We know you like to lock in. So do we. We don't gatekeep the science behind what we make. Here are some key peer-reviewed research, clinical trials, and systematic reviews, with a quick description of what's in each one.
Nootropics as Cognitive Enhancers
A comprehensive peer-reviewed review covering the four main categories of nootropics, their mechanisms of action, recommended dosages, and known side effects. Covers everything from classical compounds like piracetam to plant extracts like Ginkgo biloba. A good starting point for understanding the full landscape.
Focus on Cognitive Enhancement: A Narrative Overview of Nootropics and “Smart Drug” Use and Misuse
A 2025 narrative review examining both therapeutic nootropics and "smart drug" use among healthy people, particularly students. Covers the clinical issues around popular cognitive enhancers and the current state of the evidence for age-related brain disorders.
Exploring Cognitive Enhancers: from neurotherapeutics to ethical and regulatory challenges
A 2025 review spanning the full spectrum of cognitive enhancers, from prescription medications to over-the-counter supplements to novel agents like gene therapy. Useful for understanding where nootropic supplements fit within the broader cognitive-enhancement landscape.
Effect of a Plant-Based Nootropic Supplement on Perceptual Decision-Making and Brain Network Interdependencies: A Randomised, Double-Blinded, and Placebo-Controlled Study
A randomized, double-blinded, placebo-controlled study using EEG brain monitoring to measure the effects of 60 days of nootropic supplementation. Found no changes in reaction time but significant improvements in brain network connectivity and energetic efficiency. One of the most sophisticated neuroimaging studies of nootropics to date.
The Efficacy of A Nootropic Supplement on Information Processing in Adults
Double-blinded, placebo-controlled study (n=105) measuring the effect of a nootropic supplement on reaction time and anticipation in healthy adults. The supplement group significantly outperformed placebo on all three cognitive measures tested.
A Standardized Single Dose of the Nootropic CILTEP® Has No Effect on Cognitive Performance in Healthy Elderly Participants
Crossover study testing a single dose of a nootropic stack in healthy elderly participants. No acute cognitive enhancement detected, providing a useful counterpoint and a reminder that most nootropics require consistent use over time.
Plant-derived nootropics and human cognition: A systematic review
Systematic review of plant-derived nootropics and human cognition covering clinical trial evidence across memory, attention, executive function, and more. Includes an evidence-rating system for each compound. The most comprehensive review of botanical nootropics available.
Supplementation with NAD+ and Its Precursors to Prevent Cognitive Decline across Disease Contexts
Literature review of NAD+ precursor supplementation for preventing cognitive decline across multiple disease contexts (Alzheimer's, vascular dementia, diabetes, stroke, TBI). Summarizes both animal and human studies, concluding that findings are mostly positive but need more human trials.
NAD+ in Brain Aging and Neurodegenerative Disorders
Authoritative review from researchers at the University of Oslo, Harvard, and Johns Hopkins on NAD+'s role in brain aging. Covers NAD+-dependent enzymes in synaptic plasticity and neuronal stress resistance, and the evidence for NAD+ supplementation in Alzheimer's and Parkinson's mouse models.
NAD+ improves cognitive function and reduces neuroinflammation by ameliorating mitochondrial damage and decreasing ROS production in chronic cerebral hypoperfusion models through Sirt1/PGC-1α pathway
Rat study demonstrating that NAD+ supplementation improved cognitive function and reduced neuroinflammation in a chronic cerebral hypoperfusion model. Identified the Sirt1/PGC-1alpha pathway as the mechanism. Relevant for understanding how NAD+ could protect against vascular-related cognitive decline.
Cognitive and Alzheimer's disease biomarker effects of oral nicotinamide riboside (NR) supplementation in older adults with subjective cognitive decline and mild cognitive impairment
Human clinical trial of nicotinamide riboside (1g/day for 8 weeks) in older adults with subjective cognitive decline or mild cognitive impairment. Did not improve cognition but showed a potentially meaningful reduction in pTau217, an Alzheimer's biomarker. One of the more rigorous human NAD+ studies to date.
