3. Fatty acids, probiotics and more for ADHD

Lipid metabolism in ADHD shows altered levels of various fatty acids, with patients having different lipid and fatty acid profiles.¹
MPH and ATX influence ADHD symptoms via lipid metabolism, among other things², in different directions³.
One study found no changes in lipid metabolism in ADHD⁴

• 3. Fatty acids for ADHD
  • 3.1. Polyunsaturated fatty acids
    • 3.1.1. Omega-3 fatty acids
      • 3.1.1.1. Omega-3 fatty acids for ADHD
      • 3.1.1.2. Administration of omega-3 fatty acids for ADHD
    • 3.1.2. Omega-6 fatty acids
      • 3.1.2.1. Omega-6 fatty acids for ADHD
      • 3.1.2.2. Administration of omega-6 fatty acids for ADHD
  • 3.2. Monounsaturated fatty acids
  • 3.3. Saturated fatty acids
• 4. Low-density lipoprotein
• 5. Treatment of the gut-brain axis in ADHD
  • 5.1. Probiotics for ADHD
  • 5.2. Fecal transplantation for ADHD
• 6. Other substances for ADHD
  • 6.1. Polyphenols
  • 6.2. Phosphatidylserine

3. Fatty acids for ADHD¶

A deficiency of polyunsaturated fatty acids in the blood serum of children with ADHD persisted into adulthood.⁵ ADHD symptoms in adults correlated with elevated levels of saturated stearic acid and monounsaturated fatty acids.⁵

3.1. Polyunsaturated fatty acids¶

Lower levels of polyunsaturated fatty acids (PUFAs) correlated with ADHD ⁶⁷
One review came to the recommendation of a combination of EPA, DHA and GLA in a ratio of 9:3:1 for ADHD.⁸ The lead author is involved in a company that sells unsaturated fatty acids.

Rats fed a high-fat diet enriched with omega-3 fatty acids during lactation, after the mother had been fed a high-fat diet enriched with omega-6 fatty acids during pregnancy, suffered microcephaly (small head circumference) with reduced GLUT3 concentrations in the brain⁹

3.1.1. Omega-3 fatty acids¶

Omega-3 PUFAs are not synthesized in the human organism and must be taken in with food. If the diet is unbalanced, they must be supplemented. Foods with a high omega-3 PUFA content are linseed oil, linseed, chia seeds, walnut oil, walnuts, rapeseed oil, tuna, herring, salmon and mackerel.
The need for omega-3 PUFA is particularly high during growth phases (first years of life and puberty).
Omega-3 PUFAs are important for the anatomical and functional brain development of the brain. They influence the maturation and function of neurons and the processes of neurogenesis, migration, synaptogenesis and neurotransmission. They are substrates for the synthesis of bioactive compounds and are involved in the control of acute and chronic inflammation and the regulation of immune cells.¹⁰

Omega-3 fatty acids are among others:

• Eicosapentaenoic acid (EPA)
• Docosahexaenoic acid (DHA)
  • A combination of the triple unsaturated fatty acids EPA and DHA in rats in stress tests¹¹
    • Prevented or compensated dendritic atrophy in the hippocampus CA3 region
    • Restored GABA release in the hippocampus CA1 region
    • Improved spatial memory.
• Roughanic acid
• Alpha-linolenic acid
• Stearidonic acid
• Eicosatetraenoic acid
• Heneicosapentaenoic acid
• Docosapentaenoic acid
• Tetracosapentaenoic acid
  (scoliodonic acid)
• Tetracosahexaenoic acid
  (nisic acid)

The clinically relevant long-term fatty acid supply is determined using the erythrocyte membrane (from EDTA blood). The fatty acid analysis in plasma, on the other hand, only determines the daily intake¹²

