Nootropics are supplements used to boost cognition and memory. In other words – smart drugs!
This article covers the published research studies on several popular nootropics. I’ll explain the research on how the substance works and the genes connected to the mechanism of action.
Let me be upfront, though…there are no research studies that directly connect genetic variants to whether a smart drug will work for you. Instead, I’m connecting some dots and giving you the background information to start your own researching and experimenting.
Please be sure to talk with your doctor or pharmacist if have any questions on a supplement – especially if you are currently on prescription medication.
Noopept (cognitive function, memory)
Noopept is a dipeptide that was discovered by the Russians in the 1960s. The Russian government had a program to develop cognitive-enhancing drugs, and noopept now has decades of research on it with both human and animal studies.
Noopept may enhance memory and cognitive function in a couple of ways:
- Noopept can increase HIF-1 activity. HIF-1 (hypoxia factor 1) is important in low oxygen states.[ref] In turn, HIF-1 then activates a bunch of other genes that help cells respond to lower oxygen levels. In the brain, this increases energy metabolism in the mitochondria as well as activating proteins responsible for controlling GABA receptors.[ref]
- Noopept also enhances BDNF (brain-derived neurotropic fact) and NGF (nerve growth factor) expression.[ref][ref] Both BDNF and NGF are important in cognitive function and brain plasticity.
- The noopept metabolite, cyclopropyl glycine, binds to AMPA receptors in the brain.[ref] AMPA receptors are glutamate receptors that are essential to brain plasticity and neuronal transmission.[ref]
Studies on noopept:
Recently, research has been focusing on using neuropeptides such as noopept for Alzheimer’s disease. Phase III and other clinical trials have been done in Russia. Unfortunately, much of the research is published in Russian – including a study on noopept in patients with APOE E4 that I would love to read. A recent cell study showed that noopept enhances neuronal cell viability by reducing the excessive production of ROS in Alzheimer’s brain cells. This protects against amyloid-beta toxicity.[ref]
Cell studies show that noopept may protect cell viability in an Alzheimer’s model.[ref]
Animal studies on noopept show that it can eliminate the symptoms of learned helplessness.[ref]
A clinical trial in Russia investigated using Noopept for cognitive dysfunction in concussion patients. Oddly, the other arm of the trial was using piracetam instead of a placebo. Both noopept and piracetam (a similar drug) showed similar efficacy. Of interest here is that there were fewer linked side effects with noopept than piracetam.[ref]
Another clinical trial in Russia found mild improvements from noopept in stroke patients. The trial (with a placebo control) used a 20 mg daily dose for 2 months.[ref]
Safety is important when looking into nootropics.
- Animal studies also show that Noopept does not seem to increase cell proliferation. This is important because HIF-1A is increased in cancer cells.[ref]
- Additionally, animal studies show that noopept is not genotoxic (does not cause DNA damage).[ref]
BDNF gene: BDNF is important in resiliency to adverse events, brain plasticity, memory, and overall brain health. Long-term (28-days) of noopept increased the expression of BDNF.[ref]
Check your genetic data for rs6265 Val66Met (23andMe v4, v5; AncestryDNA):
- T/T: decreased BDNF[ref] referred to in studies as Met/Met[ref][ref][ref][ref],
- C/T: somewhat decreased BDNF, referred to as Val/Met
- C/C: typical BDNF, referred to as Val/Val
Members: Your genotype for rs6265 is —.
Check your genetic data for rs56164415 C270T (23andMe v4; AncestryDNA):
- A/A: less BDNF in regions of the brain[ref][ref][ref]
- A/G: less BDNF in specific regions of the brain
- G/G: typical BDNF
Members: Your genotype for rs56164415 is —.
AMPA receptor: Noopept acts on the AMPA receptor, which is made up of four protein subunits. GRIA1 – 4 genes encode the subunits of AMPA receptors. Interestingly, GRIA1 and GRIA4 genetic variants are linked to migraine susceptibility
Check your genetic data for rs548294 (23andMe v4; AncestryDNA):
- C/C: typical
- C/T: increased risk of migraines, possibly due to decreased AMPA receptor function
- T/T: increased risk of migraines, possibly due to decreased AMPA receptor function)[ref]
Members: Your genotype for rs548294 is —.
HIF1a gene: Noopept increases HIF-1. There are two well-studied HIF1A genetic variants that generally increase the amount of HIF-1a that is available in cells. These variants are linked to an increased relative risk of certain cancers. On the plus side, the variants may give advantages in athletic training and decreased risk of certain inflammatory conditions.
Check your genetic data for rs11549465 Pro582Ser (23andMe v4, v5; AncestryDNA):
- C/C: typical HIF-1a levels
- C/T: increased HIF-1a; overall higher risk of several types of cancer; decreased risk of diabetes; greater gains following endurance training; more likely to be an elite athlete; less likely to have a hamstring injury[ref]; decreased risk of knee osteoarthritis
- T/T: increased HIF-1a; overall higher risk of several types of cancer[ref][ref]; decreased risk of diabetes[ref]; greater gains following endurance training[ref]; more likely to be an elite athlete[ref]; decreased risk of knee osteoarthritis[ref]
Members: Your genotype for rs11549465 is —.
