Signs/symptoms of high GABA and the top 12 supplements to lower it

GABA is a major inhibitory neurotransmitter in the body, meaning, it is calming, anti-anxiety and helps you to relax. The feeling of high GABA is best described by you just wanting to sit or lay down and enjoy the day, getting ready to dose off, not having racing thoughts, not being able to be creative or focused, or produce strategic thinking… it’s that very relaxing, mind switching off feeling. It gives a very null feeling. Not necessarily happy, or sad, more neutral like and in some cases, no feeling at all.

This differs from serotonin, as serotonin induces more defeatism, hopeless and dark thoughts, while feeling depressed and restless.

GABA inhibits glutamate (resulting in less excitation and more anti-anxiety) (1), dopamine (less motivation), noradrenaline (less ability to pay attention and focus) (2) and acetylcholine (less ability to form memories) (34). It also inhibits serotonin firing (less depression), lowers cortisol, ACTH, histamine (put the brake on histamine release) and prolactin (5, 6, 7, 8). So it’s not all bad as it also lowers prolactin and cortisol, but the lowering of dopamine, noradrenaline and glutamate is not very good when you want to stay motivated and focused.

If your GABA is very high, you might have less energy and motivation to learn and to focus on tasks. However, it also lowers serotonin, cortisol and prolactin, which will clear your mind, calm you down and help you sleep better.

Here I’ve listed some symptoms related to elevated GABA.
Keep in mind though that high GABA levels and the sensitivity to it will differ from person to person.

Symptoms that may be experienced due to high GABA:

  • Impaired short term memory (9)
  • Inhibited memory retrieval (10)
  • Impaired coordination and performance (11)
  • Impaired working memory (1213)
  • Impaired spatial memory (14)
  • Reduced taste memory and taste preference and sometimes reduction in taste sensation (15)
  • Low motivation (low dopamine) (16)
  • Low awareness and anticipation (17)
  • Little to no fear and anxiety (18)
  • In the pontine reticular of the brain, it leads to wakefulness and decreases REM sleep. In brain regions containing neurons that promote wakefulness, GABAergic inhibition has been shown to cause an increase in sleep. These brain regions include the dorsal raphé nucleus, tuberomamillary nucleus of the posterior hypothalamus, medial preoptic area and ventrolateral periaqueductal gray (19)
  • (Is associated with) Behavioral disinhibition and no/little restraint of own words (20)
  • Dysphoria & anesthesia (2122)
  • (Is associated with) Depression, apathy and little capacity for emotional connections (23)
  • Could cause intolerance to alcohol, or strong sensitivity to alcohol and other sedatives (24)
  • Dilated pupils and relatively unresponsive to light and dark changes (25)
  • Aggressive behaviors (activation of GABAB receptors) (26)
  • Low libido
  • Rarely get sick, as it enhances immunity (27) (Also a sign of low histamine)
  • Hypotonia (29)
  • Ataxia (30)
  • Feel little to no pain (31)
  • Dependand on stimulants to keep you going and motivated and less inhibited
  • Struggling to lose weight (due to excessive parasympathetic nervous system activation via GABA)

Inhibiting/lowering GABA can improve your alertness, memory/cognition, motivation, focus, libido and make you feel more empathetic.

 

Next I will be listing supplements to lower GABA and then interaction between GABA and other hormones and substances that can be manipulated to lower GABA.

Supplements

1) Gingko biloba

The sesquiterpene trilactone bilobalide is one of the active constituents of the 50:1 Ginkgo biloba leaf extract is widely used to enhance memory and learning. Also, one of it’s actions is to antagonize GABA-A receptors. (32)

 

2) Nicotine

Increasing cholinergic levels in the hippocampus or entorhinal cortex (in the brain) is sufficient to reverse the impairing effect of septal GABA receptor activation on memory and learning. (33) Nicotinic receptor activation (α7-nAChRs) is shown to reduce GABAergic inhibitory action by generating a calcium influx. (34) That’s one reason how smoking (nicotine ingestion) enhances focus, by inhibiting GABA. I definitely wouldn’t advise smoking, but instead, getting a nicotine skin patch or chewing gum would be a much healthier option.

