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GABA

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GABA

Other names for GABA are:

german: gamma-aminobutyric acid, γ-aminobutyric acid, 4-aminobutyric acid, piperidic acid
english: gamma-Aminobutyric acid

GABA (around 33% of all synapses)1 and glutamate are the most common neurotransmitters in the brain.

While glutamate is excitatory, GABA has an inhibitory effect. GABA is an antagonist (inhibitor) of glutamate.
GABA and glutamate are essential for controlling the HPA axis.

Glutamine is synthesized to glutamate by glutamate synthase.2
Glutamate is synthesized to GABA by glutamate decarboxylase using vitamin B6.2
Serotonin stimulates GABA synthesis and GABA receptor affinity.2

1. GABA and stress

A large number of studies on rats show that acute stress alters the GABA response differently depending on gender, stressor and receptor type.3 Studies on humans under stress showed increased glutamate levels4 and decreased GABA levels.5
Another study in male volunteers found no change in GABA and glutamate levels in response to acute psychological stress.6

Exposure to stress increases the (stimulating) glutamate level in the PFC7 and the (inhibiting) GABA level in some areas of the brain (hypothalamus, PFC),89 while the GABA level in other areas of the brain (hippocampus) decreases. In contrast, stimulation by a new environment increases the GABA level in the hippocampus.10

Hippocampus, amygdala and PFC communicate inhibitory via GABA and excitatory via glutamate to the HPA axis.11

3 hours of yoga per week improved mood and reduced anxiety in healthy subjects, which correlated with increased GABA levels in the thalamus. 3 hours of walking per week were less effective.12

2. GABA neurons, receptors, transporters

2.1. GABA neurons

GABA neurons exist

  • Outside the brain: in the enteric nervous system (intestine)
  • In the brain:
    • Effector GABA neurons (rare), project into the periphery, i.e. into the body.
    • GABA interneurons (frequent), regulate the activity of other neurons that mostly work with biogenic amines. Mainly found in:
      • Thalamus
      • Hippocampus
      • Cerebral cortex
      • Striatum (95 % GABAerg)
      • Globus pallidus
      • Cerebellum
      • Substantia nigra

2.2. GABA receptors

2.2.1. GABA-A

2.2.1.1. Structure of GABA-A receptors

GABA-A receptors usually consist of 2 α-, 2 β- and 1 γ-subunit.
GABA-A-rho receptors consist only of ρ-subunits.