Check your genetic data for rs11549467 Ala588Thr (23andMe v4, v5; AncestryDNA):
Members: Your genotype for rs11549467 is —.
Bacopa monnieri (memory):
Bacopa monnieri, also known as Brahmi, is a native plant found in the wetlands of Australia and India. It has been used in traditional Ayurvedic medicine for over 1400 years as a way to sharpen intellect and help with memory.[ref]
How does it work?
- The active compounds in Bacopa include bacosides, which can cross the blood-brain barrier easily.[ref]
- Studies show that Bacopa monnieri has antioxidant properties that may be neuroprotective against oxidative stress in the brain.[ref]
- Animal studies show that it restores acetylcholine levels in aged brains to that of young animals. Additionally, Bacopa monnieri modulates neurotransmitter levels.[ref]
- Cell studies show that Bacopa monnieri inhibits the release of proinflammatory cytokines – reducing TNF-alpha and IL-6 in brain cells.[ref]
- Animal studies also show that the improvements in learning and memory with Bacopa monnieri accompany an increase in amygdala function via dendritic growth.[ref]
Studies on Bacopa monnieri:
- A randomized controlled trial of adults age 40-65 showed that after three months of Bacopa supplements, the study participants increased memory of new information.[ref]
- A randomized trial in medical students found that 150 mg Bacopa monnieri twice daily for six weeks improved cognitive function.[ref]
- Studies of Bacopa supplements for children and teens show that it helps to improve memory. Study participants also showed improvements in attention and a reduction in hyperactivity. [ref]
- A meta-analysis of nine studies concluded that Bacopa monnieri improves cognition and speed of attention.[ref]
NPTN gene: A study that looked at which genes were upregulated in brain cells with Bacopa found that it increases neuroplastin (NPTN gene). Interestingly, this is the same gene that has been identified as impacting the thickness of the cortex of the brain.
Check your genetic data for rs7171755 (23andMe v4; AncestryDNA):
- A/A: thinner cortex in the left hemisphere of the brain, lower expression of NPTN in the brain[ref]
- A/G: thinner cortex in the left hemisphere of the brain, lower expression of NPTN in the brain
- G/G: typical
Members: Your genotype for rs7171755 is —.
Neuroinflammation genes: TNF-alpha and IL-6 genetic variants are linked to mood disorders due to heightened inflammation. Bacopa has been shown to reduce TNF-alpha and IL-6.[ref]
There are several genetic variants linked to naturally more active TNF-alpha. Learn more about TNF-alfa and inflammation here.
Check your genetic data for rs1800629 -308A/G (23andMe v4, v5; AncestryDNA):
- A/A: Higher TNF-alpha levels[ref][ref][ref][ref][ref]
- A/G: somewhat higher TNF-alpha levels
- G/G: typical
Members: Your genotype for rs1800629 is —.
Check your genetic data for rs361525 (23andMe v4, v5; AncestryDNA):
- A/A: higher TNF-alpha levels[ref][ref][ref][ref][ref][ref]
- A/G: somewhat higher TNF-alpha levels
- G/G: typical
Members: Your genotype for rs361525 is —.
Methylene blue (mitochondria, brain energy)
Methylene blue was first developed as a textile dye, but it was quickly found to stain cells under a microscope. Early medical uses included using methylene blue to treat malaria. When used in higher amounts, methylene blue turns urine a blue color, and thus, it was included with psychiatric medications to see if the patient was being compliant with taking the drugs. This lead to the discovery that methylene blue itself had antipsychotic effects through inhibiting MAOA.[ref]
Currently, methylene blue is primarily used as a medication for methemoglobinemia and during certain types of heart surgery to increase oxygenation in the blood. It is also used in periodontal health along with phototherapy.
What else does methylene blue do? Methylene blue acts as a redox recycler, moving electrons.
In the mitochondria, methylene blue can act in complex I and complex IV as an alternative electron transporter. This can protect against oxidative stress produced in the mitochondria.[ref]
Methylene blue easily crosses the blood-brain barrier. The brain uses a lot of energy, produced in mitochondria, of course. A decrease in mitochondrial function in the brain is thought to be at the root of neurodegenerative diseases.
Methylene blue clinical trials:
- A double-blind crossover study using 15 mg methylene blue in bipolar patients showed that it improved depression symptoms.[ref]
- In COVID-19 patients, methylene blue improved blood oxygen levels, decreased hospitalization days, and decreased mortality.[ref]
- Clinical trials in Alzheimer’s patients showed that higher doses of methylene blue didn’t have a benefit compared to the placebo. But the placebo group was taking a lower dose of methylene blue to turn their urine blue also. Re-analysis of the data shows that methylene blue (or derivative, patentable molecules) may be helpful in Alzheimer’s at low doses.[ref][ref]
- An fMRI study found that methylene blue alters cerebral blood flow. The randomized-controlled trial found that methylene blue enhances resting-state functional connectivity in the areas of the brain related to perception and memory.[ref]
As a nootropic, methylene blue is used in very low doses (microdoses) to enhance cognitive function.