 

3) Kudzu

The major isoflavones of Kudzu extract – puerarin, daidzin and daidzein, are GABA-A antagonists and help to reduce alcohol cravings. (35, 36) However, kudzu root contains abundant estrogen-like isoflavones in the forms of glycosides and aglycones, such as daidzein, daidzin, genistin, glycitein, and puerarin. So personally I’d stay away from this supplement. (37)

 

4) α-Thujone

α-Thujone is the active ingredient in sage, wormwood and absinthe (a liqueur that was popular in the 19th and early 20th centuries), and is shown to antagonize GABA-A receptors. (38) The toxic properties of absinthe are attributable to wormwood oil used in making the beverage. Wormwood oil is in itself a prevalent herbal medicine for treating loss of appetite, dyspeptic disorders, as well as liver and gallbladder complaints. It is safe to use in small amounts.

  • Sage – 285mg per cap, 100 caps

 

5) Aspirin

Salicylate, the active ingredient in aspirin, was found to reduce GABA-A signalling, in a dose dependent manner. (45) However, chronic treatment with salicylate increases both GAD and GABAA receptor sensitivity as a compensatory effect. (46) So I wouldn’t advise using a chronic large doses for the purpose of lowering GABA.

 

6) Caffeine

Caffeine antagonizes adenosine and activates the dopamine system, which lowers GABA. (59) However, chronic use of caffeine increases GABA receptor content.

 

7) Histidine

Histamine, acting on the H2 receptor will reduce GABA signalling. (65) Supplement with some histidine powder (500mg), which is the direct precursor to histamine, or maca powder which contains lots of histidine. However it isn’t advised to use histidine if you are prone to allergies (such as seasonal allergies).

 

8) Zinc

Zinc inhibits GABA-A receptors (66), increases total GABA levels and inhibits GAT (67), which will increase the action of GABA on the B receptor. (68) Histidine also potentiates the inhibitory effect of zinc. (69) Zinc further inhibits NMDA receptors, and lowers glutamate release from neurons. More on zinc here…

 

9) Copper

Copper is a GABA-A receptor antagonist (70). Zinc displaces Cu from the receptor and histidine forms complexes with Cu2+, and chelates it from the body. (71) The copper and zinc balance is important in the body, as too much copper will increase estrogen and lead to toxicity thereof. Try to get your copper from foods only (as supplementing with it will easily lead to a build up and side effects).

 

10) Forskolin/cAMP

Forskolin induced cAMP, inhibits GABA signalling through a PKA dependent pathway. Mutations in the cAMP pathway is associated with reduced learning. (72) Caffeine and forskolin are great cAMP inducers.

  • Forskolin – 25mg extract per cap, 60 caps

 

11) Pregnenolone sulfate

Pregnenolone sulfate (PS) is a sulfated neurosteroid that is present in the brain at a relatively high concentration compared with many other neurosteroids; which blocks the activation of GABA-A receptors, preventing its activation. (77) Pregnenolone will not cause anxiety (because it antagonizes GABA), but is actually successfully used against anxiety.

 

12) DHEA and DHEA sulfate

DHEA and DHEA sulfate, similarly to pregnenolone, inhibits the GABAA receptor. (78)

  • IdealabsDC Pansterone – 5mg DHEA per serving, 90 servings (very high topical absorption)
  • DHEA – 25mg per cap, 100 caps (try taking it sublingual)

 

13) Corydalis

Corydalis is a source of bicuculline, which is an GABA antagonist. (85)

  • Corydalis – 500mg (4:1 extract) per cap, 60 caps

Two other not so common GABA antagonists include picrotoxin (found in Anamirta cocculus) and cicutoxin (found in water hemlock).

 

Interactions

1) Opioids

Glycine and GABA, but not glutamate, are antagonized by opioids (39, 40).
Endogenous opioids in the brain act as pain killers, and cyclooxygenase inhibitors, such as aspirin, synergize with opioids for the analgesic effect. Interestingly, opioids inhibit acetylcholine release in the brain, and elevated opioids can reduce cognitive ability. (41)

Interestingly, μ-selective opioid agonist increases hunger. That’s why you get munchies from smoking weed. GABA-A antagonism synergizes with opioids to increase hunger, and GABA-B antagonism decreases hunger stimulated by opioids. (42)

 

2) Exercise

During exercise, ammonia levels in the brain rise. The body detoxifies it by converting it to glutamine. As a result of reduced pre-cursor availability (glutamate), GABA levels also drop. (43) Aerobic exercise increases serum BDNF which in turn reduces GABA-A receptor activity, and therefor exerts an anxioletic effect. (44) Both aerobic and anaerobic exercises will have a short term GABA lowering effect. Plus exercising also increases opioids which will also contribute to the lowering of GABA levels.