  • GABA-A receptor subunits
    • Α1 - α6 (Alpha)
      • Α1 sedating
        • Benzodiazepines
      • Α2 anxiolytic (anxiolytic)
      • Α3 muscle relaxant
    • Β1 - β3 (Beta)
    • Γ1 - γ3 (gamma)
    • Δ (Delta)
    • Ε
    • Π
    • Θ
    • Ρ1 - ρ3 (rho)
2.2.1.2. Agonists of GABA-A
  • Benzodiazepines
    • High dependency potential (within 2 weeks)
  • Barbiturates13
    • High dependency potential
    • No longer approved as a sleeping pill in D and CH
  • Clomethiazole
  • Allopregnanolone
    • Pregnane steroid
    • GABA-A agonist14
    • Upregulation of the GABA-A-α4 receptor15
    • Depending on the estrogen level.
      • Prooestrus (2-day pre-rut)16
        • Hippocampus: higher allopregnanolone level
        • Hypothalamus: low allopregnanolone level
      • Estrus (oestrus) and Dieoestrus16
        • Hippocampus: low allopregnanolone level
        • Hypothalamus: high allopregnanolone level
    • Prolonged exposure to allopregnanolone downregulates the GABA-A-1 and GABA-A-4 receptors.
  • Pregnanolone
    • Pregnane steroid
    • GABA-A agonist14
  • AllotetrahydroDOC
    • Pregnane steroid
    • GABA-A agonist16
  • Alcohol
  • Muscimol
    • Poison of the fly agaric, hallucinogenic
  • Magnolol17
    • Extract from the bark of certain magnolia species
    • Biphenolic isomer
    • GABA-A agonist
  • Honokiol17
    • Extract from the bark of certain magnolia species
    • Biphenolic isomer
    • GABA-A agonist
2.2.1.3. Antagonists of GABA-A
  • Α-Thujone, antispasmodic
  • Picrotoxinin
  • DHEA
    • Also called dehydroepiandrosterone, prasterone (INN), dehydroepiandrosterone, dehydroepiandrostenedione, didehydroepiandrosterone, DHEA, androstenolone, prasterone (INN)18
    • Non-competitive GABA-A antagonist16
  • DHEA sulphate
    • Dehydroepiandrosterone sulfate18
  • Progesterone
    • Non-competitive GABA-A antagonist16
  • Pregnelonone sulfate
    • Non-competitive GABA-A antagonist19
  • Oroxylin A
    • Oroxylin A appears to improve ADHD-like behaviors in SHR via enhancement of DA neurotransmission and not via modulation of the GABA pathway as previously reported20
2.2.1.4. Involvement of GABA-A deficiency or excess
  • Memory and learning problems15
    • Region: Hippocampus
    • GABA-A subtype: α5, δ
  • Anxiety and emotional problems21
    • Region: hippocampus, amygdala
    • GABA-A subtype: α2, α4, β3,δ
  • Fatigue, drowsiness, exhaustion15
    • Region: not restricted
    • GABA-A subtype: α1
  • Stress-induced depression15
    • Region: not restricted
    • GABA-A subtype: α1, α3, β1, β3, γ2, δ
  • Eating disorders15
    • Region: Hypothalamus
    • GABA-A subtype: β3
  • Alcohol addiction / relapse21
    • Region: not restricted
    • GABA-A subtype: α6
  • Balance and movement disorders21
    • Region: Cerebellum
    • GABA-A subtype: α6, β2, δ
  • Epilepsy and neuronal excitation disorders15
    • Region: not restricted
    • GABA-A subtype: α1, α3, β1, β3, γ2, δ
  • ADHD
    THC is a GABA and CB1 receptor antagonist.
    GABA neurons inhibit dopamine neurons.
    THC inhibits GABA, which reduces the dopamine inhibition of GABA.
    As a result, dopamine is increased.2223

2.2.2. GABA-B

  • Agonist of GABA-B:
    • Baclofen

2.2.3. GABA-C

Subtypes 1 -3 of the GABA-C receptor are now known as GABA-A-rho receptors.

2.3. GABA transporter

GABA transporters by GABA affinity, descending:

  • GAT-1 (more than 3/4 of GABA reuptake in the brain)
    • Mice with a blocked GAT-1 GABA transporter show hyperactivity and inattention.24
  • GAT-3
  • GAT-2
  • GAT-4

3. Drug effect on GABA

3.1. GABA agonists (reinforcing)

The receptor binding of these agonists is still unknown to us:

  • Progesterone (oral): sleep-promoting
    • Other opinion: non-competitive GABA-A antagonist: Paoletti et al25
  • L-theanine2613
  • Taurine (acts primarily via glutamate inhibition)1326
  • Rhodiola2613
  • N-pantoyl-GABA (hopantenic acid, pantogam)
    Pantogam is a drug commonly used in the former Soviet Union to treat a variety of mental disorders. It is reported to have a helpful effect on ADHD.27
  • Neuroactive steroids13
  • Gabapentin
    Contrary to some reports, gabapentin is not a GABA agonist.
    Although gabapentin was developed as a GABA analog, it is neither a GABA agonist nor does it inhibit the uptake or degradation of GABA. Gabapentin is thought to bind to the α2δ1 subunit of Ca2+ channels, which affect Ca2+ currents that are widely distributed in the brain and spinal cord. This may explain the benefit of gabapentin in seizures, pain and several disorders.28
    Gabapentin has considerable side effect potential.
  • Vitamin D329
  • Electroconvulsive therapy is said to have a GABA-agonistic effect30

3.2. GABA antagonists (inhibitory)

  • Bicuculline13
  • Inverse agonists13
  • DBI peptides13
  • Convulsives13
    • Picrotoxin
    • TBPS
  • Flumazenil
    Although flumazenil is a GABA antagonist, one study surprisingly found an anxiolytic and tension-reducing effect on stress.31

Serotonin stimulates GABA synthesis and increases GABA receptor affinity (not verified).32
Serotonin deficiency inhibits the effectiveness of GABA.

