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

Stress exposure increases the (excitatory) glutamate level in the PFC7 and the (inhibitory) GABA level in some brain areas (hypothalamus, PFC),89 while the GABA level in other brain areas (hippocampus) decreases. Stimulation by new environment, on the other hand, increases GABA levels in the hippocampus.10

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

3 yoga hours per week produced improved mood and decreased anxiety in healthy subjects, which correlated with increased GABA levels in the thalamus. 3 walking hours 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 to the periphery, i.e., the body.
    • GABA interneurons (common), regulate the activity of other neurons, mostly working with biogenic amines. Occur mainly 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 are mostly composed 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 sedative
        • Benzodiazepines
      • Α2 anxiolytic (anti-anxiety)
      • 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 dependence potential (within 2 weeks)
  • Barbiturates13
    • High dependency potential
    • No longer approved as a sleeping pill in D and CH
  • Clomethiazole
  • Allopregnanolone
    • Pregnan 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 level of allopregnanolone
      • Estrus (oestrus) and Dieoestrus:16
        • Hippocampus: low level of allopregnanolone
        • Hypothalamus: high level of allopregnanolone
    • Prolonged allopregnanolone exposure downregulates GABA-A-1 and GABA-A-4 receptors.
  • Pregnanolone
    • Pregnan Steroid
    • GABA-A agonist14
  • AllotetrahydroDOC
    • Pregnan Steroid
    • GABA-A agonist16
  • Alcohol
  • Muscimol
    • Poison of fly agaric, hallucinogenic
  • Magnolol17
    • Extract from the bark of certain species of magnolia trees
    • Biphenolic isomer
    • GABA-A agonist
  • Honokiol17
    • Extract from the bark of certain species of magnolia trees
    • Biphenolic isomer
    • GABA-A agonist
2.2.1.3. Antagonists of GABA-A
  • Α-Thujone, spasm-inducing
  • Picrotoxinin
  • DHEA
    • Also called dehydroepiandrosterone, prasterone (INN), dehydroepiandrosterone, dehydroepiandrostenedione, didehydroepiandrosterone, DHEA, androstenolone, prasterone (INN)18
    • Non-competitive GABA-A antagonist16
  • DHEA sulfate
    • Dehydroepiandrosterone sulfate18
  • Progesterone
    • Non-competitive GABA-A antagonist16
  • Pregnelonon sulfate
    • Non-competitive GABA-A antagonist19
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 problems20
    • 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 / relapse20
    • Region: not restricted
    • GABA-A subtype: α6
  • Balance and movement disorders20
    • 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.2122

2.2.2. GABA-B

  • Agonist of GABA-B
    • Baclofen

2.2.3. GABA-C

Subtype 1 -3 of the GABA-C receptor are now referred to 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.23
  • GAT-3
  • GAT-2
  • GAT-4

3. Drug effect on GABA

3.1. GABA agonists (reinforcing)

For these agonists, receptor binding is still unknown to us:

  • Progesterone (oral): sleep-inducing
    • Other view: non-competitive GABA-A antagonist: Paoletti et al24
  • L-Theanine2513
  • Taurine (acts primarily via glutamate inhibition)1325
  • Rhodiola2513
  • N-pantoyl-GABA (hopanteen acid, pantogam)
    Pantogam is a drug commonly used in the former Soviet Union for a variety of mental disorders. It is reported to be helpful in ADHD.26
  • Neuroactive steroids13
  • Gabapentin
    Contrary to several mentions, 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 that affect Ca2+ currents that are widely distributed in the brain and spinal cord. This may explain the benefit of gabapentin in seizures, pain, and multiple disorders.27
    Gabapentin has significant potential for side effects.
  • Vitamin D328
  • Electroconvulsive therapy should have a GABA agonist effect29

3.2. GABA antagonists (inhibitory)

  • Bicuculline13
  • Inverse agonists13
  • DBI Peptides13
  • Convulsives13
    • Picrotoxin
    • TBPS
  • Flumazenil
    Although flumazenil is a GABA antagonist, one study surprisingly found anxiolytic and tension-reducing effects in stress.30

Serotonin stimulates GABA synthesis and increases GABA receptor affinity (not verified).31
Serotonin deficiency inhibits the effectiveness of GABA.

4. Effect of GABA

  • Anxiolytic (anxiety relieving)
  • Analgesic (pain relieving)
  • Relaxing (unwinding)
  • Anticonvulsant (preventing epilepsy)
  • Blood pressure stabilizing
  • Sleep-inducing

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

While GABA inhibits ACTH release from the HPA axis (by directly addressing the nucleus paraventricularis (PVN) in the hypothalamus, glutamate promotes ACTH release via projections from the hypothalamus and brainstem.32

In addition to its neuronal effects, GABA has multiple paracrine and endocrine effects.
It acts centrally on hypothalamic secretion of releasing factors, GABAergic neurons
innervate the pituitary gland. GABA is conducted paracrine via the portal vein system to the pituitary gland.