3.1.1.1. Omega-3 fatty acids for ADHD¶

Omega 3 fatty acids correlate with ADHD symptoms

• in serum (daily supply)
  • found a review of 2 meta-analyses:¹³
    • reduced omega-3 blood levels (k = 9, n = 586)
    • Improvement of ADHD symptoms by omega-3 administration (k = 16, n = 1,408) at low potency (SMD according to Hedges g = 0.26) on hyperactivity (teacher and parent ratings) and inattention (only parent, not teacher ratings)
  • decreased¹⁴, which correlated with increased ADHD symptoms¹⁵¹⁶
  • unchanged for ADHD¹⁷
  • Alpha-linolenic acid
    • reduced in plasma¹⁸
  • Docosahexaenoic acid (DHA)
    • reduced; without correlation to ADHD symptoms⁵
    • significantly reduced¹⁹
    • increased in plasma¹⁸
  • Eicosapentaenoic acid (EPA)
    • significantly reduced¹⁹
    • increased in plasma¹⁸
• in erythrocyte membranes (long-term supply)
  • reduces¹⁴,
  • Docosahexaenoic acid reduces²⁰

3.1.1.2. Administration of omega-3 fatty acids for ADHD¶

A review of 2 meta-analyses found a small ((SMD according to Hedges g = 0.26)) Improvement in ADHD symptoms through omega-3 administration (k = 16, n = 1,408) with regard to hyperactivity (teacher and parent ratings) and inattention (only parent, not teacher ratings).¹³
A meta-analysis of k = 7 studies on n = 926 subjects found a statistically non-significant slight improvement in ADHD symptoms with omega 3 alone.²¹
An administration of 635 mg eicosapentaenoic acid (EPA) and 195 mg docosahexaenoic acid (DHA) (unsaturated fatty acids) reduced serum CRP and IL-6 levels in children with ADHD and improved ADHD symptoms within 8 weeks in a double-blind placebo study.²²

A combination of the triple unsaturated fatty acids EPA and DHA in rats in stress tests¹¹

• Prevented or compensated dendritic atrophy in the CA3 region of the hippocampus
• Restored GABA release in the CA1 region of the hippocampus
• Improved spatial memory.

A placebo-controlled double-blind study found improvements in attention in children with ADHD as well as in children not affected by omega-3 fatty acids.²³
A study of healthy adolescents found a trend towards an improvement in sustained attention and ADHD symptoms in those participants who consumed nuts more consistently when consuming walnuts over 6 months.²⁴ This could reflect the fact that young people who perceive a benefit (even unconsciously) from consuming nuts are more likely to continue doing so.

One RCT found no improvement in ADHD-RS intention score or inattention with omega-3/6 supplementation at either 6 or 12 months. There was a positive response of 46.3% in the omega-3/6 group and 45.6% in the placebo group. The study used two capsules per day, each containing 279 mg eicosapentaenoic acid [EPA], 87 mg docosahexaenoic acid [DHA], 30 mg gamma-linolenic acid [GLA].²⁵

Conclusion: Supplementation of omega-3 fatty acids could have a supportive effect. The achievable Effect size of 0.26 is too low to detect an improvement in an individual. Below an Effect size of 0.5, an improvement is only statistically detectable in one group. Treatment of ADHD with omega-3 fatty acids alone is therefore hopeless.

3.1.2. Omega-6 fatty acids¶

Omega-6 fatty acids are among others:

• Arachidonic acid (AA)
• Linoleic acid (LA)
• Gamma-linolenic acid (GLA)
• Dihomo-gamma-linolenic acid (DHGLA)
• Adrenic acid

3.1.2.1. Omega-6 fatty acids for ADHD¶

• Omega 6 fatty acids for ADHD:
  • in serum (daily supply)
    • increased¹⁵, which correlated with increased ADHD symptoms¹⁶¹⁷
    • Arachidonic acid
      • reduced; without correlation to ADHD symptoms⁵
      • significantly reduced{Yonezawa, Nonaka, Iwakura, Kusano, Funamoto, Kanchi, Yamaguchi, Kusumoto, Imamura, Ozawa (2018): Investigation into the plasma concentration of ω3 polyunsaturated fatty acids in Japanese attention-deficit hyperactivity disorder patients. J Neural Transm (Vienna). 2018 Jun 20. doi: 10.1007/s00702-018-1895-z.; n = 24}}
    • Dihomogammalinolenic acid reduced; without correlation to ADHD symptoms⁵
    • Adrenic acid increased¹⁷
      -Increased gamma-linolenic acid (GLA)¹⁷
  • in erythrocyte membranes (long-term supply)
    • Gamma-linolenic acid (GLA) increases²⁰
    • Arachidonic acid reduces²⁰