4. Effect of GABA

  • Anxiolytic (anxiety-relieving)
  • Analgesic (pain-relieving)
  • Relaxing (relaxing)
  • Anticonvulsant (prevents epilepsy)
  • Blood pressure stabilizing
  • Sleep-promoting

GABA itself does not have a direct inhibitory effect, but inhibits the presynaptic release of excitatory neurotransmitters. GABA is the primary antagonist of the excitatory glutamate.

While GABA inhibits ACTH release from the HPA axis (by directly addressing the paraventricular nucleus (PVN) in the hypothalamus), glutamate promotes ACTH release via projections from the hypothalamus and brainstem.33

In addition to its neuronal effects, GABA has a variety of paracrine and endocrine effects.
It has a central effect on the hypothalamic secretion of releasing factors, GABAergic neurons
innervate the pituitary gland. GABA is transmitted paracrine via the portal vein system to the pituitary gland.

Prenatal stress delays the migration of GABAergic cell precursors from their place of origin in the medial ganglionic eminence (in the forebrain) to their destination in the cortex.3435 This GABAergic cell migration is crucial for later cortical function, e.g. in schizophrenia.343637 The subsequent maturation of GABAergic cells is also influenced by prenatal stress and correlates with altered social and anxiety-like behavior after prenatal stress. An IL-6 antagonist can prevent a maternal stress-induced delay in the migration of GABAergic cell precursors in mice.34353834

5. Measurement of GABA

The GABA neurotransmitter level in the brain should be easy to measure in blood plasma.1
However, this is contradicted by the fact that GABA cannot cross the blood-brain barrier. In addition, all recent studies use complex MRI methods to measure the GABA level in the brain.

However, lipophilic GABA derivatives such as gabapentin or pregabalin can cross the blood-brain barrier and are used as first-choice drugs for generalized anxiety syndrome.

The activation of GABA-B receptors is to be measured by transcranial magnetic stimulation single pulse measurement of the contralateral cortical silent period.39

6. Effects of GABA deficiency

Very low to low GABA levels correlate with:26

  • Chronic exhaustion (adrenal fatigue syndrome)
  • High blood pressure
  • Chronic pain
  • Irritable colon (irritable bowel syndrome)
  • Premenstrual syndrome
  • Depression
  • Epilepsy
  • Schizophrenia
  • Mania
  • Cravings for sugar/sweets (carbohydrates)
  • Paresthesia (symptoms of paralysis)
  • Muscle tension, muscle pain or muscle stiffness
  • Ringing in the ears (tinnitus)
  • Altered olfactory sensations
  • Headache
  • Insomnia
    • Insomnia correlated with a 30% reduction in GABA levels in the brain40
    • GABAergic drugs have a sleep-promoting effect.4142
  • Night sweats, sweaty hands, cold sweat
  • Hyperventilation
  • Tachycardia
  • Memory loss
  • Concentration problems
  • Impulsiveness
  • Impatience
  • Increased nervousness
  • Inner restlessness
  • Irritability
  • Mood swings
  • Fears, panic attacks
    • In contrast, high GABA levels and low glutamate levels in the ACC have been reported to correlate with high levels of harm-avoidance43 and higher anxiety.44

In rats, the GABA-A receptor antagonist picrotoxin decreased GABA levels in the mPFC and the GABA-A receptor agonist muscimol increased GABA levels in the mPFC.45

  • A reduced GABA level in the mPFC caused:
    • Attention problems45
    • Motor hyperactivity 45
      • Mice with a blocked GAT-1 GABA transporter show hyperactivity and inattention.24
    • Increased rate of fire, especially in bursts45
    • Increased bursts45
    • Significantly increased prefrontal LFP power45
    • Impatience/irritability correlated with lower GABA levels in the dorsolateral PFC.46

A reduced GABA level in the anterior cingulate cortex (ACC) correlated in women with ADHD with47

  • Increased impulsivity
  • Increased glutamate levels in the anterior cingulate cortex (ACC).

