafinil may only be effective in improving cognition for those with a lower IQ.
Researchers at Kings College in London analyzed two previous studies on the effects of modafinil with healthy university students. Modafinil (100 and 200 mg) significantly improved target sensitivity in a test. But only in the group of lower IQ students. And not students with a higher IQ.
In other tests using modafinil, researchers found the same results. A significant improvement in test scores. But only in students with a lower IQ.
The researchers concluded that “the results indicate that high IQ may limit modafinil’s positive effects”.[xxiii]
So if you try modafinil, are not happy with the result. It may be because you’re too smart for the drug.
Modafinil in Summary
Research indicates that modafinil is the ‘safer’ smart drug compared to the others in this post.[xxiv] And of all the stimulants used for cognitive improvement, there seems to be less addictive potential with modafinil.
Similar to methylphenidate, modafinil shows improvements in working memory in healthy adults and sleep-deprived neurohackers.
Both MPH and modafinil affect dopamine levels through blockade of dopamine reuptake transporters. And changes in glutamate signaling.
But modafinil at certain doses can cause a reduction in NMDA receptor levels which impairs working memory. While at the same time, promoting long-term potentiation and long-term memory.
Smart Drugs alter the developing brain. So anyone aged 5 – 35 years should think twice before dosing with this drug. Because it could negatively affect neuroplasticity of your developing brain. The results of using modafinil could stay with you for life. Long after you stop using it.
And finally, research shows that if you try modafinil. And are not happy with its effects. It could be because you’re too smart. Modafinil benefits seem to be limited to those with a lower IQ.
Amphetamine was first synthesized in Berlin in 1887 as 1-methyl-2-phenethylamine. It was the first of several chemicals which include methamphetamine and methylenedioxymethamphetamine.
Current prescription versions of amphetamine include names you likely recognize. They include salts of d-amphetamine (DextroStat, Dexedrine), mixed d- and l-amphetamine (Adderall™), d-methamphetamine (Desoxyn), and an amphetamine pro-drug compound, lisdexamfetamine dimesylate (Vyvanse™).
Ecstasy (methylenedioxymethamphetamine) also belongs to the amphetamine family. But is not currently contained in any prescription drug.
Amphetamine is one of the most potent central nervous system stimulants. And commonly used for treating ADHD, narcolepsy and obesity.
Amphetamine works primarily by increasing the neurotransmitters dopamine and norepinephrine in the brain. It also triggers the release of other hormones and neurotransmitters including epinephrine, histamine and serotonin.
Adderall Mechanism of Action
In your brain (not on drugs), vesicular monoamine transporter 2 (VMAT2) moves monoamines (dopamine, histamine, norepinephrine and serotonin) from inside the neuron, into its synaptic vesicles. These vesicles are like the neuron’s chemical storage units.[xxv]
When you take an amphetamine like Adderall, and it enters a neuron. It interacts with VMAT2. And the transporter reverses direction of transport. Which releases stored neurotransmitters from inside synaptic vesicles back into the neuron.
Amphetamine also activates the protein trace amine-associated receptor 1 (TAAR1) which is located in the presynaptic neuron.[xxvi]
When TAAR1 is activated, the receptor causes the neurons monoamine transporters (dopamine transporter, norepinephrine transporter, serotonin transporter) to either stop transporting those neurotransmitter molecules altogether. Or like VMAT2, transport them in reverse.
In plain English; the reversed neurotransmitter transporter pushes dopamine, norepinephrine and serotonin out of the neuron and back into the synaptic cleft.
Amphetamines like Adderall help those with ADHD and narcolepsy by increasing the activity of dopamine and norepinephrine in the brain.
The Dark Side of Amphetamines
The problem with continued or chronic use of amphetamines like Adderall is brain damage.
Amphetamines have been shown to be toxic to dopamine neurons. This “neurotoxicity” shows up as damage to dopamine dendrites and axons. Resembling the brain alterations in patients with schizophrenia. And this damage to dopamine neurons continues for years. Long after stopping use of amphetamines.[xxvii]
Long-term use of amphetamines are associated with disruption of a neuron’s vesicular storage. Leading to an accumulation of reactive oxygen species and severe oxidative stress which damage dopamine neurons.[xxviii]
It’s interesting to note that researchers have found no evidence that this neurotoxicity happens with long-term use of methylphenidate (Ritalin). Likely because MPH only blocks dopamine reuptake without disrupting the vesicular storage pool.[xxix]
Another important reason to consider avoiding amphetamines. It’s hard to stop. And I’m not talking about their addiction potential here. Which is a major concern for anyone with addictive tendencies.
If you’re using amphetamines to help cram for an exam, keep you awake on a long-haul drive, improve athletic performance, or simply enhance your experience at a party. For whatever reason, regular use of these smart drugs motivates many to continue use. Simply because it’s a bitch to stop. The withdrawal symptoms from use of any stimulant are uncomfortable to say the least.
And research shows that stimulant use during the years of brain development (ages 5 – early 30’s) can be a major problem.