3.1.2.2. Administration of omega-6 fatty acids for ADHD¶

One RCT found no improvement in ADHD-RS intention score or inattention with omega-3/6 supplementation at either 6 or 12 months. There was a positive response of 46.3% in the omega-3/6 group and 45.6% in the placebo group. The study used two capsules per day, each containing 279 mg eicosapentaenoic acid [EPA], 87 mg docosahexaenoic acid [DHA], 30 mg gamma-linolenic acid [GLA].²⁵

Conclusion: Supplementation of omega-6 fatty acids has no effect on ADHD. The administration of omega-6 fatty acids (with the exception of arachidonic acid) could tend to have a detrimental effect.

3.2. Monounsaturated fatty acids¶

A study of genetic analyses found no evidence of a causal link between unsaturated fatty acids and ADHD.²⁶
One study found no change ADHD in serum.¹⁷
Two very small studies found increased monounsaturated fatty acids in ADHD:

• Omega-7 fatty acids
  • Palmitoleic acid elevated in serum, without correlation to ADHD symptoms⁵
• Omega-9 fatty acids
  • Nervonic acid (reduces ADHD found in erithrocyte membranes mapping the long-term supply)²⁰
  • Oleic acid
    • increased in erithrocyte membranes, which reflect the long-term supply)²⁰
    • increased without correlation to ADHD symptoms⁵
    • reduced in plasma¹⁸

3.3. Saturated fatty acids¶

A large study of 432 children found significantly higher serum levels of saturated fat in children with ADHD.²⁷ This correlated with an increased intake of nutrient-poor foods such as foods high in sugar and fat and a lower intake of vegetables, fruit and protein-rich foods than healthy children. It remains to be seen whether the change in diet is a cause, a consequence or a vicious circle.
Another study also found increased levels of saturated fatty acids in the blood (daily supply) and eritrhrocyte membranes (long-term supply) ¹⁴,
One study found no change ADHD in serum.¹⁷

4. Low-density lipoprotein¶

In children with ADHD, one study found significantly increased blood levels of total cholesterol and low-density lipoprotein (LDL), while high-density lipoprotein (HDL) and triglyceride (TG) levels did not differ from those of people with ADHD.²⁸ In contrast, another study found significantly lower blood levels of total cholesterol, high-density lipoprotein (HDL) and low-density lipoprotein (LDL) in boys with ADHD (regardless of subtype).²⁹
In adults, a large cohort study found a slightly reduced low-density lipoprotein (LDL) level.³⁰
A KIGGS study found no differences in serum lipid parameters between ADHD (n = 1,219) and controls (n = 9,741) for total cholesterol, LDL, HDL, or triglycerides, either at baseline or at 10-year follow-up, even when MPH use was taken into account.³¹

Treatment of bipolar adults with comorbid ADHD with lisdexamfetamine (Vyvanse) resulted in significant decreases in weight, body mass index, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, but not triglycerides or blood glucose levels.³²

A study suggests a genetic alteration of the receptor for low-density lipoprotein in ADHD³³
LDL cholesterol elevated in serum, without correlation to ADHD symptoms
The fact that lipoprotein metabolism is altered in ADHD was also the result of another small study.³⁴

Among other things, methylphenidate reduces the low-density lipoprotein level.³⁵

Further studies on fats and fatty acids in ADHD did not lead to a clear result.³⁶

5. Treatment of the gut-brain axis in ADHD¶

5.1. Probiotics for ADHD¶

For background information on gut bacteria, gut-brain axis and their role in the development of ADHD, see Gut bacteria, gut-brain axis (gut-brain axis) In the article Age-independent physical stress as an environmental cause of ADHD in the chapter Development.

Various studies report positive effects of probiotics in children with ADHD.