Prenatal stress delays the migration of GABAergic cell precursors from their site of origin in the medial ganglionic eminence (in the forebrain) to their target in the cortex.3334 This GABAergic cell migration is critical for subsequent cortical function, e.g., in schizophrenia.333536 Subsequent maturation of GABAergic cells is also affected by prenatal stress and correlates with altered social and anxiety-like behavior after prenatal stress. An IL-6 antagonist can prevent maternal stress-induced delay in migration of GABAergic cell precursors in mice.33343733

5. Measurement of GABA

GABA neurotransmitter levels in the brain should be easily measured in blood plasma.1
However, this is contradicted by the fact that GABA cannot cross the blood-brain barrier. Moreover, all recent studies use sophisticated MRI methods to measure GABA levels in the brain.

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

6. Effects of GABA deficiency

Very low to low GABA levels correlate with:25

  • Chronic fatigue (adrenal exhaustion syndrome)
  • Hypertension
  • Chronic pain
  • Irritable colon (irritable bowel syndrome)
  • Premenstrual syndrome
  • Depression
  • Epilepsy
  • Schizophrenia
  • Mania
  • Cravings for sugar/sweets (carbohydrates)
  • Paresthesias (signs of paralysis)
  • Muscle tension, muscle pain or muscle stiffness
  • Ringing in the ears (tinnitus)
  • Altered olfactory sensations
  • Headache
  • Insomnia
    • Insomnia correlated with a 30% decrease in GABA levels in the brain38
    • GABAergic drugs have a sleep-promoting effect.3940
  • Night sweats, sweaty hands, cold sweat
  • Hyperventilation
  • Tachycardia
  • Memory loss
  • Concentration problems
  • Impulsivity
  • Impatience
  • Increased nervousness
  • Inner restlessness
  • Irritability
  • Mood swings
  • Anxieties, panic attacks
    • In contrast, high GABA levels and low glutamate levels in the ACC have been reported to correlate with high harm-avoidance41 and higher anxiety.42

In rats, the GABA-A receptor antagonist picrotoxin produced decreased GABA levels in the mPFC and the GABA-A receptor agonist muscimol produced increased GABA levels in the mPFC.43

  • Decreased GABA levels in the mPFC caused
    • Attention problems43
    • Motor hyperactivity 43
      • Mice with a blocked GAT-1 GABA transporter show hyperactivity and inattention.23
    • Increased firing rate, especially in bursts43
    • Increased bursts43
    • Significantly increased prefrontal LFP power43
    • Impatience/irritability correlated with lower GABA levels in the dorsolateral PFC.44

Decreased GABA levels in the anterior cingulate cortex (ACC) in women with ADHD correlated with45

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

7. Effects of GABA excess

In rats, the GABA-A receptor antagonist picrotoxin produced decreased GABA levels in the mPFC and the GABA-A receptor agonist muscimol produced increased GABA levels in the mPFC.43

  • Increased GABA level in mPFC caused:43
    • Attention problems
    • Increased premature reactions (reaction errors)
    • Decreased open-field motion activity (dose-dependent)
    • Reduced firing rate
    • Reduced bursts

Increased GABA levels in the anterior cingulate cortex (ACC) in women with ADHD correlated with45

  • Aggression increased
  • Unchanged glutamate level

GABA inhibits long-term potentiation, which is essential for long-term memory.46

8. Treatment of GABA deficiency

Bieger47 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 act synergistically to promote sleep, relax, and pave the way for nocturnal regeneration of the endocrine system
  • Treatment of GABA deficiency in the body by paracrine GABA
  • Modified sublingual GABA preparations can transport GABA to the brain via the oral mucosa “on side routes
    fast action within minutes, therefore suitable for immediate treatment of anxiety
  • Lipophilic GABA derivatives
    • GABA coupled to niacin (cavinacea)
  • GABA coupled to phenol (phenibut)
    Acts as a GABA mimetic, primarily as a GABA-B receptor agonist and (at higher doses) to some extent as a GABA-A receptor agonist. Stimulates dopamine receptors and antagonizes β-phenethylamine (PEA), a putative endogenous anxiogen.48
    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 effect is said to 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.49
    Phenibut is freely available in Europe as a food supplement
    • Dosage of Phenibut (Noofen, historical):50
      • “Asthenic and anxious-neurotic states:
        • Adults - 250-500 mg three times a day. 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 daily
          Doctor determines treatment duration
      • Meniere’s disease / dizziness associated with vestibular apparatus 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 form of disease; 250 mg twice daily for 5-7 days, then 250 mg once daily for 7-10 days
      • Vertigo due to dysfunction of the vestibular system of vascular and traumatic origin
        • 250 mg 3 times a day for 12 days.
      • Kinetosis prophylaxis:
        • 250-500 mg one hour before expected sway or at the first symptoms of kinetosis (e.g., nausea)
      • in case of pronounced symptoms (vomiting, etc.), the use of the drug is less effective.
      • Prevention of alcohol abstinence syndrome:
        • in the first days - 250-500 mg 3 times a day.
          and 750 mg before bedtime; thereafter, gradual dose reduction.
      • The development of drug dependence and addiction, abstinence syndrome were not noticed.“
    • An isolated case of dependence in a self-treatment51 and a report of withdrawal symptoms from Phenibut52 obtained on the Internet, however, give reason to warn against careless use.
    • Suppliers of Phenibut as a dietary supplement do not recommend continuous intake to avoid tolerance development and dependence. It is recommended to limit intake to once or twice a week.
    • In addition, the risk that phenibut is broken down via the liver is pointed out, so 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.53
  • Pregabalin
  • GABA-related drugs that are better at crossing the blood-brain barrier than GABA itself
    • Enhanced GABA effect by inhibiting GABA degradation
      • Valproic acid (Ergenyl)
      • Vigabatrin (Sabril)
    • Increasing GABA levels by GABA synthesis and by GABA reuptake inhibitors
      • Vigabatrin
    • CNS-targeted 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 the unaffected). After 8 weeks of treatment with 2000 IU D3 daily, the GABA level of 0.080 had approached that of the unaffected, while the symptoms of mania and depression were significantly attenuated at the same time.28