The young brain in constantly in flux as it develops. Pruning of frontal cortex synapses. Decreases in receptors of different neurotransmitter systems. And substantial reorganization of dopamine neuron circuits.[xxx]
Rather than repeating what we already covered about stimulant use and neuroplasticity. I’m going to refer you back to the section on “Methylphenidate and Neuroplasticity” on why stimulant use during brain development from 5 – 35 years of age has real-life consequences.
Amphetamines and Psychosis
One clinical study of healthy adults used repeated administrations of 5 – 10 mg of dextroamphetamine. Which produced paranoid delusions in all subjects at cumulative dosages between 55 and 75 mg.[xxxii]
And it’s not difficult to meet the criteria for amphetamine psychosis. About 30 – 40% of amphetamines are excreted unchanged after you take it. The rest of the drug is converted to metabolites. And the portion of amphetamine that is metabolized is strongly affected by urinary pH.
Eating anything acidic (peanuts, walnuts, sunflower seeds, blueberries, corn oil, sugar, etc.) causes faster elimination of amphetamine. But eating anything alkaline (i.e. antacids) can dramatically increase both retention and absorption of amphetamines. Sometimes to dangerously high levels.
Studies suggest that the accumulation of metabolites may contribute to the generation of psychotic symptoms.[xxxiii] And neurotoxicity.
One case study concluded that a daily dose of 10 mg of Adderall taken over five weeks for ADHD induced classic psychosis symptoms in a 12 year old girl. The study reported that…
“She had flight of ideas, tangential thought, a flat affect, psychomotor retardation, loss of short-term memory, and extremely poor hygiene. She also displayed magical thought, describing a personal acquaintance with characters from Greek mythology, and described visual hallucinations: disembowelment of her baby brother and bugs crawling on the walls. She had command auditory hallucinations instructing her to “stab holes in [her] brother. And bugs crawling under her skin”.[xxxiv]
Chances are you’ll not experience psychotic episodes while taking an amphetamine like Adderall. Just consider this when deciding whether amphetamines are worth the risk.
Amphetamines in Summary
Amphetamines have been around since 1887. Their safety has been in debate since. But if you have been diagnosed ADD or ADHD and prescribed Adderall or its equivalent, I’m certainly not suggesting you avoid taking your medication. Just be aware of what amphetamines could be doing to your brain. And take whatever protective measures you can.
There is little doubt that amphetamines are bad news for the developing brain. Anyone aged 5 – 35 years should take pause before dosing with these smart drugs. Because they negatively affect the developing brain. The results of using amphetamines could stay with you for life. Long after you stop using it.
And the chances of experiencing psychotic episodes while taking amphetamines are low. But certainly worth considering.
Preventing Brain Damage Caused by Amphetamines with Nootropics
In a relevant animal model, researchers looked at amphetamine use in baboons and squirrel monkeys. The animals matched human ADHD patients after clinical treatment with Adderall.
The animals showed a 30 – 50% reduction in dopamine, its major metabolite, its rate-limiting enzyme, its membrane transporter, and its vesicular transporter.[xxxv]
Parkinson’s Disease typically requires about 80 – 90% reductions in dopamine resulting in symptoms. So we’re not equating amphetamine use to Parkinson’s.
So if you are using Adderall or a similar medication for treating ADHD. I’m not suggesting you stop taking your meds. I am suggesting that you take precautionary measures to protect your brain. Here’s how…
Recent animal studies have produced evidence for neuroprotection against amphetamine-caused toxicity by supplementing with:
Prescription Ampakine Alzheimer’s Drugs
The last class of smart drug we’ll look at in this post are prescription ampakines.
Ampakines are a class of smart drugs that bind to the glutamate AMPA receptor. Which enhances the receptor’s activity by slowing deactivation. And reduces desensitization of AMPA receptor currents. Which increases synaptic response and long-term potentiation.
All nootropic ampakines are considered non-toxic and safe when dosed correctly. But if you are using any of these natural or synthetic nootropics, and are under the age of 35, this section on prescription ampakines also applies to you.
But AMPA receptors do not work solo. Another glutamate receptor called NMDA receptors actually trigger the induction of long-term potentiation. But these receptors are normally blocked by magnesium at resting membrane potentials.
Activation of AMPA receptors induces Excitatory Post-Synaptic Currents (EPSCs), which polarize the neuron. And remove the magnesium block of NMDA. Which allows long-term potentiation.
Activated NMDA receptors then increase trafficking of more AMPA receptors to the synapse. And this is how long-term potentiation is maintained. For the encoding of long-term memory.
No ampakines are currently FDA-approved. But are being investigated by several drug companies for Alzheimer’s, Parkinson’s, ADHD, Rhett syndrome, schizophrenia, depression, autism, and other cognitive problems.
Some of these ampakine drugs have shown effectiveness for improving memory and cognition in healthy adults.[xliv] And the reason why there is significant interest in nootropic communities like reddit and Longecity for these drugs.
Several studies by DARPA (Defense Advanced Research Projects Agency) have been done using ampakines with the US Military. To give them the edge on the battlefield.