7. Effects of excess GABA

In rats, the GABA-A receptor antagonist picrotoxin decreased GABA levels in the mPFC and the GABA-A receptor agonist muscimol increased GABA levels in the mPFC.45

  • An increased GABA level in the mPFC caused45
    • Attention problems
    • Increased premature reactions (reaction errors)
    • Reduced open-field movement activity (dose-dependent)
    • Reduced rate of fire
    • Reduced bursts

An increased GABA level in the anterior cingulate cortex (ACC) correlated in women with ADHD with47

  • Aggression increased
  • Unchanged glutamate level

GABA inhibits long-term potentiation, which is essential for long-term memory.48

8. Treatment of a GABA deficiency

Bieger49 suggests the following treatment options for GABA deficiency:

  • GABA substitution with glutamine (precursor of glutamate and GABA)
  • Combined administration of glutamine and glycine
    • Glutamine/GABA and glycine work synergistically to promote sleep, relax and pave the way for the nightly regeneration of the endocrine system
  • Treatment of a GABA deficiency in the body with paracrine GABA
  • Modified sublingual GABA preparations can transport GABA to the brain via the oral mucosa “via secondary routes”
    fast effect within minutes, therefore suitable for the immediate treatment of anxiety
  • Lipophilic GABA derivatives
    • GABA coupled to niacin (cavinace)
  • GABA coupled to phenol (phenibut)
    Acts as a GABA mimetic, mainly as a GABA-B receptor agonist and (at higher doses) also to some extent as a GABA-A receptor agonist. Stimulates dopamine receptors and antagonizes β-phenethylamine (PEA), a putative endogenous anxiogen.50
    The half-life is a good 5 hours. One and a half to three hours elapse between ingestion and effect. The maximum effect occurs between 4 and 6 hours. A second (subjective) phase of action should occur after 12 to 24 hours.
    Phenibut, which crosses the blood-brain barrier, is a phenylethylamine and GABA derivative. It was discovered in the Soviet Union and is still used there today to treat ADHD.51
    Phenibut is freely available in Europe as a food supplement.
    • Dosage of Phenibut (Noofen, historical)52
      • “Asthenic and anxious-neurotic states:
        • Adults - 250-500 mg three times daily. Maximum single value
          Dose -750 mg, for patients over 60 years - 500 mg.
          over 2-3 weeks, max. 4-6 weeks
        • Children up to 8 years - single dose 125 mg
        • Children 8 to 14 years - 250 mg 3 times a day
          Doctor determines duration of treatment
      • Meniere’s disease / dizziness in connection with vestibular dysfunction
        • infectious dysfunction of the vestibular apparatus / exacerbation of Meniere’s disease: 750 mg 3 times a day, 5-7 days
        • to reduce vestibular disorders: 250 mg - 500 mg 3 times a day for 5-7 days, then - 250 mg per day for 5 days more
        • for mild forms of the disease; 250 mg twice daily for 5-7 days, then 250 mg once daily for 7-10 days
      • Dizziness due to dysfunction of the vestibular apparatus of vascular and traumatic origin
        • 250 mg 3 times a day for 12 days.
      • Kinetosis prophylaxis:
        • 250-500 mg one hour before the expected swaying or at the first symptoms of kinetosis (e.g. nausea)
      • in the case of severe symptoms (vomiting etc.), the use of the medication is less effective.
      • Prevention of alcohol abstinence syndrome:
        • in the first few days - 250-500 mg 3 times a day.
          and 750 mg before bedtime; then gradually reduce the dose.
      • The development of drug dependence and addiction, abstinence syndrome were not noticed.“
    • However, an individual case of addiction during self-treatment53 and a report of withdrawal symptoms from Phenibut54 obtained on the Internet give cause for caution against careless use.
    • Suppliers of Phenibut as a dietary supplement do not recommend continuous use in order to avoid tolerance development and dependence. It is recommended to limit the intake to once or twice a week.
    • In addition, the risk that Phenibut is broken down by the liver is pointed out, so that alcohol, benzodiazepines or opioids should be avoided when taking it and, regardless of this, liver values should be checked when taking it.
    • A combination with drugs can be life-threatening.
  • Gabapentin
    • A high correlation with opiod abuse is reported for gabapentin abuse.55
  • Pregabalin
  • GABA-related drugs that can cross the blood-brain barrier better than GABA itself
    • Increased GABA effect through inhibition of GABA degradation:
      • Valproic acid (Ergenyl)
      • Vigabatrin (Sabril)
    • Increase in GABA levels through GABA synthesis and through GABA reuptake inhibitors:
      • Vigabatrin
    • CNS-active GABA drugs:
      • Progabid (only in France as Gabrene)
    • Glutamate antagonists:
      • Pregabalin (Lyrica)
      • Gabapentin (Neurontin)
  • Vitamin D3
    • A study of adolescent bipolar patients found a GABA deficiency in the anterior cingulate cortex (0.066 compared to 0.082 in non-affected patients). After 8 weeks of treatment with 2000 IU D3 daily, the GABA value of 0.080 had equalized with that of non-affected persons, while the symptoms of mania and depression were significantly weakened at the same time.29

