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
    • 3.1.3. Administration of omega-3 and omega-6 fatty acids for ADHD
  • 3.2. Monounsaturated fatty acids
  • 3.3. Saturated fatty acids
  • 3.4. Fatty acid-binding proteins
• 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 administration 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.

A double-blind placebo-controlled study found no improvement in ADHD symptoms with DHA.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 in ADHD:
  • in serum (daily supply)
    • increased¹⁵, which correlated with increased ADHD symptoms¹⁶¹⁷
    • Arachidonic acid
      • reduced; without correlation to ADHD symptoms⁵
      • significantly reduced¹⁹
    • 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].²⁶

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.

3.1.3. Administration of omega-3 and omega-6 fatty acids for ADHD¶

A double-blind RCT on 41 children with ADHD and learning disorders found improvements with a daily dose of EPA (186 mg), DHA (480 mg), gamma-linolenic acid (96 mg), vitamin E (as DL-alpha-tocopherol, 60 IU), cis-linoleic acid (864 mg), AA (42 mg) and thyme oil (8 mg). The placebo group received olive oil.²⁷
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] and 30 mg gamma-linolenic acid [GLA].²⁶
.

3.2. Monounsaturated fatty acids¶

A study of genetic analyses found no evidence of a causal link between unsaturated fatty acids and ADHD.²⁸
One study found no change in serum in ADHD.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 erythrocyte membranes mapping the long-term supply)²⁰
  • Oleic acid
    • increased in erythrocyte 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.²⁹ 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 erythrocyte membranes (long-term supply) ¹⁴,
One study found no change in serum in ADHD.¹⁷

3.4. Fatty acid-binding proteins¶

Fatty acid binding proteins (FABPs) are small cytoplasmic proteins that are involved in cellular lipid metabolism through the uptake and intracellular transport of hydrophobic substances such as fatty acids, cholesterol and retinoids. Among other things, they transport long-chain polyunsaturated fatty acids (PUFAs), which are essential for brain development and neurotransmission.³⁰

It is possible that FABPs are the primary targets of endocannabinoid transport inhibitors such as AM404, VDM-11, LY-2183240, URB597, AM1172, O-2093, OMDM-2, UCM-707, guineensin, WOBE437 and RX-055 and thus an important element in their in vivo mediated effects such as regulation of pain, inflammation, neuroprotection and neuronal signaling.³¹

Subtypes:

• FABP1 (not executed here)
• FABP2 (not executed here)
• FABP3³⁰
  • Other names: Fatty acid-binding protein 3, H-FABP, M-FABP (Muscle Fatty Acid-Binding Protein), MDGI (Mammary-derived growth inhibitor), O-FABP (Cardiac fatty acid-binding protein), FABP11
  • In the brain
    • In
      • Hippocampus
      • Olfactory bulb
      • Cerebellum
      • Thalamus
      • Hypothalamus
      • Caudatus putamen
    • In the cytoplasm
    • In neuron nuclei
    • Activation of nuclear receptors
      • FABP3 transports ligands preferentially to PPARα³¹
    • Associated with functional signaling processes rather than long-term structural changes
  • Ligands
    • High affinity for epoxyeicosatrienoic acids (endocannabinoids derived from arachidonic acid)
    • Arachidonic acid: Ki 0.03³¹
    • AEA: Ki 3.07³¹
    • OEA: Ki 4.69³¹
  • FABP3 binds to D2R and regulates D2R³²³⁰
• FABP4 (not executed here)
• FABP5³⁰
  • Other names: Fatty acid-binding protein 7, Epidermal fatty acid-binding protein 5 (E-FABP), Psoriasis-associated fatty acid-binding protein (PA-FABP), Epidermal type fatty acid-binding protein
  • In the brain in
    • Hippocampus
    • Olfactory bulb
    • Cerebellum
    • Thalamus
    • Hypothalamus
    • Caudatus putamen
    • Amygdala
    • Cerebral cortex
    • Corpus callosum
    • Retina
    • Lens
    • In neurons and glial cells
      • In the Soma
      • In the cores
      • In the extensions
  • Functions
    • Key role in early development
      • Involved in neuronal cell differentiation
      • Involved in neurite growth
    • Highest expression in prenatal and early postnatal neurons
    • Associated with functional signaling processes rather than long-term structural changes
    • Activation of nuclear receptors
      • PPAR³³³¹
      • FABP5 enhances the activation of PPARβ/δ³¹
      • RXR³⁰
    • FABP5 protects against 6-OHDA-induced Parkinson’s disease via the PPARγ/SIRT1/PGC-1α signaling pathway³⁴
    • Key role in the regulation of central endocannabinoid signaling
      • At glutamatergic synapses³⁵
      • Reduces AEA³³
      • FABP5 deletion³⁶
        • Increases AEA in striatum, PFC, midbrain and thalamus
        • Increases 2-AG in the midbrain
        • Impaired tonic 2-AG and AEA signaling at GABAergic synapses of medium spiny neurons in the striatum
        • Reduced phasic 2-AG-mediated short-term synaptic plasticity
        • Left CB1R expression and function unchanged
      • FABP5 deletion in astrocytes, but not in neurons³⁷
        • Suppressed the 2-AG-mediated depolarization-induced suppression of inhibition in the hippocampus
  • FABP5 and dopamine
    • FABP5 facilitates the uptake of DHA through the blood-brain barrier into the brain³⁸
      • The PPARγ agonist pioglitazone increased FABP5 expression and DHA uptake into the brain³⁹
    • DHA appears to facilitate dopamine transport⁴⁰
    • DHA deficiency in the brain of female rats decreased D2-like receptors in the ventral striatum and increased D1-like receptors in the caudate nucleus⁴¹
  • Ligands
    • High affinity for epoxyeicosatrienoic acids (endocannabinoids derived from arachidonic acid)
    • Are probably closely linked to disorders associated with altered neurotransmission
    • Arachidonic acid: Ki 0.12³¹
    • AM404: Ki 0.39³¹
    • AM1172: Ki 0.49³¹
    • GW7647; Ki 0.70³¹
    • BMS309403: Ki 0.89³¹
    • AEA: Ki 1.26³¹
    • VDM11: Ki 1.75³¹
    • OEA: Ki 2.22³¹
    • OMDM1: Ki 2.67³¹
    • OMDM2: Ki 3.85³¹
• FABP6 (not executed here)
• FABP7³⁰
  • Other names: Fatty acid-binding protein 7, B-FABP, Brain-type fatty acid-binding protein, Brain lipid-binding protein (BLBP), Mammary-derived growth inhibitor relate
  • In the brain in
    • Hippocampus
    • Olfactory bulb
    • Cerebellum
    • Thalamus
    • Hypothalamus
    • Amygdala
    • Cerebral cortex
    • Corpus callosum
    • Radial glial cells and immature astrocytes
      • In the cytoplasm
      • At the core
  • Functions
    • PUFA metabolism
    • Neuronal migration
    • Development of neural progenitor cells
    • Pattern formation of the neural axis
    • Sleep
    • Clock-controlled gene, involved in sleep-wake regulation
    • Metabolic function
    • Potentially involved in developmental disorders and neurodegeneration
    • Associated with long-term structural changes rather than functional signaling processes
  • Ligands
    • No strong preference for a certain type of fatty acid at body temperature
    • When bound to docosahexaenoic acid
      • Localization of FABP7 in the cell nucleus
      • Influencing gene expression
    • Arachidonic acid: Ki 0.09³¹
    • AEA: Ki 0.80³¹
    • OEA: Ki 0.35³¹
  • FABP7 deletion causes³⁰
    • Abnormal dendritic morphology
    • Reduced density of spinous processes in astrocytes and cortical pyramidal neurons
    • Reduced number of excitatory synapses in the mPFC
    • Reduced frequency and amplitude of excitatory postsynaptic miniature currents
    • Reduced brain glucose metabolism in the striatum, cortex, hypothalamus and amygdala
    • Increased brain glucose metabolism in the hippocampus, thalamus, periaqueductal gray, superior colliculi, inferior colliculi, cerebellum and midbrain
    • Anxiety and stronger fear memory and lower DHA brain levels during the neonatal period of null mutant FABP7 mice⁴²
  • FABP7 expression fluctuates with the circadian rhythm
  • FABP7 upregulation in the PFC is said to correlate with the severity of autism⁴³
• FABP8 (not executed here)
• FABP9 (not executed here)