• L. rhamnosus GG
  • Administration during the first 6 months of life reduced risk of later ADHD³⁷
  • Giving children improved ADHD symptoms in the parent rating, but not in the teacher rating³⁸
• Bacteroidetes bifidum Bf-688
  • Administration to children improved inattention, hyperactivity/impulsivity, increased weight³⁹⁴⁰
    • Firmicutes reduced
    • Ratio of Firmicutes to Bacteroidetes (F/B ratio) reduced
    • Proteobacteria increased
    • improved neuropsychological performance (with co-medication with MPH)
    • reduced N-glycan biosynthesis (with co-medication with MPH)
    • significant improvement in omission errors in the CPT (with co-medication with MPH)
    • significant improvement in hit response time in CPT and CATA (with co-medication with MPH)
• B. subtilis, B. bifidum, B. breve, B. infantis, B. longum, L. acidophilus, L. delbrueckii, L. casei, L. plantarum L. lactis, L. salivarius, S. thermophiles
  • Administration in addition to MPH improved ADHD symptoms in children compared to placebo⁴¹
• L. reuteri, L. acidophilus, L. fermentum, B. bifidum
  • Administration improved ADHD symptoms RS in children compared to placebo. In addition, serum high-sensitivity C-reactive protein (hs-CRP) decreased and total antioxidant plasma volume (TAC) increased compared to placebo. CDI and other metabolic characteristics unchanged.⁴²
• L. mesenteroides, L. paracasei, L. plantarum, B-glucan, inulin
  • ADHD symptoms in children and adults improved to the same extent in the treatment group and placebo group, ASD symptoms remained unchanged⁴³
• Lactobacillus plantarum PTCC 1896™ (A7), Bifidobacterium animalis subsp. lactis (BB-12®)
  • Significant decrease in ADHD total scores on the CPRS (Connor Parent Rating Scale) after 4 weeks of administration in addition to MPH compared to placebo in addition to MPH, but no longer after 8 weeks of intervention.⁴⁴
• L. helveticus, B. animalis ssp. lactis, Enterococcus faecium, B. longum, Bacillus subtilis
  • Improvements in hyperactivity and academic performance. Improvements in ADHD symptoms correlated with lower cortisol levels. Double-blind RCT study over 3 months compared to placebo that observed ADHD symptoms, academic performance, FCC, gastrointestinal symptoms and sleep quality in college students with ADHD.⁴⁵

A meta-analysis found no improvement with probiotics in ADHD.⁴⁶

5.2. Fecal transplantation for ADHD¶

To date, the studies needed to assess whether fecal transplants are a treatment option for ADHD are lacking.

One study found that mice whose guts were contaminated with gut bacteria from people with ADHD had structural changes in the brain (white matter, gray matter, hippocampus, internal capsule), decreased connectivity between motor and visual cortices right in the resting state, and higher anxiety than mice in which gut bacteria from people without ADHD were used.⁴⁷
A single case study reported an improvement in ADHD symptoms in a young woman with gut bacteria replacement related to a recurrent Clostridioides difficile infection.⁴⁸

6. Other substances for ADHD¶

6.1. Polyphenols¶

Polyphenols are aromatic compounds with two or more hydroxyl groups directly bound to an aromatic ring. Polyphenols are formed from phenylalanine, which in turn is formed from shikimic acid.

Natural polyphenols (of which there are said to be over 8,000) are often contained in plants as bioactive substances (colorants, flavorings, tannins), e.g.

• Flavonoids (colorants)
  • Flavonoids appear to have a glutamate-antagonistic and GABA-agonistic effect.⁴⁹
• Anthocyanins (colorants)
• Procyanidins
• Benzoic acid derivatives, e.g.
  • Vanillic acid
  • Gallic acid
  • Protocatechuic acid
• Cinnamic acid derivatives, e.g.
  • Caffeic acid
  • Coumaric acid
• Style derivatives, e.g.
  • Resveratrol
    • Component of red wine

Certain polyphenols are said to be able to influence neurophysiological changes caused by early childhood stress:⁵⁰ e.g:

• Reduction of depressive symptoms through
  • Xanthohumol
  • Quercetin
  • Phlorotannins
• Reduction of anxiety symptoms through
  • Quercetin
  • Phlorotannins
• Elimination of the BDNF reduction by
  • Xanthohumol
• No correction of the dopamine and serotonin level changes in the brain stem triggered by early stress
• Reduction of the cortisol stress response to acute stress through
  • Xanthohumol

One study found a correlation of increased polyphenol intake with reduced risk of ADHD in preschool children.⁵¹

6.2. Phosphatidylserine¶

Phosphatidylserine is not a vitamin, but a phospholipid.

Source: Bieger.⁵²