9. Possible side effects of GABA / indications of GABA overdose

Source, unless otherwise stated: Vitalstoffmedizin.com.56

  • Tiredness
  • Dizziness
  • Slowed thinking
  • Impaired coordination up to the impossibility of driving a car
  • Suicidal thoughts or completed suicide in one in 500 people treated
  • Severe depression
  • Severe restlessness
  • Panic attacks
  • Sleep disorders (actually an indication for the analog)
  • Irritability
  • Aggressiveness47
  • Willingness to use violence
  • Extreme increase in activity and verbal rage
  • Otitis media
  • Respiratory tract infections
  • Pancreatitis
  • Leukocytopenia
  • Thrombocytopenia
  • Weight gain
  • Pronounced dry mouth
  • Hallucinations
  • Amnesia

Prolonged GABA-A receptor stimulation with GABA-A receptor agonists leads to downregulation of the GABA-A receptors.21 Prolonged treatment with benzodiazepines, barbiturates or alcohol is therefore associated with a considerable risk of addiction. Hormone treatments with GABA agonists should also be treated with extreme caution. Exposure to allopregnanolone for as little as 90 minutes causes the GABA-A receptors to develop tolerance.

A natural exposure to allopregnanolone occurs during pregnancy. According to our hypothesis, the loss of this exposure with simultaneous downregulation of the GABA-A receptors could possibly be one of the reasons for postnatal depression.

The production of GABA and cortisol is increased during stress. A combination of prolonged elevated cortisol and GABA levels leads to irreversible cognitive damage.15

The effect of prolonged exposure to benzodiazepines or alcohol on GABA receptors is similar to that of prolonged chronic stress15

10. GABA for ADHD

There are multiple indications of the involvement of GABA and glutamate abnormalities in ADHD.
In our opinion, it is striking that the typical symptoms of GABA deficiency described are phenotypically more likely to be found in ADHD-I and the typical symptoms of GABA overdose described are phenotypically more likely to be found in ADHD-HI. We have not yet been able to identify any studies on this.

10.1. GABA imbalance in ADHD

An MRI study of 50 unmedicated children (26 with ADHD, 24 controls) aged 5 to 9 years found:57

  • GABA significantly reduced in the striatum
  • GABA unchanged in ACC, dlPFC and premotor cortex (PMC).
  • Glutamate unchanged in striatum, ACC, dlPFC and PMC.

