Genetics of caffeine and brain-related outcomes - a systematic review of observational studies and randomized trials.

This systematic review investigated how common genetic variations interact with caffeine consumption to influence brain-related outcomes in humans.

The interventions and exposures examined across the included studies were:

**Caffeine consumption:** This included both habitual daily caffeine intake (e.g., from coffee, tea, energy drinks) and controlled caffeine supplementation (specific doses given in experimental settings).

**Genetic variations:** The primary focus was on polymorphisms (common variations) in genes associated with how the body processes caffeine (metabolism) and how the brain responds to it (effect). Specifically, the review highlighted the CYP1A2 gene (related to caffeine metabolism speed, categorizing individuals as 'fast' or 'slow' metabolisers) and the ADORA2A gene (related to caffeine sensitivity and its binding to adenosine receptors in the brain, categorizing individuals as 'high' or 'low' sensitivity). Other genetic variants were also considered.

The comparators used in the primary studies included:

Different levels of habitual caffeine intake.

Different doses of caffeine supplementation.

Placebo (for experimental studies).

Comparisons between individuals with different genetic variants (e.g., comparing those with a 'variant allele' to those with an 'ancestral allele', or different genetic scores/haplotypes).

The outcome measures, all related to brain function, were:

**Cognitive performance:** This broadly included measures such as reaction times, attention, reasoning, abstract reasoning, verbal-numerical reasoning, prospective memory, visual memory and search, processing speed, mental flexibility, and executive function. Some studies assessed cognition under normal conditions, during sleep deprivation, or during/post-exercise.

**Anxiety:** Measures related to mood and anxiety levels.

**Sleep disturbance / Insomnia:** Measures related to sleep quality, sleep onset, and the presence of insomnia symptoms.

This systematic review synthesized findings from 22 records representing 19 independent studies. The populations across these studies consistently involved **healthy adult participants aged 18 years and older**.

While the exact sample sizes varied widely across the individual studies included in the review, the review itself did not provide a cumulative total.

Regarding the demographic characteristics of the participants in the included studies:

**Ethnicity:** The review noted that 14 of the studies were conducted on populations described as "whites / Caucasian / Europeans." Two studies involved "mixed populations," and for six studies, the ethnicity of the population was "unknown."

**Setting:** The studies were conducted in various settings, including clinical trials and observational community-based studies, reflecting the diverse nature of the included research designs.

It's important to remember that this section describes the populations *within* the studies reviewed, not the population of the review itself.

The specific instruments and scales used to measure brain-related outcomes varied across the 22 studies included in this systematic review. However, the review categorized these measurements into three main groups:

**Cognitive Performance:** This was assessed using a variety of tests designed to measure different aspects of cognition. These included, but were not limited to, tests for:

* Abstract reasoning

* Verbal-numerical reasoning

* Prospective memory

* Visual memory and search

* Processing speed

* Mental flexibility

* Executive function

* Reaction times

* Attention

The review did not specify particular standardized cognitive batteries (e.g., CANTAB, Cogstate) but indicated that these broad categories of cognitive function were assessed.

**Anxiety:** Measures of anxiety and mood were used. The review did not list specific anxiety scales (e.g., State-Trait Anxiety Inventory, Hamilton Anxiety Rating Scale) but indicated that these studies aimed to quantify anxiogenic (anxiety-provoking) effects of caffeine.

**Sleep Disturbance / Insomnia:** These outcomes were assessed to understand caffeine's impact on sleep. Again, specific instruments were not detailed, but they would typically include measures of sleep onset latency, total sleep time, sleep quality, and self-reported insomnia symptoms.

For the genetic component, studies performed **genetic analysis for polymorphisms** (variations) in genes such as CYP1A2 and ADORA2A. This involved genotyping participants to identify their specific alleles (versions of a gene) at particular Single Nucleotide Polymorphisms (SNPs), such as rs762551 for CYP1A2 and rs5751876 for ADORA2A. Some studies also used genetic scores or tested haplotypes (combinations of alleles on the same chromosome) to assess genetic influence.

Caffeine intake was measured either through **self-reported data** on habitual intake (e.g., number of cups of coffee/tea) or through **controlled supplementation** with specific doses of caffeine in experimental settings.

This paper is a **systematic review** of existing literature, not a primary research study. It followed the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) guidelines and was registered with PROSPERO (registration no. CRD42021257556), indicating a pre-defined and transparent methodology.

**Search Strategy:**

**Databases:** PubMed and Embase were independently searched by two investigators.

**Date:** The search was conducted until April 21