Effects of nicotinamide riboside on NAD+ levels, cognition, and symptom recovery in long-COVID: a randomized controlled trial
Double-blind, placebo-controlled trial of nicotinamide riboside in people with long-COVID brain fog. NR successfully increased NAD+ levels but primary outcomes (cognition, fatigue, sleep, mood) did not reach significance vs. placebo. Exploratory post-hoc analysis suggested potential benefits after 10 weeks.
Dose-Response of Paraxanthine on Cognitive Function
The first dose-response study of paraxanthine on cognitive function. Double-blind, placebo-controlled crossover trial testing 50, 100, and 200 mg in healthy adults. Found improvements in cognition, memory, reasoning, and sustained attention at 100-200 mg, with a good safety profile across 7 days of use.
Acute Paraxanthine Ingestion Improves Cognition and Short-Term Memory and Helps Sustain Attention in a Double-Blind, Placebo-Controlled, Crossover Trial
Placebo-controlled crossover trial in 13 healthy adults showing that 200 mg of paraxanthine improved short-term memory, reasoning, response time, and helped sustain attention over a 6-hour testing window.
Paraxanthine provides greater improvement in cognitive function than caffeine after performing a 10-km run
Study comparing paraxanthine to caffeine during a 10-km run. Paraxanthine improved executive function and mitigated exercise-induced cognitive fatigue, with some evidence of outperforming caffeine. Relevant for anyone interested in mental performance during physical activity.
Paraxanthine enhances memory and neuroplasticity more than caffeine in rats
Preclinical comparison showing paraxanthine enhanced memory and neuroplasticity more than caffeine in both young and aged rats. Also increased acetylcholine, dopamine, BDNF, and cyclic GMP. The most direct head-to-head animal comparison of paraxanthine vs. caffeine for brain health.
Paraxanthine, the primary metabolite of caffeine, provides protection against dopaminergic cell death via stimulation of ryanodine receptor channels
Foundational study showing paraxanthine (not caffeine) provided strong neuroprotection for dopaminergic neurons through ryanodine receptor channels. Important for understanding paraxanthine's unique protective mechanism beyond standard caffeine-like effects.
Psychostimulant pharmacological profile of paraxanthine, the main metabolite of caffeine in humans
Demonstrated that paraxanthine, but not caffeine, significantly increases dopamine release in the striatum via a nitric oxide/cGMP pathway. This is the key study establishing that paraxanthine has a distinct mechanism of action from caffeine.
Paraxanthine safety and comparison to caffeine
Comprehensive safety comparison of paraxanthine vs. caffeine. Covers toxicity data, blood pressure effects, clastogenicity, and teratogenicity. Concludes that paraxanthine has a better safety profile than caffeine across multiple measures.
Effects of L-Theanine Administration on Stress-Related Symptoms and Cognitive Functions in Healthy Adults
Randomized, placebo-controlled, crossover, double-blind trial in 30 healthy adults. Four weeks of 200 mg/day L-theanine significantly reduced depression, anxiety, and improved sleep quality scores, while also improving verbal fluency and executive function. One of the most-cited L-theanine studies.
Safety and Efficacy of AlphaWave® l-Theanine Supplementation for 28 Days in Healthy Adults with Moderate Stress
RCT of 400 mg/day L-theanine for 28 days in adults with moderate stress. Significantly decreased perceived stress and light sleep, improved sleep quality, and enhanced cognitive attention. Demonstrates L-theanine's dual benefit of calming effects and improved alertness.
Effects of Tea (Camellia sinensis) or its Bioactive Compounds l-Theanine or l-Theanine plus Caffeine on Cognition, Sleep, and Mood in Healthy Participants
Systematic review and meta-analysis of randomized controlled trials on tea, L-theanine, and L-theanine + caffeine combinations. Confirmed that theanine + caffeine improves attentional accuracy, and that theanine alone improves stress, anxiety, and objective sleep measures.
Promising, but Not Completely Conclusive - The Effect of l-Theanine on Cognitive Performance Based on the Systematic Review and Meta-Analysis of Randomized Placebo-Controlled Clinical Trials
Meta-analysis of placebo-controlled RCTs evaluating L-theanine's effects on cognitive function in healthy adults. Found that 200-400 mg/day reduced stress and anxiety under acute stress conditions. Noted that cognitive improvements are likely partly mediated through the stress-reduction pathway.