Another MRI study found reduced GABA levels in the ACC in women with ADHD. Reduced GABA also correlated with aggression and impulsivity, while increased glutamate also correlated with impulsivity.58

A meta-study found no changes in GABA levels in ADHD.59

In the Spontaneously Hypertensive Rat (SHR), which serves as a genetic rat model for hypertension and ADHD-HI (with hyperactivity), downregulation of dopamine D1-like GABA receptors was found, which may indicate an excess of GABA in ADHD-HI.60
Another study found evidence of reduced tonic GABA levels in the hippocampus of the SHR.61

Further reports point to an imbalance of the glutamate/GABA balance in ADHD,6263 64 . However, this is only a statement about the entirety of those affected and by no means excludes the possibility that a disturbance of the GABA balance can be the cause of ADHD in individual patients.
A small study of 13 children with ADHD (10 with ADHD-HI and 3 with ADHD-I), found that overall GABA levels in the sensorimotor cortex are reduced in ADHD.65
One study found an involvement of the genes responsible for glutamate in hyperactivity problems and the genes responsible for GABA in inhibition problems.66
Children with ADHD were found to have increased glutamine (but not glutamate) levels and unchanged GABA levels in the brain. In contrast, adults showed a normalized glutamine level and an increased GABA level. Glutamine is a precursor of glutamate.67

In women with ADHD, impulsivity correlated with reduced GABA and increased glutamate levels in the anterior cingulate cortex (ACC). In contrast, aggression correlated only with increased GABA levels and was independent of glutamate levels.47

A study on a mouse model for hyperactivity (GIT-1-KO mice) found evidence of a GABA deficiency in the cerebellum.68
A study in humans found no differences in cerebellar GABA levels between ADHD, ASD, OCD and controls.69

10.2. GABA and dopamine

Tonic GABA inhibits the (axonal) release of dopamine in the (dorsal) striatum (of the mouse) via GABA-A and GABA-B receptors. Only a few GABA-ergic synapses are present at the dopamine axons. Therefore, the tonic inhibition of dopamine release by striatal GABA is probably mediated by extrasynaptic effects of extracellular GABA on receptors presumably located on dopamine axons. GABA therefore shows extrasynaptic effects on other neurons.
The gamma-aminobutyric acid transporter subtype 1 and subtype 3 reuptake GABA. If GAT1 or GAT3 are reduced or switched off, this increases the extracellular GABA and thus reduces the release of dopamine in the dorsal striatum, but not in the nucleus accumbens.7071

The two isoforms of the GAT in the striatum are:

  • GAT-1 (Slc6a1)
    • common in axons of GABA-ergic neurons
    • in striatal astrocytes
    • in DA midbrain neurons
    • on striatal DA axons
  • GAT-3 (Slc6a11)
    • moderately expressed
    • especially occurring on (striatal) astrocytes
      • Dysregulation of GAT-3 on striatal astrocytes causes profound changes in SPN activity and striatal-driven behavior through decreased extralellular dopamine72
    • in DA midbrain neurons
    • on striatal DA axons

(GAT1)-KO mice (GAT-1-/- mice) show typical ADHD symptoms:7374

  • Hyperactivity
    • AMP and MPH reduce these
  • motor problems
    • Ataxia, characterized by deficiencies in motor coordination and balance
  • Attention problems
    • Impairment of attentional focus in an “incentive runway test”
  • Impulsiveness in an incentive test for passive avoidance
  • Memory problems
    • Deficits in spatial reference memory

GABA-A and GABA-B receptors in the nucleus accumbens modulate a behavior in rats that is mediated via dopamine and acetylcholine receptors. This indicates a controlling influence of GABA on dopamine.75 A connection between GABA and dopamine was also found in the mPFC.45 GABA-serotonin interactions modulate MDMA-induced dopamine release in the mesolimbic system.7677

Studies on the use of GABA-influencing treatments for ADHD are rare. An individual case report on the use of a GABA-ergic dietary supplement by a mother and son with ADHD did not produce any noticeable results.78

Basically, research suffers from the fact that most studies do not record separate values for the different ADHD subtypes.


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  18. doccheck: Dehydroepiandrosteron

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