Changes in FABP expression and PUFAs in the brain influence important regulatory proteins and signaling pathways such as peroxisome proliferator-activating receptors (PPARs) and retinoid X receptors (RXRs).

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.⁴⁴ 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).⁴⁵
In adults, a large cohort study found a slightly reduced low-density lipoprotein (LDL) level.⁴⁶
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.⁴⁷

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.⁴⁸

A study suggests a genetic alteration of the receptor for low-density lipoprotein in ADHD⁴⁹
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.⁵⁰

Among other things, methylphenidate reduces the low-density lipoprotein level.⁵¹

Further studies on fats and fatty acids in ADHD did not lead to a clear result.⁵²

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 ADHD⁵³
  • Giving children improved ADHD symptoms in the parent rating, but not in the teacher rating⁵⁴
• Bacteroidetes bifidum Bf-688
  • Administration to children improved inattention, hyperactivity/impulsivity, increased weight⁵⁵⁵⁶
    • 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)
  • Bacteroidetes bifidum BD1 administration to neonatal female SHR rats (109 CFU daily via gavage for 3 weeks) resulted after 7 weeks in⁵⁷
    • congenital hyperactivity significantly reduced
    • DAT and tyrosine hydroxylase increased in the striatum
    • activated microglia significantly reduced
    • Treg cells in the spleen significantly increased
    • α-Diversity in the gut microbiota improved
    • Firmicutes/Bacteroidota ratio reduced
    • Muribaculaceae increased
    • Proliferation of Clostridia_UCG-014 suppressed
  • Bifidobacterium bifidum TMC3115 in combination with 2’-fucosyllactose (2’-FL) induced in newborn female SHR⁵⁸
    • Hyperactivity reduced
    • Expression of tyrosine hydroxylase and dopamine transporter increased in the striatum
    • Increased diversity of the intestinal microbiota
    • Bacillus and Turicibacter reduced
• 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 placebo⁵⁹
• L. reuteri, L. acidophilus, L. fermentum, B. bifidum
  • Administration improved ADHD symptoms in children compared to placebo. In addition, high-sensitivity C-reactive protein (hs-CRP) in serum decreased and total antioxidant plasma volume (TAC) increased compared to placebo. CDI and other metabolic characteristics unchanged.⁶⁰
• 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 unchanged⁶¹
• 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.⁶²
• L. helveticus, B. animalis ssp. lactis, Enterococcus faecium, B. longum, Bacillus subtilis⁶³
  • Administration over 3 months improved hyperactivity, gastrointestinal symptoms, improved school performance in a double-blind RCT
  • younger test subjects showed greater improvements
  • Improvements correlated with reduced cortisol levels

A meta-analysis found no improvement with probiotics in ADHD.⁶⁴

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.⁶⁵
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.⁶⁶

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.⁶⁷
• 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:⁶⁸ 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.⁶⁹

6.2. Phosphatidylserine¶

Phosphatidylserine is not a vitamin, but a phospholipid.

Source: Bieger.⁷⁰