Ampakines are being studied for use as cognitive enhancers and alertness promoters for soldiers in high-stress combat situations.[xlv]
Ampakines are some of the most low-risk cognitive enhancers we have available. But they do present a danger for the young, developing brain (ages 5 – 35).
Ampakines and Glutamate Toxicity
Glutamate toxicity typically occurs when excess glutamate attacks AMPA and NMDA receptors in your brain. Causing a massive influx of calcium. This excess calcium activates enzymes like proteases and phospholipases. Which damage the brain cell membrane and DNA.[xlvi]
Using prescription ampakines has the potential to cause a similar mass influx of cations (positive ions) that could also cause excitotoxicity.
One example is an ampakine called CX929 that has been tested on Angelman syndrome (AS) in animals. AS is mostly caused by an abnormal expression of the UBE3A gene leading to the deletion of E6-associated protein.
The result is severe intellectual and developmental disability, sleep disturbance, seizures, jerky movements and usually a happy demeanor. And there is no cure.
Researchers at the University of Southern California found that in mice, the ampakine CX929 reduced dendritic spine abnormality and learning impairments. And significantly enhanced long-term potentiation.
The team suggested the drug CX929 held promise for treating the currently untreatable Angelman Syndrome.[xlvii]
But this type of ampakine drug bought on the gray market. And used as a cognitive enhancer by someone with a developing brain (ages 5 – 30 years) could cause serious problems in the young brain.
It’s not difficult to imagine that CX929 would have a similar effect on synaptic transmission and neuron communication in a normal brain. And enhancing neuroplasticity in brain regions associated with emotions and other functions.
This would likely lead to the inability to control emotions and other behaviors. Especially if neuroplasticity is excessive and unregulated.
One of the critical mechanisms involved in brain connections – they are maintained and tuned through synaptic pruning. Where highly active synapses are strengthened. And less active synapses are removed (pruning).
We use ampakine nootropics to provide faster learning and improved cognition. But excessive neuroplasticity could lead to high activity in all synapses. And as a result, reduce synaptic pruning. Impairments in synaptic pruning have been associated with autism.[xlviii]
This is a classic example of how ampakines can strengthen synapses, increase neuroplasticity by promoting dendritic spine growth. But could lead to autism-like syndrome.
Ampakines in Summary
Both natural nootropic compounds, and ampakines under development by drug companies have the potential to boost neuroplasticity. Leading to long-term potentiation that can improve the main aspects of learning and cognition.
We know how nootropic ampakines work through personal use. And feedback from thousands of our neurohacking peers. But experimental drugs bought on the gray market could lead unsuspecting people to take far more than safe doses. And suffer neuronal damage from glutamate toxicity.
And since the action of ampakines is to promote neuroplasticity. We know we can lower the threshold for inducing long-term potentiation and increase the magnitude of LTP.
While this alteration in neuroplasticity can help boost learning and cognition. It also comes with a decrease in long-term depression (LTD). LTD is vital for formation of spatial memory. And likely plays a role in motor learning as well.
This shifting in favor of neuroplasticity to raise long-term potentiation could lead to problems with spatial memory and possibly even motor function. Particularly in younger brains.
Smart Drugs Not So ‘Smart’
Dr. Giurgea described a nootropic as having the characteristics of enhancing learning and memory. It should protect the brain while increasing natural cognitive processes. And should not be toxic, nor stimulate or depress the brain.
By this definition, smart drugs are not nootropics.
And anyone who writes about, or refers to prescription stimulants and beta blockers as “nootropics”, either don’t know what they’re talking about. Or are intentionally attempting to categorize these prescription meds as nootropics for marketing purposes. And corporate profits.
If you are dealing with clinically-diagnosed ADD or ADHD. And using prescription stimulants like Ritalin, Adderall, Modafinil or their cousins to manage your symptoms. I am NOT suggesting you stop taking your medication.
But after contemplating what you read in this post. You may want to consider asking your doctor to switch you to relatively safer methylphenidate (Ritalin), or modafinil (Provigil).
You may also want to consider supplementing with nootropics to safeguard your brain from potential damage. And possibly even boost the efficacy of the prescription meds you are taking.
You can read more about managing ADHD and ADD symptoms in this post Best Nootropics for ADHD & ADD.
If you are currently using, or plan to use, amphetamines (i.e. Adderall) or beta blockers to boost learning and memory. I encourage you to consider safer alternatives that can help you achieve the same or similar goals. Check out this post for Best Nootropics for Learning and Memory.
And one final thing… Studies show that Smart Drugs alter the developing brain.[l]
So if you are 5 – 35 years old and using prescription stimulants to help cram for an exam or finish a paper. Or using smart drugs to keep you awake on long-haul drives. Or for whatever reason. I ask you the please, please reconsider.
You are messing with the natural neuroplasticity that the developing brain is designed to go through. So you can enjoy a happy, healthy rest of your life. As tempting as smart drugs may sound, spend some time on NootropicsExpert.com and find safer alternatives.
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