 

3) Dopamine

Dopamine is shown to reduce GABAergic and glycinergic neurotransmission by acting on D2, D3 and D4 receptors (474849). It also decreases GABAA receptors (50, 51), and increases glutamine conversion to GABA, thus reducing excitatory potential and increasing total GABA (52). (Related article: Boost dopamine)

 

4) Adenosine

The activation of the Adenosine A1A receptor (A1AR) is shown to reduce dopamine and GABA through a protein kinase C transduction pathway (54).

A2AR reduces histamine and increases GABA, as well as promotes sleep (55).
However, it also activates adenylate cyclase/cAMP/PKA transducing pathways, which increases GABA transporter, GAT-1, and increases GABA uptake, via reducing PKC (56). This study (57) suggests that A2AR activation indirectly increases GABA, by lowering dopamine and D2 activation, or via increasing glutamate release and providing more precursors for GABA synthesis. However, A2A antagonists show clear neuroprotective effects by inhibiting glutamate release and preventing excitotoxic neuronal death (58).

Adenosine has other beneficial functions, such as anti-depressant, anti-inflammatory, and anti-oxidant. However, adenosine is prone to cause fatigue, possibly through A2AR which increase GABA.

So adenosine will lower GABA through A1AR, but higher adenosine levels will increase GABA via A2AR activation.

 

5) Adrenergic activation

A1-adrenergic activation increases GABA, whereas a2 antagonism and beta-adrenergic agonism inhibits GABA release. (60) A2-adrenergic antagonists include rauwolscine and yohimbine (61, 62). However, rauwolscine is only a a2 antagonist, whereas yohimbine is both an a2 and a GABA receptor antagonist. (63, 64) If you are prone to anxiety, just take magnolia bark extract with yohimbine to offset the anxiogenic effect.

  • Yohimbine – 3mg yohimbine HCL per serving, 60 servings

 

6) Cortisol

Mildly elevated cortisol increases GABA, whereas high cortisol lowers GABA. (73) GABA is actually high during adrenal fatigue, but this may be due to copper blocking the receptor, or GABA is upregulated as a compensatory effect to lower cortisol back down. This might also give you symptoms of adrenal fatigue, such as trouble waking up in the morning, no motivation or energy, muscle weakness, etc.

I don’t advise to skyrocket cortisol to lower GABA, but rather to keep it low and sensitive. Read here to see if you have high cortisol symptoms.

 

7) Cannabinoids

Cannabinoid receptors, CB1 and CB2, can be activated by the use a cannabis, as well as by PUFA metabolites such as anandamide (AEA), 2-arachidonoyl glycerol (2-AG) and oleamide; which inhibit GABA release (74, 75) and increase dopamine release. (76) Oleamide is actually a stronger agonist to serotonin receptors than serotonin itself, so try to keep that as low as possible, by inhibiting the aromatase and preventing ammonia accumulation.

 

8) Serotonin

5-HT1A presynaptic activation reduces both GABA and serotonin release, and synergizes with μ-opioid receptor activation in reducing GABA (79, 80).

Also, 5-HT1B receptor presynaptic activation inhibits the release of GABA onto GABAB but not GABAA receptors. (81)

Both 5-HT1A and 1B is autoreceptors, which will reduce serotonin levels.

Read here on signs/symptoms of high serotonin and how to lower it.

 

9) Enviromental heat/stressors

A rise in temperature inhibits GABA and increases cholinergic activity (82). Environmental heat activates the opioidergic neuron, which inhibits GABA release, and increases cholinergic activity, which enhances body temperature. (83) GABA antagonsim will increase body heat, whereas GABA agonism will reduce body heat.

 

10) PUFAs

Arachidonic acid and it’s precursor, linoleic acid, inhibits GABA receptors, but not via LOX, COX or P-450 pathways, but via active oxygen radicals produced by arachidonic acid. (84) Monounsaturated and saturated fats did not have this effect.
I however, do not advise the consumption of PUFAs because they inhibit the thyroid, normal oxidative metabolism, cause inflammation and age spots, etc.

 

 


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