MTHFR, Low Folate and ADHD

Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder, which means it affects how the brain develops and functions. People with ADHD struggle with inattentiveness, hyperactivity and/or impulsivity.

The DSM-5 defines ADHD as comprising three subtypes: predominantly inattentive, predominantly hyperactive, or combined type.¹ Within the three major subtypes, additional behavioral distinctions are sometimes defined, with some experts referring to seven types of ADHD:

1. Classic ADHD
2. Inattentive ADHD
3. Overfocused ADHD
4. Temporal Lobe ADHD
5. Limbic ADHD
6. Ring of Fire ADHD
7. Anxious ADHD

ADHD can only be diagnosed by a qualified healthcare professional as per criteria in the DSM-5-TR.

The DSM-5-TR was released in 2022 with several updates to ADHD diagnosis, including age of onset and how symptoms impacted daily life.
There are five criteria (A to E) for ADHD. Symptoms and/or behaviors must have persisted for at least six months in at least two settings (e.g., school, home, work) and these symptoms must have negatively impacted the individual’s ability to function academically, socially or at work.

In children and young adults (aged under 17), diagnosis requires at least six symptoms for diagnosis. In those older than 17, at least five symptoms are necessary.

In children, impulsiveness and hyperactivity are the most common symptoms. These symptoms decrease in adulthood, where inattentiveness becomes the leading symptom.

Inattentive type:

• Poor listening skills
• Loses and/or misplaces items needed to complete activities or tasks
• Sidetracked by external or unimportant stimuli
• Forgets daily activities
• Diminished attention span
• Lacks ability to complete schoolwork and other assignments or to follow instructions
• Avoids or is disinclined to begin homework or activities requiring concentration
• Fails to focus on details and/or makes thoughtless mistakes in schoolwork or assignments

Hyperactive type:

• Marked restlessness and fidgeting that is difficult to control
• Appears to be driven by “a motor” or is often “on the go”
• Lacks ability to play and engage in leisure activities in a quiet manner
• Incapable of staying seated in class
• Overly talkative

Impulsive type:

• Difficulty waiting turn
• Interrupts or intrudes into conversations and activities of others
• Impulsively blurts out answers before questions completed

Combined type:

• The individual meets both inattentive and hyperactive/impulsive criteria for the past six months.

Predominantly inattentive type:

• The individual meets criteria for inattentiveness, but not for hyperactivity/impulsivity.

Predominantly hyperactive/impulsive type:

• Meets hyperactivity/impulsivity criteria, but not inattentiveness.

Symptoms may be classified as mild, moderate, or severe based on symptom severity.

Genetic research shows that ADHD has a heritability of around 80%, which is higher than most other psychiatric conditions. In fact, ADHD has been described as “one of the most heritable” psychiatric disorders, and siblings have twice the risk of being diagnosed as the general population.⁴

ADHD heritability is largely due to many common genetic variants, although each variant has a very small effect.

A 2018 study found certain genetic variants involved in the folate metabolism pathway were significantly linked to ADHD. These variants included MTRR, RFC1, MTHFR, and BHMT genes, which suggests that genetic variants related to folate metabolism may influence ADHD traits.⁵

A 2020 study also showed that single-nucleotide polymorphisms (SNPs) explain about 22% of ADHD's heritability.⁶ This is about a third of the total heritability estimated from twin studies. However, the remaining genetic links are yet to be explained.

Another 2020 study with over 20,000 ADHD cases found only 12 significant genetic links, suggesting that genetic effects in ADHD are either very small or linked to very rare variants. Researchers have stated that apart from defined genetic syndromes (such as 22q11-DS, also known as DiGeorge syndrome), there is no proven rare variant that determines or predicts ADHD.⁷

More recently, however, a 2022 meta-analysis of 66 studies concluded that MTHFR A1298C is related to ADHD. It also found that other genetic mutations in the folate-homocysteine pathway may be linked to the development of ADHD due to their impact on folate levels.

The MTHFR C677T variant is known to contribute to folate deficiency, and as both DNA methylation and folate are required for cognitive development, reduced MTHFR activity or folate deficiency have been associated with several psychiatric disorders, including schizophrenia, bipolar disorder, depression, autism, and ADHD.⁸

People with ADHD are also more likely to be affected by autism, obesity, bipolar disorder and depression, anxiety, and substance use disorder. This suggests common underlying genetic factors.⁹

Yes, some studies have suggested that folate deficiency may be linked to ADHD.

Folate (vitamin B9) plays a vital role in brain function, particularly during pregnancy when the fetus is developing. Folate is critical in several key processes required for normal neurodevelopment and brain functioning, including DNA synthesis, regulation of gene expression, synthesis of phospholipids and neurotransmitters, and maintenance of healthy homocysteine levels.¹⁰

Deficiencies in folate have been linked to cognitive deficits and neurodevelopmental issues (including ADHD) in children. Low folate may impair DNA methylation involved in normal brain development and the regulation of cortical circuits, as well as reduced levels of tetrahydrobiopterin (BH4), a cofactor necessary for synthesizing key neurotransmitters. Low levels of these neurotransmitters have been linked to a higher risk of developing ADHD, which suggests that genetic variations affecting folate metabolism may contribute to ADHD-related traits.¹¹

The MTHFR and MTR genes are both linked to folate and homocysteine metabolism. MTHFR is required for converting folate to its active form, while MTRR (methionine synthase reductase) reactivates methionine synthase, the enzyme required for converting homocysteine to methionine. Mutations in either gene can impact these processes, potentially leading to elevated homocysteine levels and other health issues.¹²

Although genetics and folate levels may play a part in ADHD,  the disorder has also been linked to environmental factors, viral infections, smoking during pregnancy, nutritional deficiency, and alcohol exposure in the fetus. Every case is different, and every individual affected will have different symptoms and different needs.

Can methylfolate be helpful for MTHFR and ADHD?

There is currently very little research into methylfolate supplementation for those with ADHD symptoms. However, multiple studies have shown that methylfolate can bypass the MTHFR genetic mutation to restore healthy folate levels.

How do you know if ADHD is related to MTHFR?

Folate deficiency and high homocysteine are both key symptoms of MTHFR. If you or members of your family have ADHD and also have a history of low folate levels and heart conditions, it may be helpful to discuss MTHFR testing with your healthcare professional.

Several nutrients have been found effective in treating ADHD symptoms.

Omega 3

Omega-3 fatty acids have important anti-inflammatory effects which may be beneficial for those with ADHD, as many symptoms are linked to neuroinflammation. Some research has suggested that high-dose eicosapentaenoic acid (EPA) improves cognitive symptoms in young people with ADHD.¹³

GABA

While research into GABA and ADHD is limited, one small study found that 12 weeks of treatment with a prescription GABA medication improved behavioral and cognitive performance in children with ADHD.¹⁴

Other studies have shown that taking 300mg GABA one hour before bed helps people fall asleep faster, suggesting that GABA can promote relaxation and calm.¹⁵

Always consult your health professional before starting GABA supplementation for ADHD.

Neurofeedback
Current pharmacological treatments are not effective in 30% of ADHD cases and have poor long-term adherence. However, neurofeedback (NFB) and respiratory biofeedback (R-BFB) have shown promise in treating ADHD symptoms.¹⁶

Neurofeedback helps individuals adjust their brain activity by focusing on their brain activity, which is measured via electrodes placed on their scalp. This can help to improve attention span and reduce impulsivity.