Activity of Choline Alphoscerate on Adult-Onset Cognitive Dysfunctions
Systematic review and meta-analysis of 8 clinical studies on alpha-GPC for adult-onset cognitive dysfunction. Found that alpha-GPC alone or combined with donepezil improved cognition, behavior, and functional outcomes in patients with cerebrovascular-related neurological conditions.
Comparison of the effects of choline alphoscerate and citicoline in patients with dementia disorders
Comparative systematic review of alpha-GPC vs. citicoline in dementia patients. Found alpha-GPC provides greater and more sustained cognitive benefits, supporting its role as a more effective cholinergic precursor.
Efficacy and safety of choline alphoscerate for amnestic mild cognitive impairment: a randomized double-blind placebo-controlled trial
Multicenter randomized placebo-controlled trial of 600 mg alpha-GPC daily for 12 weeks in 100 subjects with mild cognitive impairment. One of the larger dedicated alpha-GPC clinical trials.
Acute Alpha-Glycerylphosphorylcholine Supplementation Enhances Cognitive Performance in Healthy Men
The first study of alpha-GPC in healthy (non-impaired) adults. Randomized, double-blind crossover design in 20 resistance-trained males. Both 315 mg and 630 mg doses improved cognitive performance on Stroop, N-Back, and Flanker tests within 60 minutes of ingestion.
Vitamin B-6
Detailed biochemistry review of vitamin B6's role in the body. Covers PLP-dependent enzymes, neurotransmitter synthesis pathways (serotonin, dopamine, GABA, norepinephrine), myelin formation, and clinical consequences of deficiency.
Vitamin B6, B9, and B12 Intakes and Cognitive Performance in Elders: National Health and Nutrition Examination Survey, 2011–2014
Cross-sectional study of 2,421 elderly adults from the US NHANES database. Found associations between B6 intake and cognitive performance, particularly via NMDA receptor function and BDNF expression in the hippocampus.
Vitamin B6 deficiency hyperactivates the noradrenergic system, leading to social deficits and cognitive impairment
Animal study demonstrating that B6 deficiency hyperactivated the noradrenergic system, causing social deficits and cognitive impairment. B6 supplementation into the CNS reversed the behavioral deficits. Provides a mechanistic explanation for why B6 matters for brain function.
Exploring neuropsychiatric manifestations of vitamin B complex deficiencies
Comprehensive 2025 review of neuropsychiatric manifestations of B vitamin deficiencies. Covers the role of B6 as a cofactor for dopamine, serotonin, and GABA synthesis, and in homocysteine metabolism and neuroprotection.
Effects of Vitamin B12 Supplementation on Cognitive Function, Depressive Symptoms, and Fatigue: A Systematic Review, Meta-Analysis, and Meta-Regression
Systematic review and meta-analysis of 16 RCTs (6,276 participants) on B12 supplementation for cognitive function and depressive symptoms. Found no evidence that B12 supplementation improves cognition in people without overt deficiency. An important study for understanding the limits of B12 supplementation.
Vitamin B12 and cognitive function: an evidence-based analysis
Evidence-based analysis of B12 and cognitive function. Found moderate-quality evidence that B12 supplementation doesn't appreciably change cognitive function, but low-to-moderate evidence that B12 + folate may slow brain atrophy in people with mild cognitive impairment.
Vitamin B12 deficiency and cognitive impairment: A comprehensive review of neurological impact
Comprehensive review of B12 deficiency and cognitive impairment. Covers the role of B12 in myelin integrity, neurotransmitter synthesis, and homocysteine metabolism. Emphasizes that deficiency leads to oxidative stress, vascular damage, and neurodegeneration, making it a critical nutrient to maintain at adequate levels.
B Vitamins and the Brain: Mechanisms, Dose and Efficacy
The definitive review of all eight B vitamins and the brain. Found that 77 cross-sectional studies (34,000+ subjects) showed negative relationships between cognitive deficits and B vitamin status. Also noted that the research field has disproportionately focused on B6, B12, and folate while ignoring other B vitamins.
Share:
What Are Nootropics, Exactly?