Nootropics and Genetics: Smart Drugs and Your Genes

Nootropics are supplements used to boost cognition and memory. In other words – smart drugs.

This article covers 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…
Research directly connecting genetic variants to whether a smart drug will work for you is slim. Instead, I’m connecting some dots and giving you the background information to start your research and experimenting.

Please talk with your doctor or pharmacist if you have any questions about a supplement – especially if you are currently on prescription medication.

Noopept (cognitive function, memory)

Noopept is a dipeptide that the Russians discovered 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 activates other genes that help cells respond to lower oxygen levels. In the brain, this increases energy metabolism in the mitochondria and activates 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 essential to brain plasticity and neuronal transmission.[ref]

Research on Noopept and the brain

Recently, research has focused on using neuropeptides such as noopept for Alzheimer’s disease. Phase III and other clinical trials have been done in Russia. Unfortunately for me, much of the research is published in Russian. 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 used 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 two months.[ref]

Safety is essential when looking into nootropics. Let’s take a look at what research shows on noopept safety.

• Animal studies also show that Noopept does not seem to increase cell proliferation. It 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]

Bacopa monnieri (memory supplement)

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 bacopa 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]

Research Studies on Bacopa monnieri

• A randomized controlled trial of adults aged 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]

Methylene blue (mitochondria, brain energy)

Methylene blue was first developed as a textile dye but 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. Thus, it was included with psychiatric medications to see if the patient was compliant with taking the drugs. It led to the discovery that methylene blue itself had antipsychotic effects by inhibiting MAOA.[ref]

Currently, methylene blue is primarily used as a medication for methemoglobinemia and during certain heart surgeries 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. It 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 also taking a lower dose of methylene blue to turn their urine blue. 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 as a nootropic?

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 (reduces inflammation in the brain).[ref]
• Methylene blue acts as an antioxidant by upregulating the Nrf2 antioxidant response pathway.[ref]

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, 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, promoters of inflammatory signaling. Thus, essentially, SJW is inhibiting an excessive inflammatory response. This inhibition 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 could 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 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.

Research studies on St. John’s Wort

There are many 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 placebo with OCD.[ref]

Positive clinical trials:

• A meta-analysis found that SJW had fewer side effects than antidepressants and similar treatment effectiveness to prescription antidepressants.[ref]
• Another meta-analysis found that St. John’s wort works better than placebo in treating 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]