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

Source unless otherwise stated: Vitalstoffmedizin.com.54

  • Fatigue
  • Dizziness
  • Slowed thinking
  • Impaired coordination up to the impossibility of driving a car
  • Suicidal ideation or completed suicide in one in 500 persons treated
  • Severe depression
  • Severe agitation
  • Panic attacks
  • Sleep disorders (actually an indication for the analogue)
  • Irritability
  • Aggressiveness45
  • Propensity to violence
  • Extreme increase in activity and talkativeness
  • Otitis media
  • Respiratory infections
  • Pancreatitis
  • Leukocytopenia
  • Thrombocytopenia
  • Weight gain
  • Pronounced dry mouth
  • Hallucinations
  • Amnesia

Prolonged GABA-A receptor stimulation by GABA-A receptor agonists leads to downregulation of GABA-A receptors.20 Therefore, prolonged treatment with benzodiazepines, barbiturates, or alcohol is associated with significant risk of addiction. Similarly, hormone treatments with GABA agonists should be viewed with extreme caution. Exposure to allopregnanolone for as little as 90 minutes causes the GABA-A receptors to develop tolerance.

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

During stress, the production of GABA and cortisol is increased. A coincidence of long-lasting elevated cortisol and GABA levels leads to irreversible cognitive damage.15

The effect of prolonged benzodiazepine or alcohol exposure on GABA receptors is equivalent to that of prolonged chronic stress15

10. GABA in ADHD

There is multiple evidence for the involvement of GABA and glutamate abnormalities in ADHD.

10.1. GABA imbalance in ADHD

All the information gathered suggests that treatment with GABA-enhancing agents might be helpful in ADHD-I, melancholic depression, or other stress-internalizing disorder patterns. In contrast, for stress-externalizing disorder patterns such as ADHD-HI or atypical depression, our understanding seems to be that GABA-inhibiting and glutamate-boosting treatment should rather be considered.

This results, in addition to the described typical symptoms of GABA deficiency that are phenotypically more likely to be found in ADHD-I and the described typical symptoms of GABA overdose that are phenotypically more likely to be found in ADHD-HI, for example, that in the Spontaneous 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.55
In contrast, another study found evidence of reduced tonic GABA levels in the hippocampus of SHR.56

Other reports suggest an imbalance of glutamate/GABA balance in ADHD.575859 One study found involvement of the genes responsible for glutamate in hyperactivity problems and the genes responsible for GABA in inhibition problems.60

Contrary to expectations on this side, a study of 13 children with ADHD (10 of them with ADHD-HI and 3 with ADHD-I) showed that the GABA level in the sensorimotor cortex is reduced overall in ADHD, which argues against an increase of the GABA level in ADHD-HI due to the majority of ADHD-HI subtypes among the subjects. However, the study did not differentiate the results by subtype.
It is not possible to tell from the published data for a typical example child whether GABA levels had dropped further relative to glutamate levels in the subjects (dominated by ADHD-HI), because it is not specified whether the child is ADHD-HI or ADHD-I subtype.61

Children with ADHD were found to have increased glutamine (but not glutamate) levels and unchanged GABA levels in the brain. In contrast, adults showed normalized glutamine levels and increased GABA levels. Glutamine is a precursor of glutamate.62

In women with ADHD, impulsivity correlated with decreased GABA and increased glutamate levels in the anterior cingulate cortex (ACC). Aggression, in contrast, correlated only with increased GABA levels and was independent of glutamate levels.45

A study in a mouse model of hyperactivity comes to results suggestive of GABA deficiency in the cerebellum.63

10.2. GABA and dopamine

GABA-A and GABA-B receptors in the nucleus accumbens modulate rat behavior mediated by dopamine and acetylcholine receptors. This indicates a controlling influence of GABA on dopamine.64 A link between GABA and dopamine was also found in mPFC.43 GABA-serotonin interactions modulate MDMA-induced dopamine output in the mesolimbic system.6566

Studies on the use of GABA-influencing treatments in ADHD are rare. A single case report of a mother and ADHD-affected son taking a GABAergic dietary supplement did not yield any noticeable results.67

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


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