How does methylene blue work?
There are several ways that methylene blue acts in the body.
- One mechanism of action is that it is an MAOA inhibitor, which should cause a slight increase in neurotransmitter levels.
- Another way that methylene blue works is to increase mitochondrial function in the brain.[ref]
- Research also shows that methylene blue decreases the activation of the NLRP3 inflammasome in the microglia (decreases inflammation in the brain).[ref]
- Methylene blue acts as an antioxidant by upregulating the Nrf2 antioxidant response pathway.[ref]
NLRP3 inflammasome: Methylene blue acts in the microglia (brain immune cells) to decrease the activation of the NLRP3 inflammasome[ref][ref] Microglial activation is thought to be at the root of many neurological conditions including Alzheimer’s disease.[ref]
Check your genetic data for rs35829419 Q705K (23andMe v4; AncestryDNA):
Members: Your genotype for rs35829419 is —. (If you don’t see your 23andMe v4 data for this one, check it on 23andMe. It doesn’t show up in some downloaded data sets.)
If you are interested in methylene blue for Alzheimer’s disease, you can check your APOE genotype here.
St. John’s Wort (mood):
Saint John’s Wort (SJW) is an herbal supplement that has been used for centuries to improve mood. With thousands of studies on it, St. John’s wort is one of the most well-studied herbal remedies for depression.[ref]
How does it work?
St. John’s wort has also been shown in recent studies to inhibit STAT-1 and NF-κB, which are promoters of inflammatory signaling. Thus, essentially, SJW is inhibiting an excessive inflammatory response. This has been shown in people with diabetes.[ref]
Cell studies show that SJW protects microglia in the brain from oxidative stress. The study also shows that it has anti-inflammatory properties in the brain as well.[ref]
Hyperforin is one of the main active components of St. John’s wort.
- Stress response: A recent study showed that hyperforin was able to reverse stress-induced increases in FKBP5.[ref] Why is this important? FKBP5 interacts with the glucocorticoid receptor in response to stress.
- Mitochondria: In a cell study looking at amyloid-beta plaque, researchers found that hyperforin acts upon FIS1, a mitochondrial protein important in fission-fusion events.[ref] Mitochondrial function, especially in the brain, is important in the prevention of neurodegeneration as well as in mood disorders. (Read more about mitochondria and MDD)
Hyperforin has also been shown in cell studies to activate TRPC6 channels. This channel is important in moving zinc and calcium across the mitochondrial membrane.[ref] Animal studies point to TRPC6 as being important in brain plasticity.
Studies on St. John’s wort:
There are a ton of studies on SJW for depression, and the results vary quite a bit.
Negative Clinical trials:
- Neither sertraline nor SJW differed from placebo in MDD.[ref]
- Again, neither SJW nor sertraline differed from placebo in depression.[ref]
- SJW did no better than a placebo with OCD.[ref]
Positive clinical trials:
- A meta-analysis found that SJW had fewer side effects than antidepressants and that it has similar treatment effectiveness to prescription antidepressants.[ref]
- Another meta-analysis found that St. John’s wort works better than placebo in the treatment of depression.[ref]
- Another trial in MDD found that SJW was more effective than fluoxetine in depression.[ref]
Stack with Zinc (if deficient): The mitochondrial impact of hyperforin includes its TRPC6 channel activation, moving zinc in the mitochondria. Studies on depression show that zinc supplementation augments antidepressant treatment even in treatment-resistant patients.[ref][ref]
ABCB1 gene: People with genetic variants in the ABCB1 gene which caused them to have lower levels of ABCB1 in the intestines had an attenuated response to SJW initially. But…long-term use increases ABCB1 levels.[ref]
Check your genetic data for rs1045642 (23andMe v4 only):
- A/A: may take longer for St. Johns wort to work (attenuated intestinal transport)[ref]
- A/G: may take longer for St. Johns wort to work (attenuated intestinal transport)
- G/G: typical
Members: Your genotype for rs1045642 is —.
GSTM1 gene: Photosensitivity is one side effect that some people have with St. John’s Wort. People with GSTM1 deficiency have increased photosensitivity to SJW.
The GSTM1 (glutathione S-transferase mu 1) enzyme helps the body by detoxifying several types of carcinogens, drugs, toxins, and oxidative stress byproducts. Learn more about GSTM1 here.
Not everyone has a functioning copy of this gene, and the non-functioning (null) genotype shows links to cancer susceptibility.[ref] The deletion is fairly common with 50 – 78% of people, depending on ethnic group, having the null genotype for GSTM1.
Check your genetic data for rs366631 (23andMe v4 only):
- A/A: deletion (null) GSTM1 gene[ref][ref][ref] (common genotype in many population groups)
- A/G: GSTM1 present
- G/G: GSTM1 present
Members: Your genotype for rs366631 is —.
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